bluuebunny/crossref_metadata_2025 huggingface dataset:
Presence and Persistence of Coxiella burnetii in the Environments of Goat Farms Associated with a Q Fever Outbreak
Authors: Kersh Gilbert J. , Fitzpatrick Kelly A. , Self Joshua S. , Priestley Rachael A. , Kelly Aubree J. , Lash R. Ryan , Marsden-Haug Nicola , Nett Randall J. , Bjork Adam , Massung Robert F. , Anderson Alicia D.
Published: January 2013

Q fever is a zoonotic disease caused by inhalation of the bacteriumCoxiella burnetii. Ruminant livestock are common reservoirs forC. burnetii, and bacteria present in aerosols derived from the waste of infected animals can infect humans. The significance of infection from material deposited in the environment versus transmission directly from infected animals is not known. In 2011, an outbreak of Q fever cases on farms in Washington and Montana was associated with infected goats. A study was undertaken to investigate the quantity and spatial distribution ofC. burnetiiin the environment of these goat farms. Soil, vacuum, and sponge samples collected on seven farms epidemiologically linked to the outbreak were tested for the presence ofC. burnetiiDNA by quantitative PCR. Overall, 70.1% of the samples were positive forC. burnetii. All farms had positive samples, but the quantity ofC. burnetiivaried widely between samples and between farms. High quantities ofC. burnetiiDNA were in goat housing/birthing areas, and only small quantities were found in samples collected more than 50 m from these areas. Follow-up sampling at one of the farms 1 year after the outbreak found small quantities ofC. burnetiiDNA in air samples and large quantities ofC. burnetiipersisting in soil and vacuum samples. The results suggest that the highest concentrations of environmentalC. burnetiiare found in goat birthing areas and that contamination of other areas is mostly associated with human movement.
Carot-4-en-9,10-Diol, a Conidiation-Inducing Sesquiterpene Diol Produced by Trichoderma virens PS1-7 upon Exposure to Chemical Stress from Highly Active Iron Chelators
Authors: Wang Mengcen , Hashimoto Makoto , Hashidoko Yasuyuki
Published: January 2013

To screen biocontrol agents against
Burkholderia plantarii
, the causative agent of rice seedling blight, we employed catechol, an analog of the virulence factor tropolone, to obtain chemical stress-resistant microorganisms. The fungal isolate PS1-7, identified as a strain of
Trichoderma virens
, showed the highest resistance to catechol (20 mM) and exhibited efficacy as a biocontrol agent for rice seedling blight. During investigation of metabolic traits of
T. virens
PS1-7 exposed to catechol, we found a secondary metabolite that was released extracellularly and uniquely accumulated in the culture. The compound induced by chemical stress due to catechol was subsequently isolated and identified as a sesquiterpene diol, carot-4-en-9,10-diol, based on spectroscopic analyses.
T. virens
PS1-7 produced carot-4-en-9,10-diol as a metabolic response to tropolone at concentrations from 0.05 to 0.2 mM, and the response was enhanced in a dose-dependent manner, similar to its response to catechol at concentrations from 0.1 to 1 mM. Some iron chelators, such as pyrogallol, gallic acid, salicylic acid, and citric acid, at 0.5 mM also showed activation of
T. virens
PS1-7 production of carot-4-en-9,10-diol. This sesquiterpene diol, formed in response to chemical stress, promoted conidiation of
T. virens
PS1-7, suggesting that it is involved in an autoregulatory signaling system. In a bioassay of the metabolic and morphological responses of
T. virens
PS1-7, conidiation in hyphae grown on potato dextrose agar (PDA) plates was either promoted or induced by carot-4-en-9,10-diol. Carot-4-en-9,10-diol can thus be regarded as an autoregulatory signal in
T. virens
, and our findings demonstrate that intrinsic intracellular signaling regulates conidiation of
T. virens
.
Phylogenetic Inferences Reveal a Large Extent of Novel Biodiversity in Chemically Rich Tropical Marine Cyanobacteria
Authors: Engene Niclas , Gunasekera Sarath P. , Gerwick William H. , Paul Valerie J.
Published: January 2013

Benthic marine cyanobacteria are known for their prolific biosynthetic capacities to produce structurally diverse secondary metabolites with biomedical application and their ability to form cyanobacterial harmful algal blooms. In an effort to provide taxonomic clarity to better guide future natural product drug discovery investigations and harmful algal bloom monitoring, this study investigated the taxonomy of tropical and subtropical natural product-producing marine cyanobacteria on the basis of their evolutionary relatedness. Our phylogenetic inferences of marine cyanobacterial strains responsible for over 100 bioactive secondary metabolites revealed an uneven taxonomic distribution, with a few groups being responsible for the vast majority of these molecules. Our data also suggest a high degree of novel biodiversity among natural product-producing strains that was previously overlooked by traditional morphology-based taxonomic approaches. This unrecognized biodiversity is primarily due to a lack of proper classification systems since the taxonomy of tropical and subtropical, benthic marine cyanobacteria has only recently been analyzed by phylogenetic methods. This evolutionary study provides a framework for a more robust classification system to better understand the taxonomy of tropical and subtropical marine cyanobacteria and the distribution of natural products in marine cyanobacteria.
Multigene-Based Analyses of the Phylogenetic Evolution of Oligotrich Ciliates, with Consideration of the Internal Transcribed Spacer 2 Secondary Structure of Three Systematically Ambiguous Genera
Authors: Li Jiamei , Liu Weiwei , Gao Shan , Warren Alan , Song Weibo
Published: January 2013

Oligotrichs are ciliates of great abundance, but their molecular systematics are rarely studied. In this study, nine species representing three genera (
Strombidium
,
Novistrombidium
, and
Omegastrombidium
) of marine oligotrich ciliates were collected from coastal waters of China. The small subunit (SSU) rRNA gene of two species and the internal transcribed spacers and 5.8S region (ITS1-5.8S-ITS2) for all nine species were sequenced for the first time. Phylogenetic trees using both the SSU rRNA gene and ITS1-5.8S-ITS2 region sequences were generated. In addition, the secondary structures of ITS2 RNA transcripts of 11 taxa representing four genera (
Novistrombidium
,
Strombidium
,
Omegastrombidium
, and
Laboea
) were investigated. The phylogenetic analyses show that (i) the family Strombidiidae is polyphyletic, (ii) the genus
Novistrombidium
is probably paraphyletic, containing at least two subclades, which is consistent with recent cladistic analyses based on morphological data, and (iii) the tail-less genus
Laboea
is separate from other genera of Strombidiidae, clustering instead with the tontoniids. Comparisons of the secondary structure of ITS2 regions also show that
Laboea
is clearly different from other strombidiids. These findings cast doubt on the monophyly of the family Strombidiidae.
Bcr1 Functions Downstream of Ssd1 To Mediate Antimicrobial Peptide Resistance in Candida albicans
Authors: Jung Sook-In , Finkel Jonathan S. , Solis Norma V. , Chaili Siyang , Mitchell Aaron P. , Yeaman Michael R. , Filler Scott G.
Published: January 2013

In order to colonize the host and cause disease,
Candida albicans
must avoid being killed by host defense peptides. Previously, we determined that the regulatory protein Ssd1 governs antimicrobial peptide resistance in
C. albicans
. Here, we sought to identify additional genes whose products govern susceptibility to antimicrobial peptides. We discovered that a
bcr1
Δ/Δ mutant, like the
ssd1
Δ/Δ mutant, had increased susceptibility to the antimicrobial peptides, protamine, RP-1, and human β defensin-2. Homozygous deletion of
BCR1
in the
ssd1
Δ/Δ mutant did not result in a further increase in antimicrobial peptide susceptibility. Exposure of the
bcr1
Δ/Δ and
ssd1
Δ/Δ mutants to RP-1 induced greater loss of mitochondrial membrane potential and increased plasma membrane permeability than with the control strains. Therefore, Bcr1 and Ssd1 govern antimicrobial peptide susceptibility and likely function in the same pathway. Furthermore,
BCR1
mRNA expression was downregulated in the
ssd1
Δ/Δ mutant, and the forced expression of
BCR1
in the
ssd1
Δ/Δ mutant partially restored antimicrobial peptide resistance. These results suggest that Bcr1 functions downstream of Ssd1. Interestingly, overexpression of 11 known Bcr1 target genes in the
bcr1
Δ/Δ mutant failed to restore antimicrobial peptide resistance, suggesting that other Bcr1 target genes are likely responsible for antimicrobial peptide resistance. Collectively, these results demonstrate that Bcr1 functions downstream of Ssd1 to govern antimicrobial peptide resistance by maintaining mitochondrial energetics and reducing membrane permeabilization.
Characterization of Escherichia coli
d
-Cycloserine Transport and Resistant Mutants
Authors: Baisa Gary , Stabo Nicholas J. , Welch Rodney A.
Published: January 2013

d
-Cycloserine (DCS) is a broad-spectrum antibiotic that inhibits
d
-alanine ligase and alanine racemase activity. When
Escherichia coli
K-12 or CFT073 is grown in minimal glucose or glycerol medium, CycA transports DCS into the cell.
E. coli
K-12
cycA
and CFT073
cycA
mutant strains display increased DCS resistance when grown in minimal medium. However, the
cycA
mutants exhibit no change in DCS sensitivity compared to their parental strains when grown in LB (CFT073 and K-12) or human urine (CFT073 only). These data suggest that
cycA
does not participate in DCS sensitivity when strains are grown in a non-minimal medium. The small RNA GvcB acts as a negative regulator of
E. coli
K-12
cycA
expression when grown in LB. Three
E. coli
K-12
gcvB
mutant strains failed to demonstrate a change in DCS sensitivity when grown in LB. This further suggests a limited role for
cycA
in DCS sensitivity. To aid in the identification of
E. coli
genes involved in DCS sensitivity when grown on complex media, the Keio K-12 mutant collection was screened for DCS-resistant strains.
dadA
,
pnp
,
ubiE
,
ubiF
,
ubiG
,
ubiH
, and
ubiX
mutant strains showed elevated DCS resistance. The phenotypes associated with these mutants were used to further define three previously characterized
E. coli
DCS-resistant strains (χ316, χ444, and χ453) isolated by Curtiss and colleagues (R. Curtiss, III, L. J. Charamella, C. M. Berg, and P. E. Harris, J. Bacteriol.
90:
1238–1250, 1965). A
dadA
mutation was identified in both χ444 and χ453. In addition, results are presented that indicate for the first time that DCS can antagonize
d
-amino acid dehydrogenase (DadA) activity.
A Genomewide Mutagenesis Screen Identifies Multiple Genes Contributing to Vi Capsular Expression in Salmonella enterica Serovar Typhi
Authors: Pickard Derek , Kingsley Robert A. , Hale Christine , Turner Keith , Sivaraman Karthikeyan , Wetter Michael , Langridge Gemma , Dougan Gordon
Published: January 2013

A transposon-based, genomewide mutagenesis screen exploiting the killing activity of a lytic ViII bacteriophage was used to identify
Salmonella enterica
serovar Typhi genes that contribute to Vi polysaccharide capsule expression. Genes enriched in the screen included those within the
viaB
locus (
tviABCDE
and
vexABCDE
) as well as
oxyR
,
barA/sirA
, and
yrfF
, which have not previously been associated with Vi expression. The role of these genes in Vi expression was confirmed by constructing defined null mutant derivatives of
S
. Typhi, and these were negative for Vi expression as determined by agglutination assays with Vi-specific sera or susceptibility to Vi-targeting bacteriophages. Transcriptome analysis confirmed a reduction in expression from the
viaB
locus in these
S
. Typhi mutant derivatives and defined regulatory networks associated with Vi expression.
Lower incidence of arm-to-head contact incidents with stricter interpretation of the Laws of the Game in Norwegian male professional football
Authors: Bjørneboe John , Bahr Roald , Dvorak Jiri , Andersen Thor Einar
Published: January 2013

Background

Video analyses reveal that the rate of incidents with a propensity for injury caused by opponent-to-player contact has increased by about 50% from 2000 to 2010 in Norwegian male professional football. The aim of the study was to assess whether a stricter interpretation of the Laws of the Game (red cards for high elbows in heading duels and for late/two foot tackles) could reduce the potential for injuries in Norwegian male professional football.

Methods

A preintervention/postintervention design was employed, where the rate of incidents and injuries from the 2010 season (pre) was compared to the 2011 season (post). An incident was recorded if the match was interrupted by the referee, and the player lay down for more than 15 s, and appeared to be in pain or received medical treatment. Time-loss injuries were recorded by the medical staff of each club.

Results

A total of 1421 contact incidents were identified, corresponding to a rate of 92.7 (95% CI 86.0 to 99.4) in the 2010 season and 86.6 (95% CI 80.3 to 99.4) in the 2011 season, with no difference between the two season. We found a reduction in the incidence of total head incidents (rate ratio (RR) 0.81, 95% CI 0.67 to 0.99), and head-incidents caused by arm-to-head contact (RR 0.72, 95% CI 0.54 to 0.97). We found no difference in tackling characteristics or contact injury rate.

Conclusions

We found no significant differences in the overall rate of incidents after the introduction of stricter rule enforcement. However, the rate of head and arm-to head incidents was lower in the 2011 season.
Effect of sport-related concussion on clinically measured simple reaction time
Authors: Eckner James T , Kutcher Jeffrey S , Broglio Steven P , Richardson James K
Published: January 2013

Background

Reaction time (RT) is a valuable component of the sport concussion assessment battery. RT is typically measured using computers running specialised software, which limits its applicability in some athletic settings and populations. To address this, we developed a simple clinical test of RT (RTclin) that involves grasping a falling measuring stick.

Purpose

To determine the effect of concussion on RTclinand its sensitivity and specificity for concussion.

Materials and methods

Concussed athletes (n=28) and non-concussed control team-mates (n=28) completed RTclinassessments at baseline and within 48 h of injury. Repeated measures analysis of variance compared mean baseline and follow-up RTclinvalues between groups. Sensitivity and specificity were calculated over a range of reliable change confidence levels.

Results

RTclindiffered significantly between groups (p<0.001): there was significant prolongation from baseline to postinjury in the concussed group (p=0.003), with a trend towards improvement in the control group (p=0.058). Sensitivity and specificity were maximised when a critical change value of 0 ms was applied (ie, any increase in RTclinfrom baseline was interpreted as abnormal), which corresponded to a sensitivity of 75%, specificity of 68% and a 65% reliable change confidence level.

Conclusions

RTclinappears sensitive to the effects of concussion and distinguished concussed and non-concussed athletes with similar sensitivity and specificity to other commonly used concussion assessment tools. Given its simplicity, low cost and minimal time requirement, RTclinshould be considered a viable component of the sports medicine provider's multifaceted concussion assessment battery.
Health economic evaluation of the Lund Integrated Medicines Management Model (LIMM) in elderly patients admitted to hospital
Authors: Ghatnekar Ola , Bondesson Åsa , Persson Ulf , Eriksson Tommy
Published: January 2013

Objective

To evaluate the cost effectiveness of a multidisciplinary team including a pharmacist for systematic medication review and reconciliation from admission to discharge at hospital among elderly patients (the Lund Integrated Medicines Management (LIMM)) in order to reduce drug-related readmissions and outpatient visits.

Method

Published data from the LIMM project group were used to design a probabilistic decision tree model for evaluating tools for (1) a systematic medication reconciliation and review process at initial hospital admission and during stay (admission part) and (2) a medication report for patients discharged from hospital to primary care (discharge part). The comparator was standard care. Inpatient, outpatient and staff time costs (Euros, 2009) were calculated during a 3-month period. Dis-utilities for hospital readmissions and outpatient visits due to medication errors were taken from the literature.

Results

The total cost for the LIMM model was €290 compared to €630 for standard care, in spite of a €39 intervention cost. The main cost offset arose from avoided drug-related readmissions in the Admission part (€262) whereas only €66 was offset in the Discharge part as a result of fewer outpatient visits and correction time. The reduced disutility was estimated to 0.005 quality-adjusted life-years (QALY), indicating that LIMM was a dominant alternative. The probability that the intervention would be cost-effective at a zero willingness to pay for a gained QALY compared to standard care was estimated to 98%.

Conclusions

The LIMM medication reconciliation (at admission and discharge) and medication review was both cost-saving and generated greater utility compared to standard care, foremost owing to avoided drug-related hospital readmissions. When implementing such a review process with a multidisciplinary team, it may be important to consider a learning curve in order to capture the full advantage.
A DEA-BASED APPROACH FOR EVALUATING THE OPPORTUNITY COST OF ENVIRONMENTAL REGULATIONS
Authors: YANG CHIH-CHING
Published: January 2013

Opportunity costs of environmental regulations (OCER) are an important consideration when governments make decisions on the formulation of environmental policies and when plants make decisions in response to environmental policies. Aimed at measuring OCER, the current paper proposes an approach in which the achievements of environmental control implemented by a production unit are considered. We quantify and define the achievements as "desirable" environmental outputs. In this way, for a production unit, producing normal desirable outputs and reaching environmental outputs is a tradeoff. OCER is measured by calculating a maximum amount of increasable normal outputs when production units do not need to produce any environmental outputs. Directional distance functions and data envelopment analysis (DEA) techniques are used to calculate OCER. The approach is applied to an empirical illustration based on Taiwan's port industry covering the period 2001–2007. It is found that the industry incurred opportunity costs due to environmental regulations equivalent to 1.8% of total revenue it creates. However, the OCER are significantly less than the economic losses due to productive inefficiency (PIE).
IMPROVING ELECTROCHEMICAL PERFORMANCE OF LiCoO2 BY TiO2 COATING AS CATHODE FOR AQUEOUS RECHARGEABLE LITHIUM BATTERIES
Authors: TIAN S. , LIU L. L. , ZHU Y. S. , HOU Y. Y. , HU C. L. , WU Y. P.
Published: January 2013

Modified LiCoO2 was prepared via a sol–gel method followed by a TiO2 coating and characterized by X-ray diffraction analysis, transmission electronic microscopy and various measurements of charge/discharge behavior. Its cycling performance and rate capability were greatly improved compared to the original LiCoO2 . The initial capacity of the TiO2 -coated LiCoO2 is 134 mAh g-1 at the current density of 5000 mA g-1. When the current density increases to 10,000 mA g-1, the cathode displays an initial capacity of 128 mAh g-1, much higher than that (<101 mAh g-1) for the virginal LiCoO2 , and shows no evident capacity fading after 100 cycles.
Hemodynamic assessment of paravalvular aortic regurgitation after TAVI: estimated myocardial supply-demand ratio and cardiovascular mortality
Authors: Patsalis Polykarpos C. , Konorza Thomas F. M. , Al-Rashid Fadi , Plicht Björn , Hildebrandt Heike A. , Wendt Daniel , Thielmann Matthias , Jakob Heinz G. , Eggebrecht Holger , Heusch Gerd , Erbel Raimund , Kahlert Philipp
Published: January 2013

A relevant (at least moderate) paravalvular regurgitation (PAR) after transcatheter aortic valve implantation (TAVI) is found in up to 20% of cases and associated with increased mortality. The ratio of the diastolic over the systolic pressure time integral (DPTI:SPTI) has been proposed to reflect an estimate of myocardial oxygen supply versus demand and the propensity for myocardial ischemia. We have now evaluated the potential of this ratio to predict PAR-associated cardiovascular mortality after TAVI, retrospectively analyzing data from 167 consecutive TAVI patients. PAR was graded angiographically, and the myocardial supply-demand ratio was estimated from the planimetric integration of the diastolic and systolic pressure-time area (DPTI and SPTI), respectively. PAR was observed in 113 patients (67%) and angiographically graded as mild in 89 (78.8%), moderate in 21 (18.6%) or moderate to severe in 3 (2.7%) cases. The DPTI:SPTI ratio decreased with increasing Sellers grade of PAR ( P < 0.001). A DPTI:SPTI of ≤0.7 predicted cardiovascular mortality (area under the curve = 0.96). Cardiovascular mortality at 30 days and 1 yr was increased in patients with DPTI:SPTI ≤ 0.7 over those with DPTI:SPTI > 0.7 (42 vs. 2% and 63 vs. 3%, respectively; P < 0.001). In conclusion, DPTI:SPTI provides an excellent cutoff value of ≤0.7 for the prediction of PAR-associated mortality.
AMPK attenuates microtubule proliferation in cardiac hypertrophy
Authors: Fassett John T. , Hu Xinli , Xu Xin , Lu Zhongbing , Zhang Ping , Chen Yingjie , Bache Robert J.
Published: January 2013

Cell hypertrophy requires increased protein synthesis and expansion of the cytoskeletal networks that support cell enlargement. AMPK limits anabolic processes, such as protein synthesis, when energy supply is insufficient, but its role in cytoskeletal remodeling is not known. Here, we examined the influence of AMPK in cytoskeletal remodeling during cardiomyocyte hypertrophy, a clinically relevant condition in which cardiomyocytes enlarge but do not divide. In neonatal cardiomyocytes, activation of AMPK with 5-aminoimidazole carboxamide ribonucleotide (AICAR) or expression of constitutively active AMPK (CA-AMPK) attenuated cell area increase by hypertrophic stimuli (phenylephrine). AMPK activation had little effect on intermediate filaments or myofilaments but dramatically reduced microtubule stability, as measured by detyrosinated tubulin levels and cytoskeletal tubulin accumulation. Importantly, low-level AMPK activation limited cell expansion and microtubule growth independent of mTORC1 or protein synthesis repression, identifying a new mechanism by which AMPK regulates cell growth. Mechanistically, AICAR treatment increased Ser-915 phosphorylation of microtubule-associated protein 4 (MAP4), which reduces affinity for tubulin and prevents stabilization of microtubules (MTs). RNAi knockdown of MAP4 confirmed its critical role in cardiomyocyte MT stabilization. In support of a pathophysiological role for AMPK regulation of cardiac microtubules, AMPK α2 KO mice exposed to pressure overload (transverse aortic constriction; TAC) demonstrated reduced MAP4 phosphorylation and increased microtubule accumulation that correlated with the severity of contractile dysfunction. Together, our data identify the microtubule cytoskeleton as a sensitive target of AMPK activity, and the data suggest a novel role for AMPK in limiting accumulation and densification of microtubules that occurs in response to hypertrophic stress.
HMGB1 promotes neutrophil extracellular trap formation through interactions with Toll-like receptor 4
Authors: Tadie Jean-Marc , Bae Hong-Beom , Jiang Shaoning , Park Dae Won , Bell Celeste P. , Yang Huan , Pittet Jean-Francois , Tracey Kevin , Thannickal Victor J. , Abraham Edward , Zmijewski Jaroslaw W.
Published: January 2013

Although neutrophil extracellular traps (NETs) form to prevent dissemination of pathogenic microorganisms, excessive release of DNA and DNA-associated proteins can also perpetuate sterile inflammation. In this study, we found that the danger-associated molecular pattern protein high-mobility group box 1 (HMGB1) can induce NET formation. NET formation was found after exposure of wild-type and receptor for advanced glycation end products-deficient neutrophil to HMGB1, whereas deficiency of Toll-like receptor (TLR)4 diminished the ability of neutrophils to produce NETs. Incubation of neutrophils with HMGB1 significantly increased the amount of DNA and histone 3 released as well as intracellular histone 3 citrullination, a signaling event that precedes chromatin decondensation. In vivo, neutrophils isolated from bronchoalveolar lavages of mice exposed to LPS and HMGB1 showed consistently greater ability to produce NETs compared with pulmonary neutrophils from mice that received LPS alone. In contrast, mice treated with LPS and neutralizing antibody to HMGB1 had decreased amounts of the inflammatory cytokines TNF-α and macrophage inflammatory protein 2, as well as of free DNA and histone 3 in bronchoalveolar lavage fluids. Airway neutrophils from LPS-exposed mice that had been treated with anti-HMGB1 antibodies showed decreased citrullination of histone 3. These results demonstrate that interactions between HMGB1 and TLR4 enhance the formation of NETs and provide a novel mechanism through which HMGB1 may contribute to the severity of neutrophil-associated inflammatory conditions.
Dual activation of CFTR and CLCN2 by lubiprostone in murine nasal epithelia
Authors: Schiffhauer Eric S. , Vij Neeraj , Kovbasnjuk Olga , Kang Po Wei , Walker Doug , Lee Seakwoo , Zeitlin Pamela L.
Published: January 2013

Multiple sodium and chloride channels on the apical surface of nasal epithelial cells contribute to periciliary fluid homeostasis, a function that is disrupted in patients with cystic fibrosis (CF). Among these channels is the chloride channel CLCN2, which has been studied as a potential alternative chloride efflux pathway in the absence of CFTR. The object of the present study was to use the nasal potential difference test (NPD) to quantify CLCN2 function in an epithelial-directed TetOn CLCN2 transgenic mouse model (TGN-K18rtTA-hCLCN2) by using the putative CLCN2 pharmacological agonist lubiprostone and peptide inhibitor GaTx2. Lubiprostone significantly increased chloride transport in the CLCN2-overexpressing mice following activation of the transgene by doxycycline. This response to lubiprostone was significantly inhibited by GaTx2 after CLCN2 activation in TGN-CLCN2 mice. Cftr −/− and Clc2 −/− mice showed hyperpolarization indicative of chloride efflux in response to lubiprostone, which was fully inhibited by GaTx2 and CFTR inhibitor 172 + GlyH-101, respectively. Our study reveals lubiprostone as a pharmacological activator of both CFTR and CLCN2. Overexpression and activation of CLCN2 leads to improved mouse NPD readings, suggesting it is available as an alternative pathway for epithelial chloride secretion in murine airways. The utilization of CLCN2 as an alternative chloride efflux channel could provide clinical benefit to patients with CF, especially if the pharmacological activator is administered as an aerosol.
Toll-like receptor 4 is not targeted to the lysosome in cystic fibrosis airway epithelial cells
Authors: Kelly Catriona , Canning Paul , Buchanan Paul J. , Williams Mark T. , Brown Vanessa , Gruenert Dieter C. , Elborn J. Stuart , Ennis Madeleine , Schock Bettina C.
Published: January 2013

The innate immune response to bacterial infection is mediated through Toll-like receptors (TLRs), which trigger tightly regulated signaling cascades through transcription factors including NF-κB. LPS activation of TLR4 triggers internalization of the receptor-ligand complex which is directed toward lysosomal degradation or endocytic recycling. Cystic fibrosis (CF) patients display a robust and uncontrolled inflammatory response to bacterial infection, suggesting a defect in regulation. This study examined the intracellular trafficking of TLR4 in CF and non-CF airway epithelial cells following stimulation with LPS. We employed cells lines [16hBE14o-, CFBE41o- (CF), and CFTR-complemented CFBE41o-] and confirmed selected experiments in primary nasal epithelial cells from non-CF controls and CF patients (F508del homozygous). In control cells, TLR4 expression (surface and cytoplasmic) was reduced after LPS stimulation but remained unchanged in CF cells and was accompanied by a heightened inflammatory response 24 h after stimulation. All cells expressed markers of the early (EEA1) and late (Rab7b) endosomes at basal levels. However, only CF cells displayed persistent expression of Rab7b following LPS stimulation. Rab7 variants may directly internalize bacteria to the Golgi for recycling or to the lysosome for degradation. TLR4 colocalized with the lysosomal marker LAMP1 in 16 hBE14o- cells, suggesting that TLR4 is targeted for lysosomal degradation in these cells. However, this colocalization was not observed in CFBE41o- cells, where persistent expression of Rab7 and release of proinflammatory cytokines was detected. Consistent with the apparent inability of CF cells to target TLR4 toward the lysosome for degradation, we observed persistent surface and cytoplasmic expression of this pathogen recognition receptor. This defect may account for the prolonged cycle of chronic inflammation associated with CF.
Sol‐Gel Synthesis, X‐Ray Diffraction Studies, and Electric Conductivity of Sodium Europium Silicate
Authors: Borisova Ekaterina V. , Ignatov Alexey V. , Get′man Eugeni I. , Loboda Stanislav N. , Ardanova Lyudmyla I. , Pasechnik Lyudmila V. , Ponurovsky Vitaly S.
Published: January 2013

Sodium europium silicate, NaEu9(SiO4)6O2, with apatite structure has been obtained and studied using X‐ray diffraction and SEM. It has been shown that sodium sublimation does not take place upon synthesis by the sol‐gel method. Rietveld refinement has revealed that sodium atoms are ordered and occupy the 4f position. O(4) atoms not related to silicate ions are placed at the centers of Eu(2) triangles. DC and AC electric conductivity and activation energy have been determined for the compound studied.
Chronic Opioid Therapy and Opioid Tolerance: A New Hypothesis
Authors: Goldberg Joel S.
Published: January 2013

Opioids are efficacious and cost-effective analgesics, but tolerance limits their effectiveness. This paper does not present any new clinical or experimental data but demonstrates that there exist ascending sensory pathways that contain few opioid receptors. These pathways are located by brain PET scans and spinal cord autoradiography. These nonopioid ascending pathways include portions of the ventral spinal thalamic tract originating in Rexed layers VI–VIII, thalamocortical fibers that project to the primary somatosensory cortex (S1), and possibly a midline dorsal column visceral pathway. One hypothesis is that opioid tolerance and opioid-induced hyperalgesia may be caused by homeostatic upregulation during opioid exposure of nonopioid-dependent ascending pain pathways. Upregulation of sensory pathways is not a new concept and has been demonstrated in individuals impaired with deafness or blindness. A second hypothesis is that adjuvant nonopioid therapies may inhibit ascending nonopioid-dependent pathways and support the clinical observations that monotherapy with opioids usually fails. The uniqueness of opioid tolerance compared to tolerance associated with other central nervous system medications and lack of tolerance from excess hormone production is discussed. Experimental work that could prove or disprove the concepts as well as flaws in the concepts is discussed.
Detection of Glaucoma in a Cohort of Chinese Subjects with Systemic Hypertension
Authors: Gangwani Rita A. , Chan Jonathan , Lee Jacky , Kwong Alfred , Lai Jimmy S. M.
Published: January 2013

Purpose. To determine the presence and type of glaucoma in a cohort of adult Chinese subjects with systemic hypertension.Methods. This prospective cohort study included 200 hypertensive Chinese adults aged >40 years old who underwent screening via frequency doubling technology (FDT) perimetry and intraocular pressure (IOP) measurement by noncontact tonometry (NCT) in a general outpatient clinic. Those withIOP>21 mmHg and/or visual field (VF) defects on FDT were referred for complete ophthalmological examination. The diagnosis of glaucoma was based on an abnormal VF on Humphrey Field Analyzer (HFA) by Hodapp-Parrish-Anderson's criteria and an increased vertical cup-disc ratio (VCDR).Results. The mean age of the subjects was64.66±9.47years, and the male:female ratio was 92 : 108. All patients were hypertensive with a mean blood pressure (BP) of131.1±15.1/76.6±11.1 mmHg whilst on systemic antihypertensive medication. Of the 111 patients that had an abnormal initial screening, 14 (7.9%) were confirmed to have glaucoma with the highest prevalence of normal tension glaucoma (NTG) (6.2%), followed by primary angle closure glaucoma (PACG) (1.1%) and primary open angle glaucoma (POAG) (0.5%). The positive predictive value of FDT perimetry was 71%.Conclusion. Nearly 8% of the adults with systemic hypertension had glaucoma, and NTG was the most prevalent type.
Omega-3 Polyunsaturated Fatty Acids Enhance Neuronal Differentiation in Cultured Rat Neural Stem Cells
Authors: Katakura Masanori , Hashimoto Michio , Okui Toshiyuki , Shahdat Hossain Md , Matsuzaki Kentaro , Shido Osamu
Published: January 2013

Polyunsaturated fatty acids (PUFAs) can induce neurogenesis and recovery from brain diseases. However, the exact mechanisms of the beneficial effects of PUFAs have not been conclusively described. We recently reported that docosahexaenoic acid (DHA) induced neuronal differentiation by decreasing Hes1 expression and increasingp27kip1expression, which causes cell cycle arrest in neural stem cells (NSCs). In the present study, we examined the effect of eicosapentaenoic acid (EPA) and arachidonic acid (AA) on differentiation, expression of basic helix-loop-helix transcription factors (Hes1, Hes6, and NeuroD), and the cell cycle of cultured NSCs. EPA also increased mRNA levels of Hes1, an inhibitor of neuronal differentiation, Hes6, an inhibitor of Hes1, NeuroD, and Map2 mRNA and Tuj-1-positive cells (a neuronal marker), indicating that EPA induced neuronal differentiation. EPA increased the mRNA levels ofp21cip1andp27kip1, a cyclin-dependent kinase inhibitor, which indicated that EPA induced cell cycle arrest. Treatment with AA decreased Hes1 mRNA but did not affect NeuroD and Map2 mRNA levels. Furthermore, AA did not affect the number of Tuj-1-positive cells or cell cycle progression. These results indicated that EPA could be involved in neuronal differentiation by mechanisms alternative to those of DHA, whereas AA did not affect neuronal differentiation in NSCs.
Management of Zinner’s Syndrome Associated with Contralateral Seminal Vesicle Hypoplasia: A Case Report
Authors: Kardoust Parizi Mehdi , Shakhssalim Nasser
Published: January 2013

A 27-year-old man presented with chronic hematospermia, painful ejaculation, and primary infertility. Physical examination, transrectal ultrasonography, and pelvic magnetic resonance imaging (MRI) demonstrated left seminal vesicle cyst, left renal agenesia, and contralateral seminal vesicle hypoplasia. Hormone workup (LH, FSH, prolactin, and testosterone) was normal. Sperm analysis showed oligoasthenozoospermia and low ejaculate volume. We performed transurethral resection of the ejaculatory duct (TUR-ED) using methylene blue vasography guidance without surgical-related complications. Hematospermia and painful ejaculation completely improved at 2-month followup, and the patient’s wife experienced a missed abortion thereafter. This patient was considered as a rare variant of Zinner’s syndrome and was managed effectively with a less invasive treatment modality (TUR-ED).
Goblet Cell Carcinoids of the Appendix
Authors: Holt Nanna , Grønbæk Henning
Published: January 2013

Goblet cell carcinoid (GCC) tumors are a rare subgroup of neuroendocrine tumors almost exclusively originating in the appendix. The tumor most often presents in the fifth or sixth decade with a clinical picture of appendicitis or in advanced cases an abdominal mass associated with abdominal pain. Histologically tumors are most often positive for chromogranin A and synaptophysin, however, less homogenous than for classic appendix carcinoids. The malignant potential is higher than that for the classic appendix carcinoids due to local spread and distant metastases at diagnosis and the proliferation markers (Ki67 index) may determine prognosis. Octreotide receptor scintigraphy is usually negative while CT/MRI scans may be useful. Chromogranin A is usually negative and other biomarkers related to the mucinous component or the tumor (CEA, CA‐19‐9, and CA‐125) may be used. Surgery is the main treatment with appendectomy and right hemicolectomy while patients with disseminated disease should be treated with chemotherapy. Overall 5‐year survival is approximately 75%. The diagnosis and treatment of GCC tumorss should be restricted to high volume NET centers in order to accumulate knowledge and improve survival in GCC NET patients. The aim of this paper is to update on epidemiology, clinical presentation, and diagnostic markers including Ki67 index, treatment, and survival.
Electrophysiological Correlates of the Threshold to Detection of Passive Motion: An Investigation in Professional Volleyball Athletes with and without Atrophy of the Infraspinatus Muscle
Authors: Salles José Inácio , Cossich Victor Rodrigues Amaral , Amaral Marcus Vinicius , Monteiro Martim T. , Cagy Maurício , Motta Geraldo , Velasques Bruna , Piedade Roberto , Ribeiro Pedro
Published: January 2013

The goal of the present study is to compare the electrophysiological correlates of the threshold to detection of passive motion (TTDPM) among three groups: healthy individuals (control group), professional volleyball athletes with atrophy of the infraspinatus muscle on the dominant side, and athletes with no shoulder pathologies. More specifically, the study aims at assessing the effects of infraspinatus muscle atrophy on the cortical representation of the TTDPM. A proprioception testing device (PTD) was used to measure the TTDPM. The device passively moved the shoulder and participants were instructed to respond as soon as movement was detected (TTDPM) by pressing a button switch. Response latency was established as the delay between the stimulus (movement) and the response (button press). Electroencephalographic (EEG) and electromyographic (EMG) activities were recorded simultaneously. An analysis of variance (ANOVA) and subsequent post hoc tests indicated a significant difference in latency between the group of athletes without the atrophy when compared both to the group of athletes with the atrophy and to the control group. Furthermore, distinct patterns of cortical activity were observed in the three experimental groups. The results suggest that systematically trained motor abilities, as well as the atrophy of the infraspinatus muscle, change the cortical representation of the different stages of proprioceptive information processing and, ultimately, the cortical representation of the TTDPM.
A Parallel Adaptive Newton-Krylov-Schwarz Method for 3D Compressible Inviscid Flow Simulations
Authors: Sala Marzio , Leyland Pénélope , Casagrande Angelo
Published: January 2013

A parallel adaptive pseudo transient Newton-Krylov-Schwarz (αΨNKS) method for the solution of compressible flows is presented. Multidimensional upwind residual distribution schemes are used for space discretisation, while an implicit time-marching scheme is employed for the discretisation of the (pseudo)time derivative. The linear system arising from the Newton method applied to the resulting nonlinear system is solved by the means of Krylov iterations with Schwarz-type preconditioners. A scalable and efficient data structure for theαΨNKS procedure is presented. The main computational kernels are considered, and an extensive analysis is reported to compare the Krylov accelerators, the preconditioning techniques. Results, obtained on a distributed memory computer, are presented for 2D and 3D problems of aeronautical interest on unstructured grids.
Methane Activation and Transformation on Polyoxometalates
Authors: Lefebvre Frédéric , Grinenval Eva , Putaj Piotr
Published: January 2013

Methane is activated at moderate temperature on polyoxometalates, leading to the evolution of hydrogen and the formation of a methoxy species which has been characterized by solid-state C13 CP-MAS NMR. In the case of a molybdic polyoxometalate, the methyl group is linked to an edge-shared oxygen atom of the polyoxometalate. Upon heating, it reacts with oxygens of the polyoxometalate resulting in the formation of formyl species and then carbon dioxide and a reduction of molybdenum. Upon treatment with water, only traces of methanol can be detected.
Using Correction Equations Based on Measured Height and Weight Weakens Associations between Obesity Based on Self-Reports and Chronic Diseases
Authors: Murray Cynthia L. , Walsh Gordon W. , Connor Gorber Sarah
Published: January 2013

Objective. Researchers have established a preponderance of height overestimation among men and weight underestimation among women in self-reported anthropometric data, which skews obesity prevalence data and obscures obesity-chronic disease relationships. The objective of this study was to reevaluate associations between obesity and chronic diseases using body mass index (BMI) correction equations derived from measured data. Methods. Measured height and weight (MHW) data were collected on a subsample of the 17,126 Atlantic Canadians who participated in the 2007-2008 Canadian Community Health Survey (CCHS). To obtain corrected BMI estimates for the 17,126 adults, correction equations were developed in the MHW subsample and multiple regression procedures were used to model BMI. To test obesity-chronic disease relationships, logistic regression models were utilized. Results. The correction procedure eliminated statistically significant relations (P<0.05) between obesity and chronic bronchitis and obesity and stroke. Also, correction attenuated many relationships between adiposity and chronic disease. For example, among obese adults, there was a 13%, 12%, and 7% reduction in the adjusted odds ratios for asthma, urinary incontinence, and cardiovascular disease, respectively. Conclusion. Further research is needed to fully understand how the usage of self-reported data alters our understanding of the relationships between overweight or obesity and chronic diseases.
An Exploration of Temperature Metrics for Further Developing the Heat-Health Weather Warning System in Hong Kong
Authors: Lam Cho Kwong Charlie , Loughnan Margaret , Tapper Nigel
Published: January 2013

Background. The current weather warning system aims to reduce mortality from heat and cold stress but still has room to be improved in terms of incorporating other temperature metrics. The aim of this study is to determine how extreme temperature affects mortality in Hong Kong. Methods. An ecological study was used; daily weather data were subdivided into seven temperature metrics. Daily detrended mortality data were stratified by disease groups and analysed using seven different metrics for temperature. The temperature metrics were then compared. Results. A diurnal temperature range (DTR) of ≥8°C leading to an increase in median mortality of up to 16% and a mean temperature change between neighbouring days of ≥4°C leading to an increase in median mortality of up to 6% were the critical thresholds for excess mortality in Hong Kong. Conclusions. This study reveals that mean net effective temperature, DTR, and temperature change between neighbouring days are effective to predict excess mortality in Hong Kong.
Mutant and Wild-type Ras: Co-conspirators in Cancer
Authors: Hayes Tikvah K. , Der Channing J.
Published: January 2013

Summary: Although the functional interplay between mutant and wild-type Ras in driving tumor initiation and growth has been described, a clear picture of the precise ramifications and mechanisms of this association remains elusive, sometimes with conflicting conclusions. A report in this issue of Cancer Discovery tackles this question, which may have important implications for therapeutic strategies to block mutant Ras for cancer treatment. Cancer Discov; 3(1); 24–6. ©2012 AACR.

See related article by Young et al., p. 112
Analysis of the Lipid Profile and Atherogenic Risk during Androgen Deprivation Therapy in Prostate Cancer Patients
Authors: Salvador C. , Planas J. , Agreda F. , Placer J. , Trilla E. , Lopez M.A. , Morote J.
Published: January 2013

Objective: To analyse changes in lipid profiles observed in patients receiving androgen deprivation therapy (ADT) and to evaluate differences between medical castration and maximal androgen blockade (MAB). Material and Methods: Serum levels of total cholesterol (TC), high-density lipoproteins (HDL), low-density lipoproteins (LDL) and triglycerides (TG) were prospectively evaluated in 33 patients with locally advanced or metastatic prostate cancer treated with ADT. The median age was 73.4 years. Serum lipids were measured at baseline and thereafter at 6 and 12 months. The modality of ADT was medical, with 3 months depot LHRH agonist, in 11 patients and MAB, by addition of 50 mg/day of bicalutamide, in 22 patients. Results: TC increased from 210 to 227 mg/dl (p < 0.05), while LDL increased from 132 to 148 mg/dl (p < 0.05) at 6 months. There were no significant changes in HDL or TG levels. There were no significant differences in any of the analysed parameters after 12 months of ADT. The comparison between the group of patients treated with LHRH agonists alone and the group treated with MAB demonstrated no significant differences in any of the analysed parameters at 6 and 12 months (p > 0.05). Conclusions: Changes observed in TC and LDL after 6 months of ADT were transitory. No significant differences were observed according to the modality of ADT.
Converting to a Capitation System for Dialysis Payment – The Portuguese Experience
Authors: Ponce Pedro , Marcelli Daniele , Guerreiro António , Grassmann Aileen , Gonçalves Carlos , Scatizzi Laura , Bayh Inga , Stopper Andrea , Da Silva Ricardo
Published: January 2013

Due to the challenge of operating within an economically strained healthcare budget, Portuguese health authorities convened with dialysis providers and agreed on a framework to change from a fee-for-service reimbursement modality to a capitation payment system for hemodialysis. This article reviews the components of the agreed capitation package implemented in 2008 as well as the necessary preparatory work undertaken by a for-profit 34-unit dialysis network (approx. 4,200 patients) to cope with the introduction of this system. Furthermore, trends in clinical quality indicators and in resource management are reviewed for 3 years immediately following capitation introduction. Here, improvements were observed over time for the specified clinical targets. Simultaneously, costs controllable by the physician could be reduced. As more countries convert to a capitation or bundled payment system for hemodialysis services, this article offers insight into the scope of the necessary preparatory work and the possible consequences in terms of costs and treatment quality.