bluuebunny/crossref_metadata_2025_split huggingface dataset:
The intrinsic innervation of the lung is derived from neural crest cells as shown by optical projection tomography in Wnt1‐Cre;YFP reporter mice
Authors: Freem Lucy J. , Escot Sophie , Tannahill David , Druckenbrod Noah R. , Thapar Nikhil , Burns Alan J. 
Published: September 2010

AbstractWithin the embryonic lung, intrinsic nerve ganglia, which innervate airway smooth muscle, are required for normal lung development and function. We studied the development of neural crest‐derived intrinsic neurons within the embryonic mouse lung by crossing Wnt1‐Cre mice with R26R‐EYFP reporter mice to generate double transgenic mice that express yellow fluorescent protein (YFP) in all neural crest cells (NCCs) and their derivatives. In addition to utilizing conventional immunohistochemistry on frozen lung sections, the complex organization of lung innervation was visualized in three dimensions by combining the genetic labelling of NCCs with optical projection tomography, a novel imaging technique that is particularly useful for the 3D examination of developing organs within embryos. YFP‐positive NCCs migrated into the mouse lung from the oesophagus region at embryonic day 10.5. These cells subsequently accumulated around the bronchi and epithelial tubules of the lung and, as shown by 3D lung reconstructions with optical projection tomography imaging, formed an extensive, branching network in association with the developing airways. YFP‐positive cells also colonized lung maintained in organotypic culture, and responded in a chemoattractive manner to the proto‐oncogene, rearranged during transfection (RET) ligand, glial‐cell‐line‐derived neurotrophic factor (GDNF), suggesting that the RET signalling pathway is involved in neuronal development within the lung. However, when the lungs of Ret−/− and Gfrα1−/− embryos, deficient in the RET receptor and GDNF family receptor α 1 (GFRα1) co‐receptor respectively, were examined, no major differences in the extent of lung innervation were observed. Our findings demonstrate that intrinsic neurons of the mouse lung are derived from NCCs and that, although implicated in the development of these cells, the role of the RET signalling pathway requires further investigation.
First‐trimester placental protein 13 and placental growth factor: markers for identification of women destined to develop early‐onset pre‐eclampsia
Authors: Wortelboer EJ , Koster MPH , Cuckle HS , Stoutenbeek Ph , Schielen PCJI , Visser GHA 
Published: September 2010

Please cite this paper as: Wortelboer E, Koster M, Cuckle H, Stoutenbeek P, Schielen P, Visser G. First‐trimester placental protein 13 and placental growth factor: markers for identification of women destined to develop early‐onset pre‐eclampsia. BJOG 2010;117:1384–1389.Objective  To investigate the predictive value of maternal serum pregnancy‐associated plasma protein A (PAPP‐A), free β subunit of human chorionic gonadotrophin (fβ‐hCG), placental protein 13 (PP13), placental growth factor (PlGF) and a desintegrin and metalloproteinase 12 (ADAM12), for first‐trimester identification of early‐onset pre‐eclampsia.Design  Nested case–control study.Setting  Routine first‐trimester screening for trisomy 21 in the Netherlands.Population  Eighty‐eight women who developed pre‐eclampsia or haemolysis, elevated liver enzymes, low platelets (HELLP) syndrome before 34 weeks of gestation and 480 controls.Methods  PP13, PlGF and ADAM12 were measured in stored first‐trimester serum, previously tested for PAPP‐A and fβ‐hCG. All marker levels were expressed in multiples of the gestation‐specific normal median (MoMs). Model predicted detection rates for fixed false‐positive rates were obtained for statistically significant markers alone and in combination.Main outcome measures  Development of pre‐eclampsia or HELLP syndrome.Results  PP13 and PlGF were reduced in women with pre‐eclampsia, with medians 0.68 MoM and 0.73 MoM respectively (P < 0.0001 for both). PAPP‐A was reduced (median 0.82 MoM, P < 0.02) whereas ADAM12 and fβ‐hCG did not differ between control women and those with pre‐eclampsia. In pre‐eclampsia complicated by a small‐for‐gestational‐age fetus, all markers except fβ‐hCG had lower values, compared with pregnancies involving fetuses of normal weight. The model‐predicted pre‐eclampsia detection rate for a combination of PP13 and PlGF was 44% and 54%, respectively, for a fixed 5% and 10% false‐positive rate.Conclusion  This study demonstrates that PP13 and PlGF in the first‐trimester might be promising markers in risk assessment for early pre‐eclampsia/HELLP syndrome but for an adequate screening test additional characteristics are necessary.
Periodontal infection and preterm birth: successful periodontal therapy reduces the risk of preterm birth
Authors: Jeffcoat M , Parry S , Sammel M , Clothier B , Catlin A , Macones G 
Published: September 2010

Please cite this paper as: Jeffcoat M, Parry S, Sammel M, Clothier B, Catlin A, Macones G. Periodontal infection and preterm birth: successful periodontal therapy reduces the risk of preterm birth. BJOG 2011;118:250–256.Objective  This study tested the hypothesis that successful periodontal treatment was associated with a reduction in the incidence of spontaneous preterm birth (PTB).Design  This was a randomised, controlled, blinded clinical trial.Setting  Hospital outpatient clinic.Population  Pregnant women of 6–20 weeks of gestation were eligible.Methods  Of 322 pregnant women with periodontal disease, 160 were randomly assigned to receive scaling and root planing (SRP, cleaning above and below the gum line), plus oral hygiene instruction, whereas the remaining 162 received only oral hygiene instruction and served as an untreated control group. Subjects received periodontal examinations before and 20 weeks after SRP, and were classified blindly according to the results of treatment into two groups: successful (‘non‐exposure’) and unsuccessful (‘exposure’) treatment. Groups were compared using standard inferential statistics; dichotomous variables were compared using the chi‐square test or logistic regression. Results are presented in terms of odds ratios.Main outcome measure  The main outcome measure was spontaneous preterm birth before 35 weeks of gestation.Results  No significant difference was found between the incidence of PTB in the control group (52.4%; n = 162) and the periodontal treatment group (45.6%; n = 160) (P < 0.13, Fisher’s exact test). The incidence of PTB was compared within the periodontal treatment group, considering the success of therapy. A logistic regression analysis showed a strong and significant relationship between successful periodontal treatment and full‐term birth (adjusted odds ratio 6.02; 95% CI 2.57–14.03). Subjects refractory to periodontal treatment were significantly more likely to have PTB.Conclusions  A beneficial effect on PTB may be dependent on the success of periodontal treatment.
THE CARDIOVASCULAR EFFECTS OF CENTRALLY ADMINISTERED 5‐HYDROXYTRYPTAMINE IN THE CONSCIOUS NORMOTENSIVE AND HYPERTENSIVE RAT
Authors: DALTON D. W. 
Published: September 2010

The cardiovascular effects of centrally administered 5‐hydroxytryptamine (5‐HT) have been analysed in conscious normotensive and hypertensive rats.
In conscious normotensive rats, 5‐HT, (1–30 μg) administered intracerebroventricularly (i.c.v.) produced profound and immediate dose‐related decreases in heart rate and small increases in blood pressure. The initial pressor responses were followed by secondary secondary depressor responses at high doses of 5‐HT.
Similar effects were produced by 5‐HT i.c.v. in conscious DOCA‐salt and spontaneously hypertensive rats, although the magnitude of the pressor responses was substantially greater in hypertensive than normotensive rats.
Pretreatment with either N‐methylatropine or atenolol intra‐arterially reduced the 5‐HT‐induced bradycardia in normotensive rats; the reduction was enhanced when both antagonists were given in combination.
The 5‐HT2 antagonist, cyproheptadine (10 μg i.c.v.) increased basal blood pressure and heart rate in normotensive rats. Subsequent administration of 5‐HT i.c.v. produced biphasic effects on heart rate consisting of an initial tachycardia followed by a marked bradycardia.
Methysergide (10 μg i.c.v.) pretreatment did not alter resting heart rate, but attenuated the 5‐HT induced bradycardia. A higher dose of methysergide, (30 μg i.c.v.), decreased resting blood pressure and heart rate.
This study has demonstrated, therefore, that the 5‐HT induced bradycardia is produced by not only a centrally mediated decrease in sympathetic tone, but also an increase in vagal drive to the heart. The bradycardia is antagonised by centrally administered methysergide, but not by cyproheptadine, which suggests that it is probably mediated through a ‘5‐HT1‐like’ receptor mechanism.
NEUROPEPTIDE Y INDUCES AND MODULATES VASOCONSTRICTION IN INTRACRANIAL AND PERIPHERAL VESSELS OF ANIMALS AND MAN
Authors: HANKO J. H. , TÖRNEBRANDT K. , HARDEBO J. E. , KÅHRSTRÖM J. , NOBIN A. , OWMAN CH. 
Published: September 2010

Neuropeptide Y (NPY) has recently been reported to coexist with noradrenaline (NA) in central as well as peripheral noradrenergic nerves. NPY‐containing nerve fibres are particularly numerous around blood vessels.
Studies were performed on isolated pial arteries as well as on arteries and veins from several peripheral vascular beds from rabbit, cat and man. NPY induced a varying degree of direct contraction of the vessels with an EAm up to 15 mN. Pial arteries were more sensitive than peripheral arteries to NPY (mean EC50 = 7.6 × 10−9 M). The presence of NPY did not cause any consistent or significant potentiation of the contractile response to NA in any of the vessels tested.
Transmural electrical stimulation of the perivascular nerves (including blockade with tetrodotoxin) was performed mainly with auricular artery from the rabbit. Blocking experiments confirmed that the neurogenic contraction was mediated by noradrenergic‐type fibres. NPY caused a concentration‐related potentiation of the neurally evoked contractile response. The peptide also potentiated the tetrodotoxin‐resistant probably non‐neurogenic contractions obtained during enhanced electrical field stimulation.
It is concluded that NPY interacts with NA during sympathetic nerve activation primarily through a presynaptic effect.
A STUDY ON THE POSTJUNCTIONAL EXCITATORY α‐ADRENORECEPTOR SUBTYPES IN THE MESENTERIC ARTERIAL BED OF THE RAT
Authors: PIPILI EVA 
Published: September 2010

The nature of the postsynaptic adrenoreceptor subtypes which mediate vasoconstriction in the mesenteric arterial bed of the rat was investigated using mixed and selective α1, α2and β‐agonists and antagonists.Phenylephrine (PE) an α1selective agonist and noradrenaline (NA) a mixed α1and α2‐agonist, produced a rise in perfusion pressure (vasoconstriction). The responses to NA remained stable with time whereas responses to PE considerably increased.UK14304 an α2‐selective agonist at low doses (10−8−10−7moles), caused small, slow contractions in most preparations. Repeated administration of these doses or slightly higher ones, desensitized the tissue to this compound but not to NA or PE. Finally, UK14304 given simultaneously with NA or PE, at doses higher than 5 × 10−7moles, reduced contractions to the latter compounds and this effect was not altered by 10−7M rauwolscine, an α2‐selective antagonist.Prazosin, an α1‐selective antagonist, as expected, reduced contractions to NA considerably at 10−10−10−8M and abolished contractions to UK14304 at 2 × 10−9M.Rauwolscine, at 10−8M, potentiated contractions to NA and at 10−6M reduced contractions to both NA and PE (when compared to time controls).When propranolol (10−6M), a β‐antagonist was included in the perfusion fluid, rauwolscine no longer potentiated responses to NA but reduced them at all concentrations. Under the same conditions rauwolscine affected the responses to PE in a similar direction to that observed in the absence of propranolol.These results suggest that in the rat mesenteric arterial bed:rauwolscine exerts an effect additional to α2‐adrenoreceptor antagonism. Modification of this effect by propranolol indicates an interaction between this effect of rauwolscine and the β‐adrenoreceptor.vasoconstriction in the mesenteric arterial bed of the rat is mainly mediated postsynaptically by α1‐adrenoreceptors although the contribution of an α2‐mediated component cannot be excluded.UK14304 is an α1‐partial agonist as well as an α2‐agonist.
PHYSIOLOGICAL AND PHARMACOLOGICAL CHARACTERIZATION OF ANINVITROVAGUS NERVE‐TRACHEA PREPARATION FROM GUINEA‐PIG
Authors: WIDMARK E. , WALDECK B. 
Published: September 2010

The trachea with the vagus nerves attached was isolated from guinea‐pigs. Contractile responses to nerve stimulation or to drugs were measured as pressure changes in the fluid‐filled lumen.Electrical stimulation of the vagus nerves caused a prompt increase in the intratracheal pressure with an optimum frequency of stimulation between 20 and 30 Hz. The response to the left vagus was somewhat stronger than the response to the right vagus.Carbachol caused a maximum pressure increase which was about twice that achieved by bilateral stimulation of the vagus nerves at 20 Hz. In the presence of physostigmine the two sources of stimuli were equally effective.The excitatory response to stimulation of the vagus nerves was completely inhibited by hexamethonium, atropine and terbutaline. This indicates that the excitatory response is mediated via ganglia with end‐organ responses mediated exclusively by muscarinic receptors and functionally antagonized by stimulation of β2‐adrenoreceptors.The trachea preparation exhibited an intrinsic tone which was reduced by terbutaline and indomethacin but not by atropine or hexamethonium. It is probable that prostaglandins are involved in the generation of intrinsic tone.Noradrenaline caused a concentration dependent inhibition of the vagally mediated contractions of the trachea which was antagonized by propranolol and yohimbine. When tracheal tone was induced by carbachol only propranolol was effective thus indicating both pre‐ and postsynaptic effects of noradrenaline.The present study has shown that the isolated vagus nerve‐trachea is a stable and useful preparation for the evaluation of drugs acting at various levels of the contractile responses of the trachea.
AUTONOMIC INTERPLAY IN VIP‐INDUCED TRACHEAL SMOOTH MUSCLERELAXATION
Authors: VENUGOPALAN C. S. , O'MALLEY NANCY A. , SRIKANDAKUMAR A. 
Published: September 2010

VIP‐induced inhibitory responses of the guinea‐pig tracheal pouch, an in vivo preparation designed to demonstrate non‐noradrenergic non‐cholinergic innervation, where determined in chloralose‐urethane anaesthetized animals under control conditions, or pretreated with atropine, propranolol, both atropine and propranolol or atropine‐propranolol with indomethacin.Of the five groups, the control group showed a significantly greater cumulative dose‐response relaxation to VIP than did the treatment groups.Among the treatment groups, the propranolol pretreated animals showed significantly greater relaxation than the remaining treatments.The group that received atropine alone and the combination of atropine and propranolol showed the least relaxation to VIP. The relaxations in these two groups did not differ significantly.The significantly greater relaxation of the pouch to VIP in the propranolol treated group suggested that the non‐noradrenergic inhibitory mechanism for VIP is dependent upon the existing smooth muscle tone of the pouch.Pretreatment of the guinea‐pigs with indomethacin did not cause a significant change in the relaxation of the pouch due to VIP suggesting that VIP caused airway smooth muscle relaxation by a mechanism other than that of the release of bronchodilator prostaglandins.
EVIDENCE FOR MEDETOMIDINE AS A SELECTIVE AND POTENT AGONIST α2‐ADRENORECEPTORS
Authors: SAVOLA J.‐M. , RUSKOAHO H. , PUURUNEN J. , SALONEN J. S. , KÄRKI N. T. 
Published: September 2010

The activity on α‐adrenoreceptors of medetomidine (±)‐4‐(α,2,3‐trimethylbenzyl)imidazole), an α‐methyl derivative of detomidine, has been characterizedin vivoandin vitrousing detomidine, MPV 207, MPV 295, azepexole, clonidine and xylazine for reference purposes.Medetomidine (1–100 μg/kg i.v.) was a hypotensive and bradycardic compound in anaesthetized rats. Furthermore, it induced vasopressor (PD501.7 μg/kg) and sympatho‐inhibitory (ID501.6 μg/kg) actions in pithed rats, the effects being antagonized by idazoxan (0.3 mg/kg i.v.) but not by prazosin (0.1 mg/kg i.v.). Medetomidine (30–300 μg/kg i.m.) had an α2‐adrenoreceptor mediated sedative effect on chicks.Medetomidine was, overall, more potent than detomidine, MPV 207, clonidine, xylazine, MPV 295 or azepexole in central (sedation in the chick) and peripheral (cardiac presynaptic in the pithed rat) actions on α2‐adrenoreceptors. Clonidine had, however, about an equal potency to medetomidine in the vascular smooth muscle of the pithed rat.Like detomidine and MPV 295, medetomidine had no agonistic activity in the rat aortic ring, but high concentrations antagonized methoxamine‐induced contractions, giving a pA2value of 5.68 for α1‐adrenoreceptor antagonism.The overall lipophilicity (log P') of medetomidine in the octanol/buffer (pH 7.4, 24–26°C, HPLC technique) was 2.80.In summary, the experimental data suggest that medetomidine is a lipophilic compound with selective α2‐adrenoreceptor‐stimulating properties and high potency. It may, therefore, prove to be a suitable pharmacologic tool for interventions in α2‐adrenoreceptor mediated effects in the autonomic nervous system.
THE EFFECT OF β‐ADRENORECEPTOR ANTAGONISTS ON THE INHIBITION OF PENDULAR MOVEMENTS OF RABBIT ILEUM PRODUCED BY PERIARTERIAL SYMPATHETIC NERVE STIMULATION AND SOME SYMPATHOMIMETIC AMINES
Authors: NGATIDJAN D. , RAND M. J. 
Published: September 2010

The effects of propranolol and of the selective β1and β2‐adrenoreceptor blocking drugs atenolol and ICI 118,551 were determined on the inhibitory responses of isolated segments of rabbit ileum to noradrenaline, isoprenaline and salbutamol and to periarterial sympathetic nerve stimulation.Responses to isoprenaline (0.04–10.24 μM) and salbutamol (1.4–89.6 μM) were blocked by propranolol in concentrations up to 5.0 and 12.8 μM, respectively. Responses to sympathetic nerve stimulation were reduced but responses to noradrenaline (0.03‐1.92 μM) were unaffected by propranolol in concentrations up to 10.0 and 5.0 μM, respectively.Atenolol in concentrations up to 30.0 μM blocked responses to isoprenaline (0.04‐2.56 μM) but did not affect responses to noradrenaline, salbutamol or sympathetic nerve stimulation in concentrations up to 3.0,3.0 and 1.0 μM, respectively. However, when responses to noradrenaline and sympathetic nerve stimulation were reduced by phentolamine (1.0 μM), atenolol then produced further reductions.Responses to isoprenaline (0.04‐2.56 μM) and salbutamol (1.4–89.6 μM) were blocked by ICI 118,551 in concentrations up to 0.5 μM. Responses to sympathetic nerve stimulation were reduced but responses to noradrenaline were unaffected by ICI 118,551 in concentrations up to 0.01 and 0.3 μM, respectively.Salbutamol (0.1 μM.) increased the inhibitory response to sympathetic nerve stimulation and this effect was blocked by ICI 118,551 (0.01 μM).It was concluded that blockade of β2‐adrenoreceptors, presumably located on sympathetic nerve terminals, decreases the release of transmitter noradrenaline and that blockade of β1‐adrenoreceptors, presumably located in longitudinal smooth muscle cells, reduces the response to transmitter noradrenaline when α‐adrenoreceptors are also blocked.
Protocatechuic acid inhibits cancer cell metastasis involving the down‐regulation of Ras/Akt/NF‐κB pathway and MMP‐2 production by targeting RhoB activation
Authors: Lin Hui‐Hsuan , Chen Jing‐Hsien , Chou Fen‐Pi , Wang Chau‐Jong 
Published: September 2010

BACKGROUND AND PURPOSE Protocatechuic acid (PCA) is plentiful in edible fruits and vegetables and is thus one anti‐oxidative component of normal human diets. However, the molecular mechanisms involved in the chemopreventive activity of PCA are poorly understood. Here, we investigated the mechanism(s) underlying the anti‐metastatic potential of PCA.EXPERIMENTAL APPROACH We used AGS cells in a wound healing model and Boyden chamber assays in vitro and injection of B16/F10 melanoma cells in mice (metastasis model in vivo) to analyse the effect of PCA on cancer cell invasion and metastasis. The activities and expression of molecular proteins were measured by zymographic assay, real‐time RT‐PCR and Western blotting.KEY RESULTS PCA inhibited cell migration and invasion at non‐cytotoxic concentrations. Decreased expression of matrix metalloproteinase (MMP)‐2 and a coincident increase in tissue inhibitor of MMP followed treatment with PCA. The PCA‐inhibited MMP‐2 activity and expression was accompanied by inactivation of NF‐κB. All these effects of PCA could be mediated via the RhoB/ protein kinase Cε (PKCε) and Ras/Akt cascade pathways, as demonstrated by inhibition of PKCε and transfection of PKCε siRNA and ras overexpression vector. Finally, PCA inhibited metastasis of B16/F10 melanoma cells to the liver in mice.CONCLUSION AND IMPLICATIONS Our data imply that PCA down‐regulated the Ras/Akt/NF‐κB pathway by targeting RhoB activation, which in turn led to a reduction of MMP‐mediated cellular events in cancer cells and provides a new mechanism for the anti‐cancer activity of PCA.
Receptor localization, native tissue binding and ex vivo occupancy for centrally penetrant P2X7 antagonists in the rat
Authors: Able SL , Fish RL , Bye H , Booth L , Logan YR , Nathaniel C , Hayter P , Katugampola SD 
Published: September 2010

BACKGROUND AND PURPOSE The P2X7 receptor is implicated in inflammation and pain and is therefore a potential target for therapeutic intervention. Here, the development of a native tissue radioligand binding, localization and ex vivo occupancy assay for centrally penetrant P2X7 receptor antagonists is described.EXPERIMENTAL APPROACH Autoradiography studies using the P2X7 antagonist radioligand [3H]‐A‐804598 were carried out in rat brain and spinal cord. Subsequent in vitro binding and ex vivo occupancy assays were performed using rat cortex homogenate.KEY RESULTS P2X7 expression was shown to be widespread throughout the rat brain, and in the grey matter of the spinal cord. In binding assays in rat cortex homogenate, ∼60% specific binding was achieved at equilibrium. In kinetic binding assays, kon and koff values of 0.0021·min−1·nM−1 and 0.0070·min−1 were determined, and the Kd derived from kinetic measurements was consistent with that derived from saturation analysis. Novel P2X7 antagonists inhibited the binding of [3H]‐A‐804598 to rat cortex P2X7 receptors with Ki values of <40 nM. In an ex vivo occupancy assay, a P2X7 antagonist dosed orally to rats caused a concentration‐dependent inhibition of the specific binding of [3H]‐A‐804598 to rat cortex.CONCLUSIONS AND IMPLICATIONS The present study describes the development of an assay that allows localization of P2X7 receptors, the measurement of the binding affinity of P2X7 receptor antagonists in native tissue, and provides a means of determining central P2X7 receptor occupancy. These assays could form an important part of a P2X7 drug discovery programme.