bluuebunny/crossref_metadata_2025_split huggingface dataset:
Genistein potentiates activity of the cation channel TRPC5 independently of tyrosine kinases
Authors: Wong Ching‐On , Huang Yu , Yao Xiaoqiang 
Published: March 2010

Background and purpose: TRPC5 is a Ca2+‐permeable channel with multiple modes of activation. We have explored the effects of genistein, a plant‐derived isoflavone, on TRPC5 activity, and the mechanism(s) involved.Experimental approach: Effects of genistein on TRPC5 channels were investigated in TRPC5‐over‐expressing human embryonic kidney 293 (HEK) cells and bovine aortic endothelial cells (BAECs) using fluorescent Ca2+imaging and electrophysiological techniques.Key results: In TRPC5‐over‐expressing HEK cells, genistein stimulated TRPC5‐mediated Ca2+influx, concentration dependently (EC50= 93 µM). Genistein and lanthanum activated TRPC5 channels synergistically. Effects of genistein on TRPC5 channels were mimicked by daidzein (100 µM), a genistein analogue inactive as a tyrosine kinase inhibitor, but not by known tyrosine kinase inhibitors herbimycin (2 µM), PP2 (20 µM) and lavendustin A (10 µM). Action of genistein on TRPC5 channels was not affected by an oestrogen receptor inhibitor ICI‐182780 (50 µM) or a phospholipase C inhibitor U73122 (10 µM), suggesting genistein did not act through oestrogen receptors or phospholipase C. In BAECs, genistein (100 µM) stimulated TRPC5‐mediated Ca2+influx. In patch clamp studies, both genistein (50 µM) and daidzein (50 µM) augmented TRPC5‐mediated whole‐cell cation current in TRPC5 over‐expressing HEK cells. Genistein stimulated TRPC5 channel activity in excised inside‐out membrane patch, suggesting that its action was relatively direct and did not require cytosolic factors.Conclusions and implications: The present study is the first to demonstrate stimulation of a TRP channel by isoflavones. Genistein is a lipophilic compound able to stimulate TRPC5 activity in TRPC5‐over‐expressing HEK cells and in native vascular endothelial cells.
Inverse agonist and neutral antagonist actions of synthetic compounds at an insect 5‐HT1receptor
Authors: Troppmann B , Balfanz S , Baumann A , Blenau W 
Published: March 2010

Background and purpose: 5‐Hydroxytryptamine (5‐HT) has been shown to control and modulate many physiological and behavioural functions in insects. In this study, we report the cloning and pharmacological properties of a 5‐HT1receptor of an insect model for neurobiology, physiology and pharmacology.Experimental approach: A cDNA encoding for thePeriplaneta americana5‐HT1receptor was amplified from brain cDNA. The receptor was stably expressed in HEK 293 cells, and the functional and pharmacological properties were determined in cAMP assays. Receptor distribution was investigated by RT‐PCR and by immunocytochemistry using an affinity‐purified polyclonal antiserum.Key results: TheP. americana5‐HT1receptor (Pea5‐HT1) shares pronounced sequence and functional similarity with mammalian 5‐HT1receptors. Activation with 5‐HT reduced adenylyl cyclase activity in a dose‐dependent manner. Pea5‐HT1was expressed as a constitutively active receptor with methiothepin acting as a neutral antagonist, and WAY 100635 as an inverse agonist. Receptor mRNA was present in various tissues including brain, salivary glands and midgut. Receptor‐specific antibodies showed that the native protein was expressed in a glycosylated form in membrane samples of brain and salivary glands.Conclusions and implications: This study marks the first pharmacological identification of an inverse agonist and a neutral antagonist at an insect 5‐HT1receptor. The results presented here should facilitate further analyses of 5‐HT1receptors in mediating central and peripheral effects of 5‐HT in insects.
Inhibition of calpain prevents NMDA‐induced cell death and β‐amyloid‐induced synaptic dysfunction in hippocampal slice cultures
Authors: Nimmrich V , Reymann KG , Strassburger M , Schöder UH , Gross G , Hahn A , Schoemaker H , Wicke K , Möller A 
Published: March 2010

Background and purpose:  Alzheimer's disease (AD) is a multifactorial, neurodegenerative disease, which is in part caused by an impairment of synaptic function, probably mediated by oligomeric forms of amyloid‐β (Aβ). While the Aβ pathology mainly affects the physiology of neurotransmission, neuronal decline is caused by excitotoxic cell death, which is mediated by the NMDA receptor. A comprehensive therapeutic approach should address both Aβ‐induced synaptic deficits, as well as NMDA receptor‐mediated neurodegeneration, via one molecular target. This study was designed to test whether calpain could be involved in both pathological pathways, which would offer a promising avenue for new treatments.Experimental approach:  Application of the specific, water‐soluble calpain inhibitor A‐705253 was used to inhibit calpain in hippocampal slice cultures. We examined whether inhibition of calpain would prevent Aβ‐induced deficits in neurotransmission in CA1, as well as NMDA‐induced neuronal cell death.Key results:  A‐705253 dose‐dependently prevented excitotoxicity‐induced neurodegeneration at low nanomolar concentrations, determined by propidium iodide histochemistry. Inhibition of the NMDA receptor similarly protected from neuronal damage. Caspase staining indicated that calpain inhibition was protective by reducing apoptosis. Electrophysiological analysis revealed that inhibition of calpain by A‐705253 also fully prevented Aβ oligomer‐induced deficits in neurotransmission. The protective effect of calpain was compared to the clinically available NMDA receptor antagonist memantine, which was also effective in this model.Conclusions and implications:  We suggest that inhibition of calpain exhibits a promising strategy to address several aspects of the pathology of AD that may go beyond the available therapeutic intervention by memantine.
Evidence for both inverse agonism at the cannabinoid CB1receptor and the lack of an endogenous cannabinoid tone in the rat and guinea‐pig isolated ileum myenteric plexus‐longitudinal muscle preparation
Authors: Makwana R , Molleman A , Parsons ME 
Published: March 2010

Background and purpose: Cannabinoid receptor agonists reduce intestinal propulsion in rodents through the CB1receptor. In addition to its antagonistic activity at this receptor, rimonabant (N‐(piperidino)‐5‐(4‐chlorophenyl)‐1‐(2,4‐dichlorophenyl)‐4‐methyl‐3‐pyrazole‐carboxyamide) alone augments intestinal transit. Using rat and guinea‐pig ileum MPLM (myenteric plexus‐longitudinal muscle) preparations, we investigated whether the latter effect was through inverse agonism or antagonism of endocannabinoid agonist(s).Experimental approach: Inverse agonism was investigated by comparing the maximal enhancement of electrically evoked contractions of the MPLM by two CB1receptor antagonists, AM 251 (N‐(piperidin‐1‐yl)‐5‐(4‐iodophenyl)‐1‐(2,4‐dichlorophenyl)‐4‐methyl‐1H‐pyrazole‐3‐carboxamide) and O‐2050 [(6aR,10aR)‐3‐(1‐methanesulphonylamino‐4‐hexyn‐6‐yl)‐6a,7,10,10a‐tetrahydro‐6,6,9‐trimethyl‐6‐H‐dibenzo[b,d]pyran], with that produced by rimonabant. To reveal ongoing endocannabinoid activity, effects of inhibiting endocannabinoid hydrolysis by fatty acid amide hydrolase (FAAH) using AA‐5HT (arachidonyl‐5‐hydroxytryptamine), PMSF (phenylmethylsulphonyl fluoride) or URB‐597 (3′‐carbamoyl‐biphenyl‐3‐yl‐cyclohexylcarbamate), or putative uptake using VDM‐11 [(5Z,8Z,11Z,14Z)‐N‐(4‐hydroxy‐2‐methylphenyl)‐5,8,11,14‐eicosatetraenamide] was evaluated.Key results: The presence of CB1receptors was revealed by antagonism of exogenous anandamide, arachidonylethanolamide (AEA) and WIN 55,212‐2 [(R)‐(+)‐[2,3‐dihydro‐5‐methyl‐3‐(4‐morpholinylmethyl)‐pyrrolo[1,2,3‐de]‐1,4‐benzoxazin‐6‐yl]‐1‐naphthalenylmethanone mesylate] by rimonabant. The rank order of potentiation of contractions was AM 251 > rimonabant > O‐2050. Neither the FAAH inhibitors nor VDM‐11 affected electrically evoked contractions. Each FAAH inhibitor increased the potency of AEA but not WIN 55,212‐2. VDM‐11 did not alter the inhibitory effect of AEA.Conclusions and implications: The different levels of maximal potentiation of contractions by the CB1receptor antagonists suggest inverse agonism. The potentiation of the action of AEA by the FAAH inhibitors showed that FAAH was present. The lack of effect of FAAH inhibitors and VDM‐11 alone on electrically evoked contractions, and on the potency of exogenous AEA suggests that pharmacologically active endocannabinoids were not released and the endocannabinoid transporter was absent. Thus, the CB1receptor antagonists behave as inverse agonists.This article is part of a themed issue on Cannabinoids. To view the editorial for this themed issue visithttp://dx.doi.org/10.1111/j.1476‐5381.2010.00831.x
Role of Probiotics in Pediatric Patients with Helicobacter pylori Infection: A Comprehensive Review of the Literature
Authors: Lionetti Elena , Indrio Flavia , Pavone Lorenzo , Borrelli Giorgia , Cavallo Luciano , Francavilla Ruggiero 
Published: March 2010

AbstractBackground:  The current guidelines suggest the use of triple therapy as first choice treatment of Helicobacter pylori infection, although the eradication failure rate is more than 30%. Current interest in probiotics as therapeutic agents against H. pylori is stimulated not only by the clinical data showing efficacy of some probiotics in different gastrointestinal diseases but also by the increasing resistance of pathogenic bacteria to antibiotics, thus the interest for alternative therapies is a real actual topic.Aim:  To review in vitro and in vivo studies on the role of probiotics in H. pylori infection focusing on the paediatric literature.Materials and methods:  Pre‐clinical and clinical paediatric studies in English assessing the role of probiotics in H. pylori infection identified by MEDLINE search (1950–2009) were reviewed.Results:  In vitro studies demonstrated an inhibitory activity of probiotics on H. pylori growth and that this effect is extremely strain specific. Available data in children indicate that probiotics seems to be efficacious for the prevention of antibiotic associated side‐effects, and might be of help for the prevention of H. pylori complications by decreasing H. pylori density and gastritis, and for the prevention of H. pylori colonization or re‐infection by inhibiting adhesion to gastric epithelial cells. There is no clear evidence that probiotics may increase the H. pylori eradication rate.Conclusion:  Both in vitro and in vivo studies provide evidence that probiotics may represent a novel approach to the management of H. pylori infection.
Genetic Characterization and Epidemiology of Helicobacters in Non‐domestic Animals
Authors: Schrenzel Mark D. , Witte Carmel L. , Bahl Justin , Tucker Tammy A. , Fabian Niora , Greger Heidi , Hollis Chrissie , Hsia Gary , Siltamaki Erin , Rideout Bruce A. 
Published: March 2010

AbstractBackground:  Novel helicobacter infections and associated disease are being recognized with increasing frequency in animals and people. Yet, the pervasiveness of infection in distantly related animal taxa, genetic diversity of helicobacters, and their transmissability are not known.Aim:  To better understand the ecology of helicobacters, we did a PCR survey and epidemiologic analysis of 154 captive or wild vertebrate taxa originating from 6 continents.Materials and Methods:  One hundred twenty nine helicobacter 16s rRNA gene segments were amplified by PCR and sequenced from ninety‐three mammalian, reptilian, avian, or amphibian host species. Prevalence estimates were generated, and univariate logistic regression analyses were used to explore relationships between infection status and the health and characteristics of the 220 individual animals.Results:  One hundred and nineteen novel helicobacter DNA sequences were found. No significant relationship between infection and host health was found; however, multi‐infection or infections with particular genotypes were associated with mild clinical signs. Phylogenetic and genetic comparisons of helicobacters suggested prolonged co‐adaptation and niche‐associated divergence as well as periodic inter‐species transmission.Conclusion:  The genus Helicobacter should accordingly be viewed as a collection of hundreds of organisms that have colonized most tetrapod taxa and have the potential to expand into new hosts as contact among animals and between animals and people increases.
Presence of Helicobacter pylori in a Sibling is Associated with a Long‐Term Increased Risk of H. pylori Infection in Israeli Arab Children
Authors: Muhsen Khitam , Athamna Abed , Bialik Anya , Alpert Gershon , Cohen Dani 
Published: March 2010

AbstractBackground and Objectives:  We examined the dynamics of Helicobacter pylori infection between pre‐school and school ages and compared the determinants of late acquisition of H. pylori infection with determinants of early and persistent H. pylori infection.Methods:  ELISA was used to detect H. pylori antigens in stool specimens collected from children at preschool age (3–5 years) and from their mothers and siblings in 2004. The children were tested again for H. pylori at school age (6–9 years) in 2007–2009. Household and socioeconomic characteristics were obtained by interviews.Results:  The prevalence of H. pylori infection increased from 49.7% (95% CI 42.8, 56.7) in 2004 to 58.9% (95% CI 51.8, 65.6) in 2007–2009. Among children tested in both examinations, 69 (49.3%) had persistent infection, 14 (10.0%) were new cases, 56 (40.0%) remained uninfected, and one (0.7%) had lost H. pylori infection. The approximate annual incidence of infection during 2004–2009 was 5%. Sibling’s H. pylori positivity at baseline increased the risk for late acquisition of H. pylori infection; adjusted prevalence ratio (PR) 4.62 (95% CI 0.76, 28.23) (p = .09), while maternal education lowered the risk; adjusted PR 0.84 (95% CI 0.69, 1.01) (p = .06). Sibling’s H. pylori positivity was the only significant variable associated with early and persistent H. pylori infection in multivariate analysis.Conclusions:  Most H. pylori infections are acquired at preschool age and transient infection beyond this age is uncommon in this population. Helicobacter pylori‐infected siblings are the major reservoir of H. pylori in early and late childhood demonstrating sustained intra‐familial transmission of H. pylori.
Helicobacter hepaticus Cytolethal Distending Toxin Causes Cell Death in Intestinal Epithelial Cells via Mitochondrial Apoptotic Pathway
Authors: Liyanage Namal P. M. , Manthey Karoline C. , Dassanayake Rohana P. , Kuszynski Charles A. , Oakley Gregory G. , Duhamel Gerald E. 
Published: March 2010

AbstractBackground:  Helicobacter hepaticus, the prototype for enterohepatic Helicobacter species, colonizes the lower intestinal and hepatobiliary tracts of mice and causes typhlocolitis, hepatitis, and hepatocellular carcinoma in susceptible mouse strains. Cytolethal distending toxin (CDT) is the only known virulence factor found in H. hepaticus. CDT of several Gram‐negative bacteria is associated with double‐stranded DNA breaks resulting in cell cycle arrest and death of a wide range of eukaryotic cells in vitro. We previously observed H. hepaticus CDT (HhCDT) mediated apoptosis in INT407 cells. However, the exact mechanism for the induction of the apoptotic pathway by HhCDT is unknown. The objective of this study was to identify the apoptotic signaling pathway induced by HhCDT in INT407 cells.Materials and Methods:  INT407 cells were incubated with or without recombinant HhCDT for 0–72 hours. H2AX phosphorylation and apoptotic parameters were analyzed.Results:  H2AX was phosphorylated 24 hours postexposure to HhCDT. Expression of pro‐apoptotic Bax protein was upregulated after 24 hours, while Bcl2 expression decreased. Cytochrome c was released from mitochondria after 12–24 hours of exposure. Concurrently, caspase 3/7 and 9 were activated. However, pretreatment of INT407 cells with caspase inhibitor (Z‐VAD‐FMK) inhibited the activation of caspase 3/7 and 9. Significant activity of caspase 8 was not observed in toxin treated cells. Activation of caspase 3/7 and caspase 9 confirms the involvement of the mitochondrial apoptotic pathway in HhCDT‐treated cells.Conclusion:  These findings show, for the first time, the ability of HhCDT to induce apoptosis via the mitochondrial pathway.
Comparing Structural Equation Models That Use Different Measures of the Level of Response to Alcohol
Authors: Schuckit Marc A. , Smith Tom L. , Trim Ryan S. , Tolentino Neil J. , Hall Shana A. 
Published: March 2010

Background:  The two measures of a low level of response (LR) to alcohol, an alcohol challenge and the retrospective Self‐Report of the Effects of Alcohol questionnaire (SRE), each identify individuals at high risk for heavy drinking and alcohol problems. These measures also perform similarly in identifying subjects with unique functional brain imaging characteristics. However, few data are available regarding whether alcohol challenge‐based and SRE‐based LRs operate similarly in structural equation models (SEMs) that search for characteristics, which help to mediate how LR impacts alcohol outcomes.Methods:  Two hundred and ninety‐four men from the San Diego Prospective Study were evaluated for their LR to alcohol using alcohol challenges at ∼age 20. At ∼age 35, the same subjects filled out the SRE regarding the number of drinks needed for effects 15 to 20 years earlier. The two different LR scores for these men were used in SEM analyses evaluating how LR relates to future heavy drinking and to drinking in peers (PEER), alcohol expectancies (EXPECT), and drinking to cope (COPE) as potential mediators of the LR to drinking pattern (ALCOUT) relationships.Results:  While the 2 LR measures that were determined 15 years apart related to each other at a modest level (r = 0.17, p < 0.01), the SEM results were similar regardless of the LR source. In both alcohol challenge‐based and SRE‐based LR models, LR related directly to ALCOUT, with partial mediation from PEER and COPE, but not through EXPECT in these 35‐year‐old men.Conclusions:  Consistent with the >60% overlap in prediction of outcomes for the 2 LR measures, and with results from functional brain imaging, alcohol challenge‐ and SRE‐based LR values operated similarly in SEM models in these men.
Subcutaneous Target Stimulation (STS) in Chronic Noncancer Pain: A Nationwide Retrospective Study
Authors: Sator‐Katzenschlager Sabine , Fiala Katharina , Kress Hans G. , Kofler Alexandra , Neuhold Josef , Kloimstein Herwig , Ilias Wilfried , Mozes‐Balla Eva‐Maria , Pinter Michaela , Loining Nadja , Fuchs Wolfgang , Heinze Georg , Likar Rudolf 
Published: March 2010

AbstractStimulation of primary afferent neurons offers a new approach for the control of localized chronic pain. We describe the results with a new neurostimulation technique, subcutaneous target stimulation (STS), for the treatment of chronic focal noncancer pain. STS applies permanent electrical stimulation directly at the painful area via a percutaneous‐placed subcutaneous lead. We reported the clinical outcomes of 111 patients with focal chronic, noncancer pain treated with STS in this first nationwide, multicenter retrospective analysis. The indications for STS were low back pain (n = 29) and failed back surgery syndrome (back pain with leg pain) (n = 37), cervical neck pain (n = 15), and postherpetic neuralgia (n = 12). Pain intensity was measured on a numerical rating scale (NRS) before and after implantation. Data on analgesic medication, stimulation systems, position, and type of leads and complications were obtained from the patients' records. After implantation, the mean pain intensity improved by more than 50% (mean NRS reduction from 8.2 to 4.0) in the entire patient group (P = 0.0009). This was accompanied by a sustained reduction in demand for analgesics. In all the patients, the STS leads were positioned directly at the site of maximum pain. Lead dislocation occurred in 14 patients (13%), infections in 7 (6%), and in 6 cases (5%), lead fractures were observed. The retrospective data analysis revealed that STS effectively provided pain relief in patients suffering from refractory focal chronic noncancer pain and that STS is an alternative treatment option. Prospective controlled studies are required to confirm these retrospective findings. This article presents a new minimally invasive technique for therapy‐resistant focal pain.
Consistent and Clinically Relevant Effects with Fentanyl Buccal Tablet in the Treatment of Patients Receiving Maintenance Opioid Therapy and Experiencing Cancer‐Related Breakthrough Pain
Authors: Zeppetella Giovambattista , Messina John , Xie Fang , Slatkin Neal E. 
Published: March 2010

AbstractFentanyl buccal tablet (FBT) has shown efficacy and tolerability in patients with cancer‐related persistent pain treated with maintenance opioids. We conducted a combined analysis of two similarly designed, randomized, placebo‐controlled studies to further evaluate the consistency and clinical relevance of analgesia outcomes. Of the 252 patients enrolled, 150 fulfilled the criteria for efficacy analysis and experienced 1,417 breakthrough pain episodes. A consistently greater effect was noted with FBT vs. placebo on the following measures: improvements from baseline of ≥33% and ≥50% in pain intensity (PI), a ≥2‐point reduction in PI, and a score of ≥2 for pain relief. Improvements in these clinically meaningful efficacy measures were seen with FBT at 15 minutes (earliest common evaluation) and remained evident at 60 minutes (final common evaluation). They were also reflected in a more favorable global medication performance assessment for FBT over placebo. FBT was generally well tolerated; most adverse events were typical of potent opioid use in a cancer population. Application‐site (buccal) abnormalities were infrequent and led to withdrawal of three patients. There were no serious adverse events or deaths attributable to FBT. This analysis suggests that FBT provides an analgesic effect that is consistent across multiple clinically relevant efficacy measures.
Peripheral Nerve Field Stimulation for Intractable Post‐Thoracotomy Scar Pain not Relieved by Conventional Treatment
Authors: Goyal Gaurav N. , Gupta Deepak , Jain Roopesh , Kumar Sunil , Mishra Seema , Bhatnagar Sushma 
Published: March 2010

AbstractPeripheral nerve field stimulation (PNFS) is being applied in individual cases where conventional treatments have failed to control pain localized to limited dermatomal distribution. We applied PNFS for unrelieved post‐thoracotomy scar pain. Although spinal cord stimulation may have resulted in good coverage in the same dermatomal distribution, we chose the more peripheral approach to minimize the risk of complications, avoiding the potential neurologic sequelae associated with stimulation of the spinal cord. In summary, PNFS was effective in relieving post‐thoractomy pain refractory to conventional pain management suggesting great potential of PNFS as a treatment option for chronic surgical‐scar pain.