bluuebunny/crossref_metadata_2025_split huggingface dataset:
A role for xanthine oxidase in the control of fetal cardiovascular function in late gestation sheep
Authors: Herrera E. A. , Kane A. D. , Hansell J. A. , Thakor A. S. , Allison B. J. , Niu Y. , Giussani D. A. 
Published: February 2012

Key points
There is growing physiological and clinical interest in the role of the enzyme xanthine oxidase in the regulation of fetal cardiovascular function.
The xanthine oxidase inhibitor allopurinol is undergoing human clinical trials in complicated pregnancy to protect the fetal brain from injury by decreasing excessive generation of reactive oxygen species (ROS) and increasing nitric oxide (NO) availability. However, the effects on fetal cardiovascular physiology of xanthine oxidase inhibition are largely unknown.
We have previously reported that the balance between ROS and NO plays an important physiological role in the control of fetal cardiovascular function. Therefore, it seems likely that allopurinol might perturb this balance and alter fetal cardiovascular homeostasis.
Here, we report that maternal allopurinol treatment in late gestation ovine pregnancy has significant in vivo effects on umbilical blood flow and the cardiovascular system of the mother and fetus by altering NO and β1‐adrenergic mechanisms.
The evidence suggests that xanthine oxidase has an important role in basal cardiovascular function in the fetus during late gestation. Therefore, further research is warranted before safe clinical application of maternal allopurinol during pregnancy in humans.
Augmented cholesterol absorption and sarcolemmal sterol enrichment slow small intestinal transit in mice, contributing to cholesterol cholelithogenesis
Authors: Xie Meimin , Kotecha Vijay R. , Andrade Jon David P. , Fox James G. , Carey Martin C. 
Published: February 2012

Key points
Peristaltic function of the small intestine is compromised in cholelithogenic humans and in animal models of cholesterol gallstones.
In a mouse gallstone model fed a cholesterol‐ and cholic acid‐enriched diet, we show that slowing of small intestinal transit is due to absorption of excess cholesterol molecules from the upper small intestine followed by their incorporation into sarcolemmal membranes of smooth muscle cells.
Blocking cholesterol absorption with ezetimibe (Zetia), an inhibitor of intestinal sterol transport, prevents cholesterol enrichment of sarcolemmal membranes and normalizes the motility disorder.
Although the primary source of intestinal cholesterol in mice is the lithogenic diet, in most cholesterol gallstone‐prone humans, the small intestine is flooded continuously with an abundance of liver‐secreted cholesterol molecules via bile.
Our findings imply that small intestinal hypomotility will amplify the cholelithogenic state because of hyperabsorption of cholesterol and ‘secondary’ bile salt synthesis by the gut's anaerobic microbiota.
Histone deacetylase 6 gates the synaptic action of acute stress in prefrontal cortex
Authors: Lee Janine B. , Wei Jing , Liu Wenhua , Cheng Jia , Feng Jian , Yan Zhen 
Published: February 2012

Key points
Acute stress, via glucocorticoid receptors (GRs), enhances glutamatergic signalling in the prefrontal cortex, a region responsible for high‐order cognitive functions.
We found that inhibition or knockdown of histone deacetylase 6 (HDAC6) blocked the enhancement of glutamatergic signalling by acute stress.
Inhibition or knockdown of the GR chaperone protein HSP90 (a substrate of HDAC6) produced a similar blockade of the acute stress‐induced enhancement of glutamatergic signalling.
These results suggest that HDAC6 is a key molecule regulating the synaptic effects of acute stress in the prefrontal cortex.
Mycobacterium tuberculosis Population Structure Determines the Outcome of Genetics-Based Second-Line Drug Resistance Testing
Authors: Streicher E. M. , Bergval I. , Dheda K. , Böttger E. C. , Gey van Pittius N. C. , Bosman M. , Coetzee G. , Anthony R. M. , van Helden P. D. , Victor T. C. , Warren R. M. 
Published: February 2012

ABSTRACT

The global emergence of multidrug-resistant tuberculosis has highlighted the need for the development of rapid tests to identify resistance to second-line antituberculosis drugs. Resistance to fluoroquinolones and aminoglycosides develops through nonsynonymous single nucleotide polymorphisms in the
gyrA
and
gyrB
genes and the
rrs
gene, respectively. Using DNA sequencing as the gold standard for the detection of mutations conferring resistance, in conjunction with spoligotyping, we demonstrated heteroresistance in 25% and 16.3% of
Mycobacterium tuberculosis
isolates resistant to ofloxacin and amikacin, respectively. Characterization of follow-up isolates from the same patients showed that the population structure of clones may change during treatment, suggesting different phases in the emergence of resistance. The presence of underlying mutant clones was identified in isolates which failed to show a correlation between phenotypic resistance and mutation in the
gyrA
or
rrs
gene. These clones harbored previously described mutations in either the
gyrA
or
rrs
gene, suggesting that rare mutations conferring resistance to ofloxacin or amikacin may not be as important as was previously thought. We concluded that the absence of a correlation between genotypic and phenotypic resistance implies an early phase in the emergence of resistance within the patient. Thus, the diagnostic utility of genetics-based drug susceptibility tests will depend on the proportion of patients whose bacilli are in the process of acquiring resistance in the study setting. These data have implications for the interpretation of molecular and microbiological diagnostic tests for patients with drug-susceptible and drug-resistant tuberculosis who fail to respond to treatment and for those with discordant results.
An Isoniazid Analogue Promotes Mycobacterium tuberculosis-Nanoparticle Interactions and Enhances Bacterial Killing by Macrophages
Authors: de Faria Tatiany J. , Roman Mariane , de Souza Nicole M. , De Vecchi Rodrigo , de Assis João Vitor , dos Santos Ana Lúcia Gomes , Bechtold Ivan H. , Winter Nathalie , Soares Maurilio José , Silva Luciano Paulino , De Almeida Mauro V. , Báfica André 
Published: February 2012

ABSTRACT

Nanoenabled drug delivery systems against tuberculosis (TB) are thought to control pathogen replication by targeting antibiotics to infected tissues and phagocytes. However, whether nanoparticle (NP)-based carriers directly interact with
Mycobacterium tuberculosis
and how such drug delivery systems induce intracellular bacterial killing by macrophages is not defined. In the present study, we demonstrated that a highly hydrophobic citral-derived isoniazid analogue, termed JVA, significantly increases nanoencapsulation and inhibits
M. tuberculosis
growth by enhancing intracellular drug bioavailability. Importantly, confocal and atomic force microscopy analyses revealed that JVA-NPs associate with both intracellular
M. tuberculosis
and cell-free bacteria, indicating that NPs directly interact with the bacterium. Taken together, these data reveal a nanotechnology-based strategy that promotes antibiotic targeting into replicating extra- and intracellular mycobacteria, which could actively enhance chemotherapy during active TB.
Crystal Structures of KPC-2 β-Lactamase in Complex with 3-Nitrophenyl Boronic Acid and the Penam Sulfone PSR-3-226
Authors: Ke Wei , Bethel Christopher R. , Papp-Wallace Krisztina M. , Pagadala Sundar Ram Reddy , Nottingham Micheal , Fernandez Daniel , Buynak John D. , Bonomo Robert A. , van den Akker Focco 
Published: February 2012

ABSTRACT

Class A carbapenemases are a major threat to the potency of carbapenem antibiotics. A widespread carbapenemase, KPC-2, is not easily inhibited by β-lactamase inhibitors (i.e., clavulanic acid, sulbactam, and tazobactam). To explore different mechanisms of inhibition of KPC-2, we determined the crystal structures of KPC-2 with two β-lactamase inhibitors that follow different inactivation pathways and kinetics. The first complex is that of a small boronic acid compound, 3-nitrophenyl boronic acid (3-NPBA), bound to KPC-2 with 1.62-Å resolution. 3-NPBA demonstrated a

K
m

value of 1.0 ± 0.1 μM (mean ± standard error) for KPC-2 and blocks the active site by making a reversible covalent interaction with the catalytic S70 residue. The two boron hydroxyl atoms of 3-NPBA are positioned in the oxyanion hole and the deacylation water pocket, respectively. In addition, the aromatic ring of 3-NPBA provides an edge-to-face interaction with W105 in the active site. The structure of KPC-2 with the penam sulfone PSR-3-226 was determined at 1.26-Å resolution. PSR-3-226 displayed a

K
m

value of 3.8 ± 0.4 μM for KPC-2, and the inactivation rate constant (
k
inact
) was 0.034 ± 0.003 s
−1
. When covalently bound to S70, PSR-3-226 forms a
trans
-enamine intermediate in the KPC-2 active site. The predominant active site interactions are generated via the carbonyl oxygen, which resides in the oxyanion hole, and the carboxyl moiety of PSR-3-226, which interacts with N132, N170, and E166. 3-NPBA and PSR-3-226 are the first β-lactamase inhibitors to be trapped as an acyl-enzyme complex with KPC-2. The structural and inhibitory insights gained here could aid in the design of potent KPC-2 inhibitors.
Pharmacokinetics of Sequential Doses of Capreomycin Powder for Inhalation in Guinea Pigs
Authors: Garcia-Contreras L. , Muttil Pavan , Fallon John K. , Kabadi Mohan , Gerety Robert , Hickey Anthony J. 
Published: February 2012

ABSTRACT

The global control of tuberculosis (TB) is at risk by the spread of multidrug-resistant TB (MDR TB). Treatment of MDR TB is lengthy and involves injected drugs, such as capreomycin, that have severe side effects. It was previously reported that a single daily dose of inhaled capreomycin had a positive effect on the bacterial burden of TB-infected guinea pigs. The modest effect observed was possibly due to a dose that resulted in insufficient time of exposure to therapeutic systemic and local levels of the drug. In order to determine the length of time that systemic and local drug concentrations are above therapeutic levels during the treatment period, the present study investigated the disposition of capreomycin powders after sequential pulmonary administration of doses of 20 mg/kg of body weight. Capreomycin concentrations in bronchoalveolar lavage fluid and lung tissue of animals receiving a series of one, two, or three doses of capreomycin inhalable powder were significantly higher (50- to 100-fold) at all time points than plasma concentrations at the same time points or those observed in animals receiving capreomycin solution by intramuscular (i.m.) injection (10- to 100-fold higher). Notably, at the end of each dosing period, capreomycin concentrations in the lungs were approximately 100-fold higher than those in plasma and severalfold higher than the MIC, suggesting that sufficient capreomycin remains in the lung environment to kill
Mycobacterium tuberculosis
. No accumulation of capreomycin powder was detected in the lungs after 3 pulmonary doses. These results indicate that the systemic disposition of capreomycin after inhalation is the same as when injected i.m. with the advantage that higher drug concentrations are present at all times in the lungs, the primary site of infection.
Expression and Function of Transforming Growth Factor β in Melioidosis
Authors: Weehuizen Tassili A. F. , Wieland Catharina W. , van der Windt Gerritje J. W. , Duitman Jan-Willem , Boon Louis , Day Nicholas P. J. , Peacock Sharon J. , van der Poll Tom , Wiersinga W. Joost 
Published: February 2012

ABSTRACT

Melioidosis, caused by the Gram-negative bacterium
Burkholderia pseudomallei
, is an important cause of community-acquired sepsis in Southeast Asia and northern Australia. An important controller of the immune system is the pleiotropic cytokine transforming growth factor β (TGF-β), of which Smad2 and Smad3 are the major signal transducers. In this study, we aimed to characterize TGF-β expression and function in experimental melioidosis. TGF-β expression was determined in 33 patients with culture-proven infection with
B. pseudomallei
and 30 healthy controls. We found that plasma TGF-β concentrations were strongly elevated during melioidosis. In line with this finding, TGF-β expression in C57BL/6 mice intranasally inoculated with
B. pseudomallei
was enhanced as well. To assess the role of TGF-β, we inhibited TGF-β using a selective murine TGF-β antibody. Treatment of mice with anti-TGF-β antibody resulted in decreased lung Smad2 phosphorylation. TGF-β blockade appeared to be protective: mice treated with anti-TGF-β antibody and subsequently infected with
B. pseudomallei
showed diminished bacterial loads. Moreover, less distant organ injury was observed in anti-TGF-β treated mice as shown by reduced blood urea nitrogen (BUN) and aspartate transaminase (AST) values. However, anti-TGF-β treatment did not have an effect on survival. In conclusion, TGF-β is upregulated during
B. pseudomallei
infection and plays a limited but proinflammatory role during experimental melioidosis.
Difference in Fine Specificity to Polysaccharides of Candida albicans Mannoprotein between Mouse SIGNR1 and Human DC-SIGN
Authors: Takahara Kazuhiko , Arita Takuya , Tokieda Sumika , Shibata Nobuyuki , Okawa Yoshio , Tateno Hiroaki , Hirabayashi Jun , Inaba Kayo 
Published: February 2012

ABSTRACT

C-type lectin SIGNR1 directly recognizes
Candida albicans
and zymosan and has been considered to share properties of polysaccharide recognition with human DC-SIGN (hDC-SIGN). However, the precise specificity of SIGNR1 and the difference from that of hDC-SIGN remain to be elucidated. We prepared soluble forms of SIGNR1 and hDC-SIGN and conducted experiments to examine their respective specificities. Soluble SIGNR1 (sSIGNR1) bound several types of live
C. albicans
clinical isolate strains in an EDTA-sensitive manner. Inhibition analyses of sSIGNR1 binding by glycans from various yeast strains demonstrated that SIGNR1 preferentially recognizes N-glycan α-mannose side chains in
Candida
mannoproteins, as reported in hDC-SIGN. Unlike shDC-SIGN, however, sSIGNR1 recognized not only
Saccharomyces cerevisiae
, but also
C. albicans
J-1012 glycan, even after α-mannosidase treatment that leaves only β1,2-mannose-capped α-mannose side chains. In addition, glycomicroarray analyses showed that sSIGNR1 binds mannans from
C. albicans
and
S. cerevisiae
but does not recognize Lewis
a/b/x/y
antigen polysaccharides as in shDC-SIGN. Consistent with these results, RAW264.7 cells expressing hDC-SIGN in which the carbohydrate recognition domain (CRD) was replaced with that of SIGNR1 (RAW-chimera) produced comparable amounts of interleukin 10 (IL-10) in response to glycans from
C. albicans
and
S. cerevisiae
, but those expressing hDC-SIGN produced less IL-10 in response to
S. cerevisiae
than
C. albicans
. Furthermore, RAW–hDC-SIGN cells remarkably reduced IL-10 production after α-mannosidase treatment compared with RAW-chimera cells. These results indicate that SIGNR1 recognizes
C. albicans
/yeast through a specificity partly distinct from that of its homologue hDC-SIGN.
Occupational and leisure time physical activity: risk of all-cause mortality and myocardial infarction in the Copenhagen City Heart Study. A prospective cohort study
Authors: Holtermann Andreas , Marott Jacob Louis , Gyntelberg Finn , Søgaard Karen , Suadicani Poul , Mortensen Ole S , Prescott Eva , Schnohr Peter 
Published: February 2012

ObjectivesMen with low physical fitness and high occupational physical activity are recently shown to have an increased risk of cardiovascular disease and all-cause mortality. The association between occupational physical activity with cardiovascular disease and all-cause mortality may also depend on leisure time physical activity.DesignA prospective cohort study.SettingThe Copenhagen City Heart Study.Participants7819 men and women aged 25–66 years without a history of cardiovascular disease who attended an initial examination in the Copenhagen City Heart Study in 1976–1978.Outcome measuresMyocardial infarction and all-cause mortality. Occupational physical activity was defined by combining information from baseline (1976–1978) with reassessment in 1981–1983. Conventional risk factors were controlled for in Cox analyses.ResultsDuring the follow-up from 1976 to 1978 until 2010, 2888 subjects died of all-cause mortality and 787 had a first event of myocardial infarction. Overall, occupational physical activity predicted all-cause mortality and myocardial infarction in men but not in women (test for interaction p=0.02). High occupational physical activity was associated with an increased risk of all-cause mortality among men with low (HR 1.56; 95% CI 1.11 to 2.18) and moderate (HR 1.31; 95% CI 1.05 to 1.63) leisure time physical activity but not among men with high leisure time physical activity (HR 1.00; 95% CI 0.78 to 1.26) (test for interaction p=0.04). Similar but weaker tendencies were found for myocardial infarction. Among women, occupational physical activity was not associated with subsequent all-cause mortality or myocardial infarction.ConclusionsThe findings suggest that high occupational physical activity imposes harmful effects particularly among men with low levels of leisure time physical activity.
HIV-associated neurocognitive disorders (HAND) in a South Asian population - contextual application of the 2007 criteria
Authors: Chan Lai Gwen , Kandiah Nagaendran , Chua Arlene 
Published: February 2012

ObjectivesTo estimate the prevalence of HIV-associated neurocognitive disorders (HAND) among HIV patients in a multiethnic South Asian population, describe the pattern of neurocognitive impairment in HAND and the factors associated with HAND.DesignA cross-sectional survey of HIV-positive outpatients and inpatients.SettingThe sole referral centre for HIV/AIDS treatment in Singapore.ParticipantsInclusion criteria were HIV positive, age between 21 and 80 years old and at least 3 years of education. Exclusion criteria included concomitant delirium, serious systemic disease or major psychiatric illness. 265 patients did not meet criteria or declined to participate. The final sample size was 132.Outcome measuresThe primary outcome measure was cognitive impairment based on performance on the Montreal Cognitive Assessment, International HIV Dementia Scale and Instrumental Activities of Daily Living. The secondary outcome measure was the classification of impairment based on the 2007 updated research nosology for HAND.ResultsThe prevalence of HAND was 22.7% of which 70% (15.9% of total) were asymptomatic neurocognitive impairment, 23.3% (5.3% of total) were mild neurocognitive disorder and 6.7% (1.5% of total) were HIV-associated dementia. Increasing age (OR 1.104, 95% CI 1.054 to 1.155, p<0.001), less education (OR 0.78, 95% CI 0.69 to 0.89, p<0.001) and low baseline CD4 count (OR 0.15, 95% CI 0.03 to 0.74, p=0.019) were associated with HAND. Delayed recall, language and abstract thinking were the domains most commonly affected, but impairment in visuospatial ability (RC 3.013, 95% CI 1.954 to 4.073, p<0.001) and attention (RC 2.205, 95% CI 1.043 to 3.367, p<0.001) were most strongly associated with HAND.ConclusionHAND is common among HIV patients in a South Asian sample, most of whom are asymptomatic. Older patients with less education and severe illness at diagnosis are at highest risk of HAND. Delayed recall is most commonly affected, but visuospatial dysfunction is most strongly associated with prevalent HAND.
Risk of tuberculosis among people with diabetes mellitus: an Australian nationwide cohort study
Authors: Dobler Claudia Caroline , Flack Jeffrey Ronald , Marks Guy Barrington 
Published: February 2012

ObjectivePrevious studies that have found an increased risk for tuberculosis (TB) in people with diabetes mellitus (DM) have been conducted in segments of the population and have not adjusted for important potential confounders. We sought to determine the RR for TB in the presence of DM in a national population with data on confounding factors in order to inform the decision-making process about latent tuberculosis infection (LTBI) screening in people with diabetes.DesignWhole population historical cohort study.SettingAll Australian States and Territories with a mean TB incidence of 5.8/100 000.ParticipantsCases of TB in people with DM were identified by record linkage using the National Diabetes Services Scheme Database and TB notification databases for the years 2001–2006.Primary and secondary outcome measuresPrimary outcome was notified cases of TB. Secondary outcome was notified cases of culture-confirmed TB. RR of TB was estimated with adjustment for age, sex, TB incidence in country of birth and indigenous status.ResultsThere were 6276 cases of active TB among 19 855 283 people living in Australia between 2001 and 2006. There were 271 (188 culture positive) cases of TB among 802 087 members of the DM cohort and 130 cases of TB among 273 023 people using insulin. The crude RR of TB was 1.78 (95% CI 1.17 to 2.73) in all people with DM and 2.16 (95% CI 1.19 to 3.93) in people with DM using insulin. The adjusted RRs were 1.48 (95% CI 1.04 to 2.10) and 2.27 (95% CI 1.41 to 3.66), respectively.ConclusionsThe presence of DM alone does not justify screening for LTBI. However, when combined with other risk factors for TB, the presence of DM may be sufficient to justify screening and treatment for LTBI.
Has there been any progress in improving the quality of hospitalised death? Replication of a US chart audit study
Authors: Parikh Purak , Brokaw Frances C , Saggar Shagun , Graves Luann , Balan Stefan , Li Zhongze , Tosteson Tor D , Bakitas Marie 
Published: February 2012

ObjectiveTo describe the experience of dying in a US tertiary academic medical centre and to compare this experience with a historical decedent sample.DesignA retrospective, observational, chart audit study of adults (N=159) who died in hospital.SettingComponent hospitals of the Dartmouth-Hitchcock Medical Center: Mary Hitchcock Memorial Hospital (MHMH), Lebanon, New Hampshire, and the affiliated Veteran's Affairs Medical Center (VAMC), White River Junction, Vermont.Participants159 hospitalised adult decedents comprising a random sample of 100 MHMH decedents and a total sample of 59 VAMC decedents.MethodsThe authors compared end-of-life (EOL) care in decedents who had a palliative care consultation (PCC) with those who did not. An exploratory analysis compared the EOL care between the 2008 decedent sample and an historical decedent sample (N=104).Results63 of 159 inpatients received a PCC. Decedents receiving a PCC were less likely to die in an intensive care unit, had fewer invasive interventions (eg, intubation, assisted ventilation, dialysis, chemotherapy) and were more likely to have advance directives, do-not-resuscitate orders and comfort measures orders than those who did not receive a PCC. Higher rates of emotional and pastoral care were also noted. Compared with the historical sample, 2008 decedents had a higher rate of invasive interventions, but fewer invasive interventions were noted in the 2008 PCC subsample.ConclusionsLess invasive EOL care was observed in decedents who received a PCC. Ongoing monitoring of EOL care is critically important for hospital quality improvement programmes.