bluuebunny/crossref_metadata_2025_split huggingface dataset:
Pharmacological Consequence of the A118G μ Opioid Receptor Polymorphism on Morphine- and Fentanyl-mediated Modulation of Ca2+Channels in Humanized Mouse Sensory Neurons
Authors: Mahmoud Saifeldin , Thorsell Annika , Sommer Wolfgang H. , Heilig Markus , Holgate Joan K. , Bartlett Selena E. , Ruiz-Velasco Victor 
Published: October 2011

Background
The most common functional single nucleotide polymorphism of the human OPRM1 gene, A118G, has been shown to be associated with interindividual differences in opioid analgesic requirements, particularly with morphine, in patients with acute postoperative pain. The purpose of this study was to examine whether this polymorphism would modulate the morphine and fentanyl pharmacological profile of sensory neurons isolated from a humanized mouse model homozygous for either the 118A or 118G allele.

Methods
The coupling of wild-type and mutant μ opioid receptors to voltage-gated Ca channels after exposure to either ligand was examined by employing the whole cell variant of the patch-clamp technique in acutely dissociated trigeminal ganglion neurons. Morphine-mediated antinociception was measured in mice carrying either the 118AA or 118GG allele.

Results
The biophysical parameters (cell size, current density, and peak current amplitude potential) measured from both groups of sensory neurons were not significantly different. In 118GG neurons, morphine was approximately fivefold less potent and 26% less efficacious than that observed in 118AA neurons. On the other hand, the potency and efficacy of fentanyl were similar for both groups of neurons. Morphine-mediated analgesia in 118GG mice was significantly reduced compared with the 118AA mice.

Conclusions
This study provides evidence to suggest that the diminished clinical effect observed with morphine in 118G carriers results from an alteration of the receptor's pharmacology in sensory neurons. In addition, the impaired analgesic response with morphine may explain why carriers of this receptor variant have an increased susceptibility to become addicted to opioids.
Invasive and Concomitant Noninvasive Intraoperative Blood Pressure Monitoring
Authors: Wax David B. , Lin Hung-Mo , Leibowitz Andrew B. 
Published: October 2011

Background
Noninvasive (NIBP) and intraarterial (ABP) blood pressure monitoring are used under different circumstances and may yield different values. The authors endeavored to characterize these differences and hypothesized that there could be differences in interventions associated with the use of ABP alone ([ABP]) versus ABP in combination with NIBP ([ABP+NIBP]).

Methods
Simultaneous measurements of ABP and NIBP made during noncardiac cases were extracted from electronic anesthesia records; the differences were subjected to regression analysis. Records of blood products, vasopressors, and antihypertensives administered were also extracted, and associations between the use of these therapies and monitoring strategy ([ABP] vs. [ABP+NIBP]) were tested using univariate, multivariate, and propensity score matched analyses.

Results
Among 24,225 cases, 63% and 37% used [ABP+NIBP] and [ABP], respectively. Systolic NIBP was likely to be higher than ABP when ABP was less than 111 mmHg and lower than ABP otherwise. Among patients with hypotension, transfusion occurred in 27% versus 43% of patients in the [ABP+NIBP] versus [ABP] group, respectively (odds ratio = 0.4; 95% CI 0.35-0.46), and 7% versus 18% of patients in the [ABP+NIBP] versus [ABP] group received vasopressor infusions, respectively (P &lt; 0.01). Among hypertensive patients, 12% versus 44% of those in the [ABP+NIBP] versus [ABP] group received antihypertensive agents, respectively (P &lt; 0.01).

Conclusions
NIBP was generally higher than ABP during periods of hypotension and lower than ABP during periods of hypertension. The use of NIBP measurements to supplement ABP measurements was associated with decreased use of blood transfusions, vasopressor infusions, and antihypertensive medications compared with the use of ABP alone.
Rewarding Electrical Brain Stimulation in Rats after Peripheral Nerve Injury
Authors: Ewan Eric E. , Martin Thomas J. 
Published: October 2011

Background
Prescription opioid abuse is a significant concern in treating chronic pain, yet few studies examine how neuropathic pain alters the abuse liability of commonly abused prescription opioids.

Methods
Normal and spinal nerve ligated (SNL) rats were implanted with electrodes into the left ventral tegmental area (VTA). Rats were trained to lever press for intracranial electrical stimulation (VTA ICSS), and the effects of methadone, fentanyl, hydromorphone, and oxycodone on facilitation of VTA ICSS were assessed. A second group of neuropathic rats were implanted with intrathecal catheters, and the effects of intrathecal clonidine, adenosine, and gabapentin on facilitation of VTA ICSS were assessed. The effects of electrical stimulation of the VTA on mechanical allodynia were assessed in SNL rats.

Results
Responding for VTA ICSS was similar in control and SNL rats. Methadone, fentanyl, and hydromorphone were less potent in facilitating VTA ICSS in SNL rats. Oxycodone produced a significant facilitation of VTA ICSS in control (maximum shift 24.10 ± 6.19 Hz) but not SNL rats (maximum shift 16.32 ± 7.49 Hz), but also reduced maximal response rates in SNL rats. Intrathecal administration of clonidine, adenosine, and gabapentin failed to facilitate VTA ICSS in SNL rats, and electrical stimulation of the VTA did not alter mechanical allodynia following nerve injury.

Conclusions
The present data suggests that the positive reinforcing effects of commonly abused prescription opioids are diminished following nerve injury. In addition, alleviation of mechanical allodynia with nonopioid analgesics does not appear to stimulate limbic dopamine pathways originating from the VTA in SNL rats.
A 18F-fluorodeoxyglucose MicroPET Imaging Study to Assess Changes in Brain Glucose Metabolism in a Rat Model of Surgery-induced Latent Pain Sensitization
Authors: Romero Asunción , Rojas Santiago , Cabañero David , Gispert Juan D. , Herance José R. , Campillo Ana , Puig Margarita M. 
Published: October 2011

Background
Neuroplastic changes involved in latent pain sensitization after surgery are poorly defined. We assessed temporal changes in glucose brain metabolism in a postoperative rat model using positron emission tomography. We also investigated brain metabolism after naloxone administration.

Methods
Rats were given remifentanil anesthetic and underwent a plantar incision, with 1 mg/kg of (-)-naloxone subcutaneously administered on postoperative days 20 and 21. Using the von Frey test, mechanical thresholds were measured pre- and postoperatively at different time points in awake animals during F-fluorodeoxyglucose (F-FDG) uptake. Brain images were also obtained the day before mechanical testing, using a positron emission tomography R4 scanner (Concorde Microsystems, Siemens, Knoxville, TN). Differences in brain activity were assessed utilizing a statistical parametric mapping.

Results
Surgery induced minor changes in F-FDG uptake in the cerebellum, hippocampus, and posterior cortex, which extended to the thalamus, hypothalamus, and brainstem on days 6 and 7. Changes were still present on day 21. Maximal postoperative hypersensitivity was observed on day 2. The administration of (-)-naloxone on day 21 induced significant hypersensitivity, greatly enhancing the effect on F-FDG uptake. In sham-operated rats, naloxone induced changes limited to the striatum and the cerebellum. Nonnociceptive stimulation with von Frey filaments had no effect on F-FDG uptake.

Conclusions
Surgery, remifentanil, and their combination induced long-lasting and significant metabolic changes in the pain brain matrix, with a positive correlation with hypersensitivity after naloxone. Changes in brain F-FDG precipitated by naloxone suggest that surgery under remifentanil anesthetic induces the greatest neuroplastic brain adaptations in opioid-related pathways involved in nociceptive processing and long-lasting pain sensitization.
Interactions between Nitrous Oxide and Tissue Plasminogen Activator in a Rat Model of Thromboembolic Stroke
Authors: Haelewyn Benoît , David Hélène N. , Colloc'h Nathalie , Colomb Denis G. , Risso Jean-Jacques , Abraini Jacques H. 
Published: October 2011

Background
Preclinical evidence in rodents has suggested that inert gases, such as xenon or nitrous oxide, may be promising neuroprotective agents for treating acute ischemic stroke. This has led to many thinking that clinical trials could be initiated in the near future. However, a recent study has shown that xenon interacts with tissue-type plasminogen activator (tPA), a well-recognized approved therapy of acute ischemic stroke. Although intraischemic xenon inhibits tPA-induced thrombolysis and subsequent reduction of brain damage, postischemic xenon virtually suppresses both ischemic brain damage and tPA-induced brain hemorrhages and disruption of the blood-brain barrier. The authors investigated whether nitrous oxide could also interact with tPA.

Methods
The authors performed molecular modeling of nitrous oxide binding on tPA, characterized the concentration-dependent effects of nitrous oxide on tPA enzymatic and thrombolytic activity in vitro, and investigated the effects of intraischemic and postischemic nitrous oxide in a rat model of thromboembolic acute ischemic stroke.

Results
The authors demonstrate nitrous oxide is a tPA inhibitor, intraischemic nitrous oxide dose-dependently inhibits tPA-induced thrombolysis and subsequent reduction of ischemic brain damage, and postischemic nitrous oxide reduces ischemic brain damage, but in contrast with xenon, it increases brain hemorrhages and disruption of the blood-brain barrier.

Conclusions
In contrast with previous studies using mechanical acute stroke models, these data obtained in a clinically relevant rat model of thromboembolic stroke indicate that nitrous oxide should not be considered a good candidate agent for treating acute ischemic stroke compared with xenon.
TASK Channel Deletion Reduces Sensitivity to Local Anesthetic-induced Seizures
Authors: Du Guizhi , Chen Xiangdong , Todorovic Marko S. , Shu Shaofang , Kapur Jaideep , Bayliss Douglas A. 
Published: October 2011

Background
Local anesthetics (LAs) are typically used for regional anesthesia but can be given systemically to mitigate postoperative pain, supplement general anesthesia, or prevent cardiac arrhythmias. However, systemic application or inadvertent intravenous injection can be associated with substantial toxicity, including seizure induction. The molecular basis for this toxic action remains unclear.

Methods
We characterized inhibition by different LAs of homomeric and heteromeric K channels containing TASK-1 (K2P3.1, KCNK3) and TASK-3 (K2P9.1, KCNK9) subunits in a mammalian expression system. In addition, we used TASK-1/TASK-3 knockout mice to test the possibility that TASK channels contribute to LA-evoked seizures.

Results
LAs inhibited homomeric and heteromeric TASK channels in a range relevant for seizure induction; channels containing TASK-1 subunits were most sensitive and IC₅₀ values indicated a rank order potency of bupivacaine &gt; ropivacaine &gt; lidocaine. LAs induced tonic-clonic seizures in mice with the same rank order potency, but higher LA doses were required to evoke seizures in TASK knockout mice. For bupivacaine, which produced the longest seizure times, seizure duration was significantly shorter in TASK knockout mice; bupivacaine-induced seizures were associated with an increase in electroencephalogram power at frequencies less than 5 Hz in both wild-type and TASK knockout mice.

Conclusions
These data suggest that increased neuronal excitability associated with TASK channel inhibition by LAs contributes to seizure induction. Because all LAs were capable of evoking seizures in TASK channel deleted mice, albeit at higher doses, the results imply that other molecular targets must also be involved in this toxic action.
Clinical and Manometric Characteristics of Allgrove Syndrome
Authors: Alhussaini Bakr , Gottrand Frédéric , Goutet Jean‐Michel , Scaillon Michèle , Michaud Laurent , Spyckerelle Claire , Viola Sheila , Lamblin Marie‐Dominique 
Published: October 2011

ABSTRACTObjective:The association of adrenocorticotropic hormone (ACTH) insensitivity with achalasia and alacrimia (Allgrove syndrome, 3A) constitutes a rare multisystem disorder. Its evolution is not well known. The aim of this study was to describe clinical and esophageal manometric characteristics and outcomes in Allgrove syndrome.Patients and Methods:This multicenter retrospective study compared clinical and manometric characteristics at diagnosis and on follow‐up of 9 children presenting with 3A (mean age at diagnosis 7.1 years) with those of 9 children with idiopathic achalasia (IA) (mean age at diagnosis 8.3 years).Results:At the time of diagnosis, 3 children with 3A presented with no digestive or respiratory signs because they were identified during a family screening; 1 remained asymptomatic 8 years later. ACTH levels were high in patients with 3A. All of the patients with IA were symptomatic at diagnosis. No significant difference was observed when comparing any of the manometric parameters of the first esophageal manometry of 3A with those of IA. Seven children with 3A were operated on using the Heller procedure, completed by pneumatic esophageal dilation in 2 of these 7. One patient with 3A was treated only by nifedipine. Failure of treatment was observed in 3 children with 3A and 1 child with IA, partial success in 4 with 3A and 1 with IA, and total success in 2 with 3A and 7 with IA (P < 0.03). Control manometry showed that in the 3A group, partial success after surgery was always associated with abnormally low or normal lower esophageal sphincter (LES) pressure, whereas failure after surgery was associated with high LES pressure.Conclusions:Our data showed that 3A presented a more severe course than IA despite presymptomatic diagnosis in cases of family screening. The high LES pressure noted in some patients with 3A is suggestive of a peculiar pattern in 3A affecting the LES and the lower part of the esophagus.
From the Tongue to the Gut
Authors: Negri Rossella , Morini Gabriella , Greco Luigi 
Published: October 2011

ABSTRACTThe physiology of human taste experienced an unprecedented expansion of knowledge brought forward by modern genetics and molecular biology. In the last 10 years, the cellular organization of taste receptors from taste buds distributed in the various papillae of the tongue and the soft palate was enlightened. This molecular revolution rapidly expanded over and above the tongue because several papers reporting the presence of taste receptors in nongustatory tissues (eg, gut, brain) appeared. Hence, the issue of perception of food molecules is no longer confined to the field of nutrition and food preferences, but is rapidly expanding to gastrointestinal (GI) function and, possibly, to gut dysfunction. In children, functional GI diseases are strictly correlated to food preference and food aversion and up to now, the tools to address these kinds of problems were basic nutritional requirements, familial good sense, and a lot of patience: blunt tools to face extremely common and disturbing complaints. The fact that taste receptors are expressed down the whole of the intestinal tract is of particular interest because of their possible role in digestive behavior and absorption of nutrients; therefore, recent and future discoveries in this field will make possible the fine‐tuning of new, sharper tools to treat children with functional GI diseases.
Crohn Disease
Authors: Lowe Wendy , Kenwright Diane , Wyeth John , Blair Nikki 
Published: October 2011

ABSTRACTBackground and Aim:Crohn disease (CD) presents a range of physical, social, and psychological challenges, and can adversely affect the quality of life of those affected by it. The present study aimed to investigate the health‐related quality of life of paediatric patients with CD in the Wellington region. Measuring health‐related quality of life assists with resource allocation decisions and assesses various forms of interventions.Methods:Patients ages 9 to 18 years with CD in the Wellington region were assessed using the IMPACT‐III inflammatory bowel disease–specific questionnaire (n = 16). Eight participants filled it out and returned it by post; the remaining 8 filled it out in a meeting with the researcher and then underwent cognitive debriefing as part of a cross‐cultural adaptation of the questionnaire.Results:Of a maximum possible value of 175, the total health‐related quality of life score had a mean value of 119.2 (standard deviation 30.7). Using Spearman rank correlation analysis, significant findings included a positive correlation between disease duration and quality of life (ρ = 0.534, sig. <0.05) and a negative correlation between disease activity and quality of life (ρ = −0.596, sig. <0.05). Qualitative information included difficulties in coping with long‐term and unpleasant treatments and feelings of isolation.Conclusions:Children with Crohn disease in the Wellington region may benefit from age‐specific social and psychological support. Because there is limited information on quality of life in young patients with CD in New Zealand, the results of the present study may be used as baseline data for future studies.
Aerophagia Among Sri Lankan Schoolchildren
Authors: Devanarayana Niranga M. , Rajindrajith Shaman 
Published: October 2011

ABSTRACTObjective:Aerophagia is a functional gastrointestinal disorder characterised by repetitive air swallowing, abdominal distension, belching, and flatulence. In severe cases, it can lead to pneumoperitonium, volvulus of the colon, and intestinal perforation. Little is known about the epidemiology and clinical profile of affected children. The main objective of the present study was to assess the epidemiology of aerophagia in 10‐ to 16‐year‐olds in Sri Lanka.Methods:A school‐based cross‐sectional survey was conducted in 8 randomly selected schools in 4 randomly selected provinces in Sri Lanka. Data were collected using a pretested, self‐administered questionnaire, which was distributed in an examination setting and collected on the same day. Trained research assistants were present during completion of the questionnaire, for any required clarification. Aerophagia was diagnosed using the Rome III criteria.Results:In the present study, aerophagia was seen in 163 (7.5%) of the 2163 children evaluated. The prevalence was higher in older children (10.5% in 15‐year‐olds) and no sex difference was observed (boys 8.2% vs girls 6.8%, P > 0.05). Intestinal‐related (abdominal pain, nausea, and anorexia) and extraintestinal symptoms (headache, limb pain, sleeping difficulty, photophobia, and lightheadedness) were more prevalent among affected children (P < 0.05). A higher percentage of affected children were found to be exposed to stressful events when compared with controls (P < 0.05).Conclusions:The present study highlights the high prevalence of aerophagia among Sri Lankan children and adolescents. This condition is more common in those exposed to emotional stress. Intestinal‐related symptoms and extraintestinal somatic symptoms are frequently seen in affected children.
No Relation Between Disease Activity Measured by Multiple Methods and REE in Childhood Crohn Disease
Authors: Wiskin Anthony E. , Wootton Stephen A. , Cornelius Victoria R. , Afzal Nadeem A. , Elia Marinos , Beattie R. Mark 
Published: October 2011

ABSTRACTBackground and Aims:Increased resting energy expenditure (REE) unmatched by dietary intake is implicated as a cause of poor nutrition in childhood inflammatory conditions. Adequate description of disease activity and correction of REE data for body composition are important to reach reliable conclusions about changes in REE associated with disease. The present study aimed to determine the effect of disease activity measured by clinical status, systemic and stool inflammatory markers on REE in children with Crohn disease using appropriate correction for confounding factors.Methods:Sixty children with Crohn disease were recruited from the regional paediatric gastroenterology unit and studied on 1 occasion. REE was measured by indirect calorimetry. Fat‐free mass (FFM) was estimated by skinfold thickness. Disease activity was measured using systemic (C‐reactive protein [CRP], erythrocyte sedimentation rate [ESR]) and faecal markers of inflammation (lactoferrin, calprotectin) and clinical scores (Paediatric Crohn Disease Activity Index).Results:Using a multiple regression model, there was no significant change in REE from active or inactive disease (β = 0.03, P = 0.7) nor from CRP (β = −0.05, P = 0.52), ESR (β = −0.07, P = 0.43), faecal calprotectin (β = −0.07, P = 0.38), and faecal lactoferrin (β = 0.01, P = 0.88). REE/kg FFM0.5 was not associated with the Paediatric Crohn Disease Activity Index (r = 0.1, P = 0.44), CRP (r = −0.3, P = 0.84) or ESR (r = 0.12, P = 0.4), faecal calprotectin (r = 0.04, P = 0.97), or faecal lactoferrin (r = 0.02, P = 0.87).Conclusions:REE corrected for physiologically relevant confounders is not associated with degree of disease activity using clinical tools or systemic and local inflammatory markers, and therefore is an unlikely mechanism for poor nutritional state.
Missense Mutation in the Amino Terminus of Phytochrome A Disrupts the Nuclear Import of the Photoreceptor
Authors: Sokolova Vladyslava , Bindics János , Kircher Stefan , Ádám Éva , Schäfer Eberhard , Nagy Ferenc , Viczián András 
Published: October 2011

AbstractPhytochromes are the red/far-red photoreceptors in higher plants. Among them, phytochrome A (PHYA) is responsible for the far-red high-irradiance response and for the perception of very low amounts of light, initiating the very-low-fluence response. Here, we report a detailed physiological and molecular characterization of the phyA-5 mutant of Arabidopsis (Arabidopsis thaliana), which displays hyposensitivity to continuous low-intensity far-red light and shows reduced very-low-fluence response and high-irradiance response. Red light-induced degradation of the mutant phyA-5 protein appears to be normal, yet higher residual amounts of phyA-5 are detected in seedlings grown under low-intensity far-red light. We show that (1) the phyA-5 mutant harbors a new missense mutation in the PHYA amino-terminal extension domain and that (2) the complex phenotype of the mutant is caused by reduced nuclear import of phyA-5 under low fluences of far-red light. We also demonstrate that impaired nuclear import of phyA-5 is brought about by weakened binding affinity of the mutant photoreceptor to nuclear import facilitators FHY1 (for FAR-RED ELONGATED HYPOCOTYL1) and FHL (for FHY1-LIKE). Finally, we provide evidence that the signaling and degradation kinetics of constitutively nuclear-localized phyA-5 and phyA are identical. Taken together, our data show that aberrant nucleo/cytoplasmic distribution impairs light-induced degradation of this photoreceptor and that the amino-terminal extension domain mediates the formation of the FHY1/FHL/PHYA far-red-absorbing form complex, whereby it plays a role in regulating the nuclear import of phyA.