bluuebunny/crossref_metadata_2025_split huggingface dataset:
Oxygen uptake is more efficient in idiopathic pulmonary arterial hypertension than in chronic thromboembolic pulmonary hypertension
Authors: Shi Xiaofang , Guo Jian , Gong Sugang , Sapkota Rikesh , Yang Wenlan , Liu Hui , Xiang Wenjing , Wang Lan , Sun Xingguo , Liu Jinming 
Published: September 2015

AbstractBackground and objectiveThe responses of oxygen uptake efficiency (OUE) during cardiopulmonary exercise training (CPET) have not been reported in patients with pulmonary hypertension. We aimed to investigate the differences in OUE between patients with idiopathic pulmonary arterial hypertension (IPAH) and chronic thromboembolic pulmonary hypertension (CTEPH).MethodsForty‐four patients with IPAH and 29 patients with CTEPH were retrospectively enrolled into our study. All patients underwent right‐heart catheterization, pulmonary function test and performed the 6‐min walk test and CPET.ResultsWe found that oxygen uptake efficiency plateau (OUEP) and oxygen uptake efficiency at anaerobic threshold (OUE@AT) was significantly higher in IPAH than that in CTEPH (both P = 0.002). However, patients with CTEPH had lower mean pulmonary artery pressure, pulmonary vascular resistance and transpulmonary gradient (all P < 0.05). The correlation between OUEP and heart rate at anaerobic threshold (HR_AT) was significant (r = 0.376, P < 0.05); however, no statistically significant correlation was found with ventilation at anaerobic threshold (VE_AT) (r = −0.074, P > 0.05) in patients with IPAH. In patients with CTEPH, both anaerobic threshold (r = 0.307, P > 0.05) and VE_AT (r = −0.709, P < 0.0001) were reduced. OUEP were higher in WHO functional class I/II patients than in WHO functional class III/IV patients (all P < 0.05).ConclusionsOUEP and OUE@AT are higher in IPAH than that in CTEPH not in proportion to haemodynamics, probably due to differences in cardiac function and pulmonary vascular occlusion. OUEP correlates well with the exercise capacity and the severity of the disease.
Functional Partial Linear Single‐index Model
Authors: Wang Guochang , Feng Xiang‐Nan , Chen Min 
Published: September 2015

AbstractThis paper deals with the problem of predicting the real‐valued response variable using explanatory variables containing both multivariate random variable and random curve. The proposed functional partial linear single‐index model treats the multivariate random variable as linear part and the random curve as functional single‐index part, respectively. To estimate the non‐parametric link function, the functional single‐index and the parameters in the linear part, a two‐stage estimation procedure is proposed. Compared with existing semi‐parametric methods, the proposed approach requires no initial estimation and iteration. Asymptotical properties are established for both the parameters in the linear part and the functional single‐index. The convergence rate for the non‐parametric link function is also given. In addition, asymptotical normality of the error variance is obtained that facilitates the construction of confidence region and hypothesis testing for the unknown parameter. Numerical experiments including simulation studies and a real‐data analysis are conducted to evaluate the empirical performance of the proposed method.
Ageing, metabolism and cardiovascular disease
Authors: Costantino Sarah , Paneni Francesco , Cosentino Francesco 
Published: September 2015

AbstractAge is one of the major risk factors associated with cardiovascular disease (CVD). About one‐fifth of the world population will be aged 65 or older by 2030, with an exponential increase in CVD prevalence. It is well established that environmental factors (overnutrition, smoking, pollution, sedentary lifestyles) may lead to premature defects in mitochondrial functionality, insulin signalling, endothelial homeostasis and redox balance, fostering early senescent features. Over the last few years, molecular investigations have unveiled common signalling networks which may link the ageing process with deterioration of cardiovascular homeostasis and metabolic disturbances, namely insulin resistance. These different processes seem to be highly interconnected and their interplay may favour adverse vascular and cardiac phenotypes responsible for myocardial infarction, stroke and heart failure. In the present review, we carefully describe novel molecular cues underpinning ageing, metabolism and CVD. In particular, we describe a dynamic interplay between emerging pathways such as FOXOs, AMPK, SIRT1, p66Shc, JunD and NF‐kB. This overview will provide the background for attractive molecular targets to prevent age‐driven pathology in the vasculature and the heart.
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Reduction of Toxoplasma gondii Development Due to Inhibition of Parasite Antioxidant Enzymes by a Dinuclear Iron(III) Compound
Authors: Portes J. A. , Souza T. G. , dos Santos T. A. T. , da Silva L. L. R. , Ribeiro T. P. , Pereira M. D. , Horn A. , Fernandes C. , DaMatta R. A. , de Souza W. , Seabra S. H. 
Published: September 2015

ABSTRACT

Toxoplasma gondii
, the causative agent of toxoplasmosis, is an obligate intracellular protozoan that can infect a wide range of vertebrate cells. Here, we describe the cytotoxic effects of the dinuclear iron compound [Fe(HPCINOL)(SO
4
)]
2
-μ-oxo, in which HPCINOL is the ligand 1-(bis-pyridin-2-ylmethyl-amino)-3-chloropropan-2-ol, on
T. gondii
infecting LLC-MK2 host cells. This compound was not toxic to LLC-MK2 cells at concentrations of up to 200 μM but was very active against the parasite, with a 50% inhibitory concentration (IC
50
) of 3.6 μM after 48 h of treatment. Cyst formation was observed after treatment, as indicated by the appearance of a cyst wall,
Dolichos biflorus
lectin staining, and scanning and transmission electron microscopy characteristics. Ultrastructural changes were also seen in
T. gondii
, including membrane blebs and clefts in the cytoplasm, with inclusions similar to amylopectin granules, which are typically found in bradyzoites. An analysis of the cell death pathways in the parasite revealed that the compound caused a combination of apoptosis and autophagy. Fluorescence assays demonstrated that the redox environment in the LLC-MK2 cells becomes oxidant in the presence of the iron compound. Furthermore, a reduction in superoxide dismutase and catalase activities in the treated parasites and the presence of reactive oxygen species within the parasitophorous vacuoles were observed, indicating an impaired protozoan response against these radicals. These findings suggest that this compound disturbs the redox equilibrium of
T. gondii
, inducing cystogenesis and parasite death.
Confirmed Plasmodium vivax Resistance to Chloroquine in Central Vietnam
Authors: Thanh Pham Vinh , Hong Nguyen Van , Van Nguyen Van , Louisa Melva , Baird Kevin , Xa Nguyen Xuan , Peeters Grietens Koen , Hung Le Xuan , Duong Tran Thanh , Rosanas-Urgell Anna , Speybroeck Niko , D'Alessandro Umberto , Erhart Annette 
Published: September 2015

ABSTRACT

Plasmodium vivax
resistance to chloroquine (CQ) is currently reported in almost all countries where
P. vivax
is endemic. In Vietnam, despite a first report on
P. vivax
resistance to chloroquine published in the early 2000s,
P. vivax
was still considered sensitive to CQ. Between May 2009 and December 2011, a 2-year cohort study was conducted in central Vietnam to assess the recommended radical cure regimen based on a 10-day course of primaquine (0.5 mg/kg/day) together with 3 days of CQ (25 mg/kg). Here we report the results of the first 28-day follow-up estimating the cumulative risk of
P. vivax
recurrences together with the corresponding CQ blood concentrations, among other endpoints. Out of 260 recruited
P. vivax
patients, 240 completed treatment and were followed up to day 28 according to the WHO guidelines. Eight patients (3.45%) had a recurrent
P. vivax
infection, at day 14 (
n
= 2), day 21 (
n
= 1), and day 28 (
n
= 5). Chloroquine blood concentrations, available for 3/8 recurrent infections (days 14, 21, and 28), were above the MIC (>100 ng/ml whole blood) in all of these cases. Fever and parasitemia (both sexual and asexual stages) were cleared by day 3. Anemia was common at day 0 (35.8%), especially in children under 10 years (50%), and hemoglobin (Hb) recovery at day 28 was substantial among anemic patients (median change from day 0 to 28, +1.7 g/dl; interquartile range [IQR], +0.7 to +3.2). This report, based on CQ blood levels measured at the time of recurrences, confirms for the first time
P. vivax
CQ resistance in central Vietnam and calls for further studies using standardized protocols for accurately monitoring the extent and evolution of
P. vivax
resistance to chloroquine in Vietnam. These results, together with the mounting evidence of artemisinin resistance in central Vietnam, further highlight the increasing threat of antimalarial drug resistance to malaria elimination in Vietnam.
Artemether-Lumefantrine Exposure in HIV-Infected Nigerian Subjects on Nevirapine-Containing Antiretroviral Therapy
Authors: Parikh Sunil , Fehintola Fatai , Huang Liusheng , Olson Alexander , Adedeji Waheed A. , Darin Kristin M. , Morse Gene D. , Murphy Robert L. , Taiwo Babafemi O. , Akinyinka Olusegun O. , Adewole Isaac F. , Aweeka Francesca T. , Scarsi Kimberly K. 
Published: September 2015

ABSTRACT
Coadministration of nevirapine-based antiretroviral therapy (ART) and artemether-lumefantrine is reported to result in variable changes in lumefantrine exposure. We conducted an intensive pharmacokinetic study with 11 HIV-infected adults who were receiving artemether-lumefantrine plus nevirapine-based ART, and we compared the results with those for 16 HIV-negative adult historical controls. Exposure to artemether and lumefantrine was significantly lower and dihydroartemisinin exposure was unchanged in subjects receiving nevirapine-based ART, compared with controls. Nevirapine exposure was unchanged before and after artemether-lumefantrine administration.
Genetic Contexts of
bla
NDM-1
in Patients Carrying Multiple NDM-Producing Strains
Authors: Wailan Alexander M. , Sartor Anna L. , Zowawi Hosam M. , Perry John D. , Paterson David L. , Sidjabat Hanna E. 
Published: September 2015

ABSTRACT

The carbapenem resistance determinant
bla
NDM-1
has been found in various Gram-negative bacteria and upon different plasmid replicon types (Inc). Here, we present four patients within two hospitals in Pakistan harboring between two and four NDM-1-producing Gram-negative bacilli of different species coresident in their stool samples. We characterize the
bla
NDM-1
genetic contexts of these 11 NDM-1-producing Gram-negative bacilli in addition to other antimicrobial resistance mechanisms, plasmid replicon profiles, and sequence types (STs) in order to understand the underlying acquisition mechanisms of carbapenem resistance within these bacteria. Two common plasmid types (IncN2 and IncA/C) were identified to carry
bla
NDM-1
among the six different bacterial species isolated from the four patients. Two of these strains were novel
Citrobacter freundii
ST 20 and ST 21. The same IncN2-type
bla
NDM-1
genetic context was found in all four patients and within four different species. The IncA/C-type
bla
NDM-1
genetic context was found in two different species and in two of the four patients. Combining genetic context characterization with other molecular epidemiology methods, we were able to establish the molecular epidemiological links between genetically unrelated bacterial species by linking their acquisition of an IncN2 or IncA/C plasmid carrying
bla
NDM-1
for carbapenem resistance. By combining plasmid characterization and in-depth genetic context assessment, this analysis highlights the importance of plasmids in antimicrobial resistance. It also provides a novel approach for investigating the underlying mechanisms of
bla
NDM-1
-related spread between bacterial species and genera via plasmids.
Using a Novel Lysin To Help Control Clostridium difficile Infections
Authors: Wang Qiong , Euler Chad W. , Delaune Aurelia , Fischetti Vincent A. 
Published: September 2015

ABSTRACT

As a consequence of excessive antibiotic therapies in hospitalized patients,
Clostridium difficile
, a Gram-positive anaerobic spore-forming intestinal pathogen, is the leading cause of hospital-acquired diarrhea and colitis. Drug treatments for these diseases are often complicated by antibiotic-resistant strains and a high frequency of treatment failures and relapse; therefore, novel nonantibiotic approaches may prove to be more effective. In this study, we recombinantly expressed a prophage lysin identified from a
C. difficile
strain, CD630, which we named PlyCD. PlyCD was found to have lytic activity against specific
C. difficile
strains. However, the recombinantly expressed catalytic domain of this protein, PlyCD
1–174
, displayed significantly greater lytic activity (>4-log kill) and a broader lytic spectrum against
C. difficile
strains while still retaining a high degree of specificity toward
C. difficile
versus commensal clostridia and other bacterial species. Our data also indicated that noneffective doses of vancomycin and PlyCD
1–174
when combined
in vitro
could be significantly more bactericidal against
C. difficile
. In an
ex vivo
treatment model of mouse colon infection, we found that PlyCD
1–174
functioned in the presence of intestinal contents, significantly decreasing colonizing
C. difficile
compared to controls. Together, these data suggest that PlyCD
1–174
has potential as a novel therapeutic for clinical application against
C. difficile
infection, either alone or in combination with other preexisting treatments to improve their efficacy.
Biochemical Evaluation of the Inhibition Properties of Favipiravir and 2′-
C
-Methyl-Cytidine Triphosphates against Human and Mouse Norovirus RNA Polymerases
Authors: Jin Zhinan , Tucker Kathryn , Lin Xiaoyan , Kao C. Cheng , Shaw Ken , Tan Hua , Symons Julian , Behera Ishani , Rajwanshi Vivek K. , Dyatkina Natalia , Wang Guangyi , Beigelman Leo , Deval Jerome 
Published: September 2015

ABSTRACT

Norovirus (NoV) is a positive-sense single-stranded RNA virus that causes acute gastroenteritis and is responsible for 200,000 deaths per year worldwide. No effective vaccine or treatment is available. Recent studies have shown that the nucleoside analogs favipiravir (T-705) and 2′-
C
-methyl-cytidine (2CM-C) inhibit NoV replication
in vitro
and in animal models, but their precise mechanism of action is unknown. We evaluated the molecular interactions between nucleoside triphosphates and NoV RNA-dependent RNA polymerase (NoVpol), the enzyme responsible for replication and transcription of NoV genomic RNA. We found that T-705 ribonucleoside triphosphate (RTP) and 2CM-C triphosphate (2CM-CTP) equally inhibited human and mouse NoVpol activities at concentrations resulting in 50% of maximum inhibition (IC
50
s) in the low micromolar range. 2CM-CTP inhibited the viral polymerases by competing directly with natural CTP during primer elongation, whereas T-705 RTP competed mostly with ATP and GTP at the initiation and elongation steps. Incorporation of 2CM-CTP into viral RNA blocked subsequent RNA synthesis, whereas T-705 RTP did not cause immediate chain termination of NoVpol. 2CM-CTP and T-705 RTP displayed low levels of enzyme selectivity, as they were both recognized as substrates by human mitochondrial RNA polymerase. The level of discrimination by the human enzyme was increased with a novel analog of T-705 RTP containing a 2′-
C
-methyl substitution. Collectively, our data suggest that 2CM-C inhibits replication of NoV by acting as a classic chain terminator, while T-705 may inhibit the virus by multiple mechanisms of action. Understanding the precise mechanism of action of anti-NoV compounds could provide a rational basis for optimizing their inhibition potencies and selectivities.
Characterization of Tn
3000
, a Transposon Responsible for
bla
NDM-1
Dissemination among Enterobacteriaceae in Brazil, Nepal, Morocco, and India
Authors: Campos Juliana Coutinho , da Silva Maria José Félix , dos Santos Paulo Roberto Nascimento , Barros Elaine Menezes , Pereira Mayne de Oliveira , Seco Bruna Mara Silva , Magagnin Cibele Massotti , Leiroz Leonardo Kalab , de Oliveira Théo Gremen Mimary , Faria-Júnior Célio de , Cerdeira Louise Teixeira , Barth Afonso Luís , Sampaio Suely Carlos Ferreira , Zavascki Alexandre Prehn , Poirel Laurent , Sampaio Jorge Luiz Mello 
Published: September 2015

ABSTRACT

In
Enterobacteriaceae
, the
bla
NDM
genes have been found in many different genetic contexts, and a wide diversity of plasmid scaffolds bearing those genes has been found. In August 2013, we identified NDM-1-producing
Escherichia coli
and
Enterobacter hormaechei
strains from a single rectal swab sample from a patient hospitalized in Rio de Janeiro, Brazil, who had no history of travel abroad. Complete DNA sequencing using the Illumina platform and annotation of the two plasmids harboring the
bla
NDM-1
gene, one from each strain, showed that they belonged to incompatibility groups IncFII
K
and IncX3 and harbored a novel transposon named Tn
3000
. Similar genetic structures have been identified among other isolates in Brazil but also on plasmids from other continents. Our findings suggest that the
bla
NDM-1
gene may be transmitted by Tn
3000
in different parts of the world.
Clinically Available Medicines Demonstrating Anti-Toxoplasma Activity
Authors: Neville Andrew J. , Zach Sydney J. , Wang Xiaofang , Larson Joshua J. , Judge Abigail K. , Davis Lisa A. , Vennerstrom Jonathan L. , Davis Paul H. 
Published: September 2015

ABSTRACTToxoplasma gondiiis an apicomplexan parasite of humans and other mammals, including livestock and companion animals. While chemotherapeutic regimens, including pyrimethamine and sulfadiazine regimens, ameliorate acute or recrudescent disease such as toxoplasmic encephalitis or ocular toxoplasmosis, these drugs are often toxic to the host. Moreover, no approved options are available to treat infected women who are pregnant. Lastly, no drug regimen has shown the ability to eradicate the chronic stage of infection, which is characterized by chemoresistant intracellular cysts that persist for the life of the host. In an effort to promote additional chemotherapeutic options, we now evaluate clinically available drugs that have shown efficacy in disease models but which lack clinical case reports. Ideally, less-toxic treatments for the acute disease can be identified and developed, with an additional goal of cyst clearance from human and animal hosts.
Reduced
In Vitro
Activity of Ceftaroline by Etest among Clonal Complex 239 Methicillin-Resistant Staphylococcus aureus Clinical Strains from Australia
Authors: Abbott I. J. , Jenney A. W. J. , Jeremiah C. J. , Mirčeta M. , Kandiah J. P. , Holt D. C. , Tong S. Y. C. , Spelman D. W. 
Published: September 2015

ABSTRACT

A total of 421 methicillin-resistant
Staphylococcus aureus
(MRSA) clinical isolates were tested for ceftaroline susceptibility by Etest (bioMérieux). A multidrug resistant phenotype was found in 40.9%, and clonal complex 239 (CC239) was found in 33.5%. Ceftaroline nonsusceptibility (MIC, >1.0 μg/ml) was 16.9% overall. Nonsusceptibility was significantly higher in CC239 (41.1%, 58/141) and in isolates with a multidrug resistant phenotype (35.5%, 61/172) compared with comparators (
P
< 0.0001). Nonsusceptibility of common multidrug resistant MRSA clones limits the empirical use of ceftaroline for these infections.
In Vitro
Activities of Ceftazidime-Avibactam, Aztreonam-Avibactam, and a Panel of Older and Contemporary Antimicrobial Agents against Carbapenemase-Producing Gram-Negative Bacilli
Authors: Vasoo Shawn , Cunningham Scott A. , Cole Nicolynn C. , Kohner Peggy C. , Menon Sanjay R. , Krause Kevin M. , Harris Kelly A. , De Partha P. , Koh Tse Hsien , Patel Robin 
Published: September 2015

ABSTRACT
Among 177 carbapenemase-producing Gram-negative bacilli (108 KPC, 32 NDM, 11 IMP, 8 OXA-48, 4 OXA-181, 2 OXA-232, 5 IMI, 4 VIM, and 3 SME producers), aztreonam-avibactam was active against all isolates except two NDM producers with elevated MICs of 8/4 and 16/4 mg/liter; ceftazidime-avibactam was active against all KPC-, IMI-, SME-, and most OXA-48 group-producing isolates (93%) but not metallo-β-lactamase producers. Among older and contemporary antimicrobials, the most active were colistin, tigecycline, and fosfomycin, with overall susceptibilities of 88%, 79%, and 78%, respectively.
The Essential Role of Cholesterol Metabolism in the Intracellular Survival of Mycobacterium leprae Is Not Coupled to Central Carbon Metabolism and Energy Production
Authors: Marques Maria Angela M. , Berrêdo-Pinho Marcia , Rosa Thabatta L. S. A. , Pujari Venugopal , Lemes Robertha M. R. , Lery Leticia M. S. , Silva Carlos Adriano M. , Guimarães Ana Carolina R. , Atella Georgia C. , Wheat William H. , Brennan Patrick J. , Crick Dean C. , Belisle John T. , Pessolani Maria Cristina V. 
Published: September 2015

ABSTRACT

Mycobacterium leprae
induces the formation of lipid droplets, which are recruited to pathogen-containing phagosomes in infected macrophages and Schwann cells. Cholesterol is among the lipids with increased abundance in
M. leprae
-infected cells, and intracellular survival relies on cholesterol accumulation. The present study investigated the capacity of
M. leprae
to acquire and metabolize cholesterol.
In silico
analyses showed that oxidation of cholesterol to cholest-4-en-3-one (cholestenone), the first step of cholesterol degradation catalyzed by the enzyme 3β-hydroxysteroid dehydrogenase (3β-HSD), is apparently the only portion of the cholesterol catabolic pathway seen in
Mycobacterium tuberculosis
preserved by
M. leprae
. Incubation of bacteria with radiolabeled cholesterol confirmed the
in silico
predictions. Radiorespirometry and lipid analyses performed after incubating
M. leprae
with [4-
14
C]cholesterol or [26-
14
C]cholesterol showed the inability of this pathogen to metabolize the sterol rings or the side chain of cholesterol as a source of energy and carbon. However, the bacteria avidly incorporated cholesterol and, as expected, converted it to cholestenone both
in vitro
and
in vivo
. Our data indicate that
M. leprae
has lost the capacity to degrade and utilize cholesterol as a nutritional source but retains the enzyme responsible for its oxidation to cholestenone. Thus, the essential role of cholesterol metabolism in the intracellular survival of
M. leprae
is uncoupled from central carbon metabolism and energy production. Further elucidation of cholesterol metabolism in the host cell during
M. leprae
infection will establish the mechanism by which this lipid supports
M. leprae
intracellular survival and will open new avenues for novel leprosy therapies.

IMPORTANCE
Our study focused on the obligate intracellular pathogen
Mycobacterium leprae
and its capacity to metabolize cholesterol. The data make an important contribution for those interested in understanding the mechanisms of mycobacterial pathogenesis, since they indicate that the essential role of cholesterol for
M. leprae
intracellular survival does not rely on its utilization as a nutritional source. Our findings reinforce the complexity of cholesterol's role in sustaining
M. leprae
infection. Further elucidation of cholesterol metabolism in the host cell during
M. leprae
infection will establish the mechanism by which this lipid supports
M. leprae
intracellular survival and will open new avenues for novel leprosy therapies.