bluuebunny/crossref_metadata_2025_split huggingface dataset:
Function and expression of ryanodine receptors and inositol 1,4,5‐trisphosphate receptors in smooth muscle cells of murine feed arteries and arterioles
Authors: Westcott Erika B. , Goodwin Erica L. , Segal Steven S. , Jackson William F. 
Published: February 2012

Key points
Feed arteries and arterioles, respectively, control the magnitude and distribution of blood flow to skeletal muscle but regional differences in the regulation of vasomotor tone are poorly understood.
To provide this insight, we investigated functional roles and molecular expression of the calcium‐release channels, ryanodine receptors (RyRs) and inositol 1,4,5‐trisphosphate receptors (IP3Rs) in smooth muscle cells (SMCs) of isolated pressurized vessels of mice.
In feed arteries, SMCs displayed localized calcium sparks and more global calcium waves. In arterioles, SMCs exhibited only calcium waves.
Calcium signalling and vasomotor tone were governed by both RyRs and IP3Rs in feed arteries, while only IP3Rs were functional in arterioles. Regional differences were also manifest in the expression profile of RyR isoforms.
This new perspective offers the potential for developing novel strategies to target therapeutic interventions to selective regions of vascular beds.
Cardiac output and sympathetic vasoconstrictor responses during upright tilt to presyncope in healthy humans
Authors: Fu Qi , Verheyden Bart , Wieling Wouter , Levine Benjamin D. 
Published: February 2012

Key points
Syncope is a common clinical condition occurring even in healthy people without manifest cardiovascular disease; we determined the role of cardiac output and sympathetic vasoconstriction in neurally mediated (pre)syncope.
Our data showed that a moderate fall in cardiac output with coincident vasodilatation occurred in the majority (64%) of the presyncopal subjects, while a marked fall in cardiac output, driven predominantly by a decrease in heart rate, with no changes in total peripheral resistance at presyncope, occurred in a smaller (36%) subset.
Sympathetic withdrawal occurred late, after the onset of hypotension.
Sympathetic vasoconstriction and baroreflex sensitivity during symptom‐free upright posture were well preserved and, thus, an intrinsic impairment of sympathetic neural control and vasomotor responsiveness was not the cause of neurally mediated (pre)syncope in this population.
These results help us better understand the mechanisms for syncope in humans.
In Vitro
Efficacy of Diallyl Sulfides against the Periodontopathogen Aggregatibacter actinomycetemcomitans
Authors: Velliyagounder Kabilan , Ganeshnarayan Krishnaraj , Velusamy Senthil Kumar , Fine Daniel H. 
Published: February 2012

ABSTRACT

The
in vitro
antibacterial effects of diallyl sulfide (DAS) against the Gram-negative periodontopathogen
Aggregatibacter actinomycetemcomitans
, the key etiologic agent of the severe form of localized aggressive periodontitis and other nonoral infections, were studied.
A. actinomycetemcomitans
was treated with garlic extract, allicin, or DAS, and the anti-
A. actinomycetemcomitans
effects of the treatment were evaluated. Garlic extract, allicin, and DAS significantly inhibited the growth of
A. actinomycetemcomitans
(greater than 3 log;
P
< 0.01) compared to control cells. Heat inactivation of the garlic extracts significantly reduced the protein concentration; however, the antimicrobial effect was retained. Purified proteins from garlic extract did not exhibit antimicrobial activity. Allicin lost all its antimicrobial effect when it was subjected to heat treatment, whereas DAS demonstrated an antimicrobial effect similar to that of the garlic extract, suggesting that the antimicrobial activity of garlic extract is mainly due to DAS. An
A. actinomycetemcomitans
biofilm-killing assay performed with DAS showed a significant reduction in biofilm cell numbers, as evidenced by both confocal microscopy and culture. Scanning electron microscopy (SEM) analysis of DAS-treated
A. actinomycetemcomitans
biofilms showed alterations of colony architecture indicating severe stress. Flow cytometry analysis of OBA9 cells did not demonstrate apoptosis or cell cycle arrest at therapeutic concentrations of DAS (0.01 and 0.1 μg/ml). DAS-treated
A. actinomycetemcomitans
cells demonstrated complete inhibition of glutathione (GSH)
S
-transferase (GST) activity. However, OBA9 cells, when exposed to DAS at similar concentrations, showed no significant differences in GST activity, suggesting that DAS-induced GST inhibition might be involved in
A. actinomycetemcomitans
cell death. These findings demonstrate that DAS exhibits significant antibacterial activity against
A. actinomycetemcomitans
and that this property might be utilized for exploring its therapeutic potential in treatment of
A. actinomycetemcomitans
-associated oral and nonoral infections.
Pulmonary Disposition of Tedizolid following Administration of Once-Daily Oral 200-Milligram Tedizolid Phosphate in Healthy Adult Volunteers
Authors: Housman Seth T. , Pope J. Samuel , Russomanno John , Salerno Edward , Shore Eric , Kuti Joseph L. , Nicolau David P. 
Published: February 2012

ABSTRACT

This study assessed the pulmonary disposition of tedizolid, an oxazolidinone, in adult volunteers receiving 200 mg of the prodrug tedizolid phosphate orally every 24 h for 3 days to steady state. Plasma samples were collected over the dosing interval, and participants were randomized to undergo bronchoalveolar lavage (BAL) at 2, 6, 12, or 24 h after the last dose. Drug concentrations in plasma, BAL fluid, and alveolar macrophages (AM) were determined by liquid chromatography-tandem mass spectrometry (LC-MS/MS), and the urea correction method was used to calculate epithelial lining fluid (ELF) concentrations. Pharmacokinetic parameters were estimated by noncompartmental methods followed by compartmental population pharmacokinetics. Penetration was calculated as the area under the concentration-time curve during the dosing interval (AUC
0–24
) for ELF and AM relative to the free AUC
0–24
(
f
AUC
0–24
) in plasma. The half-life and volume of distribution in plasma were 9.23 ± 2.04 h and 108.25 ± 20.53 liters (means ± standard deviations), respectively. Total AUC
0–24
in plasma was 25.13 ± 5.78 μg · h/ml. Protein binding was 89.44% ± 1.58%, resulting in a mean
f
AUC
0–24
of 2.65 ± 0.72 μg · h/ml in plasma. Mean concentrations (μg/ml) at 2, 6, 12, and 24 h were 9.05 ± 3.83, 4.45 ± 2.18, 5.62 ± 1.99, and 1.33 ± 0.59 in ELF and 3.67 ± 1.02, 4.38 ± 2.18, 1.42 ± 0.63, and 1.04 ± 0.52 in AM. ELF and AM penetration ratios were 41.2 and 20.0. The mean ELF penetration ratio after population analyses was 39.7. This study demonstrates that tedizolid penetrates into ELF and AM to levels approximately 40-fold and 20-fold, respectively, higher than free-drug exposures in plasma.
Efficacy of Posaconazole in Murine Experimental Sporotrichosis
Authors: Fernández-Silva Fabiola , Capilla Javier , Mayayo Emilio , Guarro Josep 
Published: February 2012

ABSTRACT

We developed a murine model of systemic sporotrichosis by using three strains of each of the two commonest species causing sporotrichosis, i.e.,
Sporothrix schenckii
sensu stricto and
Sporothrix brasiliensis
, in order to evaluate the efficacy of posaconazole (PSC). The drug was administered at a dose of 2.5 or 5 mg/kg of body weight twice a day by gavage, and one group was treated with amphotericin B (AMB) as a control treatment. Posaconazole, especially at 5 mg/kg, showed good efficacy against all the strains tested, regardless of their MICs, as measured by prolonged survival, tissue burden reduction, and histopathology.
Sustained Release of the CCR5 Inhibitors CMPD167 and Maraviroc from Vaginal Rings in Rhesus Macaques
Authors: Malcolm R. Karl , Veazey Ronald S. , Geer Leslie , Lowry Deborah , Fetherston Susan M. , Murphy Diarmaid J. , Boyd Peter , Major Ian , Shattock Robin J. , Klasse Per Johan , Doyle Lara A. , Rasmussen Kelsi K. , Goldman Laurie , Ketas Thomas J. , Moore John P. 
Published: February 2012

ABSTRACT

Antiretroviral entry inhibitors are now being considered as vaginally administered microbicide candidates for the prevention of the sexual transmission of human immunodeficiency virus. Previous studies testing the entry inhibitors maraviroc and CMPD167 in aqueous gel formulations showed efficacy in the macaque challenge model, although protection was highly dependent on the time period between initial gel application and subsequent challenge. In this paper, we describe the sustained release of maraviroc and CMPD167 from matrix-type silicone elastomer vaginal rings both
in vitro
and
in vivo
. Both inhibitors were released continuously during 28 days from rings
in vitro
at rates of 100 to 2,500 μg/day. In 28-day pharmacokinetic studies in rhesus macaques, the compounds were measured in the vaginal fluid and vaginal tissue; steady-state fluid concentrations were ∼10
6
-fold greater than the 50% inhibitory concentrations (IC
50
s) for simian human immunodeficiency virus 162P3 inhibition in macaque lymphocytes
in vitro
. Plasma concentrations for both compounds were very low. The pretreatment of macaques with Depo-Provera (DP), which is commonly used in macaque challenge studies, was shown to significantly modify the biodistribution of the inhibitors but not the overall amount released. Vaginal fluid and tissue concentrations were significantly decreased while plasma levels increased with DP pretreatment. These observations have implications for designing macaque challenge experiments and also for ring performance during the human female menstrual cycle.
Therapeutic Equivalence Requires Pharmaceutical, Pharmacokinetic, and Pharmacodynamic Identities: True Bioequivalence of a Generic Product of Intravenous Metronidazole
Authors: Agudelo M. , Vesga O. 
Published: February 2012

ABSTRACT

Animal models of infection have been used to demonstrate the therapeutic failure of “bioequivalent” generic products, but their applicability for this purpose requires the accurate identification of those products that are truly bioequivalent. Here, we present data comparing one intravenous generic product of metronidazole with the innovator product in a neutropenic mouse thigh anaerobic infection model. Simultaneous experiments allowed comparisons (generic versus innovator) of potency and the concentration of the active pharmaceutical ingredient (API), analytical chemistry (liquid chromatography/mass spectrometry [LC/MS]),
in vitro
susceptibility testing, single-dose serum pharmacokinetics (PK) in infected mice, and
in vivo
pharmacodynamics (PD) against
Bacteroides fragilis
ATCC 25825 in synergy with
Escherichia coli
SIG-1 in the neutropenic mouse thigh anaerobic infection model. The Hill dose-response model followed by curve-fitting analysis was used to calculate and compare primary and secondary PD parameters. The generic and the innovator products were identical in terms of the concentration and potency of the API, chromatographic and spectrographic profiles, MIC and minimal bactericidal concentrations (MBC) (2.0 mg/liter), and mouse PK. We found no differences between products in bacteriostatic doses (BD) (15 to 22 mg/kg of body weight per day) or the doses needed to kill 1 log (1LKD) (21 to 29 mg/kg per day) or 2 logs (2LKD) (28 to 54 mg/kg per day) of
B. fragilis
under dosing schedules of every 12 h (q12h), q8h, or q6h. The area under the concentration-time curve over 24 h in the steady state divided by the MIC (AUC/MIC ratio) was the best PD index to predict the antibacterial efficacy of metronidazole (adjusted coefficient of determination [AdjR
2
] = 84.6%), and its magnitude to reach bacteriostasis
in vivo
(56.6 ± 5.17 h) or to kill the first (90.8 ± 9.78 h) and second (155.5 ± 22.2 h) logs was the same for both products. Animal models of infection allow a thorough demonstration of the therapeutic equivalence of generic antimicrobials.
Pharmacokinetics of Rifampin in Peruvian Tuberculosis Patients with and without Comorbid Diabetes or HIV
Authors: Requena-Méndez Ana , Davies Geraint , Ardrey Alison , Jave Oswaldo , López-Romero Sonia L. , Ward Stephen A. , Moore David A. J. 
Published: February 2012

ABSTRACT

For drug-compliant patients, poor responses to tuberculosis (TB) treatment might be attributable to subtherapeutic drug concentrations. An impaired absorption of rifampin was previously reported for patients with diabetes mellitus (DM) or HIV. The objectives of this study were to determine whether TB drug pharmacokinetics differed in Peruvian TB patients with DM or HIV. In this cross-sectional study, TB patients, recruited from health centers in Lima, Peru, had blood samples taken at 2 and 6 h after directly observed TB drug ingestion, to determine plasma concentrations of rifampin. Of 105 patients, 50 had TB without a comorbidity, 26 had coexistent DM, and 29 had coexistent HIV. Unexpectedly, the overall median 2- and 6-h levels of rifampin were 1.6 and 3.2 mg/liter, respectively, and the time to the peak concentration was 6 h (slow absorber) instead of 2 h (fast absorber) for 61 patients (62.2%). The geometric mean peak concentration of drug in serum (
C
max
) was significantly higher in fast absorbers than in slow absorbers (5.0 versus 3.8 mg/liter;
P
= 0.05). The rifampin
C
max
was significantly lower in male patients than in female patients (3.3 versus 6.3 mg/liter;
P
< 0.001). Neither slow nor fast absorbers with comorbidities (DM or HIV) had significantly different
C
max
results compared to those of TB patients without comorbidities. An analysis of variance regression analysis showed that female gender (
P
< 0.001) and the time to maximum concentration of drug in serum (
T
max
) at 2 h (
P
= 0.012) were independently correlated with increased exposure to rifampin. Most of this Peruvian study population exhibited rifampin pharmacokinetics different from those conventionally reported, with delayed absorption and low plasma concentrations, independent of the presence of an HIV or DM comorbidity.
Effect of Natural Polymorphisms in the HIV-1 CRF02_AG Protease on Protease Inhibitor Hypersusceptibility
Authors: Santos André F. A. , Tebit Denis M. , Lalonde Matthew S. , Abecasis Ana B. , Ratcliff Annette , Camacho Ricardo J. , Diaz Ricardo S. , Herchenröder Ottmar , Soares Marcelo A. , Arts Eric J. 
Published: February 2012

ABSTRACTHypersusceptibility (HS) to inhibition by different antiretroviral drugs (ARVs) among diverse HIV-infected individuals may be a misnomer because clinical response to treatment is evaluated in relation to subtype B infections while drug susceptibility of the infecting virus, regardless of subtype, is compared to a subtype B HIV-1 laboratory strain (NL4-3 or IIIB). Mounting evidence suggests that HS to different ARVs may result in better treatment outcome just as drug resistance leads to treatment failure. We have identified key amino acid polymorphisms in the protease coding region of a non-B HIV-1 subtype linked to protease inhibitor HS, namely, 17E and 64M in CRF02_AG. These HS-linked polymorphisms were introduced in the BD6-15 CRF02_AG molecular clone and tested for inhibition using a panel of protease inhibitors. In general, suspected HS-linked polymorphisms did increase susceptibility to specific protease inhibitors such as amprenavir and atazanavir, but the combination of the 17E/64M polymorphisms showed greater HS. These two mutations were found at low frequencies but linked in a sequence database of over 700 protease sequences of CRF02_AG. In direct head-to-head virus competitions, CRF02_AG harboring the 17E/64M polymorphisms also had higher replicative fitness than did the 17E or the 64M polymorphism in the CFR02_AG clone. These findings suggest that subtype-specific, linked polymorphisms can result in hypersusceptibility to ARVs. Considering the potential benefit of HS to treatment outcome, screening for potential HS-linked polymorphisms as well as preexisting drug resistance mutations in treatment-naïve patients may guide the choice of ARVs for the best treatment outcome.
Incidence and outcome of procedural distal emboli using the Penumbra thrombectomy for acute stroke
Authors: Todo Akira , Minaeian Artin , Sahni Ramandeep , Chao Kuo H 
Published: February 2012

BackgroundThe Penumbra system is effective for recanalization of the primary arterial occlusion (PAO) in acute stroke. However, clinical outcomes are not as promising. The authors hypothesized that the formation of procedural distal emboli (PDE) during mechanical thrombectomy may lead to poorer patient outcomes.Design/methodsA retrospective review of patients with acute ischemic stroke treated with the Penumbra system was undertaken. Patients' outcome was evaluated by comparing discharge National Institute of Health stroke scale and modified Rankin score (mRS) of patients with and without PDE.ResultsOut of 20 patients reviewed, recanalization of PAO was 100%. Six patients (30%) were confirmed to have PDE, of which two died (33.3%) and one (16.7%) had mRS of 2 or less. Of the 14 patients without PDE, three died (21.4%) and six (42.9%) had mRS of 2 or less. In the patient group who survived, mean National Institute of Health stroke scale decrease was only 2.3 in patients with PDE versus a decrease of 10.6 in patients without PDE.ConclusionsIn spite of PAO recanalization, distal emboli formed subsequent to Penumbra thrombectomy may contribute to poorer clinical outcome in acute stroke patients.
Prostaglandin E1 dose-dependently promotes stability of atherosclerotic plaque in a rabbit model
Authors: Bai Wanjun , Zheng Xue , Zhou Liaosheng , Li Hongjian 
Published: February 2012

This study evaluated the effect of prostaglandin E1 (PGE1) on the stability of atherosclerotic plaque. A vulnerable plaque model was established in rabbits, using balloon injury combined with a high-cholesterol diet. The rabbits were distributed into a control group, a low-dose PGE1 treatment group, a moderate-dose PGE1 treatment group, a high-dose PGE1 treatment group, and a simvastatin treatment group, with treatments lasting for 4 weeks. At week 13 (at the end of the experiments), atherosclerotic plaque was triggered by injection of Russell’s viper venom (Chinese) and histamine. Serological, pathological, immunohistochemical, and gene-expression studies were subsequently performed. PGE1 treatment did not alter serum lipid levels; however, PGE1 dose-dependently increased the thickness of the fibrous caps, and decreased the plaque vulnerability index. The plaque contents of macrophage- and the mRNA levels of monocyte-chemotactic protein-1, matrix metalloproteinase-1, and matrix metalloproteinase-9 were markedly reduced in all of the PGE1 treatment groups, with the high-dose of PGE1 being more effective than the simvastatin treatment. These findings suggest that PGE1 dose-dependently enhances the stability of atherosclerotic plaque. The high-dose of PGE1 presented more protection in terms of inhibiting macrophage accumulation and inflammatory expression in plaque. Our findings suggest a novel drug for the treatment of atherosclerosis.
Incidence of Tissue Coring During Transseptal Catheterization When Using Electrocautery and a Standard Transseptal Needle
Authors: Greenstein Eugene , Passman Rod , Lin Albert C. , Knight Bradley P. 
Published: February 2012

Background—
The application of radiofrequency electrocautery to a standard, open-ended transseptal needle has been used to facilitate transseptal puncture (TSP). The purpose of this study was to determine the incidence of cardiac tissue coring when this technique is used.

Methods and Results—

A model using excised swine hearts submerged in a saline-filled basin was developed to simulate TSP with electrocautery and a standard transseptal needle. Punctures were performed without the use of electrocautery and by delivering radiofrequency energy to the transseptal needle using a standard electrocautery pen at 3 target sites (fossa ovalis, non–fossa ovalis septum, and aorta). The tissue of the submerged heart was gently tented, and the needle was advanced on delivery of radiofrequency. The devices were retracted, and the needle was flushed in a collection basin. None of the TSPs without cautery caused tissue coring. For TSPs using electrocautery, the frequency of coring was at least 21% for any puncture permutation used in the study and averaged 37% at septal sites (
P
<0.001 compared with punctures without cautery). Tissue coring occurred in 33 of 96 (35%) punctures through the fossa ovalis and in 38 of 96 (40%) punctures through non–fossa ovalis septum. The frequency of tissue coring at aortic sites was 62 of 96 (65%), which was significantly higher than at the septal sites (
P
<0.001).

Conclusions—
In an animal preparation, TSP at the level of the fossa ovalis using electrocautery and a standard open-ended Brockenbrough needle resulted in coring of the septal tissue in 35% of cases (33 of 96 punctures).
Processing of Emotional Distraction Is Both Automatic and Modulated by Attention: Evidence from an Event-related fMRI Investigation
Authors: Shafer Andrea T. , Matveychuk Dmitriy , Penney Todd , O'Hare Aminda J. , Stokes Jared , Dolcos Florin 
Published: February 2012

Abstract
Traditionally, emotional stimuli have been thought to be automatically processed via a bottom–up automatic “capture of attention” mechanism. Recently, this view has been challenged by evidence that emotion processing depends on the availability of attentional resources. Although these two views are not mutually exclusive, direct evidence reconciling them is lacking. One limitation of previous investigations supporting the traditional or competing views is that they have not systematically investigated the impact of emotional charge of task-irrelevant distraction in conjunction with manipulations of attentional demands. Using event-related fMRI, we investigated the nature of emotion–cognition interactions in a perceptual discrimination task with emotional distraction by manipulating both the emotional charge of the distracting information and the demands of the main task. Our findings show that emotion processing is both automatic and modulated by attention, but emotion and attention were only found to interact when finer assessments of emotional charge (comparison of most vs. least emotional conditions) were considered along with an effective manipulation of processing load (high vs. low). The study also identified brain regions reflecting the detrimental impact of emotional distraction on performance as well as regions involved in coping with such distraction. Activity in the dorsomedial pFC and ventrolateral pFC was linked to a detrimental impact of emotional distraction, whereas the dorsal ACC and lateral occipital cortex were involved in helping with emotional distraction. These findings demonstrate that task-irrelevant emotion processing is subjective to both the emotional content of distraction and the level of attentional demand.