bluuebunny/crossref_metadata_2025_split huggingface dataset:
Measurement of gastric emptying by radiopaque markers in patients with diabetes: correlation with scintigraphy and upper gastrointestinal symptoms
Authors: Olausson E. A. , Brock C. , Drewes A. M. , Grundin H. , Isaksson M. , Stotzer P. , Abrahamsson H. , Attvall S. , Simrén M. 
Published: January 2013

AbstractBackground  Scintigraphy, the gold standard to measure gastric emptying, is expensive and not widely available. Therefore, we compared emptying of radiopaque markers (ROM) from the stomach, by use of fluoroscopy, with scintigraphy in patients with insulin‐treated diabetes.Methods  On the same day we measured gastric emptying of 20 ROM using fluoroscopy and scintigraphic emptying of a standard solid meal. The subjects also completed a validated gastrointestinal (GI) symptom questionnaire.Key Results  We included 115 patients with insulin‐treated diabetes (median age 53, range 21–69 years; 59 women). A moderately strong correlation was demonstrated between scintigraphic (% retained at 2 h) and ROM emptying (markers retained at 6 h) (r = 0.47; P < 0.0001). Eighty‐three patients had delayed gastric emptying with scintigraphy, whereas only 29 patients had delayed emptying of ROM. Of the 29 patients with delayed emptying of ROM, 28 also had delayed scintigraphic emptying. The sensitivity and specificity of the ROM test was 34% and 97%, respectively. Significant correlations were only noted between scintigraphic gastric emptying and GI symptom severity, with the strongest correlations for fullness/early satiety (r = 0.34; P < 0.001) and nausea/vomiting (r = 0.30; P < 0.001).Conclusions & Inferences  A gastric emptying test with ROM is a widely available screening method to detect delayed gastric emptying in patients with diabetes, where a positive result seems reliable. However, a normal ROM test does not exclude delayed gastric emptying, and if the clinical suspicion of gastroparesis remains, scintigraphy should be performed. Results from scintigraphy also correlate with GI symptom severity, which ROM test did not.
Treatment of Infantile Hemangiomas with Sirolimus in a Patient with PHACE Syndrome
Authors: Kaylani Samer , Theos Amy J. , Pressey Joseph G. 
Published: January 2013

AbstractInfantile hemangiomas (IHs) are common benign tumors of childhood. IHs often regress satisfactorily without intervention, but a subset of IHs may lead to functional or cosmetic morbidity necessitating therapy. PHACE syndrome is characterized by a variety of neurocutaneous and vascular anomalies that typically include segmental hemangiomas. We present an infant with PHACE syndrome and segmental IH that failed conventional first‐line therapies. Treatment with sirolimus provided benefit with regression of the cutaneous IH. As an inhibitor of the mammalian target of rapamycin (mTOR) pathway, the effective use of sirolimus may shed light on the emerging role of mTOR signaling in the development and pathogenesis of IHs.
Sound‐induced perturbations of the brain network in non‐REM sleep, and network oscillations in wake
Authors: Wu Weiwei , Sheth Bhavin R. 
Published: January 2013

AbstractDuring sleep, the brain network processes sensory stimuli without awareness. Stimulation must affect differently brain networks in sleep versus wake, but these differences have yet to be quantified. We recorded cortical activity in stage 2 (SII) sleep and wake using EEG while a tone was intermittently played. Zero‐lag correlation measured input to pairs of sensors in the network; cross‐correlation and phase‐lag index measured pairwise corticocortical connectivity. Our analysis revealed that under baseline conditions, the cortical network, in particular the central regions of the frontoparietal cortex, interact at a characteristic latency of 50 ms, but only during wake, not sleep. Nonsalient auditory stimulation causes far greater perturbation of connectivity from baseline in sleep than wake, both in the response to common input and corticocortical connectivity. The findings have key implications for sensory processing.
Nitric oxide‐mediated cutaneous microvascular function is impaired in polycystic ovary sydrome but can be improved by exercise training
Authors: Sprung V. S. , Cuthbertson D. J. , Pugh C. J. A. , Daousi C. , Atkinson G. , Aziz N. F. , Kemp G. J. , Green D. J. , Cable N. T. , Jones H. 
Published: January 2013

Key points
Polycystic ovary syndrome (PCOS) is associated with cardiovascular disease.
Nitric oxide (NO) is a naturally occurring molecule that possesses anti‐atherogenic properties.
The contribution of NO to the dilatation of microvessels in the skin is currently unknown in women with PCOS.
In this study, it was found that women with PCOS display impaired NO bioavailability compared with obese matched control women.
Exercise training improves the microvascular dysfunction displayed in women with PCOS, via the upregulation of NO.
These findings suggest exercise training can be a preventive strategy in women with PCOS.
Abstract  Polycystic ovary syndrome (PCOS) is associated with cardiovascular disease. The contribution of the nitric oxide (NO) dilator system to cutaneous endothelial dysfunction is currently unknown in PCOS. Our aim was to examine whether women with PCOS demonstrate impaired cutaneous microvascular NO function and whether exercise training can ameliorate any impairment. Eleven women with PCOS (age, 29 ± 7 years; body mass index, 34 ± 6 kg m−2) were compared with six healthy obese control women (age, 29 ± 7 years; body mass index, 34 ± 5 kg m−2). Six women with PCOS (30 ± 7 years; 31 ± 6 kg m−2) then completed 16 weeks of exercise training. Laser Doppler flowmetry, combined with intradermal microdialysis of l‐NG‐monomethyl‐l‐arginine, a nitric oxide antagonist, in response to incremental local heating of the forearm was assessed in women with PCOS and control women, and again in women with PCOS following exercise training. Cardiorespiratory fitness, homeostasis model assessment for insulin resistance, hormone and lipid profiles were also assessed. Differences between women with PCOS and control women and changes with exercise were analysed using Student's unpaired t tests. Differences in the contribution of NO to cutaneous blood flow [expressed as a percentage of maximal cutaneous vasodilatation (CVCmax)] were analysed using general linear models. At 42°C heating, cutaneous NO‐mediated vasodilatation was attenuated by 17.5%CVCmax (95% confidence interval, 33.3, 1.7; P = 0.03) in women with PCOS vs. control women. Exercise training improved cardiorespiratory fitness by 5.0 ml kg−1 min−1 (95% confidence interval, 0.9, 9.2; P = 0.03) and NO‐mediated cutaneous vasodilatation at 42°C heating by 19.6% CVCmax (95% confidence interval, 4.3, 34.9; P = 0.02). Cutaneous microvascular NO function is impaired in women with PCOS compared with obese matched control women but can be improved with exercise training.
Repeated in vivo exposure of cocaine induces long‐lasting synaptic plasticity in hypocretin/orexin‐producing neurons in the lateral hypothalamus in mice
Authors: Rao Yan , Mineur Yann S. , Gan Geliang , Wang Alex Hanxiang , Liu Zhong‐Wu , Wu Xinyuan , Suyama Shigetomo , de Lecea Luis , Horvath Tamas L. , Picciotto Marina R. , Gao Xiao‐Bing 
Published: January 2013

Key points
Repeated, but not single, in vivo cocaine exposure leads to an experience‐dependent potentiation of glutamatergic synapses on hypocretin‐producing neurons (hypocretin neurons) in mice.
The locus of synaptic potentiation is at the postsynaptic site of glutamatergic synapses on hypocretin neurons and the up‐regulation of AMPA‐type glutamate receptors may be involved.
Cocaine‐induced synaptic potentiation is long‐lasting and exists during the abstinence of cocaine.
The expression of tetanus‐induced long‐term potentiation is facilitated in hypocretin neurons in cocaine‐treated mice.
These results may help us better understand the role of the hypocretin system in behavioural changes related to cocaine addiction in animals and humans.
Abstract  Hypocretin (orexin), a neuropeptide synthesized exclusively in the perifornical/lateral hypothalamus, is critical for drug seeking and relapse, but it is not clear how the circuitry centred on hypocretin‐producing neurons (hypocretin neurons) is modified by drugs of abuse and how changes in this circuit might alter behaviours related to drug addiction. In this study, we show that repeated, but not single, in vivo cocaine administration leads to a long‐lasting, experience‐dependent potentiation of glutamatergic synapses on hypocretin neurons in mice following a cocaine‐conditioned place preference (CPP) protocol. The synaptic potentiation occurs postsynaptically and probably involves up‐regulation of AMPA‐type glutamate receptors on hypocretin neurons. Phosphorylation of cAMP response element‐binding protein (CREB) is also significantly increased in hypocretin neurons in cocaine‐treated animals, suggesting that CREB‐mediated pathways may contribute to synaptic potentiation in these cells. Furthermore, the potentiation of synaptic efficacy in hypocretin neurons persists during cocaine withdrawal, but reverses to baseline levels after prolonged abstinence. Finally, the induction of long‐term potentiation (LTP) triggered by a high‐frequency stimulation is facilitated in hypocretin neurons in cocaine‐treated mice, suggesting that long‐lasting changes in synapses onto hypocretin neurons would probably be further potentiated by other stimuli (such as concurrent environmental cues) paired with the drug. In summary, we show here that hypocretin neurons undergo experience‐dependent synaptic potentiation that is distinct from that reported in other reward systems, such as the ventral tegmental area, following exposure to cocaine. These findings support the idea that the hypocretin system is important for behavioural changes associated with cocaine administration in animals and humans.
Direct inhibition of arcuate proopiomelanocortin neurons: a potential mechanism for the orexigenic actions of dynorphin
Authors: Zhang Xiaobing , van den Pol Anthony N. 
Published: January 2013

Key points
In conjunction with fast amino acid transmitters, neuropeptides such as dynorphin play key roles in regulating energy homeostasis.
Dynorphin immunoreactive axons are abundant in the hypothalamic arcuate nucleus and terminate near or on proopiomelanocortin (POMC) neurons.
Dynorphin directly inhibits POMC cells by a mechanism based on activation of GIRK channels, mediated by kappa‐2 opioid receptors.
Dynorphin indirectly modulates the activity of POMC neurons by depressing afferent glutamate and GABA synaptic neurotransmission.
These data suggest that dynorphin‐containing neurons could modulate food intake and energy homeostasis by directly attenuating the activity of the anorexigenic POMC cell.
Abstract  Dynorphin, an endogenous ligand of kappa (κ) opioid receptors, has multiple roles in the brain, and plays a positive role in energy balance and food intake. However, the mechanism for this is unclear. With immunocytochemistry, we find that axonal dynorphin immunoreactivity in the arcuate nucleus is strong, and that a large number of dynorphin‐immunoreactive boutons terminate on or near anorexigenic proopiomelanocortin (POMC) cells. Here we provide evidence from whole‐cell patch‐clamp recording that dynorphin‐A (Dyn‐A) directly and dose‐dependently inhibits arcuate nucleus POMC neurons. Dyn‐A inhibition was eliminated by the κ opioid receptor antagonist nor‐BNI, but not by the μ receptor antagonist CTAP. The inhibitory effect was mimicked by the κ2 receptor agonist GR89696, but not by the κ1 receptor agonist U69593. No presynaptic effect of κ2 agonists was found. These results suggest that Dyn‐A inhibits POMC neurons through activation of the κ2 opioid receptor. In whole‐cell voltage clamp, Dyn‐A opened G‐protein‐coupled inwardly rectifying potassium (GIRK)‐like channels on POMC neurons. Dynorphin attenuated glutamate and GABA neurotransmission to POMC neurons. In contrast to the strong inhibition of POMC neurons by Dyn‐A, we found a weaker direct inhibitory effect of Dyn‐A on arcuate nucleus neuropeptide Y (NPY) neurons mediated by both κ1 and κ2 receptors. Taken together, these results indicate a direct inhibitory effect of Dyn‐A on POMC neurons through activation of the κ2 opioid receptor and GIRK channels. A number of orexigenic hypothalamic neurons release dynorphin along with other neuropeptides. The inhibition of anorexigenic POMC neurons may be one mechanism underlying the orexigenic actions of dynorphin.
N152G, -S, and -T Substitutions in CMY-2 β-Lactamase Increase Catalytic Efficiency for Cefoxitin and Inactivation Rates for Tazobactam
Authors: Skalweit Marion J. , Li Mei , Conklin Benjamin C. , Taracila Magdalena A. , Hutton Rebecca A. 
Published: January 2013

ABSTRACT

Class C cephalosporinases are a growing threat, and clinical inhibitors of these enzymes are currently unavailable. Previous studies have explored the role of Asn152 in the
Escherichia coli
AmpC and P99 enzymes and have suggested that interactions between C-6′ or C-7′ substituents on penicillins or cephalosporins and Asn152 are important in determining substrate specificity and enzymatic stability. We sought to characterize the role of Asn152 in the clinically important CMY-2 cephalosporinase with substrates and inhibitors. Mutagenesis of CMY-2 at position 152 yields functional mutants (N152G, -S, and -T) that exhibit improved penicillinase activity and retain cephamycinase activity. We also tested whether the position 152 substitutions would affect the inactivation kinetics of tazobactam, a class A β-lactamase inhibitor with
in vitro
activity against CMY-2. Using standard assays, we showed that the N152G, -S, and -T variants possessed increased catalytic activity against cefoxitin compared to the wild type. The 50% inhibitory concentration (IC
50
) for tazobactam improved dramatically, with an 18-fold reduction for the N152S mutant due to higher rates of enzyme inactivation. Modeling studies have shown active-site expansion due to interactions between Y150 and S152 in the apoenzyme and the Michaelis-Menten complex with tazobactam. Substitutions at N152 might become clinically important as new class C β-lactamase inhibitors are developed.
Defining the Timing of Action of Antimalarial Drugs against Plasmodium falciparum
Authors: Wilson Danny W. , Langer Christine , Goodman Christopher D. , McFadden Geoffrey I. , Beeson James G. 
Published: January 2013

ABSTRACT

Most current antimalarials for treatment of clinical
Plasmodium falciparum
malaria fall into two broad drug families and target the food vacuole of the trophozoite stage. No antimalarials have been shown to target the brief extracellular merozoite form of blood-stage malaria. We studied a panel of 12 drugs, 10 of which have been used extensively clinically, for their invasion, schizont rupture, and growth-inhibitory activity using high-throughput flow cytometry and new approaches for the study of merozoite invasion and early intraerythrocytic development. Not surprisingly, given reported mechanisms of action, none of the drugs inhibited merozoite invasion
in vitro
. Pretreatment of erythrocytes with drugs suggested that halofantrine, lumefantrine, piperaquine, amodiaquine, and mefloquine diffuse into and remain within the erythrocyte and inhibit downstream growth of parasites. Studying the inhibitory activity of the drugs on intraerythrocytic development, schizont rupture, and reinvasion enabled several different inhibitory phenotypes to be defined. All drugs inhibited parasite replication when added at ring stages, but only artesunate, artemisinin, cycloheximide, and trichostatin A appeared to have substantial activity against ring stages, whereas the other drugs acted later during intraerythrocytic development. When drugs were added to late schizonts, only artemisinin, cycloheximide, and trichostatin A were able to inhibit rupture and subsequent replication. Flow cytometry proved valuable for
in vitro
assays of antimalarial activity, with the free merozoite population acting as a clear marker for parasite growth inhibition. These studies have important implications for further understanding the mechanisms of action of antimalarials, studying and evaluating drug resistance, and developing new antimalarials.
Daptomycin versus Vancomycin in Treatment of Methicillin-Resistant Staphylococcus aureus Meningitis in an Experimental Rabbit Model
Authors: Bardak-Ozcem Selin , Turhan Tuncer , Sipahi Oguz Resat , Arda Bilgin , Pullukcu Husnu , Yamazhan Tansu , Isikgoz-Tasbakan Meltem , Sipahi Hilal , Ulusoy Sercan 
Published: January 2013

ABSTRACT

In this study, we aimed to compare the antibacterial activities of daptomycin and vancomycin in the treatment of methicillin-resistant
Staphylococcus aureus
(MRSA) meningitis (induced by MRSA strain ATCC 43300) in an experimental rabbit meningitis model. After an 8-h period of treatment, bacterial counts decreased significantly in both treatment groups compared to the control group (
P
< 0.05). However, there was no statistically significant difference between treatment groups. Our results suggest that the antibacterial activity of daptomycin is similar to vancomycin for treatment in the experimental MRSA meningitis model in rabbits.
Solithromycin Inhibition of Protein Synthesis and Ribosome Biogenesis in Staphylococcus aureus, Streptococcus pneumoniae, and Haemophilus influenzae
Authors: Rodgers Ward , Frazier Ashley D. , Champney W. Scott 
Published: January 2013

ABSTRACT

The continuing increase in antibiotic-resistant microorganisms is driving the search for new antibiotic targets and improved antimicrobial agents. Ketolides are semisynthetic derivatives of macrolide antibiotics, which are effective against certain resistant organisms. Solithromycin (CEM-101) is a novel fluoroketolide with improved antimicrobial effectiveness. This compound binds to the large 50S subunit of the ribosome and inhibits protein biosynthesis. Like other ketolides, it should impair bacterial ribosomal subunit formation. This mechanism of action was examined in strains of
Streptococcus pneumoniae
,
Staphylococcus aureus
, and
Haemophilus influenzae
. The mean 50% inhibitory concentrations (IC
50
s) for solithromycin inhibition of cell viability, protein synthesis, and growth rate were 7.5, 40, and 125 ng/ml for
Streptococcus pneumoniae
,
Staphylococcus aureus
, and
Haemophilus influenzae
, respectively. The net formation of the 50S subunit was reduced in all three organisms, with IC
50
s similar to those given above. The rates of 50S subunit formation measured by a pulse-chase labeling procedure were reduced by 75% in cells growing at the IC
50
of solithromycin. Turnover of 23S rRNA was stimulated by solithromycin as well. Solithromycin was found to be a particularly effective antimicrobial agent, with IC
50
s comparable to those of telithromycin and significantly better than those of azithromycin and clarithromycin in these three microorganisms.
Antibodies to Escherichia coli-Expressed C-Terminal Domains of Plasmodium falciparum Variant Surface Antigen 2-Chondroitin Sulfate A (VAR2CSA) Inhibit Binding of CSA-Adherent Parasites to Placental Tissue
Authors: Saveria Tracy , Oleinikov Andrew V. , Wiliamson Kathryn , Chaturvedi Richa , Lograsso Joe , Keitany Gladys J. , Fried Michal , Duffy Patrick 
Published: January 2013

ABSTRACT

Placental malaria (PM) is characterized by infected erythrocytes (IEs) that selectively bind to chondroitin sulfate A (CSA) and sequester in placental tissue. Variant surface antigen 2-CSA (VAR2CSA), a
Plasmodium falciparum
erythrocyte membrane protein 1 (PfEMP1) protein family member, is expressed on the surface of placental IEs and mediates adherence to CSA on the surface of syncytiotrophoblasts. This transmembrane protein contains 6 Duffy binding-like (DBL) domains which might contribute to the specific adhesive properties of IEs. Here, we use laboratory isolate 3D7 VAR2CSA DBL domains expressed in
Escherichia coli
to generate antibodies specific for this protein. Flow cytometry results showed that antibodies generated against DBL4ε, DBL5ε, DBL6ε, and tandem double domains of DBL4-DBL5 and DBL5-DBL6 all bind to placental parasite isolates and to lab strains selected for CSA binding but do not bind to children's parasites. Antisera to DBL4ε and to DBL5ε inhibit maternal IE binding to placental tissue in a manner comparable to that for plasma collected from multigravid women. These antibodies also inhibit binding to CSA of several field isolates derived from pregnant women, while antibodies to double domains do not enhance the functional immune response. These data support DBL4ε and DBL5ε as vaccine candidates for pregnancy malaria and demonstrate that
E. coli
is a feasible tool for the large-scale manufacture of a vaccine based on these VAR2CSA domains.
Intestinal Microbiota Containing Barnesiella Species Cures Vancomycin-Resistant Enterococcus faecium Colonization
Authors: Ubeda Carles , Bucci Vanni , Caballero Silvia , Djukovic Ana , Toussaint Nora C. , Equinda Michele , Lipuma Lauren , Ling Lilan , Gobourne Asia , No Daniel , Taur Ying , Jenq Robert R. , van den Brink Marcel R. M. , Xavier Joao B. , Pamer Eric G. 
Published: January 2013

ABSTRACT

Bacteria causing infections in hospitalized patients are increasingly antibiotic resistant. Classical infection control practices are only partially effective at preventing spread of antibiotic-resistant bacteria within hospitals. Because the density of intestinal colonization by the highly antibiotic-resistant bacterium vancomycin-resistant
Enterococcus
(VRE) can exceed 10
9
organisms per gram of feces, even optimally implemented hygiene protocols often fail. Decreasing the density of intestinal colonization, therefore, represents an important approach to limit VRE transmission. We demonstrate that reintroduction of a diverse intestinal microbiota to densely VRE-colonized mice eliminates VRE from the intestinal tract. While oxygen-tolerant members of the microbiota are ineffective at eliminating VRE, administration of obligate anaerobic commensal bacteria to mice results in a billionfold reduction in the density of intestinal VRE colonization. 16S rRNA gene sequence analysis of intestinal bacterial populations isolated from mice that cleared VRE following microbiota reconstitution revealed that recolonization with a microbiota that contains
Barnesiella
correlates with VRE elimination. Characterization of the fecal microbiota of patients undergoing allogeneic hematopoietic stem cell transplantation demonstrated that intestinal colonization with
Barnesiella
confers resistance to intestinal domination and bloodstream infection with VRE. Our studies indicate that obligate anaerobic bacteria belonging to the
Barnesiella
genus enable clearance of intestinal VRE colonization and may provide novel approaches to prevent the spread of highly antibiotic-resistant bacteria.