bluuebunny/crossref_metadata_2025_split huggingface dataset:
GASTROINTESTINAL ENDOCANNABINOID SYSTEM: MULTIFACETED ROLES IN THE HEALTHY AND INFLAMED INTESTINE
Authors: Smid Scott D 
Published: July 2008

SUMMARYThe endogenous cannabinoid (endocannabinoid) system is emerging as a key modulator of intestinal physiology, influencing motility, secretion, epithelial integrity and immune function in the gut, in addition to influencing satiety and emesis.Accumulating evidence suggests that the endocannabinoid system may play a pivotal role in the pathophysiology of gastrointestinal disease, particularly in the light of recent studies demonstrating an effect of endocannabinoids on the development of experimental inflammation and linkages with functional clinical disorders characterized by altered motility.The predominant endocannabinoids, anandamide and 2‐arachidonoylglycerol, not only mediate their effects via two recognized cannabinoid receptor subtypes, namely CB1and CB2, but emerging evidence now shows they are also substrates for cyclo‐oxygenase (COX)‐2, generating a distinct and novel class of prostaglandin ethanolamides (prostamides) and prostaglandin glycerol esters. These compounds are bioactive and may mediate an array of biological effects distinct to those of conventional prostanoids.The effects of prostamides on gastrointestinal motility, secretion, sensation and immune function have not been characterized extensively. Prostamides may play an important role in gastrointestinal inflammation, particularly given the enhanced expression of both COX‐2 and endocannabinoids that occurs in the inflamed gut.Further preclinical studies are needed to determine the therapeutic potential of drugs targeting the endocannabinoid system in functional and inflammatory gut disorders, to assist with the determination of feasibility for clinical translation.
MECHANISMS OF FATIGUE INDUCED BY ISOMETRIC CONTRACTIONS IN EXERCISING HUMANS AND IN MOUSE ISOLATED SINGLE MUSCLE FIBRES
Authors: Place Nicolas , Bruton Joseph D , Westerblad Håkan 
Published: July 2008

SUMMARY

Muscle fatigue (i.e. the decrease in muscle performance during exercise) has been studied extensively using a variety of experimental paradigms, from mouse to human, from single cell to whole‐body exercise. Given the disparity of models used to characterize muscle fatigue, it can be difficult to establish whether the results of basic in vitro studies are applicable to exercise in humans.
In the present brief review, our attempt is to relate neuromuscular alterations caused by repeated or sustained isometric contraction in humans to changes in excitation–contraction (E‐C) coupling observed in intact single muscle fibres, where force and the free myoplasmic [Ca2+] can be measured.
Accumulated data indicate that impairment of E‐C coupling, most likely located within muscle fibres, accounts for the fatigue‐induced decrease in maximal force in humans, whereas central (neural) fatigue is of greater importance for the inability to continue a sustained low‐intensity contraction. Based on data from intact single muscle fibres, the fatigue‐induced impairment in E‐C coupling involves: (i) a reduced number of active cross‐bridges owing to a decreased release of Ca2+; (ii) a decreased sensitivity of the myofilaments to Ca2+; and/or (iii) a reduced force produced by each active cross‐bridge.
In conclusion, data from single muscle fibre studies can be used to increase our understanding of fatigue mechanisms in some, but not all, types of human exercise. To further increase the understanding of fatigue mechanisms in humans, we propose future studies using in vitro stimulation patterns that are closer to the in vivo situation.
Prenatal restraint stress differentially modifies basal and stimulated dopamine and noradrenaline release in the nucleus accumbens shell: an ‘in vivo’ microdialysis study in adolescent and young adult rats
Authors: Silvagni Alessandra , Barros Virginia G. , Mura Cristina , Antonelli Marta C. , Carboni Ezio 
Published: July 2008

AbstractGestational stress [prenatal stress (PNS)] has been associated with low birth weight, preterm delivery, and higher vulnerability to psychiatric disorders such as schizophrenia, depression or attention deficit with hyperactivity disorder. The alteration of catecholamine transmission has been attributed a major role in the etiology of psychiatric disturbances. We investigated the effect of PNS on basal and stimulated dopamine and noradrenaline output in the nucleus accumbens of freely moving adolescent and young adult rats (30–35 and 60–70 postnatal days respectively) because of the importance of this area in drug dependence and possibly in psychiatric disorders that are treated with drugs that act on dopamine and noradrenaline transmission. Stimulation was obtained with intraperitoneal amphetamine (0.25 mg/kg) or subcutaneous nicotine (0.4 mg/kg). The results showed the following: (i) basal and amphetamine‐stimulated dopamine output in adolescent and adult PNS rats is higher than in controls; (ii) nicotine‐stimulated dopamine output is lower than in controls in adolescent but not in adult PNS rats; (iii) basal noradrenaline output is lower than in controls in adolescent but not in adult PNS rats; (iv) amphetamine‐stimulated noradrenaline output is higher than in controls in adult but not in adolescent PNS rats; (v) nicotine‐stimulated noradrenaline output in PNS rats is higher than in controls, although only in adults. These results show that PNS may produce a complex change in accumbal dopamine and noradrenaline transmission. We discuss the possibility that these changes might be correlated with the development of psychiatric disorders or with an increased vulnerability to drug addiction.
Stromal‐cell‐derived factor 1α /CXCL12 modulates high‐threshold calcium currents in rat substantia nigra
Authors: Guyon A. , Skrzydelski D. , Rovère C. , Apartis E. , Rostène W. , Kitabgi P. , Mélik Parsadaniantz S. , Nahon J. L. 
Published: July 2008

AbstractDopaminergic neurons of the substantia nigra constitutively express the CXCR4 receptor for the chemokine stromal‐cell‐derived factor 1α (CXCL12) but, to date, no direct effect of CXCR4 activation by CXCL12 on membrane conductance of dopaminergic neurons has been demonstrated. We tested the effects of CXCL12 on whole‐cell currents of dopaminergic neurons recorded in patch clamp in substantia nigra slices and showed that CXCL12 (0.01–10 nm) increased the amplitude of total high‐voltage‐activated (HVA) Ca currents through CXCR4 activation. This effect was reversibly reduced by ϖ‐conotoxin‐GVIA, suggesting that CXCL12 acted on N‐type Ca currents, known to be involved in dopamine (DA) release. We therefore investigated the effects of CXCL12 on DA release from cultured dopaminergic neurons from the rat mesencephalon. In basal conditions, CXCL12 alone had no effect on DA release. When neurons were depolarized with KCl (20 mm), and thus when HVA Ca currents were activated, low CXCL12 concentrations (1–50 nm) increased DA release via CXCR4 stimulation. These data strongly suggest that the chemokine CXCL12 can act directly as a neuromodulator of dopaminergic neuronal electrical activity through the modulation of HVA currents.
An attractor hypothesis of obsessive–compulsive disorder
Authors: Rolls Edmund T. , Loh Marco , Deco Gustavo 
Published: July 2008

AbstractWe propose a top‐down approach to the symptoms of obsessive–compulsive disorder (OCD) based on a statistical dynamical framework. An increased depth in the basins of attraction of attractor network states in the brain makes each state too stable, so that it tends to remain locked in that state and can not easily be moved on to another state. We suggest that the different symptoms that may be present in OCD could be related to changes of this type in different brain regions. For example, the difficulty in attentional and cognitive set switching could be related to networks operating in this way in the prefrontal cortex. Repetitive actions and a difficulty in moving to new actions could be related to overstability in networks in the higher order motor, including cingulate areas. In integrate‐and‐fire network simulations, an increase in the N‐methyl‐d‐aspartate (NMDA) and/or α‐amino‐3‐hydroxy‐5‐methyl‐4‐isoxazolepropionic acid (AMPA) receptor conductances, which increases the depth of the attractor basins, increases the stability of attractor networks, and makes them less easily moved on to another state by a new stimulus. Increasing γ‐aminobutyric acid (GABA)‐receptor activated currents can partly reverse this overstability. There is now some evidence for overactivity in glutamate transmitter systems in OCD, and the hypothesis presented here shows how some of the symptoms of OCD could be produced by the increase in the stability of attractor networks that is produced by increased glutamatergic activity.
Pain relief as an opponent process: a psychophysical investigation
Authors: Leknes Siri , Brooks Jonathan C. W. , Wiech Katja , Tracey Irene 
Published: July 2008

AbstractRelief from pain in humans is frequently measured by computing the reduction on an 11‐point pain intensity scale. However, this definition of relief may be insufficient to capture the utility of pain relief for the individual. Based on pain literature and evidence from studies examining relief and reward, it is clear that pain relief is a broad concept comprising several factors, only one of which is pain intensity reduction. According to opponent process theory, all sensations consist of a primary process and a slow ‘opponent process’ of opposite valence, the purpose of which is to reduce the deviation from homeostatic balance. Here, opponent process theory provided a framework to explore the interaction between pain, relief and reward. We devised three psychophysical studies examining the temporal (Experiment I) and magnitude (Experiments I and II) relationships between pain severity and its subsequent relief. In Experiment III, we further manipulated the magnitude and pleasantness of relief experienced by applying innocuous cooling following noxious heat stimulation of capsaicin‐sensitized skin. Results confirmed predictions from opponent process theory and showed that pain intensity reduction was significantly stronger than relief intensity ratings. Furthermore, continuous relief ratings appeared to reflect the speed of pain intensity reduction. Varying pain intensity parametrically confirmed that relief increases with pain intensity. That innocuous cooling following primary hyperalgesia intervention significantly increased the intensity, pleasantness and duration of relief provides further evidence that pain relief encapsulates more than a reduction in pain intensity. Importantly, the high relief pleasantness ratings confirmed the hypothesized link between relief and reward.
The brain‐derived neurotrophic factor receptor TrkB is critical for the acquisition but not expression of conditioned incentive value
Authors: Johnson Alexander W. , Chen Xi , Crombag Hans S. , Zhang Chao , Smith Dani R. , Shokat Kevan M. , Gallagher Michela , Holland Peter C. , Ginty David D. 
Published: July 2008

AbstractStimuli paired with reward acquire incentive properties that are important for many aspects of motivated behavior, such as feeding and drug‐seeking. Here we used a novel chemical–genetic strategy to determine the role of the brain‐derived neurotrophic factor (BDNF) receptor TrkB, known to be critical to many aspects of neural development and plasticity, during acquisition and expression of positive incentive value by a cue paired with food. We assessed that cue’s learned incentive value in a conditioned reinforcement task, in which its ability to reinforce instrumental responding later, in the absence of food itself, was examined. In TrkB F616A knock‐in mice, TrkB kinase activity was suppressed by administering the TrkB inhibitor 1NMPP1 during the period of initial cue incentive learning only (i.e. Pavlovian training), during nose‐poke conditioned reinforcement testing only, during both phases, or during neither phase. All mice acquired cue–food associations as indexed by approach responses. However, TrkB F616A mice that received 1NMPP1 during initial cue incentive learning failed to show conditioned reinforcement of nose‐poking, regardless of their treatment in testing, whereas administration of 1NMMP1 only during the testing phase had no effect. The effects of 1NMPP1 administration were due to inhibition of TrkBF616A, because the performance of wild‐type mice was unaffected by administration of the compound during either phase. These data indicate that BDNF or NT4 signaling through TrkB receptors is required for the acquisition of positive incentive value, but is not needed for the expression of previously acquired incentive value in the reinforcement of instrumental behavior.
Spontaneous discharge characteristic of neurons in the ventromedial nucleus of the rat hypothalamus in vivo
Authors: Sabatier Nancy , Leng Gareth 
Published: July 2008

AbstractThe ventromedial nucleus of the hypothalamus (VMN) is one of the main central regulators of two vital behaviours in rat: feeding behaviour and sexual behaviour. To better understand how these behaviours are regulated in the brain requires assessing how physiological stimuli are encoded by the electrical activity of populations of neurons, but there is still little known about the electrical activity of neurons in the VMN, in particular how it is regulated in vivo. Here, we recorded spontaneous firing activity from single VMN neurons in urethane‐anaesthetized rats in vivo, and characterized their electrophysiological identities. For each of 271 cells, we constructed hazard functions from interspike interval histograms to show how the excitability of the cell changes with time after a spike. We completed the statistical characterization of each cell by analysis of its mean firing rate and coefficient of variation, and features of its interspike interval distribution, including kurtosis and skew (around the mean and around the mode). We thereby identified nine subpopulations of neurons in the VMN, which we named according to the main features of their firing pattern. One of the subpopulations fires very regularly, another almost randomly and another in intermittent clusters of two–three spikes, but perhaps the most interesting subpopulation are ‘oscillatory cells’ whose activity seems to be governed by an extrinsic 3‐Hz rhythm. Whether these electrophysiologically distinct populations are also functionally and neurochemically distinct has now to be tested.
Chronic pain in children in the UK: a survey of pain clinicians and general practitioners
Authors: BHATIA ANUJ , BRENNAN LIAM , ABRAHAMS MARK , GILDER FAY 
Published: July 2008

SummaryBackground:  There is a lack of information about the prevalence, manifestations, and management of chronic pain in children in the UK. We surveyed consultants with an interest in chronic pain management and general practitioners (GPs) in the UK in order to understand their perspective on chronic pain in children.Methods:  We conducted a postal survey of clinicians with an interest in chronic pain management and GPs in the UK. The survey contained questions relating to the following aspects of managing children with chronic pain: (i) clinicians’ training and experience; (ii) available resources; (iii) perceived prevalence, presentation, and referral patterns; (iv) interventions; and (v) outcomes.Results:  472 pain clinicians and 131 GPs were contacted. The response rates were 55% and 61% respectively. Of the respondents, 77% of pain clinicians and 95% of GPs acknowledged a lack of adequate training for managing children with chronic pain. 57% of the pain clinicians and 63% of the GPs reported that the prevalence of chronic pain in children was <5%. In the comments section, 22% of those respondents who frequently manage children with chronic pain reported an increase in the incidence of this problem over the last 5 years. The common chronic pain syndromes in children were reported to be: musculoskeletal and limb pain, recurrent abdominal and pelvic pain, and headache. 15% of the respondents advised that children with chronic pain would be best managed in specialist pediatric centers and 75% opined that majority of children with chronic pain have a fair to good prognosis.Conclusions:  More information is required about prevalence, manifestations and long‐term effects of chronic pain in children in the UK. There is a need for increasing training and resources amongst GPs and pain clinicians for managing chronic pain in the pediatric age group.
Cerebral hemispherectomy in infants and young children
Authors: FLACK SEAN , OJEMANN JEFF , HABERKERN CHARLES 
Published: July 2008

SummaryBackground:  Children with seizure disorders unresponsive to medical management may undergo surgical disconnection of a cerebral hemisphere, or hemispherectomy, in order to reduce or eliminate seizures. Because early cessation of seizures is thought to improve developmental outcomes, infants and young children with intractable seizures are undergoing hemispherectomies with increasing frequency. Previously, these procedures have been noted to be accompanied by severe cardiovascular, pulmonary, neurologic and coagulopathic complications. Newer surgical techniques (i.e. ‘functional’ rather than ‘anatomic’ hemispherectomy) and improved anesthetic management may reduce the perioperative complication rate of this procedure. The aim of this case series was to determine the incidence of major complication of functional hemispherectomy in our institution.Methods:  A retrospective chart review was conducted of all children <3 years of age undergoing functional hemispherectomies for intractable seizures over a 4‐year period at our institution.Results:  Seven children were identified. No serious cardiovascular, pulmonary, neurologic or coagulopathic adverse events occurred. Perioperative blood loss and its sequelae were the most common complication. Postoperative management was generally uncomplicated, although one patient required readmission to the ICU for treatment of diabetes insipidus. All children survived and, at latest follow‐up, all but one remained seizure‐free.Conclusion:  This small case series suggests that improvements in anesthetic and surgical techniques may be associated with a decreased complication rate for infants and small children undergoing seizure surgery than previously reported.
Blood pressure changes associated with sibutramine and weight management – an analysis from the 6‐week lead‐in period of the sibutramine cardiovascular outcomes trial (SCOUT)*
Authors: Sharma A. M. , Caterson I. D. , Coutinho W. , Finer N. , Van Gaal L. , Maggioni A. P. , Torp‐Pedersen C. , Bacher H. P. , Shepherd G. M. , James W. P. T. ,   SCOUT Investigators
Published: July 2008

Objective:  To explore vital sign changes among patient subgroups during the 6‐week lead‐in period of the sibutramine cardiovascular outcomes (SCOUT) trial.Methods:  SCOUT is an ongoing, double‐blind, randomized, placebo‐controlled outcome trial in overweight/obese patients at high risk of a cardiovascular event. During the 6‐week lead‐in period, 10 742 patients received sibutramine and weight management. Vital sign changes were assessed post hoc by initial blood pressure (mmHg) categorized as normal (<130/<85), high‐normal (130 to <140/85 to <90) or hypertensive (≥140/≥90); weight change categories (weight gain/no weight change, >0 to 2.5% weight loss, >2.5 to 5% weight loss and >5% weight loss) and current antihypertensive medication class use (none, one, or two or more). To assess the impact of sibutramine on blood pressure and pulse rate, only patients (N = 10 025) who reported no change in the class of antihypertensive medication used and who did not report an increase in antihypertensive medication use were analysed.Results:  At entry, approximately 50% of patients were hypertensive and 26% were high‐normal. In hypertensive patients, blood pressure changes (mmHg) decreased by median [5th, 95th percentile] of −6.5 systolic [−27.0, 8.0] and −2.0 diastolic [−15.0, 8.0] (p < 0.001). Hypertensive patients with no weight loss or with weight gain had median decreases of −3.5 systolic [−26.0, 10.0] and −1.5 diastolic [−16.0, 9.0] (p < 0.001). Normotensive patients had median increases of 1.5 systolic [−15.0, 19.5] and 1.0 diastolic [−10.5, 13.0] (p < 0.001) attenuated with increasing weight loss. Approximately 43% of patients initially categorized as hypertensive had a lower blood pressure category at end‐point. Concomitant antihypertensive medication classes did not affect blood pressure reductions. Pulse rates were uniformly elevated (median 1–4 bpm, p < 0.001) across blood pressure and weight change categories.Conclusions:  In hypertensive patients (≥140/≥90), blood pressure decreases were observed during 6‐week treatment with sibutramine even when body weight was unchanged. In patients with normal blood pressure (<130/<85), weight loss of >5% induced decreases in systolic blood pressure; otherwise, small increases were observed. Small pulse rate increases were observed regardless of blood pressure or weight change status.
Glycaemic separation and risk factor control in the Veterans Affairs Diabetes Trial: an interim report
Authors: Abraira C. , Duckworth W. C. , Moritz T. 
Published: July 2008

Objective:  The Veterans Affairs Diabetes Trial (VADT) will assess the effect of intensive (INT) vs improved standard (STD) glycaemic control on major cardiovascular (CV) events, treating other risk factors equally in both arms. Four‐year results of main metabolic parameters are presented.Research design and methods:  VADT is a 7.5 years prospective randomized study of 1791 patients, 20 centres, of men and women of age 60.5 ± 8.7 years, diagnosed for 11.5 ± 7.5 years. Their body mass index (BMI) at baseline was 31 ± 4 kg/m2 and mean A1C 9.4 ± 1.5% after maximum dose of oral agents or insulin treatment. Step treatment consists of glimepiride or metformin, rosiglitazone, insulin and other agents; A1C goals are 8–9% in STD and <6% in INT. Lifestyle, blood pressure and lipids are treated uniformly in both arms.Results:  A1C improved in both arms. INT kept median A1C <7% all years, A1C separation is 1.5–1.7%. From year 1 to 4, mean blood pressure is <129/74 mmHg, similar throughout. Median LDL‐C was <97 mg/dl by year 1 and triglycerides 150 or less by 2 years. Triglycerides were lower in INT (12–16 mg/dl; p < 0.01). By 4 years, 88% are on lipid‐lowering agents and 93% are on antiplatelet/anticoagulant agents. BMI is higher in INT every year (0.9–1.6 kg/m2; p < 0.01).Conclusion:  VADT is maintaining the expected A1C in both STD and INT, and LDL‐C, triglycerides and blood pressure are at target. The trial is continuing to June 2008. It will be the first long‐term completed type 2 diabetes study of the role of glycaemia on CV disease with modern treatments.