bluuebunny/crossref_metadata_2025 huggingface dataset:
Antifungal Properties of Cationic Phenylene Ethynylenes and Their Impact on β-Glucan Exposure
Authors: Pappas Harry C. , Sylejmani Rina , Graus Matthew S. , Donabedian Patrick L. , Whitten David G. , Neumann Aaron K.
Published: May 2016

Candida
species are the cause of many bloodstream infections through contamination of indwelling medical devices. These infections account for a 40% mortality rate, posing a significant risk to immunocompromised patients. Traditional treatments against
Candida
infections include amphotericin B and various azole treatments. Unfortunately, these treatments are associated with high toxicity, and resistant strains have become more prevalent. As a new frontier, light-activated phenylene ethynylenes have shown promising biocidal activity against Gram-positive and -negative bacterial pathogens, as well as the environmental yeast
Saccharomyces cerevisiae
. In this study, we monitored the viability of
Candida
species after treatment with a cationic conjugated polymer [poly(
p
-phenylene ethynylene); PPE] or oligomer [“end-only” oligo(
p
-phenylene ethynylene); EO-OPE] by flow cytometry in order to explore the antifungal properties of these compounds. The oligomer was found to disrupt
Candida albicans
yeast membrane integrity independent of light activation, while PPE is able to do so only in the presence of light, allowing for some control as to the manner in which cytotoxic effects are induced. The contrast in killing efficacy between the two compounds is likely related to their size difference and their intrinsic abilities to penetrate the fungal cell wall. Unlike EO-OPE-DABCO (where DABCO is quaternized diazabicyclo[2,2,2]octane), PPE-DABCO displayed a strong propensity to associate with soluble β-glucan, which is expected to inhibit its ability to access and perturb the inner cell membrane of
Candida
yeast. Furthermore, treatment with PPE-DABCO unmasked
Candida albicans
β-glucan and increased phagocytosis by Dectin-1-expressing HEK-293 cells. In summary, cationic phenylene ethynylenes show promising biocidal activity against pathogenic
Candida
yeast cells while also exhibiting immunostimulatory effects.
The Investigational Drug VT-1129 Is a Highly Potent Inhibitor of Cryptococcus Species CYP51 but Only Weakly Inhibits the Human Enzyme
Authors: Warrilow Andrew G. S. , Parker Josie E. , Price Claire L. , Nes W. David , Garvey Edward P. , Hoekstra William J. , Schotzinger Robert J. , Kelly Diane E. , Kelly Steven L.
Published: May 2016

Cryptococcosis is a life-threatening disease often associated with HIV infection. Three
Cryptococcus
species CYP51 enzymes were purified and catalyzed the 14α-demethylation of lanosterol, eburicol, and obtusifoliol. The investigational agent VT-1129 bound tightly to all three CYP51 proteins (dissociation constant [

K
d

] range, 14 to 25 nM) with affinities similar to those of fluconazole, voriconazole, itraconazole, clotrimazole, and ketoconazole (

K
d

range, 4 to 52 nM), whereas VT-1129 bound weakly to human CYP51 (

K
d

, 4.53 μM). VT-1129 was as effective as conventional triazole antifungal drugs at inhibiting cryptococcal CYP51 activity (50% inhibitory concentration [IC
50
] range, 0.14 to 0.20 μM), while it only weakly inhibited human CYP51 activity (IC
50
, ∼600 μM). Furthermore, VT-1129 weakly inhibited human CYP2C9, CYP2C19, and CYP3A4, suggesting a low drug-drug interaction potential. Finally, the cellular mode of action for VT-1129 was confirmed to be CYP51 inhibition, resulting in the depletion of ergosterol and ergosta-7-enol and the accumulation of eburicol, obtusifolione, and lanosterol/obtusifoliol in the cell membranes.
A Pathogen-Selective Antibiotic Minimizes Disturbance to the Microbiome
Authors: Yao Jiangwei , Carter Robert A. , Vuagniaux Grégoire , Barbier Maryse , Rosch Jason W. , Rock Charles O.
Published: May 2016

Broad-spectrum antibiotic therapy decimates the gut microbiome, resulting in a variety of negative health consequences. Debio 1452 is a staphylococcus-selective enoyl-acyl carrier protein reductase (FabI) inhibitor under clinical development and was used to determine whether treatment with pathogen-selective antibiotics would minimize disturbance to the microbiome. The effect of oral Debio 1452 on the microbiota of mice was compared to the effects of four commonly used broad-spectrum oral antibiotics. During the 10 days of oral Debio 1452 treatment, there was minimal disturbance to the gut bacterial abundance and composition, with only the unclassified S24-7 taxon reduced at days 6 and 10. In comparison, broad-spectrum oral antibiotics caused ∼100- to 4,000-fold decreases in gut bacterial abundance and severely altered the microbial composition. The gut bacterial abundance and composition of Debio 1452-treated mice were indistinguishable from those of untreated mice 2 days after the antibiotic treatment was stopped. In contrast, the bacterial abundance in broad-spectrum-antibiotic-treated mice took up to 7 days to recover, and the gut composition of the broad-spectrum-antibiotic-treated mice remained different from that of the control group 20 days after the cessation of antibiotic treatment. These results illustrate that a pathogen-selective approach to antibiotic development will minimize disturbance to the gut microbiome.
Large-Scale Screening and Identification of Novel Ebola Virus and Marburg Virus Entry Inhibitors
Authors: Anantpadma Manu , Kouznetsova Jennifer , Wang Hang , Huang Ruili , Kolokoltsov Andrey , Guha Rajarshi , Lindstrom Aaron R. , Shtanko Olena , Simeonov Anton , Maloney David J. , Maury Wendy , LaCount Douglas J. , Jadhav Ajit , Davey Robert A.
Published: May 2016

Filoviruses are highly infectious, and no FDA-approved drug therapy for filovirus infection is available. Most work to find a treatment has involved only a few strains of Ebola virus and testing of relatively small drug libraries or compounds that have shown efficacy against other virus types. Here we report the findings of a high-throughput screening of 319,855 small molecules from the Molecular Libraries Small Molecule Repository library for their activities against Marburg virus and Ebola virus. Nine of the most potent, novel compounds that blocked infection by both viruses were analyzed in detail for their mechanisms of action. The compounds inhibited known key steps in the Ebola virus infection mechanism by blocking either cell surface attachment, macropinocytosis-mediated uptake, or endosomal trafficking. To date, very few specific inhibitors of macropinocytosis have been reported. The 2 novel macropinocytosis inhibitors are more potent inhibitors of Ebola virus infection and less toxic than ethylisopropylamiloride, one commonly accepted macropinocytosis inhibitor. Each compound blocked infection of primary human macrophages, indicating their potential to be developed as new antifiloviral therapies.
Silver and Nitrate Oppositely Modulate Antimony Susceptibility through Aquaglyceroporin 1 in Leishmania (Viannia) Species
Authors: Andrade Juvana M. , Baba Elio H. , Machado-de-Avila Ricardo A. , Chavez-Olortegui Carlos , Demicheli Cynthia P. , Frézard Frédéric , Monte-Neto Rubens L. , Murta Silvane M. F.
Published: May 2016

Antimony (Sb) resistance in leishmaniasis chemotherapy has become one of the major challenges to the control of this spreading worldwide public health problem. Since the plasma membrane pore-forming protein aquaglyceroporin 1 (AQP1) is the major route of Sb uptake inLeishmania, functional studies are relevant to characterize drug transport pathways in the parasite. We generated AQP1-overexpressingLeishmania guyanensisandL. braziliensismutants and investigated their susceptibility to the trivalent form of Sb (SbIII) in the presence of silver and nitrate salts. Both AQP1-overexpressing lines presented 3- to 4-fold increased AQP1 expression levels compared with those of their untransfected counterparts, leading to an increased SbIIIsusceptibility of about 2-fold. Competition assays using silver nitrate, silver sulfadiazine, or silver acetate prior to SbIIIexposure increased parasite growth, especially in AQP1-overexpressing mutants. Surprisingly, SbIII-sodium nitrate or SbIII-potassium nitrate combinations showed significantly enhanced antileishmanial activities compared to those of SbIIIalone, especially against AQP1-overexpressing mutants, suggesting a putative nitrate-dependent modulation of AQP1 activity. The intracellular level of antimony quantified by graphite furnace atomic absorption spectrometry showed that the concomitant exposure to SbIIIand nitrate favors antimony accumulation in the parasite, increasing the toxicity of the drug and culminating with parasite death. This is the first report showing evidence of AQP1-mediated SbIIIsusceptibility modulation by silver inLeishmaniaand suggests the potential antileishmanial activity of the combination of nitrate salts and SbIII.
Role of Plasmodium vivax Dihydropteroate Synthase Polymorphisms in Sulfa Drug Resistance
Authors: Pornthanakasem Wichai , Riangrungroj Pinpunya , Chitnumsub Penchit , Ittarat Wanwipa , Kongkasuriyachai Darin , Uthaipibull Chairat , Yuthavong Yongyuth , Leartsakulpanich Ubolsree
Published: May 2016

Dihydropteroate synthase (DHPS) is a known sulfa drug target in malaria treatment, existing as a bifunctional enzyme together with hydroxymethyldihydropterin pyrophosphokinase (HPPK). Polymorphisms in key residues of
Plasmodium falciparum
DHPS (
Pf
DHPS) have been characterized and linked to sulfa drug resistance in malaria. Genetic sequencing of
P. vivax
dhps
(
Pvdhps
) from clinical isolates has shown several polymorphisms at the positions equivalent to those in the
Pfdhps
genes conferring sulfa drug resistance, suggesting a mechanism for sulfa drug resistance in
P. vivax
similar to that seen in
P. falciparum
. To characterize the role of polymorphisms in the
Pv
DHPS in sulfa drug resistance, various mutants of recombinant
Pv
HPPK-DHPS enzymes were expressed and characterized. Moreover, due to the lack of a continuous
in vitro
culture system for
P. vivax
parasites, a surrogate
P. berghei
model expressing
Pvhppk-dhps
genes was established to demonstrate the relationship between sequence polymorphisms and sulfa drug susceptibility and to test the activities of
Pv
DHPS inhibitors on the transgenic parasites. Both enzyme activity and transgenic parasite growth were sensitive to sulfadoxine to different degrees, depending on the number of mutations that accumulated in DHPS.

K
i

values and 50% effective doses were higher for mutant
Pv
DHPS enzymes than the wild-type enzymes. Altogether, the study provides the first evidence of sulfa drug resistance at the molecular level in
P. vivax
. Furthermore, the enzyme inhibition assay and the
in vivo
screening system can be useful tools for screening new compounds for their activities against
Pv
DHPS.
Glutathione-Disrupted Biofilms of Clinical Pseudomonas aeruginosa Strains Exhibit an Enhanced Antibiotic Effect and a Novel Biofilm Transcriptome
Authors: Klare William , Das Theerthankar , Ibugo Amaye , Buckle Edwina , Manefield Mike , Manos Jim
Published: May 2016

Pseudomonas aeruginosainfections result in high morbidity and mortality rates for individuals with cystic fibrosis (CF), with premature death often occurring. These infections are complicated by the formation of biofilms in the sputum. Antibiotic therapy is stymied by antibiotic resistance of the biofilm matrix, making novel antibiofilm strategies highly desirable. WithinP. aeruginosabiofilms, the redox factor pyocyanin enhances biofilm integrity by intercalating with extracellular DNA. The antioxidant glutathione (GSH) reacts with pyocyanin, disrupting intercalation. This study investigated GSH disruption by assaying the physiological effects of GSH and DNase I on biofilms of clinical CF isolates grown in CF artificial sputum medium (ASMDM+). Confocal scanning laser microscopy showed that 2 mM GSH, alone or combined with DNase I, significantly disrupted immature (24-h) biofilms of Australian epidemic strain (AES) isogens AES-1R and AES-1M. GSH alone greatly disrupted mature (72-h) AES-1R biofilms, resulting in significant differential expression of 587 genes, as indicated by RNA-sequencing (RNA-seq) analysis. Upregulated systems included cyclic diguanylate and pyoverdine biosynthesis, the type VI secretion system, nitrate metabolism, and translational machinery. Biofilm disruption with GSH revealed a cellular physiology distinct from those of mature and dispersed biofilms. RNA-seq results were validated by biochemical and quantitative PCR assays. Biofilms of a range of CF isolates disrupted with GSH and DNase I were significantly more susceptible to ciprofloxacin, and increased antibiotic effectiveness was achieved by increasing the GSH concentration. This study demonstrated that GSH, alone or with DNase I, represents an effective antibiofilm treatment when combined with appropriate antibiotics, pendingin vivostudies.
Structural Insights into Recognition of Hydrolyzed Carbapenems and Inhibitors by Subclass B3 Metallo-β-Lactamase SMB-1
Authors: Wachino Jun-ichi , Yamaguchi Yoshihiro , Mori Shigetarou , Jin Wanchun , Kimura Kouji , Kurosaki Hiromasa , Arakawa Yoshichika
Published: May 2016

Metallo-β-lactamases (MBLs) confer resistance to carbapenems, and their increasing global prevalence is a growing clinical concern. To elucidate the mechanisms by which these enzymes recognize and hydrolyze carbapenems, we solved 1.4 to 1.6 Å crystal structures of SMB-1 (

S

erratia
m
etallo-
β
-lactamase 1), a subclass B3 MBL, bound to hydrolyzed carbapenems (doripenem, meropenem, and imipenem). In these structures, SMB-1 interacts mainly with the carbapenem core structure via elements in the active site, including a zinc ion (Zn-2), Q157[113] (where the position in the SMB-1 sequence is in brackets after the BBL number), S221[175], and T223[177]. There is less contact with the carbapenem R2 side chains, strongly indicating that SMB-1 primarily recognizes the carbapenem core structure. This is the first report describing how a subclass B3 MBL recognizes carbapenems. We also solved the crystal structure of SMB-1 in complex with the approved drugs captopril, an inhibitor of the angiotensin-converting enzyme, and 2-mercaptoethanesulfonate, a chemoprotectant. These drugs are inhibitors of SMB-1 with

K
i

values of 8.9 and 184 μM, respectively. Like carbapenems, these inhibitors interact with Q157[113] and T223[177] and their thiol groups coordinate the zinc ions in the active site. Taken together, the data indicate that Q157[113], S221[175], T223[177], and the two zinc ions in the active site are key targets in the design of SMB-1 inhibitors with enhanced affinity. The structural data provide a solid foundation for the development of effective inhibitors that would overcome the carbapenem resistance of MBL-producing multidrug-resistant microbes.
Regulation of Coenzyme A Biosynthesis in the Hyperthermophilic Bacterium Thermotoga maritima
Authors: Shimosaka Takahiro , Tomita Hiroya , Atomi Haruyuki
Published: May 2016

Regulation of coenzyme A (CoA) biosynthesis in bacteria and eukaryotes occurs through feedback inhibition targeting type I and type II pantothenate kinase (PanK), respectively. In contrast, the activity of type III PanK is not affected by CoA. As the hyperthermophilic bacterium
Thermotoga maritima
harbors only a single type III PanK (
Tm
-PanK), here we examined the mechanisms that regulate CoA biosynthesis in this organism. We first examined the enzyme responsible for the ketopantoate reductase (KPR) reaction, which is the target of feedback inhibition in archaea. A classical KPR homolog was not present on the
T. maritima
genome, but we found a homolog (TM0550) of the ketol-acid reductoisomerase (KARI) from
Corynebacterium glutamicum
, which exhibits KPR activity. The purified TM0550 protein displayed both KPR and KARI activities and was designated
Tm
-KPR/KARI. When
T. maritima
cell extract was subjected to anion-exchange chromatography, the fractions containing high levels of KPR activity also displayed positive signals in a Western blot analysis using polyclonal anti-TM0550 protein antisera, strongly suggesting that
Tm
-KPR/KARI was the major source of KPR activity in the organism. The KPR activity of
Tm
-KPR/KARI was not inhibited in the presence of CoA. We thus examined the properties of
Tm
-PanK and the pantothenate synthetase (
Tm
-PS) of this organism.
Tm
-PS was not affected by CoA. Surprisingly however,
Tm
-PanK was inhibited by CoA, with almost complete inhibition in the presence of 400 μM CoA. Our results suggest that CoA biosynthesis in
T. maritima
is regulated by feedback inhibition targeting PanK, although
Tm
-PanK is a type III enzyme.

IMPORTANCE
Bacteria and eukaryotes regulate the biosynthesis of coenzyme A (CoA) by feedback inhibition targeting type I or type II pantothenate kinase (PanK). The hyperthermophilic bacterium
Thermotoga maritima
harbors a single type III PanK (
Tm
-PanK), previously considered to be unaffected by CoA. By examining the properties of three enzymes involved in CoA biosynthesis in this organism, we found that
Tm
-PanK, although a type III enzyme, is inhibited by CoA. The results provide a feasible explanation of how CoA biosynthesis is regulated in
T. maritima
, which may also apply for other bacteria that harbor only type III PanK enzymes.
Classifying β-Barrel Assembly Substrates by Manipulating Essential Bam Complex Members
Authors: Mahoney Tara F. , Ricci Dante P. , Silhavy Thomas J.
Published: May 2016

The biogenesis of the outer membrane (OM) of
Escherichia coli
is a conserved and vital process. The assembly of integral β-barrel outer membrane proteins (OMPs), which represent a major component of the OM, depends on periplasmic chaperones and the heteropentameric β-barrel assembly machine (Bam complex) in the OM. However, not all OMPs are affected by null mutations in the same chaperones or nonessential Bam complex members, suggesting there are categories of substrates with divergent requirements for efficient assembly. We have previously demonstrated two classes of substrates, one comprising large, low-abundance, and difficult-to-assemble substrates that are heavily dependent on SurA and also Skp and FkpA, and the other comprising relatively simple and abundant substrates that are not as dependent on SurA but are strongly dependent on BamB for assembly. Here, we describe novel mutations in
bamD
that lower levels of BamD 10-fold and >25-fold without altering the sequence of the mature protein. We utilized these mutations, as well as a previously characterized mutation that lowers wild-type BamA levels, to reveal a third class of substrates. These mutations preferentially cause a marked decrease in the levels of multimeric proteins. This susceptibility of multimers to lowered quantities of Bam machines in the cell may indicate that multiple Bam complexes are needed to efficiently assemble multimeric proteins into the OM.

IMPORTANCE
The outer membrane (OM) of Gram-negative bacteria, such as
Escherichia coli
, serves as a selective permeability barrier that prevents the uptake of toxic molecules and antibiotics. Integral β-barrel proteins (OMPs) are assembled by the β-barrel assembly machine (Bam), components of which are conserved in mitochondria, chloroplasts, and all Gram-negative bacteria, including many clinically relevant pathogenic species. Bam is essential for OM biogenesis and accommodates a diverse array of client proteins; however, a mechanistic model that accounts for the selectivity and broad substrate range of Bam is lacking. Here, we show that the assembly of multimeric OMPs is more strongly affected than that of monomeric OMPs when essential Bam complex components are limiting, suggesting that multiple Bam complexes are needed to assemble multimeric proteins.
Case of eastern equine encephalitis presenting in winter
Authors: Shah Kairav J , Cherabuddi Kartikeya
Published: May 2016

A 50-year-old man was admitted in midwinter with fever, altered mental status and new onset generalised tonic-clonic seizure with urinary incontinence. Cerebrospinal fluid (CSF) analysis revealed an opening pressure of 14.5 cm of water, normal glucose and protein 82 mg/dL (reference range: 15–45 mg/dL). Cell count showed: red cells 11 (reference range: <5 mm3), white cell count 1 (reference range: <5 mm3). The patient's blood and CSF cultures had no growth. MRI of the brain with and without gadolinium contrast showed abnormal T2 and fluid-attenuated inversion recovery signals within bilateral ventricular nuclei, hippocampi, left frontal and parietal regions. Eastern equine encephalitis (EEE) antibody, IgG titre was 1:64 and IgM titre was <1:16. Three weeks later, his repeat/convalescent titres increased to 1:1024 and 1:32, respectively. Hence, a diagnosis of EEE was established. The patient was treated with supportive care. He recovered well with mildly impaired memory but no other cognitive deficits.
A cohort study of regional migration and the risks of attempted suicide and violent assault injury
Authors: Yiannakoulias N , Sanchez-Ramirez D , Svenson L W , Voaklander D C
Published: May 2016

Objectives

We study the association between changing residence and risks of attempted suicide and violent assault injury in Alberta, Canada. Our primary objective is to understand whether a change in residence between urban, rural and semiurban areas is associated with increased risk of intentional injury.

Methods

Study subjects are a cohort of residents linked to data on emergency department and inpatient hospital admissions between 1999 and 2010. We used generalised estimating equations to model the effects of changing residence on risk of intentional injury while controlling for the influence of age, sex, socio-economic status, Aboriginal status and history of intentional injury.

Results

Changing residence is associated with an increase in the risk of both attempted suicide and violent assault injury. In the case of attempted suicide, this effect is strongest for persons between 20 and 35 years of age. For violent assault injuries, persons from rural regions that have recently moved to urban regions have higher risk of injuries, and women of rural origin are at higher risk of violent assault injury than women of urban origin.

Conclusions

Our findings reveal an association between risk of intentional injuries and change of residence adjusting for geographical differences in injury risk. These findings suggest that intentional injury risk is associated with change in community at intraregional scales and that these populations may benefit from support that helps integrate them into their new communities.
1: COMPARATIVE EFFECT OF SELECTIVE AND NON-SELECTIVE COX-2 INHIBITORS ON LIPID ACCUMULATION IN HUMAN MACROPHAGES
Authors: Kasselman LJ , Voloshyna I , Littlefield MJ , Siegart N , Carsons SE , Gomolin I , De Leon J , Reiss AB
Published: May 2016

Purpose of Study

It is the second decade of controversy regarding the cardiovascular (CV) effects of cycloxygenase-2 (COX-2) inhibitors. COX-2 inhibitors possess anti-inflammatory and analgesic effects comparable with conventional non-steroidal anti-inflammatory drugs, but produce fewer gastrointestinal adverse effects. Here we demonstrate that only selective COX-2 inhibitors cause disruption of the delicate balance between cholesterol efflux and influx that leads to lipid overload and macrophage foam cell formation (FCF).

Methods Used

THP-1 human macrophages were incubated with: celecoxib (10 µM, 25 µM); rofecoxib (10 µM, 25 µM); naproxen (10 µM, 25 µM); acetaminophen (0.5 mM, 1 mM)±oxidized low density lipoprotein (oxLDL, 25 µg/ml, 48 h) or 5 µg/ml (Dil)-oxLDL. FCF (% oil red O stained cells) and oxLDL accumulation were determined (fluorescent intensity). Scavenger receptors: CD36, LOX-1, SR-A1 and CXCL16 and cholesterol efflux proteins: ATP-binding cassette transporter (ABC) A1 and ABCG1 were detected in macrophages by QRT-PCR and immunocytochemistry.

Summary of Results

Celecoxib decreased ABCA1 and ABCG1 message in a concentration dependent manner: 68.2±13.36% for ABCA1 and 65.7±13.36% for ABCG1 (control set at 100%, n=6, P<0.01). Neither naproxen nor acetaminophen significantly affected expression of cholesterol efflux proteins. Both specific and nonspecific COX-2 inhibitors had a significant impact on expression of scavenger receptors CD36, LOX-1 and SR-A1–nearly double control (n=6, P<0.05). However, only specific COX-2 inhibitors significantly increased FCF in THP-1 differentiated macrophages (62.2±5.2% for celecoxib and 56.3±3.4% for rofecoxib vs. 33.5±5.1% for untreated cells, P<0.05).

Conclusions

Here we report that only specific COX-2 inhibitors might contribute to atherogenesis by promoting lipid overload and lipoprotein accumulation. This may explain, in part, the increased CV risk in patients taking COX-2 inhibitors for extended periods. Despite increased scavenger receptor expression, naproxen and acetaminophen do not impact lipid content, perhaps because efflux pathways remain intact.
Parasympathetic Effects on Heart Rate Recovery after Exercise
Authors: Kannankeril Prince J. , Le Francis K. , Kadish Alan H. , Goldberger Jeffrey J.
Published: May 2016

Background

Exercise and its recovery period are associated with increased risk of death relative to sedentary periods. They are also accompanied by dynamic changes in autonomic tone. Little information is available regarding parasympathetic effects during high-intensity exercise and recovery.

Methods

Ten normal subjects (five women; age 33 ± 2 years) underwent exercise testing on a bicycle ergometer. On day 1, subjects exercised to maximum tolerated workload using a graded protocol with 5 minutes at maximal workload (peak heart rate achieved 174.7 ± 5.4 bpm). On day 2, subjects performed the identical exercise protocol as on day 1; 1 minute into the maximum exercise stage, atropine (0.04 mg/kg) was administered. Heart rate was recorded every minute during exercise, and an electrocardiogram was recorded every minute in recovery for 10 minutes. The parasympathetic effect on heart rate was defined by the difference in heart rate with and without atropine.

Results

The parasympathetic effect during maximal exercise was 3.4 to 6 bpm (p < .05). During recovery, a large parasympathetic effect on heart rate was noted by 1 minute (22.8 bpm; p < .0002), increased until 4 minutes, and then remained stable until 10 minutes. Despite faster heart rates with parasympathetic blockade, the P-R interval was shorter (p < .002), consistent with a significant parasympathetic effect on the atrioventricular node in recovery. Evaluation of the Q-T-R-R relationship on the 2 days demonstrated significant changes in both the slope (p < .0001) and the intercept (p < .0001), consistent with a modification of ventricular repolarization by parasympathetic tone in recovery.

Conclusion

These data indicate that in normal subjects, parasympathetic effects persist during high-intensity exercise and are prominent in the early phases of recovery. These parasympathetic effects may play an important role in prevention of sudden cardiac death during these periods of increased risk.
Ectonucleotidase NTPDase2 Is Selectively Down-Regulated in Biliary Cirrhosis
Authors: Dranoff Jonathan A. , Kruglov Emma A. , Toure Joahd , Braun Norbert , Zimmermann Herbert , Jain Dhanpat , Knowles Aileen F. , Sévigny Jean
Published: May 2016

Background

Portal fibroblasts are newly identified, potentially fibrogenic liver cells that are distinct from hepatic stellate cells. The ectonucleotidase* nucleoside triphosphate diphosphohydrolase 2 (NTPDase2) is restricted to portal fibroblasts in the normal liver. However, the fate of NTPDase2 after bile duct ligation (BDL) is unknown.

*Extracellular enzymes that mediate the degradation of adenosine triphosphate (ATP) and other nucleotides.

Aims

The aim of this study was to assess the effect of experimental rat and disease-mediated human biliary cirrhosis on NTP-Dase2 expression in the liver.

Methods

Cirrhosis was induced in experimental rats via BDL and carbon tetrachloride (CCl4) administration. Archived human liver biopsy specimens from normal liver, primary biliary cirrhosis, or hepatitis C cirrhosis were examined. Changes in expression of NTPDase2 were determined using confocal immunofluorescence, immunoblot, and real-time polymerase chain reaction.

Results

Confocal immunofluorescence demonstrated a decrease in NTPDase2 expression after BDL. Immunoblot and real-time polymerase chain reaction demonstrated a decrease in NTPDase2 expression by portal fibroblasts after BDL. No decrease in NTP-Dase2 protein was noted after CCl4 administration, and NTPDase2 messenger ribonucleic acid was markedly up-regulated after CCl4 administration. Confocal immunofluorescence demonstrated a shift of NTPDase2 expression from portal areas to central areas that colocalized with α-smooth muscle actin after CCl4 administration. In human biopsy specimens, NTPDase2 expression was lost in cirrhosis owing to primary biliary cirrhosis, whereas NTPDase2 expression was shifted to bridging fibrous bands in cirrhosis owing to hepatitis C.

Conclusions

Loss of NTPDase2 is a common pathway in both rat and human manifestations of biliary cirrhosis. Conversely, in nonbiliary cirrhosis, NTPDase2 is shifted from the portal area to bridging fibrous bands. Elucidations of the mechanisms regulating NTP-Dase2 expression may lead to new therapeutic approaches to fibrotic liver disease.
Intercellular Adhesion Molecule 1 (ICAM-1) Gene Variant Is Associated with Coronary Artery Calcification Independent of Soluble ICAM-1 Levels
Authors: Reilly Muredach P. , Wolfe Megan L. , Dykhouse Jennifer , Reddy Karthik , Localio Russell A. , Rader Daniel J.
Published: May 2016

Background

Although circulating levels of soluble intercellular adhesion molecule 1 (sICAM-1) predict cardiovascular events, no studies have examined intercellular adhesion molecule 1 (ICAM-1) gene variants, plasma sICAM-1 levels, and atherosclerosis in the same sample.

Methods

We examined the association of the ICAM-1 K469E gene variant and plasma sICAM-1 with coronary artery calcification (CAC) in 632 asymptomatic subjects, recruited on the basis of a family history of premature cardiovascular disease.

Results

In age-adjusted ordinal regression, sICAM-1 levels were associated with CAC (odds ratio [OR] [95% confidence interval (CI)] 1.30 [1.04-1.6] per 100 ng/dL sICAM-1; p = .02), but this association was lost after adjusting for traditional risk factors (OR [95% CI] 0.9 [0.69-1.16]). In men, but not women (interaction p = .018), the ICAM-1 K469E GG genotype predicted lower CAC after adjusting for traditional risk factors (OR [95% CI] 0.33 [0.17-0.61]; p = .001) and further controlling for plasma sICAM-1 (OR [95% CI] 0.27 [0.14-0.52]; p < .001).

Conclusions

In a study sample specifically selected for the characteristic of a family history of premature coronary heart disease, ICAM K469E GG was associated with lower CAC scores in men but not women even after controlling for plasma levels of sICAM-1. These studies suggest that ICAM-1 variants may modulate atherosclerosis in humans and provide support for the concept that inflammatory gene polymorphisms may influence atherosclerosis independent of plasma levels of their gene products.
Effects of Carbon Monoxide Poisoning on Neutrophil Responses in Patients Treated with Hyperbaric Oxygen
Authors: Schnittger Vendela , Rosendahl Kerstin , Lind Folke , Palmblad Jan
Published: May 2016

Background

Carbon monoxide (CO) poisoning can cause tissue injury. Neutrophil granulocytes have been proposed to contribute to the injury, which may be ameliorated by hyperbaric oxygen (HBO2) treatment. We sought to assess the relationship between acute CO poisoning and blood neutrophil count, plasma cytokine, and cortisol responses, as well as the mechanism behind the observed beneficiary effects of HBO2 treatment.

Methods

Eight patients (age 26-82 years) with severe acute CO poisoning were enrolled, concomitant with eight healthy controls (age 27-42 years), in a prospective, controlled, clinical study. The patients were given three HBO2 treatments (2.8 atmospheres absolute, 100 minutes) within the first 24 hours. The controls were given identical simultaneous HBO2treatments. Venous blood samples were taken before and after each treatment.

Results

At the start of the HBO2 treatment, patients displayed significantly higher blood neutrophil counts (p < .0001) and plasma cortisol levels (p = .020) than controls, but the two groups had similar values for interleukin-8, granulocyte colony-stimulating factor (G-CSF), neutrophil H2O2 generation, and CD16 and CD18 surface expression. During the observation time, neutrophil H2O2 accumulation declined in patients and in controls (p = .031), whereas the up-regulation of CD18 expression increased (p = .002) in both groups. Moreover, G-CSF levels became significantly higher in patients than in controls (p = .015). G-CSF levels also correlated significantly with neutrophil counts.

Conclusion

CO poisoning was associated with discrete changes of blood neutrophil counts, cortisol, and G-CSF plasma concentrations. HBO2 treatment modulated neutrophil generation of H2O2 and surface expression of CD18. These changes may be part of the cascade of events leading to the sequelae of CO poisoning and their attenuation by HBO2.
Ultralight gravitons with tiny electric dipole moment are seeping from the vacuum
Authors: Novikov Evgeny A.
Published: May 2016

Mass and electric dipole moment (EDM) of graviton, which is identified as dark matter particle (DMP), are estimated. This change the concept of dark matter and can help to explain the baryon asymmetry of the universe. The calculations are based on quantum modification of the general relativity (Qmoger) with two additional terms in the Einstein equations, which takes into account production/absorption of gravitons. In this theory, there are no Big Bang in the beginning (some local bangs during the evolution of the universe are probable), no critical density of the universe, no dark energy (no need in cosmological constant) and no inflation. The theory (without fitting) is in good quantitative agreement with cosmic data.
OPTIMAL CONTROL OF AN ENERGY STORAGE FACILITY UNDER A CHANGING ECONOMIC ENVIRONMENT AND PARTIAL INFORMATION
Authors: SHARDIN ANTON A. , SZÖLGYENYI MICHAELA
Published: May 2016

In this paper, we consider an energy storage optimization problem in finite time in a model with partial information that allows for a changing economic environment. The state process consists of the storage level controlled by the storage manager and the energy price process, which is a diffusion process the drift of which is assumed to be unobservable. We apply filtering theory to find an alternative state process which is adapted to our observation filtration. For this alternative state process, we derive the associated Hamilton–Jacobi–Bellman equation and solve the optimization problem numerically. This results in a candidate for the optimal policy for which it is a priori not clear whether the controlled state process exists. Hence, we prove an existence and uniqueness result for a class of time-inhomogeneous stochastic differential equations with discontinuous drift and singular diffusion coefficient. Finally, we apply our result to prove admissibility of the candidate optimal control.
A European Approach to Irritable Bowel Syndrome Management
Authors: Delvaux Michel , Frexinos Jacques
Published: May 2016

Irritable bowel syndrome (IBS) is characterized by a
number of clinical features and probably comprises a cluster of different
conditions. The most frequent symptom reported by IBS
patients is abdominal pain, although for a number of patients,
bowel disturbances are the most prominent symptoms. Diarrhetic
patients are seen in referral centres in continental Europe less frequently
than in the United Kingdom or the United States. On the
contrary, patients with constipation‐prone IBS may comprise up
to 80% of the IBS population referred to these centres. The
pathophysiology of IBS is based on multiple factors. Most of the
therapeutics proposed for the management of patients with IBS
have been developed on the assumption that motility disorders of
the gut are the most reliable pathological findings among these patients.
Consequently, antispasmodics and motility regulatory
agents have been widely used, alone or in association with intestinal
adsorbents (clay‐derived preparations), and laxatives or
antidiarrhetic agents. Most of these drugs were developed several
decades ago, and studies showing their efficacy have not reached
the level of quality that is now required of randomized controlled
trials. Therefore, following a complete and detailed review published
in 1989, these drugs have not been used extensively in the
United Kingdom or the United States. Large inquiries have also
shown that the duration of prescription is quite different among
countries. In European countries, maintenance therapy is frequently
prescribed for several weeks to attempt to decrease the
number of acute episodes. In contrast, psychotropic drugs are less
popular among European gastroenterologists than among American
gastroenterologists. However, multidisciplinary approaches to
the treatment of these patients are frequent, and such drugs are often
prescribed by home physicians. The results of large surveys estimated
the yearly cost of such treatments to be around US$850.
Patients with constipation and elderly patients with chronic disease
receive more expensive treatments.
Stress‐Induced Changes in the Gastrointestinal Motor System
Authors: Plourde Victor
Published: May 2016

Several autonomic, hormonal, behavioural and neuropeptidergic
bodily responses to stressful stimuli have been described over the
past few decades. Both animal models and human paradigms have
been explored. It is acknowledged that stress modulates gastrointestinal
(GI) motility through central mechanisms including
corticotropin‐releasing‐factor. This process requires the integrity
of autonomic neural pathways. It has become evident that the effects
of stress on GI motility vary according to the stressful
stimulus, its intensity, the animal species under study and the time
course of the study. Recent evidence suggests that chronic or possibly
permanent changes develop in enteric smooth muscle properties
in response to stress. In animals, the most consistent findings
include retardation of gastric emptying in response to various
stressors; acceleration of gastric emptying upon cold stress, presumably
through the secretion of brain thyroglobulin‐hormone;
acceleration of intestinal transit; and stimulation of colonic transit
and fecal output. In humans, the cold water immersion test has
been associated with an inhibition of gastric emptying, while labyrinthine
stimulation induces the transition from postprandial to
fasting motor patterns in the stomach and the small bowel. Psychological
stress has been shown to induce a reduction in the
number and amplitude of intestinal migrating motor complexes
and to neither affect nor stimulate colonic motility. These various
responses to stress are presumably attributed to the preferential activation
of specific neuronal pathways under the influence of a
given stimulus or its intensity. The significance of these findings
and the directions of further studies are discussed.
Approaches to the Modulation of Abdominal Pain
Authors: Mayer Emeran A , Lembo Tony , Chang Lin
Published: May 2016

Despite their high prevalence and significant economic
impact on the health care system, functional gastrointestinal
disorders have evaded successful therapy. Conventional
medical therapies are based on inadequate disease models, and the
great majority of published treatment trials are flawed in their design,
permitting no conclusions to be drawn about the true efficacy
of any particular treatment. During the past several years, a new,
comprehensive disease model based on alterations in brain‐gut interactions
has rapidly evolved. Even though the precise mechanisms
and sites underlying these alterations remain incompletely
understood, plausible targets for the development of effective
pharmacological treatments are receptors on peripheral terminals
of visceral afferent nerves (opioids and serotonin), ion channels
and receptors on dorsal horn neurons within the spinal cord
(opioids, glutamate, calcitonin gene‐related peptide and
neurokinin‐1), and supraspinal targets in the brainstem within
the limbic system and in the prefrontal cortex (serotonin, catecholamines,
dopamine and acetylcholine). Regardless of the primary
pathophysiology underlying functional gastrointestinal
disorders (ie, central versus peripheral), different pharmacological
strategies targeted at different sites in the periphery or within the
central nervous system may become effective therapies in the future.
Role of Opioid Ligands in the Irritable Bowel Syndrome
Authors: Corazziari Enrico
Published: May 2016

Endogenous
opioid peptides – enkephalins, beta‐endorphin and
dynorphins – are located in specific sites of the brain, the spinal
cord, the autonomic ganglia and the enteric nervous system. Endogenous
opioids participate in the regulation of nervous visceral
afference and sensitivity as well as of several visceral motor function
induced by the central nervous system and through the
enteroenteric and the myoenteric reflexes. Their final effect on
gut physiology is the net and harmonically balanced result of their
binding to mu, delta and kappa opioid receptor subtypes. Exogenous
opioid receptor ligands with different affinities for the opioid
receptor subtypes have been effectively used to modify and normalize
altered gut functions. Themureceptor agonists – morphine
and, to a greater extent, the meperidine congeners diphenoxylate
and loperamide – have been shown to slow gastrointestinal transit
by their effects on the circular and longitudinal muscle of the intestine.
Diphenoxylate and, more efficiently, loperamide, for the
lack of any effect on the central nervous system, have been usefully
employed in the treatment of diarrhea in irritable bowel syndrome
(IBS) patients. Unlike the mu receptor agonists morphine
and loperamide, which invariably stimulate colonic motility,
trimebutine, which has almost equal affinity for mu, delta and
kappa receptors, has no effect on normal colonic activity but reduces
the abnormal increase in postprandial motor activity in IBS
patients and accelerates slow large bowel transit in constipated patients.
Opioid ligands can be usefully employed to normalize altered
visceral sensitivity in IBS patients. The kappa receptor
agonist fedotozine exerts its antinociceptive effect by acting on
peripheral nerve endings of sensory vagal and nonvagal afferent
pathways. Fedotozine has been shown to increase the threshold of
perception to colonic distension in experimental conditions and
to affect favourably symptoms of IBS in clinical trials.
The Impact of Asthma Management Guideline Dissemination on the Control of Asthma in the Community
Authors: Cowie Robert L , Underwood Margot F , Mack Sally
Published: May 2016

OBJECTIVE: To measure the impact of asthma management education on the control of asthma in the community.

DESIGN: A cross‐sectional study comparing three communities.

SETTING: Three rural communities in southern Alberta.

PATIENTS AND METHODS: A population sample of patients with asthma attending a pharmacy to fill a prescription for asthma medication were selected from three communities. Patients were asked to complete a questionnaire relating to their asthma management and control.

INTERVENTION: Three levels of asthma management education were provided in the three communities with populations of 6000 to 10,000. The levels of education ranged from standard continuing medical education programs relating to the national asthma guidelines and a visiting asthma nurse educator to the establishment of an asthma clinic and a multiple‐target, intensive education program for health professionals, town leaders, local media, schools and the public. The survey of the population with asthma was conducted approximately one year after the education program had been completed.

RESULTS: A total of 327 completed questionnaires were submitted. Analysis showed that there was no significant difference that could be attributed to the intervention in the management of asthma or in the level of asthma control among the patients from the three communities.

RESULTS: A total of 327 completed questionnaires were submitted. Analysis showed that there was no significant difference that could be attributed to the intervention in the management of asthma or in the level of asthma control among the patients from the three communities.
Control of Asthma in Canada: Failure to Achieve Guideline Targets
Authors: Chapman Kenneth R , Ernst Pierre , Grenville A , Dewland P , Zimmerman Sabrina
Published: May 2016

OBJECTIVE: To assess the degree of asthma control achieved by patients with asthma in Canada and to describe the impact of poor asthma control.

DESIGN: Population‐based, cross‐sectional telephone interview survey of Canadians with doctor‐diagnosed asthma.

SUBJECTS AND METHODS: Random digit dialing was used to identify a representative sample of Canadians with asthma. A total of 801 adults and 200 parents of children aged four to 15 years were interviewed over the telephone. Telephone interviews were also conducted with 266 physicians.

RESULTS: Only 24% of patients achieved disease control by meeting the six symptom‐based criteria listed by the 1996 Canadian Asthma Consensus Guidelines as appropriate treatment targets. Fifty‐seven per cent of patients failed to meet two or more of the six control criteria and were considered poorly controlled. Fifty‐one per cent had required urgent care for out of control asthma at least once in the year before the survey. Nonetheless, 91% of patients thought that their asthma was adequately controlled. Physicians shared this optimism: 77% of family physicians and 90% of respirologists believed that they were usually able to achieve optimal asthma control in their patients. Few physicians gauged asthma control by tracking more than one or two symptoms, and just over one‐half (54%) of patients surveyed recalled ever having had a lung function test. One‐half (48%) of patients with poorly controlled asthma who used inhaled steroids did not understand the role of inhaled steroids; onethird (32%) of patients with poorly controlled asthma who used short acting bronchodilators misunderstood the action of quick relief bronchodilators.

CONCLUSIONS: The majority of Canadians with asthma suffer from inadequate control of their disease. Suboptimal control of asthma is associated with excess health care use. Inadequate monitoring by physicians and poor patient education may be factors contributing to this problem.