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Central Mechanisms (central + mechanism)
Selected AbstractsTHE CONTRIBUTION OF AN HOURGLASS TIMER TO THE EVOLUTION OF PHOTOPERIODIC RESPONSE IN THE PITCHER-PLANT MOSQUITO, WYEOMYIA SMITHIIEVOLUTION, Issue 10 2003W. E. Bradshaw Abstract Photoperiodism, the ability to assess the length of day or night, enables a diverse array of plants, birds, mammals, and arthropods to organize their development and reproduction in concert with the changing seasons in temperate climatic zones. For more than 60 years, the mechanism controlling photoperiodic response has been debated. Photoperiodism may be a simple interval timer, that is, an hourglasslike mechanism that literally measures the length of day or night or, alternatively, may be an overt expression of an underlying circadian oscillator. Herein, we test experimentally whether the rhythmic response in Wyeomyia smithii indicates a causal, necessary relationship between circadian rhythmicity and the evolutionary modification of photoperiodic response over the climatic gradient of North America, or may be explained by a simple interval timer. We show that a day-interval timer is sufficient to predict the photoperiodic response of W. smithii over this broad geographic range and conclude that rhythmic responses observed in classical circadian-based experiments alone cannot be used to infer a causal role for circadian rhythmicity in the evolution of photoperiodic time measurement. More importantly, we argue that the pursuit of circadian rhyth-micity as the central mechanism that measures the duration of night or day has distracted researchers from consideration of the interval-timing processes that may actually be the target of natural selection linking internal photoperiodic time measurement to the external seasonal environment. [source] Conservation of DNA methylation in dipteran insectsINSECT MOLECULAR BIOLOGY, Issue 2 2004J. Marhold Abstract DNA methylation is a central mechanism of epigenetic regulation. Whereas vertebrate DNA methylation requires at least four different DNA methyltransferases, Drosophila melanogaster only utilizes a single, Dnmt2-like enzyme. This profound difference has raised the question of the evolutionary significance of the Drosophila methylation system. We have now identified Dnmt2-like open reading frames in the genome sequences of Drosophila pseudoobscura and Anopheles gambiae. These genes represent the only candidate DNA methyltransferases in their respective genomes. Consistent with a catalytic activity of Dnmt2 proteins, we could also demonstrate low but significant levels of DNA methylation in genomic DNA from these species. Lastly, we were also able to detect highly conserved Dnmt2-like open reading frames and concomitant DNA methylation in several additional Drosophila species, which suggests that Dnmt2-mediated DNA methylation has been conserved over a considerable evolutionary distance. [source] An integrative formulation-based cognitive treatment of bipolar disorders: Application and illustrationJOURNAL OF CLINICAL PSYCHOLOGY, Issue 5 2007Warren Mansell An integrative cognitive treatment for mood swings and bipolar disorders is summarized and then illustrated in a clinical case. In essence, it is proposed that multiple, extreme, and conflicting beliefs about changes in internal state, and the reciprocal impact of these beliefs on behavior, physiology, and the social environment, constitute the central mechanism that maintain and escalate bipolar symptoms. Using a case illustration with examples of therapy dialogue, several key aspects of cognitive-behavioral therapy are explained, including the assessment of mood, beliefs, distressing imagery, and recurrent thinking; case formulation; therapeutic techniques; self-awareness; interpersonal factors during therapy; and systemic issues. © 2007 Wiley Periodicals, Inc. J Clin Psychol: In Session 63: 447,461, 2007. [source] CAT4 (Cable Actuated Truss,4 Degrees of Freedom): A Novel 4 DOF Cable Actuated Parallel ManipulatorJOURNAL OF FIELD ROBOTICS (FORMERLY JOURNAL OF ROBOTIC SYSTEMS), Issue 12 2002Craig Kossowski The CAT4 (Cable Actuated Truss,4 degrees of freedom) robot is a novel, passively jointed, parallel robot utilizing six control cables for actuation. The architecture has been under development at the Queen's University Robotics Laboratory. The robot utilizes a passive jointed linkage with 18 revolute joints to constrain the end effector motion and provide the desired structural stability, restricting the end effector to 3 translational degrees of freedom (DOF) and 1 DOF for end effector pitch. This central mechanism together with winched cable actuation gives a number of important benefits for applications where the advantages of a parallel robot are required in conjunction with light weight. Six electric motor driven winches control the length of the cable actuators that extend from the top frame to points on the end effector raft and jointed linkage to create a stiff, but lightweight, actuated robot. Simulation work on the robot is presented giving the kinematics, including a computational estimate of the workspace for a specific configuration. Results of computational simulation of the motion of the manipulator and a discussion of the advantages and potential difficulties are also presented. © 2002 Wiley Periodicals, Inc. [source] Use of volumetric computerized tomography as a primary outcome measure to evaluate drug efficacy in the prevention of peri-prosthetic osteolysis: A 1-year clinical pilot of etanercept vs. placeboJOURNAL OF ORTHOPAEDIC RESEARCH, Issue 6 2003Edward M. Schwarz Although total hip replacement (THR) is amongst the most successful and beneficial medical procedures to date, long-term outcomes continue to suffer from aseptic loosening secondary to peri-prosthetic osteolysis. Extensive research over the last two decades has elucidated a central mechanism for osteolysis in which wear debris generated from the implant stimulates inflammatory cells to promote osteoclastogenesis and bone resorption. The cytokine tumor necrosis factor alpha (TNF,) has been demonstrated to be central to this process and is considered to be a leading target for intervention. Unfortunately, even though FDA approved TNF antagonists are available (etanercept), currently there are no reliable outcome measures that can be used to evaluate the efficacy of a drug to prevent peri-prosthetic osteolysis. To the end of developing an effective outcome measure, we evaluated the progression of lesion size in 20 patients with established peri-acetabular osteolysis (mean = 29.99 cm3, range = 2.9,92.7 cm3) of an uncemented primary THR over 1-year, using a novel volumetric computer tomography (3D-CT) technique. We also evaluated polyethylene wear, urine N-telopeptides and functional assessments (WOMAC, SF-36 and Harris Hip Score) for comparison. At the time of entry into the study baseline CT scans were obtained and the patients were randomized to etanercept (25 mg s.q., twice/week) and placebo in a double-blinded fashion. CT scans, urine and functional assessments were also obtained at 6 and 12 months. No serious adverse drug related events were reported, but one patient had to have revision surgery before completion of the study due to aseptic loosening. No remarkable differences between the groups were observed. However, the study was not powered to see significant drug effects. 3D-CT data from the 19 patients was used to determine the mean increase in lesion size over 48 weeks, which was 3.19 cm3 (p < 0.0013). Analysis of the urine N-telopeptides and functional assessment data failed to identify a significant correlation with wear or osteolysis. In conclusion, volumetric CT was able to measure progression of osteolysis over the course of a year, thus providing a technology that could be used in therapeutic trials. Using the data from this pilot we provide a model power calculation for such a trial. © 2003 Orthopaedic Research Society. Published by Elsevier Science Ltd. All rights reserved. [source] Liver carcinogen aflatoxin B1 as an inducer of mitotic recombination in a human cell lineMOLECULAR CARCINOGENESIS, Issue 3 2001Peter Markus Stettler Abstract The mycotoxin aflatoxin B1 (AFB1) is one of the most potent rodent and human liver carcinogens. Upon cytochrome P450,specific metabolism, it induces mutations as well as mitotic recombination events in in vitro systems. We have found that in the lower eukaryote yeast, the recombinagenic activity of AFB1 surpasses its mutagenic activity, and we speculated on possible consequences in terms of the mechanism of liver carcinogenesis. In this study we investigated whether the recombinagenic activity of AFB1 also would be identified in human cells. To address this question, we followed the fate of a heterozygous thymidine kinase (tk) allele in the human lymphoblastoid cell line TK6 upon exposure to AFB1. Individual mutants that had lost tk activity were subjected to loss of heterozygosity analysis of the tk locus and its flanking markers. Fluorescence in situ hybridization analysis on chromosome 17 also was performed. In parallel, a similar analysis was performed on TK6 cells exposed to the alkylating agent N -nitrosomethylurea, a well-known classic point mutagen. Our analysis showed a difference in the molecular mechanism leading to inactivation of the tk allele upon exposure to these two mutagens. In AFB1 -exposed cells the fraction of recombination-derived mutants predominated, whereas in N -nitrosomethylurea,exposed cells the fraction of point mutants was higher. Thus, the recombinagenic activity of AFB1 previously identified in a lower eukaryote also was found in the human cell line TK6. Our data support the hypothesis that mitotic recombination represents a central mechanism of action in AFB1 -induced liver carcinogenesis. © 2001 Wiley-Liss, Inc. [source] Transforming growth factor-, and Smad signalling in kidney diseasesNEPHROLOGY, Issue 1 2005Review Article SUMMARY: Extensive studies have demonstrated that transforming growth factor-beta (TGF-,) plays an important role in the progression of renal diseases. TGF-, exerts its biological functions mainly through its downstream signalling molecules, Smad2 and Smad3. It is now clear that Smad3 is critical for TGF-,'s pro-fibrotic effect, whereas the functions of Smad2 in fibrosis in response to TGF-, still need to be determined. Our recent studies have demonstrated that Smad signalling is also a critical pathway for renal fibrosis induced by other pro-fibrotic factors, such as angiotensin II and advanced glycation end products (AGE). These pro-fibrotic factors can activate Smads directly and independently of TGF-,. They can also cause renal fibrosis via the ERK/p38 MAP kinase,Smad signalling cross-talk pathway. In contrast, blockade of Smad2/3 activation by overexpression of an inhibitory Smad7 prevents collagen matrix production induced by TGF-,, angiotensin II, high glucose and AGE and attenuates renal fibrosis in various animal models including rat obstructive kidney, remnant kidney and diabetic kidney diseases. Results from these studies indicate that Smad signalling is a key and final common pathway of renal fibrosis. In addition, TGF-, has anti-inflammatory and immune-regulatory properties. Our most recent studies demonstrated that TGF-, transgenic mice are protected against renal inflammation in mouse obstructive and diabetic models. Upregulation of renal Smad7, thereby blocking NF.,B activation via induction of I,B,, is a central mechanism by which TGF-, inhibits renal inflammation. In conclusion, TGF-, signals through Smad2/3 to mediate renal fibrosis, whereas induction of Smad7 inhibits renal fibrosis and inflammation. Thus, targeting Smad signalling by overexpression of Smad7 may have great therapeutic potential for kidney diseases. [source] Donitriptan, but not sumatriptan, inhibits capsaicin-induced canine external carotid vasodilatation via 5-HT1B rather than 5-HT1D receptorsBRITISH JOURNAL OF PHARMACOLOGY, Issue 1 2006E Muñoz-Islas Background and purpose: It has been suggested that during a migraine attack capsaicin-sensitive trigeminal sensory nerves release calcitonin gene-related peptide (CGRP), resulting in cranial vasodilatation and central nociception; hence, trigeminal inhibition may prevent this vasodilatation and abort migraine headache. This study investigated the effects of the agonists sumatriptan (5-HT1B/1D water-soluble), donitriptan (5-HT1B/1D lipid-soluble), PNU-142633 (5-HT1D water-soluble) and PNU-109291 (5-HT1D lipid-soluble) on vasodilator responses to capsaicin, , -CGRP and acetylcholine in dog external carotid artery. Experimental approach: 59 vagosympathectomized dogs were anaesthetized with sodium pentobarbitone. Blood pressure and heart rate were recorded with a pressure transducer, connected to a cannula inserted into a femoral artery. A precalibrated flow probe was placed around the common carotid artery, with ligation of the internal carotid and occipital branches, and connected to an ultrasonic flowmeter. The thyroid artery was cannulated for infusion of agonists. Key results: Intracarotid infusions of capsaicin, , -CGRP and acetylcholine dose-dependently increased blood flow through the carotid artery. These responses remained unaffected after intravenous (i.v.) infusions of sumatriptan, PNU-142633, PNU-109291 or physiological saline; in contrast, donitriptan significantly attenuated the vasodilator responses to capsaicin, but not those to , -CGRP or acetylcholine. Only sumatriptan and donitriptan dose-dependently decreased the carotid blood flow. Interestingly, i.v. administration of the antagonist, SB224289 (5-HT1B), but not of BRL15572 (5-HT1D), abolished the inhibition by donitriptan. Conclusions and implications: Our results suggest that the inhibition produced by donitriptan of capsaicin-induced external carotid vasodilatation is mainly mediated by 5-HT1B, rather than 5-HT1D, receptors, probably by a central mechanism. British Journal of Pharmacology (2006) 149, 82,91. doi:10.1038/sj.bjp.0706839 [source] Gastrointestinal motility and the brain-gut axisDIGESTIVE ENDOSCOPY, Issue 2 2003TADASHI ISHIGUCHI The role of the brain-gut axis in gastrointestinal motility is discussed according to the specific organs of the gastrointestinal tract. Not only clinical studies but basic animal research are reviewed. Although the mechanism of functional gut disorders remains to be clarified, recent data suggest that there is evidence that the brain-gut axis has significant effects on gastrointestinal motility. The major role of endoscopy in the diagnosis of functional gastrointestinal disorders is to exclude organic gastrointestinal disorders. In the esophagus, the lower esophageal sphincter and a gamma-aminobutyric acid B mechanism are considered to play important roles in gastroesophageal reflux disease. In the stomach, corticotropin-releasing factor, neuropeptide Y and other substances might be involved in the pathogenesis of non-ulcer dyspepsia. In the small intestine, corticotropin-releasing factor, gamma-aminobutyric acid B and other substances are considered to modulate intestinal transit via central mechanisms. In the colon, it is known that psychiatric factors are related to the onset and clinical course of irritable bowel syndrome. Serotonin, corticotropin-releasing factor, gamma-aminobutyric acid, orphanin FQ and neuropeptide Y have been reported as putative neurotransmitters. More efforts in basic science studies and animal and human studies of physiology of the gastointestinal tract are still required. These efforts will elucidate further mechanisms to clarify the etiology of motility disorders and encourage the investigation of new therapies in this field. [source] Association between Endothelial Function and Chronotropic Incompetence in Subjects with Chronic Heart Failure Receiving Optimal Medical TherapyECHOCARDIOGRAPHY, Issue 3 2010M.D., Timothy J. Vittorio M.S. Objective: Impairment of flow-mediated, endothelium-dependent vasodilatation (FMD) of the brachial artery identifies peripheral endothelial dysfunction in subjects with chronic congestive heart failure (CHF) and is associated with increased morbidity and mortality. To further elucidate the interaction of peripheral and central mechanisms in the syndrome of CHF, we examined the association between endothelial function and chronotropic incompetence, an emerging prognostic marker in CHF. Methods: Thirty subjects with stable New York Heart Association (NYHA) functional class II,III CHF were studied. A vascular ultrasound study was performed to measure brachial artery FMD. The percentage of age-adjusted maximal predicted heart rate (MPHR) reached during cardiopulmonary exercise tolerance testing (CPETT) was used to assess the degree of chronotropic competence. All patients received ACE inhibitors and ,-adrenoceptor blockers. Results: Brachial artery FMD averaged 1.3 ± 2.4% and age-adjusted % MPHR 74.1 ± 11.7%. FMD correlated with % MPHR among all patients (r = 0.60, P = 0.01). FMD and resting heart rate (RHR) did not significantly correlate (r = 0.13, P = 0.55). Conclusions: FMD, a measure of peripheral endothelial dysfunction, and % MPHR, a central determinant of cardiac output, are moderately correlated in heart failure patients receiving optimal medical therapy. Whether a cause-effect relationship underlies this association remains to be investigated. (Echocardiography 2010;27:294-299) [source] Effects of amphetamine on salivary secretionEUROPEAN JOURNAL OF ORAL SCIENCES, Issue 3 2009Bengt Götrick Amphetamine induces xerogenic effects, but its mechanism of action and xerogenic potency are unknown. In the current in vivo study on the rat parotid gland, the effects of amphetamine on reflex-evoked and acetylcholine-evoked salivation were examined in the absence and presence of adrenergic and dopaminergic antagonists. Under anaesthesia, amphetamine increased the secretion of salivary fluid and the amount of protein therein in response to acetylcholine. Phentolamine abolished the increase in salivary flow and had no effect on the salivary protein concentration, whereas propranolol only reduced the salivary protein concentration. Reflex activation of the secretion evoked a well-maintained level of secretion that was reduced by amphetamine [50% inhibitory dose (ID50) 1.9 ± 0.1 mg kg,1 intravenously); the salivary protein concentration was increased in the presence of amphetamine. Phentolamine and haloperidol reduced the amphetamine-inhibitory effect on the reflex-evoked fluid response, whereas propranolol had no effect on the fluid response. The xerogenic effect of amphetamine is mainly exerted by central mechanisms involving ,-adrenoceptors, while, indirectly, amphetamine causes secretion of protein by inducing the release of noradrenaline from glandular nerve terminals. [source] The Discursive Origins of a DoctrineFOREIGN POLICY ANALYSIS, Issue 3 2007George W. Bush, Identity, Norms, Securitization under Harry S. Truman Previous research on the Bush Doctrine has tended to largely focus on its contents, more or less automatically assuming 9/11 to be the sole factor for the doctrine coming into existence. This article argues, on the contrary, that such a focus gives us an insufficient understanding of U.S. foreign policy since it underproblematizes how a doctrine comes into existence and why it takes a particular form. Instead, this article analyzes the political and societal discourses that are inextricably interlinked to doctrines, exploring how actors' views both are reflections of discourses and also serve to reinforce them. Focusing on specific discursive mechanisms,securitization process, settled norms, and identity constructions,facilitates the explanation of both the origins of a doctrine and its contents. This article analyzes the discourses of the 3-month time period preceding the Bush and the Truman Doctrines. Comparing the Bush Doctrine with the Truman Doctrine, this article finds that the discourses of these two cases are very similar. In both cases the same central mechanisms are prominent, constructing a certain discursive linkage between the two. Finally, this article argues that a constructivist approach that employs a structured design is able to present more persuasive arguments than the traditional inductive-style narrative favored by many constructivist studies. [source] Ontogeny of the Enhanced Fetal-Ethanol-Induced Behavioral and Neurophysiologic Olfactory Response to Ethanol OdorALCOHOLISM, Issue 2 2010Amber M. Eade Background:, Studies report a fundamental relationship between chemosensory function and the responsiveness to ethanol, its component orosensory qualities, and its odor as a consequence of fetal ethanol exposure. Regarding odor, fetal exposed rats display enhanced olfactory neural and behavioral responses to ethanol odor at postnatal (P) day 15. Although these consequences are absent in adults (P90), the behavioral effect has been shown to persist into adolescence (P37). Given the developmental timing of these observations, we explored the decay in the response to ethanol odor by examining ages between P37 and young adulthood. Moreover, we sought to determine whether the P15 neurophysiologic effect persists, at least, to P40. Methods:, Behavioral and olfactory epithelial (OE) responses of fetal ethanol exposed and control rats were tested at P40, P50, P60, or P70. Whole-body plethysmography was used to quantify each animal's innate behavioral response to ethanol odor. We then mapped the odorant-induced activity across the OE in response to different odorants, including ethanol, using optical recording methods. Results:, Relative to controls, ethanol exposed animals showed an enhanced behavioral response to ethanol odor that, while significant at each age, decreased in magnitude. These results, in conjunction with previous findings, permitted the development of an ontologic odor response model of fetal exposure. The fitted model exemplifies that odor-mediated effects exist at birth, peak in adolescence and then decline, becoming absent by P90. There was no evidence of an effect on the odor response of the OE at any age tested. Conclusions:, Fetal exposure yields an enhanced behavioral response to ethanol odor that peaks in adolescence and wanes through young adulthood. This occurs absent an enhanced response of the OE. This latter finding suggests that by P40 the OE returns to an ethanol "neutral" status and that central mechanisms, such as ethanol-induced alterations in olfactory bulb circuitry, underlie the enhanced behavioral response. Our study provides a more comprehensive understanding of the ontogeny of fetal-ethanol-induced olfactory functional plasticity and the behavioral response to ethanol odor. [source] Review article: a critical view on impaired accommodation as therapeutic target for functional dyspepsiaALIMENTARY PHARMACOLOGY & THERAPEUTICS, Issue 11 2006B. D. J. VAN DEN ELZEN Summary Several important pathophysiological mechanisms have been identified in functional dyspepsia, however a complete understanding of these mechanisms and beneficial therapeutic strategies are still lacking. Based on the currently available literature we aimed at providing a critical view on one of these pathophysiological mechanisms, impaired accommodation. Although impaired gastric accommodation is identified as a major pathophysiological mechanism, the clinical evidence supporting its role as an important therapeutic target is currently still lacking. Treatment with fundic relaxant drugs has shown conflicting results and has been rather disappointing in general. These negative findings could be explained by the fact that impaired fundic accommodation is part of a more complex disorder involving other regions of the proximal gut or by the increasing insight that central mechanisms may play an important role. Future studies of impaired accommodation should take these considerations into account. [source] Myoclonus of the scapula after acute long thoracic nerve lesion: A case report,MOVEMENT DISORDERS, Issue 1 2006Filippo Camerota MD Abstract We describe a patient who presented myoclonus in the left scapula 3 months after a traumatic lesion of the left long thoracic nerve. Myoclonic activity was recorded as pseudorhythmic electromyographic bursts repeated at a frequency of 2 to 4 Hz, each lasting between 100 and 200 msec, in the left serratus,dorsalis muscle region, trapezius, and deltoid muscles. A combination of peripheral and central mechanisms may have induced the myoclonus in this case. © 2005 Movement Disorder Society [source] Gene duplications and the time thereafter , examples from plant secondary metabolismPLANT BIOLOGY, Issue 4 2010D. Ober Abstract Gene duplications are regarded as one of the central mechanisms for the origin of new genes. Recent studies in plant secondary metabolism have provided several examples of genes that originated by duplication with successive diversification. In this review, the mechanisms of gene duplication are explained and several models discussed that suggest the way that gene duplicates develop into genes with new functions. Signatures of gene duplication and diversification processes are discussed using the biosynthesis of benzoxazinones and of pyrrolizidine alkaloids as examples. [source] Synergistic interactions between airway afferent nerve subtypes regulating the cough reflex in guinea-pigsTHE JOURNAL OF PHYSIOLOGY, Issue 2 2005Stuart B. Mazzone Cough initiated from the trachea and larynx in anaesthetized guinea-pigs is mediated by capsaicin-insensitive, mechanically sensitive vagal afferent neurones. Tachykinin-containing, capsaicin-sensitive C-fibres also innervate the airways and have been implicated in the cough reflex. Capsaicin-sensitive nerves act centrally and synergistically to modify reflex bronchospasm initiated by airway mechanoreceptor stimulation. The hypothesis that polymodal mechanoreceptors and capsaicin-sensitive afferent nerves similarly interact centrally to regulate coughing was addressed in this study. Cough was evoked from the tracheal mucosa either electrically (16 Hz, 10 s trains, 1,10 V) or by citric acid (0.001,2 m). Neither capsaicin nor bradykinin evoked a cough when applied to the trachea of anaesthetized guinea-pigs, but they substantially reduced the electrical threshold for initiating the cough reflex. The TRPV1 receptor antagonist capsazepine prevented the increased cough sensitivity induced by capsaicin. These effects of topically applied capsaicin and bradykinin were not due to interactions between afferent nerve subtypes within the tracheal wall or a direct effect on the cough receptors, as they were mimicked by nebulizing 1 mg ml,1 bradykinin into the lower airways and by microinjecting 0.5 nmol capsaicin into nucleus of the solitary tract (nTS). Citric acid-induced coughing was also potentiated by inhalation of bradykinin. The effects of tracheal capsaicin challenge on cough were mimicked by microinjecting substance P (0.5,5 nmol) into the nTS and prevented by intracerebroventricular administration (20 nmol h,1) of the neurokinin receptor antagonists CP99994 or SB223412. Tracheal application of these antagonists was without effect. C-fibre activation may thus sensitize the cough reflex via central mechanisms. [source] The Influence of Testosterone Combined with a PDE5-inhibitor on Cognitive, Affective, and Physiological Sexual Functioning in Women Suffering from Sexual DysfunctionTHE JOURNAL OF SEXUAL MEDICINE, Issue 3 2009Flip Van Der Made MD ABSTRACT Introduction., Women with female sexual dysfunction have a reduced sensitivity to sexual stimuli. Activation of central mechanisms may open a window for phosphodiesterase type 5 inhibitors (PDE5) to be effective; as a consequence, the combination of testosterone and a PDE5 inhibitor will restore sexual function. Aim., To demonstrate that the combination of testosterone and vardenafil will increase the sensitivity for sexual stimuli and will improve the desire and arousal components of the sexual response. Methods., In a double-blind randomly assigned placebo-controlled crossover design, 28 women with desire and/or arousal disorder underwent four different drug treatments on four separate experimental days. A masked version of the emotional Stroop task with sexual and nonsexual words was used to measure sensitivity for sexual content. Neutral and erotic film fragments were used to determine genital,physiological and subjective reactions. Main Outcome Measures., A masked version of the emotional Stroop task, vaginal pulse amplitude. For subjective measurement, responses were collected continuously with a lever and two self-report measures were used. Results., In two subgroups, which were differentiated on the basis of their initial preconscious attentional bias for sexual cues, a different sexual response profile was found. In an initially low-attention group, preconscious attentional bias for sexual cues increased under the testosterone condition. In these women, the combination of testosterone and vardenafil caused an improvement in genital response and subjective indices of sexual functioning. In the group that had initially a high attention for sexual cues, preconscious attentional bias for sexual cues decreased under the condition of testosterone. In these women, the combination of testosterone and vardenafil had no effect on any of the indices of their sexual functioning. Conclusion., In women suffering from low sexual desire,associated with low attention for sexual cues,the combination of testosterone and vardenafil may be a promising new treatment. van der Made F, Bloemers J, Yassem WE, Kleiverda G, Everaerd W, van Ham D, Olivier B, Koppeschaar H, and Tuiten A. The influence of testosterone combined with a PDE5-inhibitor on cognitive, affective, and physiological sexual functioning in women suffering from sexual dysfunction. J Sex Med 2009;6:777,790. [source] FTY720 (fingolimod) in Multiple Sclerosis: therapeutic effects in the immune and the central nervous systemBRITISH JOURNAL OF PHARMACOLOGY, Issue 5 2009Volker Brinkmann FTY720 (fingolimod) is a first-in-class sphingosine 1-phosphate (S1P) receptor modulator that was highly effective in Phase II clinical trials for Multiple Sclerosis (MS). FTY720 is phosphorylated in vivo by sphingosine kinase-2 to form the active moiety FTY720-phosphate that binds to four of the five G protein-coupled S1P receptor subtypes. Studies using conditional S1P1 receptor-deficient and sphingosine kinase-deficient mice showed that the egress of lymphocytes from lymph nodes requires signalling of lymphocytic S1P1 receptors by the endogenous ligand S1P. The S1P mimetic FTY720-phosphate causes internalization and degradation of cell membrane-expressed S1P1, thereby antagonizing S1P action at the receptor. In models of human MS and demyelinating polyneuropathies, functional antagonism of lymphocytic S1P1 slows S1P-driven egress of lymphocytes from lymph nodes, thereby reducing the numbers of autoaggressive TH17 cells that recirculate via lymph and blood to the central nervous system and the sciatic/ischiatic nerves. Based on its lipophilic nature, FTY720 crosses the blood,brain barrier, and ongoing experiments suggest that the drug also down-modulates S1P1 in neural cells/astrocytes to reduce astrogliosis, a phenomenon associated with neurodegeneration in MS. This may help restore gap-junctional communication of astrocytes with neurons and cells of the blood,brain barrier. Additional effects may result from (down-) modulation of S1P3 in astrocytes and of S1P1 and S1P5 in oligodendrocytes. In conclusion, FTY720 may act through immune-based and central mechanisms to reduce inflammation and support structural restoration of the central nervous system parenchyma. Beyond the autoimmune indications, very recent studies suggest that short-term, low-dose administration of FTY720 could help treat chronic (viral) infections. Differential effects of the drug on the trafficking of naïve, central memory and effector memory T cell subsets are discussed. [source] Agmatine, an endogenous ligand at imidazoline binding sites, does not antagonize the clonidine-mediated blood pressure reactionBRITISH JOURNAL OF PHARMACOLOGY, Issue 3 2002Walter Raasch Since agmatine has been identified as a clonidine displacing substance (CDS), the aim of this study was to investigate whether agmatine can mimic CDS-induced cardiovascular reactions in organ bath experiments, pithed spontaneously hypertensive rats (SHR) and anaesthetized SHR. Intravenously-administered agmatine significantly reduced the blood pressure and heart rate of anaesthetized SHR at doses higher than 1 and 3 mg kg,1, respectively. These effects are probably mediated via central mechanisms, since there was an approximate 8 fold rightward shift of the dose-response curve in the pithed SHR (indicating a weakened cardiovascular effect). Moreover, in organ bath experiments, agmatine failed to alter the contractility of intact or endothelium-denuded aortal rings. When agmatine was administered i.c.v. to anaesthetized SHR, blood pressure was increased without any alteration of heart rate, whereas blood pressure was unchanged and heart rate was increased after injection into the 4th brain ventricle. This suggests that haemodynamic reaction patterns after central application are related to distinct influences on central cardiovascular mechanisms. Agmatine reduces noradrenaline release in pithed SHR while ,2 -adrenoceptors are irreversibly blocked with phenoxybenzamine, but not while I1 -binding sites are selectively blocked with AGN192403. This suggests that agmatine may modulate noradrenaline release in the same way that clonidine does, i.e. via imidazoline binding sites; this involves a reduction in sympathetic tone which in turn reduces blood pressure and heart rate. Finally, CDS-like cardiovascular activity appears not to be due to agmatine, since (i) blood pressure in anaesthetized SHR is decreased by agmatine and clonidine, and (ii) agmatine did not antagonize the blood pressure reaction to clonidine in pithed or anaesthetized SHR. British Journal of Pharmacology (2002) 135, 663,672; doi:10.1038/sj.bjp.0704513 [source] Cancer stem cells and chemoradiation resistanceCANCER SCIENCE, Issue 10 2008Hideshi Ishii Cancer is a disease of genetic and epigenetic alterations, which are emphasized as the central mechanisms of tumor progression in the multistepwise model. Discovery of rare subpopulations of cancer stem cells (CSCs) has created a new focus in cancer research. The heterogeneity of tumors can be explained with the help of CSCs supported by antiapoptotic signaling. CSCs mimic normal adult stem cells by demonstrating resistance to toxic injuries and chemoradiation therapy. Moreover, they might be responsible for tumor relapse following apparent beneficial treatments. Compared with hematopoietic malignancies, conventional therapy regimes in solid tumors have improved the overall survival marginally, illustrating the profound impact of treatment resistance. This implies that the present therapies, which follow total elimination of rapidly dividing and differentiated tumor cells, need to be modified to target CSCs that repopulate the tumor. In this review article, we report on recent findings regarding the involvement of CSCs in chemoradiation resistance and provide new insights into their therapeutic implications in cancer. (Cancer Sci 2008; 99: 1871,1877) [source] Allergen-specific antibody and cytokine responses, mast cell reactivity and intestinal permeability upon oral challenge of sensitized and tolerized miceCLINICAL & EXPERIMENTAL ALLERGY, Issue 1 2010C. Perrier Summary Background Food allergy has reached an epidemic level in westernized countries and although central mechanisms have been described, the variability associated with genetic diversity underscores the still unresolved complexity of these disorders. Objective To develop models of food allergy and oral tolerance, both strictly induced by the intestinal route, and to compare antigen-specific responses. Methods BALB/c mice were mucosally sensitized to ovalbumin (OVA) in the presence of the mucosal adjuvant cholera toxin, or tolerized by intra-gastric administrations of OVA alone. Antibody titres and cytokines were determined by ELISA, and allergic status was determined through several physiologic parameters including decline in temperature, diarrhoea, mast cell degranulation and intestinal permeability. Results OVA-specific antibodies (IgE, IgGs and IgA in serum and feces) were produced in sensitized mice exclusively. Upon intra-gastric challenge with OVA, sensitized mice developed anaphylactic reactions associated with a decline of temperature, diarrhoea, degranulation of mast cells, which were only moderately recruited in the small intestine, and increased intestinal permeability. Cytokines produced by immune cells from sensitized mice included T-helper type 2 cytokines (IL-5, IL-13), but also IL-10, IFN-, and IL-17. In contrast, all markers of allergy were totally absent in tolerized animals, and yet the latter were protected from subsequent sensitization, demonstrating that oral tolerance took place efficiently. Conclusion This work allows for the first time an appropriate comparison between sensitized and tolerized BALB/c mice towards OVA. It highlights important differences from other models of allergy, and thus questions some of the generally accepted notions of allergic reactions, such as the protective role of IFN-,, the importance of antigen-specific secretory IgA and the role of mucosal mast cells in intestinal anaphylaxis. In addition, it suggests that IL-17 might be an effector cytokine in food allergy. Finally, it demonstrates that intestinal permeability towards the allergen is increased during challenge. Cite this as: C. Perrier, A.-C. Thierry, A. Mercenier and B. Corthésy, Clinical & Experimental Allergy, 2010 (40) 153,162. [source] | |||||||||||||||||||||||||