bluuebunny/crossref_metadata_2025_split huggingface dataset:
Release of endogenous opioids during a chronic IBD model suppresses the excitability of colonic DRG neurons
Authors: Valdez‐Morales E. , Guerrero‐Alba R. , Ochoa‐Cortes F. , Benson J. , Spreadbury I. , Hurlbut D. , Miranda‐Morales M. , Lomax A. E. , Vanner S. 
Published: September 2012

AbstractBackground  Endogenous opioids are implicated in pain‐regulation in chronic inflammatory bowel disease (IBD). We sought to examine whether endogenous opioids suppress the excitability of colonic nociceptive dorsal root ganglia (DRG) neurons during chronic IBD, and if so, whether modulation of underlying voltage‐gated K+ currents was involved.Methods  The effects of chronic dextran sulfate sodium (DSS) colitis on afferent signaling in mice was studied using patch clamp recordings. Colonic DRG neurons were identified using Fast Blue retrograde labeling and recordings obtained from small DRG neurons (<40 pF).Key Results  In current‐clamp recordings, the rheobase of neurons was increased 47% (P < 0.01) and action potential discharge at twice rheobase decreased 23% (P < 0.05) following incubation in colonic supernatants from chronic DSS mice. β‐endorphin increased 14‐fold, and tissue opioid immunoreactivity and expression in CD4+ cells observed by flow cytometry increased in chronic DSS colons. Incubation of naïve neurons in the μ‐opioid receptor agonist D‐Ala2, N‐ MePhe4, Gly‐ol (DAMGO) (10 nM) partially recapitulated the effects of supernatants from DSS mice on rheobase. Supernatant effects were blocked by the μ‐opioid receptor antagonist naloxone. In voltage clamp, chronic DSS supernatants and DAMGO increased IA K+ currents.Conclusions & Inferences  The release of endogenous opioids during chronic inflammation in mice suppresses the excitability of nociceptive DRG neurons. Targeting immune cells may provide a novel means of modulating IBD pain.
Submucous rather than myenteric neurons are activated by mucosal biopsy supernatants from irritable bowel syndrome patients
Authors: Buhner S. , Li Q. , Berger T. , Vignali S. , Barbara G. , De Giorgio R. , Stanghellini V. , Schemann M. 
Published: September 2012

AbstractBackground  We previously showed that colonic mucosal biopsy supernatants from patients with irritable bowel syndrome (IBS) activate neurons of the human submucous plexus, an area with densely packed immune cells. Based on the concept that mucosa‐nerve signaling is altered in IBS, we tested in this study whether the nerve sensitizing effect of IBS mucosal biopsy supernatants is more prominent in the submucous than myenteric plexus.Methods  Fast neuroimaging with the voltage‐sensitive dye Di‐8‐ANEPPS was used to record activity of guinea‐pig submucous and myenteric neurons after application of constipation (C)‐ and diarrhea (D)‐IBS supernatants (three each) and four supernatants from healthy control subjects. Results are based on recordings from 4731 neurons.Key Results  Control supernatants did not evoke significant responses in submucous or myenteric neurons. In contrast, all IBS supernatants evoked a significant spike discharge (median 3.6 Hz) in 46% of submucous neurons. This activation was significantly stronger than in the myenteric plexus where even twice the amount of supernatants evoked a lower spike frequency (median 2.1 Hz) in only 8.5% of neurons. Pharmacological studies revealed serotonin, histamine, and proteases as components mediating neuronal activation. Individual application of these components revealed that only serotonin evoked a significantly stronger activation of submucous compared with myenteric neurons.Conclusions & Inferences  Direct neuronal activation by IBS mucosal biopsy supernatants is primarily a feature of submucous rather than myenteric neurons. This is associated with a stronger excitation of submucous neurons by serotonin. The plexus‐specific effects support the concept that altered mucosa‐nerve signaling underlies disturbances in IBS.
Association between craniofacial asymmetry and unilateral temporomandibular joint sounds in adult patients using 3D‐computed tomography
Authors: Yáñez‐Vico R‐M , Iglesias‐Linares A , Torres‐Lagares D , Gutiérrez‐Pérez J‐L , Solano‐Reina E 
Published: September 2012

ObjectivesThe purpose of this study was to investigate the possible relationship between unilateral temporomandibular joint (TMJ) sounds and craniofacial asymmetry, using 3D‐computed tomography (CT) measurements.Subjects and MethodsForty‐one reconstructed 3D‐CT models of adult subjects were measured to analyze craniofacial asymmetry. Subjects were divided into two groups depending on the presence (n = 20) or absence (n = 21) of unilateral joint sounds, and the results compared using the Mann–Whitney U‐test. To investigate the association between these parameters, the Pearson correlation coefficient was calculated.ResultsAsymmetries in the maxillary and mandibular structures were statistically significant (P < 0.05) for subjects with unilateral TMJ sounds and for controls, except in the case of maxillary rotation and mandibular ramus height (P > 0.05). The highest deviations found were frontal and lateral ramal inclination, goniac angle and canting of occlusal plane.ConclusionsAdult patients with unilateral joint sounds may have skeletal jaw asymmetry and a canted occlusal plane.
SIZ1 deficiency causes reduced stomatal aperture and enhanced drought tolerance via controlling salicylic acid‐induced accumulation of reactive oxygen species in Arabidopsis
Authors: Miura Kenji , Okamoto Hiroyuki , Okuma Eiji , Shiba Hayato , Kamada Hiroshi , Hasegawa Paul M. , Murata Yoshiyuki 
Published: September 2012

SummaryTranspiration and gas exchange occur through stomata. Thus, the control of stomatal aperture is important for the efficiency and regulation of water use, and for the response to drought. Here, we demonstrate that SIZ1‐mediated endogenous salicylic acid (SA) accumulation plays an important role in stomatal closure and drought tolerance. siz1 reduced stomatal apertures. The reduced stomatal apertures of siz1 were inhibited by the application of peroxidase inhibitors, salicylhydroxamic acid and azide, which inhibits SA‐dependent reactive oxygen species (ROS) production, but not by an NADPH oxidase inhibitor, diphenyl iodonium chloride, which inhibits ABA‐dependent ROS production. Furthermore, the introduction of nahG into siz1, which reduces SA accumulation, restored stomatal opening. Stomatal closure is generally induced by water deficit. The siz1 mutation caused drought tolerance, whereas nahG siz1 suppressed the tolerant phenotype. Drought stresses also induced expression of SA‐responsive genes, such as PR1 and PR2. Furthermore, other SA‐accumulating mutants, cpr5 and acd6, exhibited stomatal closure and drought tolerance, and nahG suppressed the phenotype of cpr5 and acd6, as did siz1 and nahG siz1. Together, these results suggest that SIZ1 negatively affects stomatal closure and drought tolerance through the accumulation of SA.
The Brauer characters of the sporadic simple Harada–Norton group and its automorphism group in characteristics 2 and 3
Authors: Hiss Gerhard , Müller Jürgen , Noeske Felix , Thackray Jon 
Published: September 2012

AbstractWe determine the 2-modular and 3-modular character tables of the sporadic simple Harada–Norton group and its automorphism group.
High blood pressure associates with the remodelling of inward rectifier K+ channels in mice mesenteric vascular smooth muscle cells
Authors: Tajada Sendoa , Cidad Pilar , Moreno‐Domínguez Alejandro , Pérez‐García M. Teresa , López‐López José R. 
Published: September 2012

Key points
Essential hypertension involves an electrical remodelling of vascular smooth muscle cells (VSMCs), particularly relevant for K+ channels, as key determinants of resting membrane potential (VM) and excitability.
We explored mRNA expression levels of inward rectifier K+ channel genes in five different vascular beds from normotensive (BPN) and hypertensive (BPH) mice. In mesenteric VSMCs, their functional contribution to cell excitability and vascular reactivity was investigated.
BPH mesenteric VSMCs show a decreased functional expression of both classical inward rectifiers (KIR, Kir2 and Kir4 channels) and ATP‐sensitive K+ channels (KATP, Kir6 channels). However, only the changes in the functional expression of KATP channels seem to contribute to the increased vascular reactivity of BPH arteries.
BPN and BPH mice are a useful model to provide integrated information of the impact in the pathophysiology of essential hypertension of the changes in ion channel functional expression.
Abstract  The increased vascular tone that defines essential hypertension is associated with depolarization of vascular smooth muscle cells (VSMCs) and involves a change in the expression profile of ion channels promoting arterial contraction. As a major regulator of VSMC resting membrane potential (VM), K+ channel activity is an important determinant of vascular tone and vessel diameter. However, hypertension‐associated changes in the expression and/or modulation of K+ channels are poorly defined, due to their large molecular diversity and their bed‐specific pattern of expression. Moreover, the impact of these changes on the integrated vessel function and their contribution to the development of altered vascular tone under physiological conditions need to be confirmed. Hypertensive (BPH) and normotensive (BPN) mice strains obtained by phenotypic selection were used to explore whether changes in the functional expression of VSMC inward rectifier K+ channels contribute to the more depolarized resting VM and the increased vascular reactivity of hypertensive arteries. We determined the expression levels of inward rectifier K+ channel mRNA in several vascular beds from BPN and BPH animals, and their functional contribution to VSMC excitability and vascular tone in mesenteric arteries. We found a decrease in the expression of Kir2.1, Kir4.1, Kir6.x and SUR2 mRNA in BPH VSMCs, and a decreased functional contribution of both KIR and KATP channels in isolated BPH VSMCs. However, only the effect of KATP channel modulators was impaired when exploring vascular tone, suggesting that decreased functional expression of KATP channels may be an important element in the remodelling of VSMCs in essential hypertension.
Reduced corticomotor excitability and motor skills development in children born preterm
Authors: Pitcher Julia B. , Schneider Luke A. , Burns Nicholas R. , Drysdale John L. , Higgins Ryan D. , Ridding Michael C. , Nettelbeck Theodore J. , Haslam Ross R. , Robinson Jeffrey S. 
Published: September 2012

Key points
Children born preterm commonly experience motor and cognitive difficulties, but the physiology underlying this dysfunction is unknown.
We used transcranial magnetic stimulation techniques and age‐appropriate assessments of motor skills development to investigate neurodevelopment in 151 children born between 25 and 41 weeks of gestation.
Reduced gestational age at birth was associated with a reduction in corticomotor excitability that persisted in late childhood, poorer development of manual dexterity skills and reduced hemispheric lateralization of hand preference.
We suggest this reduced corticomotor excitability at least partly reflects reduced white matter integrity and functional connectivity in the brain regions subserving movement control.
These findings show that preterm birth, which is increasingly common, impacts neuromotor development and related physiology into adolescence. Whether this altered neurophysiology and motor function persists in adulthood is unknown.
Abstract  The mechanisms underlying the altered neurodevelopment commonly experienced by children born preterm, but without brain lesions, remain unknown. While individuals born the earliest are at most risk, late preterm children also experience significant motor, cognitive and behavioural dysfunction from school age, and reduced income and educational attainment in adulthood. We used transcranial magnetic stimulation and functional assessments to examine corticomotor development in 151 children without cerebral palsy, aged 10–13 years and born after gestations of 25–41 completed weeks. We hypothesized that motor cortex and corticospinal development are altered in preterm children, which underpins at least some of their motor dysfunction. We report for the first time that every week of reduced gestation is associated with a reduction in corticomotor excitability that remains evident in late childhood. This reduced excitability was associated with poorer motor skill development, particularly manual dexterity. However, child adiposity, sex and socio‐economic factors regarding the child's home environment soon after birth were also powerful influences on development of motor skills. Preterm birth was also associated with reduced left hemisphere lateralization, but without increasing the likelihood of being left handed per se. These corticomotor findings have implications for normal motor development, but also raise questions regarding possible longer term consequences of preterm birth on motor function.
Partial opening and subconductance gating of mechanosensitive ion channels in dystrophic skeletal muscle
Authors: Vasquez Ivan , Tan Nhi , Boonyasampant Mark , Koppitch Kari A. , Lansman Jeffry B. 
Published: September 2012

Key points
Mechanosensitive (MS) channels in skeletal muscle are heteromeric proteins composed of TRPV4 and other subunits. Experiments investigated subconductance fluctuations associated with gating of independent subunits.
MS channels open by passing through subconductance states and fluctuate between at least four subconductance levels.
MS channels in mdx muscle spend ∼60% of the time at smaller subconductance levels; applying pressure to the membrane increases occupancy of the fully open state. Channels in wild‐type muscle spend more time at the open state.
Recordings show partial opening of MS channels that fail to reach the open state. Partial openings occur ∼3–4 times more frequently in mdx than wild‐type muscle.
During single activations, burst durations and charge/burst are greater in mdx than in wild‐type muscle.
Partial opening and prolonged burst duration are distinct mechanisms contributing to excess Ca2+ entry through MS channels in dystrophic muscle
Abstract  We recorded the activity of single mechanosensitive (MS) ion channels in skeletal muscle from the mdx mouse, a deletion mutant that lacks the cytoskeletal protein, dystrophin. Experiments were designed to examine the influence of dystrophin, a major component of skeletal muscle costameres, on the behaviour of single MS channels. In the majority of recordings from cell‐attached patches, MS channels have a conductance of ∼23 pS. Recordings from some patches, however, showed a smaller conductance channel of ∼7–14 pS. Large and small conductance channels were detected in a single patch and showed serial, non‐random gating, suggesting different opening levels of a single channel. Analysis of the distribution of current amplitudes within the open channel showed MS channels fluctuate between subconductance levels. MS channels in dystrophic muscle spend ∼60% of the time at smaller subconductance levels, often failing to reach the fully open level. Applying pressure to the membrane of mdx fibres increases in a graded manner occupancy of the fully open state, while reducing occupancy of subconductance levels. Recordings also show partial openings of MS channels in both wild‐type and mdx muscle that fail to reach the fully open state. Partial openings occur at a higher frequency in mdx muscle and reflect occupancy of subconductance levels seen during complete activations. In muscle from mdx/utrn−/− double knockout mice, MS channels also spend more time at subconductance levels than the fully open state. Conductance variability of MS channels may represent gating of a heteromeric protein composed of different channel subunits. The results also show that partial opening and prolonged burst duration are distinct mechanisms that contribute to excess Ca2+ entry in dystrophic muscle.
A First-in-Human, Randomized, Double-Blind, Placebo-Controlled, Single- and Multiple-Ascending Oral Dose Study To Assess the Safety and Tolerability of LFF571 in Healthy Volunteers
Authors: Ting Lillian S. L. , Praestgaard Jens , Grunenberg Nicole , Yang Jenny C. , Leeds Jennifer A. , Pertel Peter 
Published: September 2012

ABSTRACT

Clostridium difficile
is the leading cause of hospital-acquired infectious diarrhea. LFF571 is a novel inhibitor of the prokaryotic translation elongation factor Tu and is active against a range of bacterial species, including
C. difficile
. This first-in-human study investigated the safety and pharmacokinetics of single and multiple ascending oral doses of LFF571 in healthy subjects. This was a randomized, double-blind, placebo-controlled study. Except for one cohort, LFF571 was given with a high-fat meal to all single-dose cohorts (25 mg, 100 mg, 400 mg, and 1,000 mg). In the multiple-dose cohorts (25 mg, 100 mg, or 200 mg every 6 h for 10 days), LFF571 was given without regard to food. A total of 56 subjects completed the study, with 32 and 25 receiving single and multiple doses, respectively. There were no deaths, no serious adverse events, and no subject withdrawals due to an adverse event. The most common adverse event was diarrhea; gastrointestinal pain or distension was also noted. Diarrhea did not develop more frequently among subjects who received LFF571 than among those who received a placebo. LFF571 had limited systemic exposure and high steady-state fecal concentrations. The highest concentration of LFF571 in serum (3.2 ng/ml) was observed after the last dose in a subject who received 200 mg every 6 h for 10 days. LFF571 was generally safe and well tolerated in single and multiple oral doses in healthy subjects. The minimal serum and high fecal concentrations support the further development of LFF571 for the treatment of
C. difficile
infections.
Comparison of the
In Vivo
Pharmacokinetics and
In Vitro
Dissolution of Raltegravir in HIV Patients Receiving the Drug by Swallowing or by Chewing
Authors: Cattaneo Dario , Baldelli Sara , Cerea Matteo , Landonio Simona , Meraviglia Paola , Simioni Emanuela , Cozzi Valeria , Fucile Serena , Gazzaniga Andrea , Clementi Emilio , Galli Massimo , Rizzardini Giuliano , Gervasoni Cristina 
Published: September 2012

ABSTRACT

The pharmacokinetics of raltegravir (RAL) in HIV patients is characterized by high interpatient/intrapatient variability. We investigated the potential contribution of the drug pharmaceutical formulation to RAL pharmacokinetics. We first compared
in vivo
the pharmacokinetics of RAL for 67 patients to whom the drug was administered by swallowing the intact tablet with those obtained from 13 HIV-infected patients who chewed the RAL tablet due to swallowing difficulties. Subsequently, we evaluated
in vitro
the dissolution of RAL tablets under different conditions. In the
in vivo
study, we found that patients given RAL by chewing the tablets presented pharmacokinetic profiles characterized by significantly higher RAL absorption than did patients receiving the drug by swallowing. The
in vitro
studies showed that when the whole tablets were exposed to an acidic medium, the release of RAL was very low, whereas when the tablets were crushed, the profiles presented significantly higher concentrations of RAL. Crushed tablets tested in water or in a pH 6.8 buffer exhibited prompt and complete dissolution of RAL. HIV-infected patients receiving RAL by chewing the tablet showed higher drug absorption and reduced pharmacokinetic variability compared with patients swallowing the intact tablet. This is related to problems in tablet disintegration and to erratic drug absorption. The amelioration of the RAL pharmaceutical formulation could improve drug pharmacokinetics.
Safety and Pharmacokinetics of Intravaginal Rings Delivering Tenofovir in Pig-Tailed Macaques
Authors: Moss John A. , Malone Amanda M. , Smith Thomas J. , Butkyavichene Irina , Cortez Cassandra , Gilman Joshua , Kennedy Sean , Kopin Etana , Nguyen Cali , Sinha Preetha , Hendry R. Michael , Guenthner Patricia , Holder Angela , Martin Amy , McNicholl Janet , Mitchell James , Pau Chou-Pong , Srinivasan Priya , Smith James M. , Baum Marc M. 
Published: September 2012

ABSTRACT

Antiretroviral-based microbicides applied topically to the vagina may play an important role in protecting women from HIV infection. Incorporation of the nucleoside reverse transcriptase inhibitor tenofovir (TFV) into intravaginal rings (IVRs) for sustained mucosal delivery may lead to increased microbicide product adherence and efficacy compared with those of conventional vaginal formulations. Formulations of a novel “pod IVR” platform spanning a range of IVR drug loadings and daily release rates of TFV were evaluated in a pig-tailed macaque model. The rings were safe and exhibited sustained release at controlled rates over 28 days. Vaginal secretion TFV levels were independent of IVR drug loading and were able to be varied over 1.5 log units by changing the ring configuration. Mean TFV levels in vaginal secretions were 72.4 ± 109 μg ml
−1
(slow releasing) and 1.84 ± 1.97 mg ml
−1
(fast releasing). The mean TFV vaginal tissue concentration from the slow-releasing IVRs was 76.4 ± 54.8 μg g
−1
and remained at steady state 7 days after IVR removal, consistent with the long intracellular half-life of TFV. Intracellular tenofovir diphosphate (TFV-DP), the active moiety in defining efficacy, was measured in vaginal lymphocytes collected in the study using the fast-releasing IVR formulation. Mean intracellular TFV-DP levels of 446 ± 150 fmol/10
6
cells fall within a range that may be protective of simian-human immunodeficiency virus strain SF162p3 (SHIV
SF162p3
) infection in nonhuman primates. These data suggest that TFV-releasing IVRs based on the pod design have potential for the prevention of transmission of human immunodeficiency virus type 1 (HIV-1) and merit further clinical investigation.
Pseudomonas aeruginosa Syntrophy in Chronically Colonized Airways of Cystic Fibrosis Patients
Authors: Qin Xuan , Zerr Danielle M. , McNutt Michael A. , Berry Jessica E. , Burns Jane L. , Kapur Raj P. 
Published: September 2012

ABSTRACT

Pseudomonas aeruginosa
isolates from cystic fibrosis (CF) patients undergo remarkable phenotypic divergence over time, including loss of pigmentation, hemolysis, motility, and quorum sensing and emergence of antibiotic hypersusceptibility and/or auxotrophism. With prolonged antibiotic treatment and steady decline in lung function in chronically infected patients, the divergent characteristics associated with CF isolates have traditionally been regarded as “adapted/unusual virulence,” despite the degenerative nature of these adaptations. We examined the phenotypic and genotypic diversity in clonally related isogenic strains of
P. aeruginosa
from individual CF patients. Our observations support a novel model of intra-airway pseudomonal syntrophy and accompanying loss of virulence. A 2007 calendar year collection of CF
P. aeruginosa
isolates (
n
= 525) from 103 CF patients yielded
in vitro
MICs of sulfamethoxazole-trimethoprim (SMX-TMP, which typically has no activity against
P. aeruginosa
) ranging from 0.02 to >32 μg/ml (median, 1.5). Coisolation of clonally related SMX-TMP-susceptible and -resistant
P. aeruginosa
strains from the same host was common (57%), as were isogenic coisolates with mutations in efflux gene determinants (
mexR
,
mexAB-oprM
, and
mexZ
) and genes governing DNA mismatch repair (
mutL
and
mutS
). In this cohort, complete
in vitro
growth complementation between auxotrophic and prototrophic
P. aeruginosa
isogenic strains was evident and concurrent with the coding sequence mosaicism in resistance determinants. These observations suggest that syntrophic clonal strains evolve
in situ
in an organized colonial structure. We propose that
P. aeruginosa
adopts a multicellular lifestyle in CF patients due to host selection of an energetically favorable, less-virulent microbe restricted within and symbiotic with the airway over the host's lifetime.