MH_dev_36

Signatures of positive selection in genes associated with human skin pigmentation as revealed from analyses of single nucleotide polymorphisms . Phenotypic variation between human populations in skin pigmentation correlates with latitude at the continental level . A large number of hypotheses involving genetic adaptation have been proposed to explain human variation in skin colour , but only limited genetic evidence for positive selection has been presented . To shed light on the evolutionary genetic history of human variation in skin colour we inspected 118 genes associated with skin pigmentation in the Perlegen dataset , studying single nucleotide polymorphisms ( SNPs ) , and analyzed 55 genes in detail . We identified eight genes that are associated with the melanin pathway ( Q9UMX9 , Q04671 REA , P17643 REA , P40126 REA , P21583 REA , P00533 REA , P14416 REA and Q03181 REA ) and presented significant differences in genetic variation between Europeans , Africans and Asians . In six of these genes we detected , by means of the EHH test , variability patterns that are compatible with the hypothesis of local positive selection in Europeans ( Q04671 REA , P17643 REA and P21583 REA ) and in Asians ( Q04671 REA , P40126 REA , P21583 REA , P00533 REA and P14416 REA ) , whereas signals were scarce in Africans ( P40126 REA , P00533 REA and P14416 REA ) . Furthermore , a statistically significant correlation between genotypic variation in four pigmentation candidate genes and phenotypic variation of skin colour in 51 worldwide human populations was revealed . Overall , our data also suggest that light skin colour is the derived state and is of independent origin in Europeans and Asians , whereas dark skin color seems of unique origin , reflecting the ancestral state in humans .

DB00316 MEN - inhibitable P35354 REA . Although paracetamol potently reduces pain and fever , its mechanism of action has so far not been satisfactorily explained . It inhibits both P23219 REA and P35354 REA weakly in vitro , but reduces prostaglandin synthesis markedly in vivo . In mouse macrophage J774 . 2 cells , P35354 REA induced for 48 hr with high concentrations of NSAIDs is more sensitive to inhibition with paracetamol than endotoxin-induced P35354 REA . In the rat pleurisy model of inflammation , a second peak of P35354 REA protein appears 48 hr after administration of the inflammatory stimulus , during the resolution phase of the inflammatory process . Inhibition of the activity of this late-appearing P35354 REA with indomethacin or a selective P35354 REA inhibitor , delays resolution and the inflammation is prolonged . Cultured lung fibroblasts also express P35354 REA activity after stimulation with IL - 1beta which is highly sensitive to inhibition with paracetamol . Thus , evidence is accumulating for the existence of a P35354 REA variant or a new P36551 REA enzyme which can be inhibited with paracetamol .

Fibroblast growth factor - 2 in hyperplastic pituitaries of D2R knockout female mice . P14416 REA ( D2R ) knockout ( KO ) female mice develop chronic hyperprolactinemia and pituitary hyperplasia . Our objective was to study the expression of the mitogen fibroblast growth factor ( P09038 REA ) and its receptor , P11362 REA , comparatively in pituitaries from KO and wild-type ( WT ) female mice . We also evaluated P09038 REA subcellular localization and P09038 REA effects on pituitary function . P09038 REA - induced prolactin release showed a similar response pattern in both genotypes , even though basal and P09038 REA - stimulated release was higher in KO . P09038 REA stimulated pituitary cellular proliferation ( MTS assay and [ ( 3 ) H ] thymidine incorporation ) , with no differences between genotypes . P09038 REA concentration ( measured by ELISA ) in whole pituitaries or cultured cells was lower in KO ( P < 0.00001 and 0.00014 ) . Immunofluorescence histochemistry showed less P09038 REA in pituitaries from KO females and revealed a distinct P09038 REA localization pattern between genotypes , being predominantly nuclear in KO and cytosolic in WT pituitaries . Finally , P09038 REA could not be detected in the conditioned media from pituitary cultures of both genotypes . P11362 REA levels ( Western blot and immunohistochemistry ) were higher in pituitaries of KO . Basal concentration of phosphorylated ERKs was lower in KO cells ( P = 0.018 ) . However , when stimulated with P09038 REA , a significantly higher increment of P29323 REA phosphorylation was evidenced in KO cells ( P < or = 0.02 ) . We conclude that disruption of the D2R caused an overall decrease in pituitary P09038 REA levels , with an increased distribution in the nucleus , and increased P11362 REA levels . These results are important in the search for reliable prognostic indicators for patients with pituitary dopamine-resistant prolactinomas , which will make tumor-specific therapy possible .

A genomic insight into diversity among tribal and nontribal population groups of Manipur , India . Twenty autosomal markers , including linked markers at two gene markers , are used to understand the genomic similarity and diversity among three tribal ( Paite , Thadou , and Kom ) and one nontribal communities of Manipur ( Northeast India ) . Two of the markers ( P01730 REA and HB9 ) are monomorphic in Paite and one ( the P01730 REA marker ) in Kom . Data suggest the Meitei ( nontribal groups ) stand apart from the three tribal groups with respect to higher heterozygosity ( 0.366 ) and presence of the highest ancestor haplotypes of P14416 REA markers ( 0.228 ) ; this is also supported by principal co-ordinate analysis . These populations are found to be genomically closer to the Chinese population than to other Indian populations .

Serotonin and dopamine receptor gene polymorphisms and the risk of extrapyramidal side effects in perphenazine-treated schizophrenic patients . RATIONALE : DB00850 MENMAX DB00850 MEN , a classical antipsychotic drug , has the potential to induce extrapyramidal side effects ( EPS ) . Dopaminergic and serotonergic pathways are involved in the therapeutic and adverse effects of the drug . OBJECTIVES : To evaluate the impact of polymorphisms in the dopamine D ( 2 ) and D ( 3 ) and serotonin 2A and 2C receptor genes ( P14416 REA , P35462 REA , P28223 REA , and P28335 REA ) on short-term effects of perphenazine monotherapy in schizophrenic patients . MATERIALS AND METHODS : Forty-seven Estonian inpatients were evaluated before and after 4-6 weeks of treatment by Simpson-Angus rating scale , Barnes scale , and Positive and Negative Symptom Scale . Genotyping was performed for common P14416 REA , P35462 REA , P28223 REA , and P28335 REA gene polymorphisms , previously reported to influence receptor expression and / or function . RESULTS : Most of the patients ( n = 37 ) responded to the treatment and no significant association was observed between the polymorphisms and antipsychotic response . The 102C allele of P28223 REA and the - 697C and 23Ser alleles of P28335 REA were more frequent among patients with EPS ( n = 25 ) compared to patients without EPS ( n = 22 ) ( p = 0.02 , 0.01 , and 0.02 , respectively ) . The difference between patients with and without EPS in variant allele frequencies remained significant after multiple model analyses including age , gender , and duration of antipsychotic treatment as covariants . There was no significant association between EPS occurrence and polymorphisms in the P14416 REA and P35462 REA genes . CONCLUSIONS : An association was observed between polymorphisms in P28223 REA and P28335 REA genes and occurrence of acute EPS in schizophrenic patients treated with perphenazine monotherapy . Larger study populations are needed to confirm our findings .

The relationship between gastric motility and nausea : gastric prokinetic agents as treatments . Nausea is one of a cluster of symptoms described subjectively by patients with delayed gastric emptying . The mechanisms and treatments are unclear ( anti-emetic drugs are not fully effective against nausea ) . Can nausea be relieved by stimulating gastric emptying ? Physostigmine ( together with atropine ) has been shown experimentally to stimulate gastric motility , relieve nausea and restore normal gastric motility . Is this mimicked by gastric prokinetic drugs ? The answer is complicated by mixed pharmacology . DB01233 SUB increases gastric motility by activating myenteric Q13639 REA receptors but also directly inhibits vomiting via D2 and 5 - Q9H205 REA receptor antagonism ; relationships between increased gastric motility and relief from nausea are therefore unclear . Similarly , the D2 receptor antagonist domperidone has direct anti-emetic activity . Nevertheless , more selective Q13639 REA and motilin receptor agonists ( erythromycin , directly stimulating gastric motility ) inhibit vomiting in animals ; low doses of erythromycin can also relieve symptoms in patients with gastroparesis . Ghrelin stimulates gastric motility and appetite mostly via vagus-dependent pathways , and inhibits vomiting in animals . To date , ghrelin receptor activation has failed to consistently improve gastric emptying or symptoms in patients with gastroparesis . We conclude that nausea can be relieved by gastric prokinetic drugs , but more clinical studies are needed using drugs with selective activity . Other mechanisms ( e . g . ghrelin , vagal and central pathways , influencing a mechanistic continuum between appetite and nausea ) also require exploration . These and other issues will be further explored in a forthcoming special issue of the European Journal of Pharmacology , which focusses on mechanisms of nausea and vomiting .

P04035 REA inhibition induces IL - 1beta release through Rac 1 / PI3K / P31749 REA - dependent caspase - 1 activation . Q03426 REA deficiency ( MKD ) is an autoinflammatory disorder characterized by recurring fever episodes and results from disturbed isoprenoid biosynthesis . Lipopolysaccharide-stimulated peripheral blood mononuclear cells from MKD patients secrete high levels of interleukin - 1beta ( IL - 1beta ) because of the presence of hyperactive caspase - 1 , and this has been proposed to be the primary cause of recurring inflammation . Here we show that inhibition of P04035 REA by simvastatin treatment , mimicking MKD , results in increased IL - 1beta secretion in a Rac 1 / PI3K - dependent manner . Simvastatin treatment was found to activate protein kinase B ( P31749 REA ) / c-akt , a primary effector of PI3K , and ectopic expression of constitutively active P31749 REA was sufficient to induce IL - 1beta release . The small GTPase Rac 1 was activated by simvastatin , and this was required for both P31749 REA activation and IL - 1beta secretion . IL - 1beta release is mediated by caspase - 1 , and simvastatin treatment resulted in increased caspase - 1 activity in a Rac 1 / PI3K - dependent manner . These data suggest that , in MKD , dysregulated isoprenoid biosynthesis activates Rac 1 / PI3K / P31749 REA , resulting in caspase - 1 activation with increased IL - 1beta release . Importantly , inhibition of Rac 1 in peripheral blood mononuclear cells isolated from MKD patients resulted in a dramatic reduction in IL - 1beta release . These data suggest that pharmacologic inhibition of Rac 1 could provide a novel therapeutic strategy for treatment of MKD .

Single-walled carbon nanotubes ( SWCNTs ) enhance DB00761 - , acetylcholine - , and serotonin-induced contractions and evoke oxidative stress on rabbit ileum . We examined the effects of intravenous administration of purified arc-discharge single-walled carbon nanotubes ( SWCNTs ) on rabbit ileum to establish the possibility of using these SWCNTs as cell markers or drug carriers for the treatment of intestinal diseases . The SWCNT purification process eliminated carbonaceous impurities and decreased the amount of metals . SWCNTs increased the contractile responses induced by DB00761 , acetylcholine ( ACh ) , and serotonin ( 5 - HT ) in rabbit ileum . Verapamil , apamin , glibenclamide , quinine and charybdotoxin reduced the contractile responses induced by ACh and 5 - HT in ileum from rabbits treated with SWCNTs , indicating that voltage-dependent Ca2 + channels and small , intermediate , and large-conductance Ca ( 2 + ) - activated , DB00171 - sensitive , and voltage-dependent K + channels are involved in these effects . Atropine and hexamethonium reduced the ACh response , indicating that muscarinic and nicotinic receptors are involved in this effect . DB00904 and GR 113808 reduced the 5 - HT response , indicating that serotonin 5 - Q9H205 REA and Q13639 REA receptors are involved in this effect . SWCNTs increased the malondialdehyde plus 4 - hydroxyalkenals and carbonyl levels in rabbit plasma and ileum , indicating that SWCNTs produce oxidative stress . SWCNTs did not produce relevant histological changes or modify the levels of the inflammatory mediators P35228 REA and P35354 REA in the ileum . In conclusion , this study demonstrates that the intravenous administration of SWCNTs can evoke oxidative stress and affect contractility in rabbit ileum . These effects could reduce the possibility of using the arc-discharge SWCNTs as cell markers or drug carriers to treat intestinal diseases .

Allele frequencies of single nucleotide polymorphisms ( SNPs ) in 40 candidate genes for gene-environment studies on cancer : data from population-based Japanese random samples . Knowledge of genetic polymorphisms in gene-environment studies may contribute to more accurate identification of avoidable risks and to developing tailor-made preventative measures . The aim of this study was to describe the allele frequencies of single nucleotide polymorphisms ( SNPs ) of select genes , which may be included in future gene-environment studies on cancer in Japan . SNP typing was performed on middle-aged Japanese men randomly selected from the general population in five areas of Japan . We genotyped and calculated allele frequencies of 153 SNPs located on 40 genes : P04798 REA , Q16678 REA , P11712 REA , P33261 REA , P05181 REA , P05093 REA , P11511 REA , P35869 REA , P03372 REA , Q92731 REA , ERRRG , P06401 REA , P07099 REA , P34913 REA , P37059 REA , P37058 REA , P28161 REA , P21266 REA , GSTT 2 , P09211 REA , NAT 1 , NAT 2 , P21964 REA , P07327 REA , P00325 REA , P00326 REA , P05091 REA , P35228 REA , NOS 3 , P01583 REA , P01584 REA , O15527 REA , P36639 REA [ P36639 REA ] , P14416 REA , P35462 REA , P21917 REA , P31645 REA , P04150 REA [ GCCR ] , P42898 REA , and P15559 REA . In the present study , the Japanese allele frequencies were verified by using nationwide population samples .

Evaluation of DNA damage in P48444 REA patients and its correlation with polymorphisms in repair genes . BACKGROUND : We investigated a potential link between genetic polymorphisms in genes P18887 REA ( Arg 399Gln ) , O15527 REA ( Ser 326Cys ) , O43542 REA ( Thr 241Met ) , and Q13426 REA ( Ile 401Thr ) with the level of DNA damage and repair , accessed by comet and micronucleus test , in 51 P48444 REA patients and 51 controls . METHODS : Peripheral blood was used to perform the alkaline and neutral comet assay ; and genetic polymorphisms by PCR / RFLP . To assess the susceptibility to exogenous DNA damage , the cells were treated with methyl methanesulphonate for 1 - h or 3 - h . After 3 - h treatment the % residual damage was calculated assuming the value of 1 - h treatment as 100 % . The cytogenetic damage was evaluated by buccal micronucleus cytome assay ( BMCyt ) . RESULTS : P48444 REA patients with the risk allele P18887 REA ( Arg 399Gln ) and O43542 REA ( Thr 241Met ) showed higher DNA damage by comet assay . The residual damage was higher for P48444 REA with risk allele in the four genes . In P48444 REA patients was showed negative correlation between BMCyt ( binucleated , nuclear bud , condensed chromatin and karyorrhexic cells ) with pulmonary function and some variant genotypes . CONCLUSION : Our results suggest a possible association between variant genotypes in P18887 REA ( Arg 399Gln ) , O15527 REA ( Ser 326Cys ) , O43542 REA ( Thr 241Met ) , and Q13426 REA ( Ile 401Thr ) , DNA damage and progression of P48444 REA .

Effects of cholinoceptor and 5 - hydroxytryptamine 3 receptor antagonism on erythromycin-induced canine intestinal motility disruption and emesis . 1 . Erythromycin administration is associated with gastrointestinal problems , disturbed gastrointestinal motility and emesis . This study in the dog investigates the underlying mechanisms . 2 . Intestinal myoelectrical activity and the occurrence and latency of emesis were recorded in eight conscious dogs . All drugs were administered intravenously . 3 . Erythromycin ( 7 mg kg - 1 ) increased contractions of the proximal small intestine , and caused emesis in all fasted dogs and in 5 dogs after food . Atropine ( 50 mg kg - 1 min - 1 ) and hexamethonium ( 10 mg kg - 1 h - 1 ) partially inhibited the GI motility effects but did not significantly reduce emesis . 4 . DB01233 SUB at a high dose ( 2 mg kg - 1 h - 1 ) reduced the incidence of emesis in the presence of increased intestinal motility , but a low dose ( 150 micrograms kg - 1 h - 1 ) was ineffective . 5 . A 5 - hydroxytryptamine 3 ( 5 - Q9H205 REA ) receptor antagonist , MDL 72222 ( 1 mg kg - 1 ) , reduced emesis when given alone and combined with metoclopramide ( low dose ) . The Q13639 REA receptor agonist BRL 24924 ( DB04917 , 1 mg kg - 1 ) had no effect on emesis either alone in combination with metoclopramide . 6 . In conclusion , erythromycin-induced GI motility disturbances and emesis are not causally related . Whereas the increase in intestinal smooth muscle activity is possibly cholinergically mediated , emesis occurs at least in part via a 5 - hydroxytryptaminergic mechanism , but does not involve the dopamine system .

DB00175 MEN - induced proangiogenic effects depend upon extracellular P09038 REA . The P04035 REA inhibitors ( statins ) have been shown to exert several protective effects on the vasculature that are unrelated to changes in the cholesterol profile , and to induce angiogenesis . The proangiogenic effect exerted by statins has been attributed to the activation of the PI3K / Akt pathway in endothelial cells ; however , it is unclear how statins activate this pathway . DB00175 MEN - mediated activation of Akt and MAPK occurs rapidly ( within 10 min . ) and at low doses ( 10 nM ) . Here , we hypothesized that P09038 REA contributes to the proangiogenic effect of statins . We found that pravastatin , a hydrophilic statin , induced phosphorylation of the FGF receptor ( FGFR ) in human umbilical vein endothelial cells . SU5402 , an inhibitor of FGFR , abolished pravastatin-induced PI3K / Akt and MAPK activity . Likewise , anti - P09038 REA function-blocking antibodies inhibited Akt and MAPK activity . Moreover , depletion of extracellular P09038 REA by heparin prevented pravastatin-induced phosphorylation of Akt and MAPK . Treatment with P09038 REA antibody inhibited pravastatin-enhanced endothelial cell proliferation , migration and tube formation . These observations indicate that pravastatin exerts proangiogenic effects in endothelial cells depending upon the extracellular P09038 REA .

P04035 REA inhibitors deplete circulating classical and non-classical monocytes following human heart transplantation . BACKGROUND : Monocytes mediate immune responses following solid organ transplantation via cytokine secretion and differentiation to macrophage / dendritic cell lineages . To date , the pleiotropic immunomodulatory effect of statins on human monocytes following human heart transplantation has yet to be elucidated . This study was designed to assess the effects of statin administration on the monocyte repertoire . METHODS : 108 patients were recruited into the study . Clinical data were collected from patients ' notes . Peripheral blood immunophenotype was determined via flow cytometry ( using CD11c , P08571 REA , CD16 , CD49d , CD64 , P33681 REA and CD195 ) . RESULTS : There were fewer circulating classical ( p= 0.0001 ) and non-classical ( p= 0.0013 ) monocytes in patients treated with a statin . CD64 expression was down-regulated ( p= 0.011 and p= 0.049 ) whereas CD49d expression was up-regulated ( p= 0.004 and p= 0.022 ) on classical and non-classical monocytes in this group . Patients receiving DB01076 had fewer circulating classical monocytes ( p= 0.001 ) compared to patients administered DB00175 MEN . Patients receiving DB00175 MEN had fewer circulating non-classical monocytes ( p= 0.029 ) compared to patients administered DB01076 . DISCUSSION : Statin administration alters the circulating monocyte repertoire following heart transplantation , including population size , FcgammaRI and VLA - 4 adhesion molecule expression . Furthermore , different statin treatments are associated with a selective depletion of macrophage or DC ( re ) generating monocytes .

A whole genome Bayesian scan for adaptive genetic divergence in West African cattle . BACKGROUND : The recent settlement of cattle in West Africa after several waves of migration from remote centres of domestication has imposed dramatic changes in their environmental conditions , in particular through exposure to new pathogens . West African cattle populations thus represent an appealing model to unravel the genome response to adaptation to tropical conditions . The purpose of this study was to identify footprints of adaptive selection at the whole genome level in a newly collected data set comprising 36,320 SNPs genotyped in 9 West African cattle populations . RESULTS : After a detailed analysis of population structure , we performed a scan for SNP differentiation via a previously proposed Bayesian procedure including extensions to improve the detection of loci under selection . Based on these results we identified 53 genomic regions and 42 strong candidate genes . Their physiological functions were mainly related to immune response ( MHC region which was found under strong balancing selection , P11912 REA , P61073 REA , P8 0370 , P48380 , Q9H3S1 REA , Q8IUC6 and P19474 REA ) , nervous system ( Q96NK8 , O95897 , MAGI 1 , Q9H3S1 REA and Q13639 REA ) and skin and hair properties ( P24530 REA , TRSP 1 and Q8IUC2 ) . CONCLUSION : The main possible underlying selective pressures may be related to climatic conditions but also to the host response to pathogens such as Trypanosoma ( sp ) . Overall , these results might open the way towards the identification of important variants involved in adaptation to tropical conditions and in particular to resistance to tropical infectious diseases .

Higher levels of activation markers and chemokine receptors on T lymphocytes in the cervix than peripheral blood of normal healthy women . Heterosexual transmission of human immunodeficiency virus ( HIV - 1 ) is the predominant mode of infection world-wide . To better understand sexual transmission of HIV - 1 in women we have analysed virus co-receptor and cellular activation marker expression on T lymphocyte subsets from the cervical epithelium and have made comparisons with peripheral blood T cells . Intraepithelial cervical T lymphocytes were obtained with a cytobrush , immunolabelled and analysed by flow cytometry . Activation markers ( Q07108 , CD25 and HLA-DR ) were found to be more highly expressed on cervical than on blood T lymphocytes . These higher levels of activation on cervical T lymphocyte subsets could facilitate HIV - 1 infection . P61073 REA was expressed at marginally higher levels than P51681 REA on T cells from the cervical epithelium and peripheral blood . Thus , the preferential transmission of macrophage tropic strains of HIV - 1 following sexual contact can not be explained solely on the expression of chemokine co-receptors by T lymphocyte subsets .

Molecular genetics of bipolar disorder . Bipolar disorder ( BPD ) is an often devastating illness characterized by extreme mood dysregulation . Although family , twin and adoption studies consistently indicate a strong genetic component , specific genes that contribute to the illness remain unclear . This study gives an overview of linkage studies of BPD , concluding that the regions with the best evidence for linkage include areas on chromosomes 2p , 4p , 4q , 6q , 8q , 11p , 12q , 13q , 16p , 16q , 18p , 18q , 21q , 22q and Xq . Association studies are summarized , which support a possible role for numerous candidate genes in BPD including P21964 REA , Q01959 REA , Q13639 REA , P21917 REA , P14416 REA , P28223 REA , 5 - HTT , the P59103 / G30 complex , Q9NRI5 , Q99572 REA , P21397 REA and P23560 REA . Animal models related to bipolar illness are also reviewed , with special attention paid to those with clear genetic implications . We conclude with suggestions for strategies that may help clarify the genetic bases of this complex illness .

Estrogenic chemicals at puberty change ERalpha in the hypothalamus of male and female rats . The effects of two environmental endocrine disruptors , the synthetic pharmaceutical estrogen DB00977 ( EE ) and bisphenol-A ( Q03001 REA ) , were analysed in male and female rats in a very sensitive developmental period , puberty . Immunohistochemistry was used to evaluate changes in the number of cells expressing estrogen receptors ( P03372 REA ) in the arcuate nucleus ( ARC ) , ventromedial nucleus ( VMH ) and medial preoptic area ( DB00603 MEN ) of the hypothalamus . Animals were treated during early puberty , from P01160 REA 23 to P01160 REA 30 , with EE and Q03001 REA given orally every day . They were then sacrificed and perfused on P01160 REA 37 or P01160 REA 90 , and blood and brains were collected for hormonal determination ( testosterone and estradiol ) and immunohistochemistry ( estrogen receptors , ER ) . At P01160 REA 37 , ER-labelled neurons were higher in males than in females in the ARC and DB00603 MEN . EE and Q03001 REA increased ER-labelled neurons in the ARC and DB00603 MEN . At P01160 REA 90 , females showed higher ER-labelled neurons in the VMH . EE and Q03001 REA increased ER-labelled neurons in the DB00603 MEN in females . EE increased testosterone in males at P01160 REA 37 and estradiol in females at P01160 REA 90 . These results indicate the ability of estrogenic chemicals to change the reproductive neural circuits during puberty in male and female rats .

Analysis of neurogenic contractions induced by ML - 1035 and other benzamides in the guinea-pig non-stimulated isolated ileum . 4 - Amino - 5 - chloro-substituted benzamides have been shown to increase gastric motility in-vivo and enhance field-stimulated and peristaltic contractions in-vitro . The present experiments examined the contractile response to a series of benzamides in the guinea-pig non-stimulated ileum . Four benzamides elicited contractions in the isolated ileum which were expressed as a percentage of the contraction induced by 1 microM acetylcholine ( % acetylcholine response = 12 + / - 2 , 19 + / - 3 , 26 + / - 2 , 51 + / - 3 , n = 13 , 8 , 17 , and 21 , with EC50 values of 0.85 , 1.8 , 5.7 , and 14.2 microM for cisapride , zacopride , metoclopramide , and ML - 1035 ( 4 - amino - 5 - chloro - 2 - ( ( 2 - methylsulphinyl ) - ethoxy ) - N - ( 2 - ( diethylamino ) - ethyl ) - benzamide hydrochloride ) , respectively ) . ML - 1035 contractions were completely blocked by atropine and tetrodotoxin , while ganglionic blockade with hexamethonium was ineffective . DB01233 SUB has been reported to sensitize postjunctional muscarinic receptors , however , ML - 1035 did not enhance acetylcholine-induced contractions . Tropisetron ( ICS 205-930 , 1 microM ) , caused a parallel rightward shift in the concentration-response curve for both ML - 1035 and zacopride ( EC50 = 14.2 + / - 1.3 and 1.8 + / - 0.8 microM in the absence , and 26 + / - 2.7 and 6.9 + / - 2.3 microM in the presence of tropisetron for ML - 1035 and zacopride , respectively ) with apparent pKB values of 5.9 and 6.0 for the respective compounds . 5 - Hydroxytryptaminergic receptor desensitization by 2 - methyl - 5 - hydroxytryptamine ( 5 - Q9H205 REA ) and 5 - methoxytryptamine ( Q13639 REA ) , attenuated the response to ML - 1035 . ( ABSTRACT TRUNCATED AT 250 WORDS )

Dopamine agonists upregulate P05231 REA and P10145 REA production in human keratinocytes . AIM : Catecholamines regulate functions of the nervous , neuroendocrine and immune systems . Dopamine may modulate the activity of keratinocytes , which play a role in secreting cytokines and chemokines . The aim of this study was to evaluate the effect of dopaminergic agonists on the production of P05231 REA and P10145 REA by a non-tumoral human keratinocyte cell line ( HaCaT ) . METHODS : Cells were stimulated with dopamine and the P14416 REA agonist cabergoline . Levels of P05231 REA and P10145 REA in culture supernatants were then determined . Cell proliferation was also assessed . Assays were carried out in the presence or absence of the dopaminergic and β-adrenergic receptor antagonists ( sulpiride and propranolol , respectively ) and ascorbic acid . RESULTS : Dopamine stimulated the production of P05231 REA and P10145 REA in a concentration-dependent manner . The effects observed on the secretion of P05231 REA were more potent than those corresponding to P10145 REA and were reduced by ascorbic acid . The dopamine-induced P05231 REA secretion was partially reduced by sulpiride and abrogated by propranolol . The latter drug was able to block the effect of dopamine on the secretion of P10145 REA . The cabergoline-induced P05231 REA release was reduced by sulpiride . Cell viability was not affected by any of the drugs . CONCLUSIONS : Dopaminergic agonists can stimulate keratinocytes to produce P05231 REA and P10145 REA which are related to inflammatory cutaneous processes . These effects are mediated by dopaminergic and β-adrenergic receptors and by receptor-independent oxidative mechanisms .

Effect of metoclopramide , ondansetron and granisetron on aldosterone secretion in man . The plasma aldosterone response following the administration of drugs with antagonist and agonist activity at Serotonin 3 and 4 ( 5 - Q9H205 REA & 4 ) receptors has been examined in 9 healthy male volunteers receiving the following four treatments i . v . in a randomised , cross-over sequence : ondansetron 8 mg , granisetron 3 mg , metoclopramide 20 mg , and saline 20 ml . DB01233 SUB significantly increased the mean plasma aldosterone level to 196 % of basal level at 5 min . It rose to 234 % at 15 min and remained at more than 185 % of basal level for the duration of the experiment . The response to ondansetron and granisetron did not differ significantly from placebo . If dopamine antagonism is discounted , the results suggest that metoclopramide-induced aldosterone secretion results from its agonist activity at Q13639 REA receptors , although slow neuronal depolarization via an unidentified receptor remains a possibility . Antagonism at the 5 - Q9H205 REA receptor plays no role , as the selective antagonist , granisetron , did not elicit a significant response . It seems unlikely that the Q13639 REA receptor is the second , low affinity binding site of ondansetron , unless it had no agonist activity at this receptor .

Characterization of plant P18887 REA and its interaction with proliferating cell nuclear antigen . In plants , there are no P06746 REA ( Pol beta ) and P49916 REA ( Lig 3 ) genes . Thus , the plant short-patch base excision repair ( short-patch BER ) pathway must differ considerably from that in mammals . We characterized the rice ( Oryza Sativa L . cv . Nipponbare ) homologue of the mammalian X-ray repair cross complementing 1 ( P18887 REA ) , a well-known BER protein . The plant P18887 REA lacks the N-terminal domain ( NTD ) which is required for Pol beta binding and is essential for mammalian cell survival . The recombinant rice P18887 REA ( OsXRCC 1 ) protein binds single-stranded DNA ( ssDNA ) as well as double-stranded DNA ( dsDNA ) and also interacts with rice proliferating cell nuclear antigen ( OsPCNA ) in a pull-down assay . Through immunoprecipitation , we demonstrated that OsXRCC 1 forms a complex with P12004 REA in vivo . OsXRCC 1 mRNA was expressed in all rice organs and was induced by application of bleomycin , but not of MMS , H ( 2 ) O ( 2 ) or UV-B . DB00290 MEN also increased the fraction of OsXRCC 1 associated with chromatin . These results suggest that OsXRCC 1 contributes to DNA repair pathways that differ from the mammalian BER system .

The P38936 REA codon 31 * C - and P14416 REA codon 313 * T-related genotypes / alleles , but not P18887 REA codon 399 , hOGG 1 codon 326 , and P21728 REA - 48 polymorphisms , are correlated with the presence of leiomyoma . OBJECTIVE : To investigate whether the gene polymorphisms for P38936 REA , X-ray repair cross-complementing group 1 ( P18887 REA ) , human 8 - oxoguanine glycosylase 1 ( hOGG 1 ) , and dopamine D1 and D2 receptors ( P21728 REA , - 2 ) are associated with leiomyoma susceptibility . DESIGN : Prospective study . SETTING : Departments of gynecology and genetics in a medical center . PATIENT ( S ) : Women were divided into two groups : leiomyoma ( n = 120 ) and nonleiomyoma ( n = 112 ) . INTERVENTION ( S ) : The P38936 REA codon 31 , P18887 REA codon 399 , hOGG 1 codon 326 , P21728 REA - 48 , and P14416 REA codon 313 polymorphisms were genotyped by polymerase chain reaction with restriction enzyme digestions ( Blp I , MspI , Fnu 4HI , Dde I , and NcoI , respectively ) . MAIN OUTCOME MEASURE ( S ) : Genotypes and allelic frequencies . RESULT ( S ) : The P38936 REA codon 31 ( * ) C - and P14416 REA codon 313 ( * ) T-related genotypes / alleles were associated with the presence of leiomyomas . The proportions of P38936 REA ( * ) CC / CA / AA and P14416 REA ( * ) CC / CT / TT in both groups were 27.5 / 68.3 / 4.2 % and 12.5 / 51.7 / 35.8 % ( leiomyoma ) ; and 14.3 / 51.8 / 33.9 % and 33.9 / 40.2 / 25.9 % ( nonleiomyoma ) . P18887 REA , hOGG 1 , and P21728 REA were not correlated with the presence of leiomyomas . P18887 REA ( * ) GG / GA / AA , hOGG 1 ( * ) TT / TA / AA , and P21728 REA ( * ) GG / GA / AA were 54.2 / 37.5 /8 . 3 % , 36.7 / 44.2 / 19.1 % , and 3.3 / 25.8 / 70.8 % ( leiomyoma ) ; and 48.2 / 47.3 / 4.5 % , 43.6 / 41/15 . 4 % , and 3.6 / 25/71 . 4 % ( nonleiomyoma ) . CONCLUSION ( S ) : The P38936 REA codon 31 ( * ) C - and P14416 REA codon 313 ( * ) T-related genotypes / alleles were associated with the presence of leiomyoma . P18887 REA , hOGG 1 , and P21728 REA were not correlated with leiomyoma development .

Enhanced incentive motivation for sucrose-paired cues in adolescent rats : possible roles for dopamine and opioid systems . Vulnerability to the effects of drugs of abuse during adolescence may be related to altered incentive motivation , a process believed to be important in addiction . Incentive motivation can be seen when a neutral stimulus acquires motivational properties through repeated association with a primary reinforcer . We compared adolescent ( postnatal day ( P01160 REA ) 24-50 ) and adult ( > P01160 REA 70 ) rats on a measure of incentive motivation : responding for a conditioned reinforcer ( CR ) . Rats learned to associate the delivery of 0.1 ml of 10 % sucrose with a conditioned stimulus ( CS ; light and tone ) ; 30 pairings per day were given over 14 days . Then , we measured responding on a lever delivering the CS ( now a CR ) after injections of amphetamine ( 0 , 0.25 or 0.5 mg / kg ) . We also examined responding for CR when the CS and sucrose were paired or unpaired during conditioning , and responding for the primary reinforcer ( 10 % sucrose ) in control experiments . Finally , we examined the effects of D ( 1 ) and P14416 REA antagonists ( P35240 REA 39166 and eticlopride , respectively ) and an opioid receptor antagonist ( naltrexone ) on responding for a CR in adolescent rats . Adolescents but not adults acquired responding for a CR , but adolescents responded less than adults for the primary reinforcer . Responding for a CR depended upon the pairing of the CS and sucrose during conditioning . Both dopamine and opioid receptor antagonists reduced responding for the CR . Therefore , incentive motivation may be enhanced in adolescents compared with adults , and incentive motivation may be mediated in part by both dopamine and opioid systems .

DB08827 MEN . Aegerion Pharmaceuticals is developing lomitapide , a small-molecule , microsomal triglyceride transfer protein ( P55157 REA ) inhibitor , for the treatment of both familial and primary hypercholesterolemia . Oral , once-daily lomitapide will be targeted at patients resistant to P04035 REA inhibitors ( statins ) either due to abnormalities in liver function or to discontinuation because of muscle pain . An oral formulation of lomitapide is in phase III development for homozygous familial hypercholesterolemia ( hyperlipoproteinemia type IIa ) in the US , Canada , Italy , and South Africa . This review discusses the key development milestones and therapeutic trials of this drug .

Investigation of Q13639 REA receptors in bronchial hyperresponsiveness in cigarette smoke-exposed mice . BACKGROUND : Chronic obstructive pulmonary disease ( P48444 REA ) arises from an interaction between genetic host factors and environmental exposures ( mainly cigarette smoke ( CS ) ) . Genome Wide Association studies have demonstrated that genetic variations in the gene encoding 5 - hydroxytryptamine 4 receptors ( 5 - HT ( 4 ) R ) , Q13639 REA , were associated with measures of airway obstruction and with P48444 REA . We hypothesised that 5 - HT ( 4 ) receptors , in addition to 5 - HT2AR and muscarinic receptors , contribute to the pathogenesis of P48444 REA by facilitating cholinergic bronchoconstriction . METHODS : The levels of pulmonary 5 - HT ( 4 ) R mRNA were measured in CS-exposed mice by qRT-PCR . We investigated the effect of CS exposure on bronchial hyperresponsiveness ( BHR ) to 5 - HT and evaluated the contribution of 5 - HT2AR , muscarinic receptors and 5 - HT ( 4 ) R in the response to 5 - HT by using the corresponding antagonists and 5 - HT ( 4 ) R knockout ( KO ) mice . RESULTS : The 5 - HT ( 4 ) R mRNA levels were significantly elevated upon acute ( 3 days ) , subacute ( 4 weeks ) and chronic ( 24 weeks ) CS exposure . Both acute and subacute CS exposure significantly increased BHR to 5 - HT . Antagonism of 5 - HT2AR abolished the CS-induced BHR to 5 - HT , and antagonism of muscarinic receptors significantly reduced the response to 5 - HT . However , pre-treatment with GR113808 , a specific 5 - HT ( 4 ) R antagonist , did not alter the response to 5 - HT in CS-exposed mice . Accordingly , the CS-induced BHR to 5 - HT was not different between wild-type and 5 - HT ( 4 ) R KO mice . CONCLUSION : CS increased the levels of 5 - HT ( 4 ) R mRNA in the lungs , concomitantly with bronchial responsiveness to 5 - HT . Our in vivo data using pharmacologic and genetic approaches suggest that 5 - HT ( 4 ) receptors are not involved in the BHR to 5 - HT in CS-exposed mice .

Microsomal transfer protein ( P55157 REA ) inhibition-a novel approach to the treatment of homozygous hypercholesterolemia . Homozygous familial hypercholesterolemia ( HoFH ) represents the most severe lipoprotein disorder , generally attributable to mutation ( s ) of the low-density lipoprotein receptor ( LDL-R ) , i . e . autosomal dominant hypercholesterolemia type 1 ( P07327 REA ) . Much lower percentages are due to alterations of apolipoprotein B ( P00325 REA ) , or gain-of-function mutations of proprotein convertase subtilisin / kexin type 9 ( Q8NBP7 ) ( P00326 REA ) . In certain geographical areas a significant number of patients may be affected by an autosomal recessive hypercholesterolemia ( Q5SW96 ) . Mutations may be also combined ( two mutations of the same gene , compound heterozygosity ) , or two in different genes ( double heterozygosity ) . Among the most innovative therapeutic approaches made available recently , inhibitors of the microsomal transfer protein ( P55157 REA ) system have shown a high clinical potential . P55157 REA plays a critical role in the assembly / secretion of very-low-density lipoproteins ( VLDL ) , and its absence leads to apo B deficiency . P55157 REA antagonists dramatically lower LDL-cholesterol ( LDL-C ) in animals , although a reported increase of liver fat delayed their clinical development . DB08827 MEN , the best-studied P55157 REA inhibitor , reduces LDL-C by 50 % or more in HoFH patients , with modest , reversible , liver steatosis . Recent US approval has confirmed an acceptable tolerability , provided patients adhere to a strictly low-fat regimen . There are no clinical data on atherosclerosis reduction / regression , but animal models provide encouraging results .

Effects of the total saponins from Rosa laevigata Michx fruit against acetaminophen-induced liver damage in mice via induction of autophagy and suppression of inflammation and apoptosis . The effect of the total saponins from Rosa laevigata Michx fruit ( RLTS ) against acetaminophen ( DB00316 MEN ) - induced liver damage in mice was evaluated in the present paper . The results showed that RLTS markedly improved the levels of liver SOD , CAT , DB00143 , DB00143 - Px , MDA , NO and P35228 REA , and the activities of serum ALT and Q9NRA2 caused by DB00316 MEN . Further research confirmed that RLTS prevented fragmentation of DNA and mitochondrial ultrastructural alterations based on TdT-mediated dUTP nick end labeling ( TUNEL ) and transmission electron microscopy ( TEM ) assays . In addition , RLTS decreased the gene or protein expressions of cytochrome P450 ( P05181 REA ) , pro-inflammatory mediators ( IL - 1β , P05112 REA , P05231 REA , P01375 REA - α , P35228 REA , Bax , HMGB - 1 and P35354 REA ) , pro-inflammatory transcription factors ( NF-κB and AP - 1 ) , pro-apoptotic proteins ( cytochrome C , p53 , caspase - 3 , caspase - 9 , p-JNK , p-p 38 and p - P29323 REA ) , and increased the protein expressions of Bcl - 2 and Bcl-xL . Moreover , the gene expression of P22301 REA , and the proteins including LC3 , Q14457 REA and Atg 5 induced by DB00316 MEN were even more augmented by the extract . These results demonstrate that RLTS has hepatoprotective effects through antioxidative action , induction of autophagy , and suppression of inflammation and apoptosis , and could be developed as a potential candidate to treat DB00316 MEN - induced liver damage in the future .

DB01233 SUB stimulates catecholamine - and granin-derived peptide secretion from pheochromocytoma cells through activation of serotonin type 4 ( Q13639 REA ) receptors . The gastroprokinetic agent metoclopramide is known to stimulate catecholamine secretion from pheochromocytomas . The aim of the study was to investigate the mechanism of action of metoclopramide and expression of serotonin type 4 ( 5 - HT ( 4 ) ) receptors in pheochromocytoma tissues . Tissue explants , obtained from 18 pheochromocytomas including the tumor removed from a 46 - year-old female patient who experienced life-threatening hypertension crisis after metoclopramide administration and 17 additional pheochromocytomas ( 9 benign and 8 malignant ) were studied . Cultured pheochromocytoma cells derived from the patient who previously received metoclopramide were incubated with metoclopramide and various 5 - HT ( 4 ) receptor ligands . In addition , total mRNAs were extracted from all the 18 tumors . Catecholamine - and granin-derived peptide concentrations were measured in pheochromocytoma cell incubation medium by HPLC and radioimmunological assays . In addition , expression of 5 - HT ( 4 ) receptor mRNAs in the 18 pheochromocytomas was investigated by the use of reverse transcriptase-PCR . RESULTS : DB01233 SUB and the 5 - HT ( 4 ) receptor agonist cisapride were found to activate catecholamine - and granin-derived peptide secretions by cultured tumor cells . DB01233 SUB - and cisapride-evoked catecholamine - and granin-derived peptide productions were inhibited by the 5 - HT ( 4 ) receptor antagonist GR 113808 . 5 - HT ( 4 ) receptor mRNAs were detected in the patient ' s tumor and the series of 17 additional pheochromocytomas . This study shows that pheochromocytomas express functional 5 - HT ( 4 ) receptors that are responsible for the stimulatory action of metoclopramide on catecholamine - and granin-derived peptide secretion . All 5 - HT ( 4 ) receptor agonists must therefore be contraindicated in patients with proven or suspected pheochromocytoma .

Effects of metoclopramide and tropisetron on aldosterone secretion possibly due to agonism and antagonism at the Q13639 REA receptor . OBJECTIVE : Part of the prokinetic activity of metoclopramide can possibly be ascribed to agonist activity at Q13639 REA receptors . The 5 - Q9H205 REA antagonist tropisetron is thought to act as an antagonist at Q13639 REA receptors . In the present study aldosterone secretion in response to the administration of these two drugs was explored to examine the role of the Q13639 REA receptor in aldosterone secretion . METHODS : Following a single-blind , random design , ten normal male volunteers received one of the following regimens on three occasions , with at least 2 - week intervals : metoclopramide 10 mg i . v . ; tropisetron 5 mg by slow i . v . i . , or ; tropisetron by slow i . v . i . , followed by 10 mg metoclopramide i . v . RESULTS : In response to metoclopramide alone the mean plasma aldosterone level rose significantly to 149 % of basal level and remained significantly elevated for the next 20 min . With tropisetron alone , there was a significant 37.8 % drop at 60 min and the aldosterone levels remained low for the duration of the experiment . DB01233 SUB reversed the decline mediated by tropisetron significantly at 30 and 90 min . DB04630 levels after the latter regimen also did not differ significantly from baseline at any time period . CONCLUSION : These results would suggest the existence of a tonic stimulatory influence of 5 - HT via Q13639 REA receptors on aldosterone secretion , which could be augmented by metoclopramide and blocked by tropisetron . However , the effect of tropisetron per se should be interpreted with caution given the lack of a saline group .

Efficacy and safety of repeated dosing of netupitant , a neurokinin - 1 receptor antagonist , in treating overactive bladder . AIM : NK - 1 receptors in sensory nerves , the spinal cord and bladder smooth muscle participate in complex sensory mechanisms that regulate bladder activity . This study was designed to assess the efficacy and safety of a new P25103 REA antagonist , netupitant , in patients with OAB . METHODS : This was a phase II , multicenter , double-blind study in which adults with OAB symptoms > 6 months were randomized to receive 1 of 3 doses of netupitant ( 50 , 100 , 200 mg ) or placebo once daily for 8 weeks . The primary efficacy endpoint was percentage change from baseline in average number of daily micturitions at week 8 . Urinary incontinence , urge urinary incontinence ( UUI ) , and urgency episodes were also assessed . RESULTS : The primary efficacy endpoint was similar in the treatment groups ( -13.85 for placebo to -16.17 in the netupitant 200 mg group ) with no statistically significant differences between netupitant and placebo . The same was true for most secondary endpoints although a significant difference for improvement in UUI episodes and a trend for the greatest decrease in urgency episodes were seen in the netupitant 100 mg group . DB09048 MEN was well tolerated with most treatment emergent adverse events ( AEs ) being mild . While the overall incidence of AEs increased with netupitant dose , there was no evidence for this dose dependency based on relationship to treatment , intensity , or time to onset . CONCLUSIONS : The study failed to demonstrate superiority of netupitant versus placebo in decreasing OAB symptoms , despite a trend favoring netupitant 100 mg . There were no safety concerns with daily administration of netupitant over 8 weeks .

[ Role of neurokinin - 1 receptor in lung injury in rats with acute necrotizing pancreatitis ] . OBJECTIVE : To investigate the expression of neurokinin - 1 receptor ( P25103 REA ) in the lung tissue , and the relationship between expression of P25103 REA and lung injury in rats with acute necrotizing pancreatitis ( P01160 REA ) . METHODS : One hundred and twenty adult Sprague-Dawley rats were randomly divided into P01160 REA and control groups . Animals in group P01160 REA were induced by the retrograde intraductal infusion of 5 % sodium taurocholate ( 0.1 ml / kg ) , and animals in normal control group received laparotomy only . The accumulation of polymorphonuclear leukocytes in lung tissues was measured with myeloperoxidase ( P05164 REA ) assay . Lung endothelial barrier destruction was measured by lung capillary permeability ( LCP ) . Reverse transcription polymerase chain reaction ( RT-PCR ) was used to determine the mRNA expression of P25103 REA , western blot analysis was used to determine P25103 REA protein expression levels , and immunohistochemistry was used to localize expression site of P25103 REA . RESULTS : P25103 REA mRNA level was enhanced in the lung of P01160 REA compared with normal control group . Western blot analysis showed overexpression of P25103 REA protein level exited in P01160 REA group . Statistical analysis revealed correlation between P25103 REA mRNA and P05164 REA ( r = 0.83 , P < 0.01 ) and LCP ( r = 0.79 , P < 0.01 ) respectively . With immunohistochemistry staining , moderate to strong P25103 REA immunoreactivity was localized to alveolar membrane , I epithelium , II epithelium and polymorphonuclear leukocytes in the lung of P01160 REA . CONCLUSION : In P01160 REA , overexpression of P25103 REA contributes to disturbance of neuropeptides loop , resulting in aggregation of neutrophilic granulocyte and promoting deterioration of lung injury .

Effects of enhancement and antagonism of 5 - hydroxytryptamine activity on the influence of metoclopramide on gastric emptying . This study examines the influence of the serotonergic system on the effect of metoclopramide on gastric emptying . Six subjects received the following pretreatments before metoclopramide and paracetamol : fluoxetine ( 5 - HT uptake inhibitor ) ; meterogoline ( 5 - HT1 antagonist ) ; pizotifen ( 5 - HT2 antagonist ) or methysergide ( 5 - HT1 and 5 - HT2 antagonist ) . One regimen consisted of metoclopramide ( 5 - Q9H205 REA antagonist and Q13639 REA agonist ) alone . Gastric emptying was measured by the mean cumulative fraction absorbed-time profiles of paracetamol . Methysergide / metoclopramide significantly delayed gastric emptying from 30 min onwards . DB01233 SUB with either metergoline or pizotifen did not retard gastric emptying to the same extent , suggesting a greater influence with simultaneous 5 - HT1 and 5HT2 blockade . DB01233 SUB / fluoxetine caused a significant decrease in the fractional absorption of paracetamol at 5 min when compared to the metoclopramide regimen . It was assumed that the influence of metoclopramide was not optimal at this stage , therefore possibly indicating domination of 5 - Q9H205 REA over Q13639 REA effects , resulting in gastric delay . It therefore seems as if all the 5 - HT receptors present in the gut have a role to play in the control of gastric emptying .

Q9NQ38 and P07550 REA haplotypes are risk factors for asthma in Mexican pediatric patients . BACKGROUND : Asthma is one of the most common respiratory diseases worldwide , and the complexity of its etiology has been widely documented . Chromosome 5q31 - 33 is one of the main loci implicated in asthma and asthma-related traits . P35225 REA , P08571 REA and P07550 REA , which are located in this risk locus , are among the genes most strongly associated with asthma susceptibility . OBJECTIVES : This study evaluated whether single-nucleotide polymorphisms or haplotypes at 5q31 - 33 conferred risk for asthma in Mexican-Mestizo pediatric patients . METHODS : We performed a case-controlled study including 851 individuals , 421 of them affected with childhood-onset asthma and 430 ethnically matched unaffected subjects . We used the TaqMan Allelic Discrimination Assay to genotype 20 single-nucleotide polymorphisms within P05113 REA , Q92878 REA , P35225 REA , P05112 REA , P08571 REA , Q9NQ38 , Q13639 REA , P07550 REA and P29460 REA . RESULTS : Although no association was detected for any risk allele , three Q9NQ38 haplotypes ( O75223 REA : p = 6 × 10 ( - 6 ) ; AATC : p = 0.0001 ; AGTT : p = 0.0001 ) and five P07550 REA haplotypes ( AGGACC : p = 0.0014 ; AGGAAG : p = 0.0002 ; TGAGAG : p = 0.0001 ; AGGAAC : p = 0.0002 ; AAGGAG : p = 0.003 ) were associated with asthma . Notably , the AGTT Q9NQ38 haplotype exhibited a male gender-dependent association ( p = 7.6 × 10 ( - 5 ) ) . CONCLUSION : Our results suggest that Q9NQ38 and P07550 REA haplotypes might play a role in the susceptibility to childhood-onset asthma .

DB01233 SUB does not increase gastric muscle contractility in newborn rats . Feeding intolerance resulting from delayed gastric emptying is common in premature neonates . DB01233 SUB ( MCP ) , the most frequently used prokinetic drug in neonates , enhances gastric muscle contractility through inhibition of dopamine receptors . Although its therapeutic benefit is established in adults , limited data are available to support its clinical use in infants . Hypothesizing that developmentally dependent differences are present , we comparatively evaluated the effect of MCP on fundus muscle contractility in newborn , juvenile , and adult rats . The muscle strips were either contracted with electrical field stimulation ( O43281 ) to induce cholinergic nerve-mediated acetylcholine release or carbachol , a cholinergic agonist acting directly on the muscarinic receptor . Although in adult rats MCP increased O43281 - induced contraction by 294 ± 122 % of control ( P < 0.01 ) , no significant effect was observed in newborn fundic muscle . MCP had no effect on the magnitude of the carbachol-induced and / or bethanechol-induced gastric muscle contraction at any age . In response to dopamine , an 80.7 ± 5.3 % relaxation of adult fundic muscle was observed , compared with only a 8.4 ± 8.7 % response in newborn tissue ( P < 0.01 ) . P14416 REA expression was scant in neonates and significantly increased in adult gastric tissue ( P < 0.01 ) . In conclusion , the lack of MCP effect on the newborn fundic muscle contraction potential relates to developmental differences in dopamine D2 receptor expression . To the extent that these novel data can be extrapolated to neonates , the therapeutic value of MCP as a prokinetic agent early in life requires further evaluation .

Chronic atrial fibrillation alters the functional properties of If in the human atrium . INTRODUCTION : Despite the evidence that the hyperpolarization-activated current ( If ) is highly modulated in human cardiomyopathies , no definite data exist in chronic atrial fibrillation ( cAF ) . We investigated the expression , function , and modulation of If in human cAF . METHODS AND RESULTS : Right atrial samples were obtained from sinus rhythm ( SR , n = 49 ) or cAF ( duration > 1 year , n = 31 ) patients undergoing corrective cardiac surgery . Among f-channel isoforms expressed in the human atrium ( O60741 REA , 2 and 4 ) , Q9Y3Q4 REA mRNA levels measured by RT-PCR were significantly reduced . However , protein expression was preserved in cAF compared to SR ( + 85 % for Q9Y3Q4 REA ) ; concurrently , miR - 1 expression was significantly reduced . In patch-clamped atrial myocytes , current-specific conductance ( gf ) was significantly increased in cAF at voltages around the threshold for If activation ( - 60 to - 80 mV ) ; accordingly , a 10 - mV rightward shift of the activation curve occurred ( P < 0.01 ) . β-Adrenergic and Q13639 REA receptor stimulation exerted similar effects on If in cAF and SR cells , while the P01160 REA - mediated effect was significantly reduced ( P < 0.02 ) , suggesting downregulation of natriuretic peptide signaling . CONCLUSIONS : In human cAF modifications in transcriptional and posttranscriptional mechanisms of HCN channels occur , associated with a slight yet significant gain-of-function of If , which may contribute to enhanced atrial ectopy .

Clinical and genetic factors associated with nausea and vomiting in cancer patients receiving opioids . BACKGROUND : This study investigates whether demographical , disease-related and genetic factors contribute to inter-individual differences in nausea and vomiting among patients receiving opioids for cancer pain . METHODS : Cancer patients receiving opioids were included from 17 centres in 11 European countries . Intensities of nausea and vomiting were reported by 1579 patients on four-point categorical scales . In stratified regression models including demographical and disease-related factors as covariates , 96 single nucleotide polymorphisms ( SNPs ) in 16 candidate genes related to opioid - or nausea / vomiting signalling pathways ( P08183 REA , P35372 REA , P41145 REA , P32121 REA , P42226 REA , P21964 REA , P20309 REA , P08912 REA , P35367 REA , P14416 REA , P35462 REA , P25103 REA , P46098 REA , O95264 REA , Q8WXA8 , P21554 REA ) were analysed for association with nausea and vomiting . FINDINGS : Age , body mass index , Karnofsky Performance Status , gender , use of antiemetics , type of opioid , type of cancer and eight SNPs were associated with the inter-individual differences in nausea and vomiting among cancer patients treated with opioids ( p < 0.01 ) . The SNPs were rs1176744 , rs3782025 and rs1672717 in O95264 REA ; rs165722 , rs4680 and rs4633 in P21964 REA ; rs10802789 and rs685550 in P20309 REA . Only the SNP rs1672717 in O95264 REA passed the Benjamini-Hochberg criterion for a 10 % false discovery rate . INTERPRETATION : Clinical characteristics and SNPs within the O95264 REA , P21964 REA and P20309 REA genes may be associated with the variability in nausea and vomiting among cancer patients receiving opioids . This knowledge may help to identify patients at particular risk for nausea and vomiting during treatment with opioids for cancer pain .

Dual P00533 REA and P42345 REA targeting in squamous cell carcinoma models , and development of early markers of efficacy . The epidermal growth factor receptor ( P00533 REA ) is a validated target in squamous cell carcinoma ( SCC ) of the head and neck . Most patients , however , do not respond or develop resistance to this agent . P42345 REA ( P42345 REA ) is involved in the pathogenesis of SCC of the head and neck ( SCCHN ) . This study aimed to determine if targeting P42345 REA in combination with P00533 REA is effective in SCC , and to develop early pharmacodynamic markers of efficacy . Two SCC cell lines , one resistant ( HEP 2 ) and one of intermediate susceptibility ( Detroit 562 ) to P00533 REA inhibitors , were xenografted in vivo and treated with an P42345 REA inhibitor ( temsirolimus ) , an P00533 REA inhibitor ( erlotinib ) or a combination of both . DB06287 MEN exerted superior growth arrest in both cell lines than erlotinib . The combined treatment resulted in synergistic antitumor effects in the Detroit 562 cell line . Immunohistochemical assessment of pharmacodynamic effects in fine-needle aspiration ( FNA ) biopsies early after treatment using phospho MAPK , Phospho-P 70 and Ki67 as end points demonstrated pathway abrogation in the Detroit 562 tumours treated with the combination , the only group where regressions were seen . In conclusion , an P42345 REA inhibitor showed antitumor activity in P00533 REA - resistant SCC cell lines . Marked antitumor effects were associated with dual pathway inhibition , which were detected by early FNA biopsies .

Oral keratinocytes support non-replicative infection and transfer of harbored HIV - 1 to permissive cells . BACKGROUND : Oral keratinocytes on the mucosal surface are frequently exposed to HIV - 1 through contact with infected sexual partners or nursing mothers . To determine the plausibility that oral keratinocytes are primary targets of HIV - 1 , we tested the hypothesis that HIV - 1 infects oral keratinocytes in a restricted manner . RESULTS : To study the fate of HIV - 1 , immortalized oral keratinocytes ( OKF 6 / O14746 REA - 2 ; O14746 REA - 2 cells ) were characterized for the fate of HIV-specific RNA and DNA . At 6 h post inoculation with X4 or R5 - tropic HIV - 1 , HIV - 1gag RNA was detected maximally within O14746 REA - 2 cells . Reverse transcriptase activity in O14746 REA - 2 cells was confirmed by VSV-G-mediated infection with HIV-NL 4-3 Deltaenv-EGFP . DB00495 MEN inhibited EGFP expression in a dose-dependent manner , suggesting that viral replication can be supported if receptors are bypassed . Within 3 h post inoculation , integrated HIV - 1 DNA was detected in O14746 REA - 2 cell nuclei and persisted after subculture . Multiply spliced and unspliced HIV - 1 mRNAs were not detectable up to 72 h post inoculation , suggesting that HIV replication may abort and that infection is non-productive . Within 48 h post inoculation , however , virus harbored by P01730 REA negative O14746 REA - 2 cells trans infected co-cultured peripheral blood mononuclear cells ( PBMCs ) or MOLT 4 cells ( P01730 REA + P51681 REA + ) by direct cell-to-cell transfer or by releasing low levels of infectious virions . Primary tonsil epithelial cells also trans infected HIV - 1 to permissive cells in a donor-specific manner . CONCLUSION : Oral keratinocytes appear , therefore , to support stable non-replicative integration , while harboring and transmitting infectious X4 - or R5 - tropic HIV - 1 to permissive cells for up to 48 h .

Genetics of bipolar disorder . Many linkage loci and candidate genes have been reported in molecular genetic studies of bipolar disorder . However , none of these findings have been consistently replicated . Meta-analyses of linkage studies have also reported conflicting results . Among recently reported candidate genes , P23560 REA , P59103 , P31749 REA , Q12879 REA , P17861 REA , P35626 REA , Q13639 REA , O14732 REA and P14867 REA may have some importance . Study of the possible roles of epigenetics or analysis of genetic diseases , in which bipolar disorder is one of phenotypes , may also be promising . In addition to monoaminergic and intracellular signaling pathways , recent studies have revealed possible roles for mitochondrial dysfunction , for glutamatergic dysfunction and for the endoplasmic reticulum stress pathway .

Identification of novel genetic alterations in samples of malignant glioma patients . Glioblastoma is the most frequent and malignant human brain tumor . High level of genomic instability detected in glioma cells implies that numerous genetic alterations accumulate during glioma pathogenesis . We investigated alterations in AP-PCR DNA profiles of 30 glioma patients , and detected specific changes in 11 genes not previously associated with this disease : Q86UP9 , Q13326 , Q13639 REA , P05556 REA , P31327 REA , P07225 REA , P55259 REA , Q9UJ96 , Q08499 REA , Q8N743 , and Q14642 REA . Further correlations revealed that 8 genes might play important role in pathogenesis of glial tumors , while changes in P55259 REA , Q9UJ96 and Q8N743 should be considered as passenger mutations , consequence of high level of genomic instability . Identified genes have a significant role in signal transduction or cell adhesion , which are important processes for cancer development and progression . According to our results , Q86UP9 might be characteristic of primary glioblastoma , Q13326 , Q13639 REA , P05556 REA , P31327 REA , P07225 REA and Q14642 REA were detected predominantly in anaplastic astrocytoma , suggesting their role in progression of secondary glioblastoma , while alterations of Q08499 REA seem to have important role in development of both glioblastoma subtypes . Some of the identified genes showed significant association with p53 , p16 , and P00533 REA , but there was no significant correlation between loss of P60484 REA and any of identified genes . In conclusion our study revealed genetic alterations that were not previously associated with glioma pathogenesis and could be potentially used as molecular markers of different glioblastoma subtypes .