One or more bound planets per Milky Way star from microlensing observations.

Most known extrasolar planets (exoplanets) have been discovered using the radial velocity or transit methods. Both are biased towards planets that are relatively close to their parent stars, and studies find that around 17-30% (refs 4, 5) of solar-like stars host a planet. Gravitational microlensing, on the other hand, probes planets that are further away from their stars. Recently, a population of planets that are unbound or very far from their stars was discovered by microlensing. These planets are at least as numerous as the stars in the Milky Way. Here we report a statistical analysis of microlensing data (gathered in 2002-07) that reveals the fraction of bound planets 0.5-10 AU (Sun-Earth distance) from their stars. We find that 17(+6)(-9)% of stars host Jupiter-mass planets (0.3-10 M(J), where M(J) = 318 M(⊕) and M(⊕) is Earth's mass). Cool Neptunes (10-30 M(⊕)) and super-Earths (5-10 M(⊕)) are even more common: their respective abundances per star are 52(+22)(-29)% and 62(+35)(-37)%. We conclude that stars are orbited by planets as a rule, rather than the exception.

Control of Hypertension In Pregnancy Study randomised controlled trial-are the results dependent on the choice of labetalol or methyldopa?

OBJECTIVE: To determine whether the difference in outcomes between 'less tight' (target diastolic blood pressure [dBP] of 100 mmHg) versus 'tight' control (target dBP of 85 mmHg) in the CHIPS Trial (ISRCTN 71416914, http://pre-empt.cfri.ca/;CHIPS) depended on the choice of labetalol or methyldopa, the two most commonly used antihypertensive agents in CHIPS. DESIGN: Secondary analysis of CHIPS Trial data. SETTING: International multicentre randomised controlled trial (94 sites, 15 countries). POPULATION OR SAMPLE: A total of 987 women with non-severe non-proteinuric pregnancy hypertension. METHODS: Logistic regression was used for comparisons of 'less tight' versus 'tight' control among women treated with labetalol (but not methydopa) versus methyldopa (but not labetalol). Analyses were adjusted for the influence of baseline factors, including use of any antihypertensive therapy at randomisation. MAIN OUTCOME MEASURES: Main CHIPS Trial outcomes: primary (perinatal loss or high-level neonatal care for > 48 hours), secondary (serious maternal complications), birthweight < 10th centile, severe maternal hypertension, pre-eclampsia, and delivery at < 34 or < 37 weeks. RESULTS: Of 987 women in CHIPS, antihypertensive therapy was taken by 566 women at randomisation (labetalol 111 ['less tight'] versus 127 ['tight'] or methyldopa 126 ['less tight'] versus 117 ['tight']) and 815 women after randomisation (labetalol 186 ['less tight'] versus 247 ['tight'] and methyldopa by 98 ['less tight'] versus 126 ['tight']). Following adjustment, odds ratios for outcomes in 'less tight' versus 'tight' control were similar between antihypertensive groups according to 'at randomisation' and 'after randomisation' therapy. CONCLUSION: Outcomes for 'less tight' versus 'tight' control were not dependent on use of methyldopa or labetalol. TWEETABLE ABSTRACT: In the CHIPS Trial, maternal and infant outcomes were not dependent on use of labetalol or methyldopa.

Do labetalol and methyldopa have different effects on pregnancy outcome? Analysis of data from the Control of Hypertension In Pregnancy Study (CHIPS) trial.

OBJECTIVE: To compare pregnancy outcomes, accounting for allocated group, between methyldopa-treated and labetalol-treated women in the CHIPS Trial (ISRCTN 71416914) of 'less tight' versus 'tight' control of pregnancy hypertension. DESIGN: Secondary analysis of CHIPS Trial cohort. SETTING: International randomised controlled trial (94 sites, 15 countries). POPULATION OR SAMPLE: Of 987 CHIPS recruits, 481/566 (85.0%) women treated with antihypertensive therapy at randomisation. Of 981 (99.4%) women followed to delivery, 656/745 (88.1%) treated postrandomisation. METHODS: Logistic regression to compare outcomes among women who took methyldopa or labetalol, adjusted for the influence of baseline factors. MAIN OUTCOME MEASURES: CHIPS primary (perinatal loss or high level neonatal care for >48 hours) and secondary (serious maternal complications) outcomes, birthweight <10th centile, severe maternal hypertension, pre-eclampsia and delivery at <34 or <37 weeks. RESULTS: Methyldopa and labetalol were used commonly at randomisation (243/987, 24.6% and 238/987, 24.6%, respectively) and post-randomisation (224/981, 22.8% and 433/981, 44.1%, respectively). Following adjusted analyses, methyldopa (versus labetalol) at randomisation was associated with fewer babies with birthweight <10th centile [adjusted odds ratio (aOR) 0.48; 95% CI 0.20-0.87]. Methyldopa (versus labetalol) postrandomisation was associated with fewer CHIPS primary outcomes (aOR 0.64; 95% CI 0.40-1.00), birthweight <10th centile (aOR 0.54; 95% CI 0.32-0.92), severe hypertension (aOR 0.51; 95% CI 0.31-0.83), pre-eclampsia (aOR 0.55; 95% CI 0.36-0.85), and delivery at <34 weeks (aOR 0.53; 95% CI 0.29-0.96) or <37 weeks (aOR 0.55; 95% CI 0.35-0.85). CONCLUSION: These nonrandomised comparisons are subject to residual confounding, but women treated with methyldopa (versus labetalol), particularly those with pre-existing hypertension, may have had better outcomes. TWEETABLE ABSTRACT: There was no evidence that women treated with methyldopa versus labetalol had worse outcomes.

Evaluation of healthcare professionals' experiences of taking telephone calls from parents of children with congenital heart disease. A risky business.

The Congenital Heart Disease Standards for England indicate that parents and children should have access to a 24-h telephone advice service, however, little is known about existing services. This paper presents phase two of a mixed-methods service evaluation, which aimed to evaluate staff experiences of telephone communication with these parents. All nursing and support staff in a single specialist children's cardiac surgical centre were invited to participate in an online survey during July-November 2019. Data were descriptively and thematically analysed. Participants (N = 39) were predominantly nurses (n = 32, 82%) with 64.1% (n = 25) working in the speciality >10 years. Positive experiences included: signposting and preventing further deterioration; supporting families to get expert advice quickly; providing reassurance. Challenging experiences included: offering advice without being able to see the child, dealing with telephone calls alongside busy workload; and parents running out of medications and telephoning out of hours. In conclusion, taking telephone calls were perceived to be time consuming and are potentially high risk. A standardised approach to assessment, intervention and documentation was deemed necessary. Implementation of an updated parental early warning tool was recommended, along with staff and parental education.

Discovery of a cool planet of 5.5 Earth masses through gravitational microlensing.

In the favoured core-accretion model of formation of planetary systems, solid planetesimals accumulate to build up planetary cores, which then accrete nebular gas if they are sufficiently massive. Around M-dwarf stars (the most common stars in our Galaxy), this model favours the formation of Earth-mass (M(o)) to Neptune-mass planets with orbital radii of 1 to 10 astronomical units (au), which is consistent with the small number of gas giant planets known to orbit M-dwarf host stars. More than 170 extrasolar planets have been discovered with a wide range of masses and orbital periods, but planets of Neptune's mass or less have not hitherto been detected at separations of more than 0.15 au from normal stars. Here we report the discovery of a 5.5(+5.5)(-2.7) M(o) planetary companion at a separation of 2.6+1.5-0.6 au from a 0.22+0.21-0.11 M(o) M-dwarf star, where M(o) refers to a solar mass. (We propose to name it OGLE-2005-BLG-390Lb, indicating a planetary mass companion to the lens star of the microlensing event.) The mass is lower than that of GJ876d (ref. 5), although the error bars overlap. Our detection suggests that such cool, sub-Neptune-mass planets may be more common than gas giant planets, as predicted by the core accretion theory.

A comprehensive transcriptomic analysis of the effect of silicon on wheat plants under control and pathogen stress conditions.

The supply of soluble silicon (Si) to plants has been associated with many benefits that remain poorly explained and often contested. In this work, the effect of Si was studied on wheat plants under both control and pathogen stress (Blumeria graminis f. sp. tritici) conditions by conducting a large transcriptomic analysis (55,000 unigenes) aimed at comparing the differential response of plants under four treatments. The response to the supply of Si on control (uninfected) plants was limited to 47 genes of diverse functions providing little evidence of regulation of a specific metabolic process. Plants reacted to inoculation with B. graminis f. sp. tritici by an upregulation of many genes linked to stress and metabolic processes and a downregulation of genes linked to photosynthesis. Supplying Si to inoculated plants largely prevented disease development, a phenotypic response that translated into a nearly perfect reversal of genes regulated by the effect of B. graminis f. sp. tritici alone. These results suggest that Si plays a limited role on a plant's transcriptome in the absence of stress, even in the case of a high-Si-accumulating monocot such as wheat. On the other hand, the benefits of Si in the form of biotic stress alleviation were remarkably aligned with a counter-response to transcriptomic changes induced by the pathogen B. graminis f. sp. tritici.

Cytotoxic doses of ketoconazole affect expression of a subset of hepatic genes.

Ketoconazole is a widely prescribed antifungal drug, which has also been investigated as an anticancer therapy in both clinical and pre-clinical settings. However, severe hepatic injuries were reported to be associated with the use of ketoconazole, even in patients routinely monitored for their liver functions. Several questions concerning ketoconazole-induced hepatic injury remain unanswered, including (1) does ketoconazole alter cytochrome P450 expression at the transcriptional level?, (2) what types of gene products responsible for cytotoxicity are induced by ketoconazole?, and (3) what role do the major metabolites of ketoconazole play in this pathophysiologic process? A mouse model was employed to investigate hepatic gene expression following hepatotoxic doses of ketoconazole. Hepatic gene expression was analyzed using a toxicogenomic microarray platform, which is comprised of cDNA probes generated from livers exposed to various hepatoxicants. These hepatoxicants fall into five well-studied toxicological categories: peroxisome proliferators, aryl hydrocarbon receptor agonists, noncoplanar polychlorinated biphenyls, inflammatory agents, and hypoxia-inducing agents. Nine genes encoding enzymes involved in Phase I metabolism and one Phase II enzyme (glutathione S-transferase) were found to be upregulated. Serum amyloid A (SAA1/2) and hepcidin were the only genes that were downregulated among the 2364 genes assessed. In vitro cytotoxicity and transcription analyses revealed that SAA and hepcidin are associated with the general toxicity of ketoconazole, and might be usefully explored as generalized surrogate markers of xenobiotic-induced hepatic injury. Finally, it was shown that the primary metabolite of ketoconazole (de-N-acetyl ketoconazole) is largely responsible for the hepatoxicity and the downregulation of SAA and hepcidin.

Current CHS and NHBPEP criteria for severe preeclampsia do not uniformly predict adverse maternal or perinatal outcomes.

OBJECTIVE: To determine the association between adverse maternal/perinatal outcomes and Canadian and U.S. preeclampsia severity criteria. METHODS: Using PIERS data (Preeclampsia Integrated Estimate of RiSk), an international continuous quality improvement project for women hospitalized with preeclampsia, we examined the association between preeclampsia severity criteria and adverse maternal and perinatal outcomes (univariable analysis, Fisher's exact test). Not evaluated were variables performed in <80% of pregnancies (e.g., 24-hour proteinuria). RESULTS: Few of the evaluated variables were associated with adverse maternal (chest pain/dyspnea, thrombocytopenia, 'elevated liver enzymes', HELLP syndrome, and creatinine >110 microM) or perinatal outcomes (dBP >110 mm Hg and suspected abruption) (at p < 0.01). CONCLUSIONS: In the PIERS cohort, most factors used in the Canadian or American classifications of severe preeclampsia do not predict adverse maternal and/or perinatal outcomes. Future classification systems should take this into account.

Patient and public involvement in Paediatric Intensive Care research: considerations, challenges and facilitating factors.

PLAIN ENGLISH SUMMARY: Paediatric Intensive Care (PIC) provides care to extremely ill children. Research in this area can be difficult because children are often too sick to discuss being involved in a study and parents are too upset about their child to think about taking part. This makes it even more important that research is well designed. We conducted a review of the literature about involving patients and the public (PPI) in PIC research. We wanted to know what PPI has taken place, who had been consulted and how this was undertaken. We reviewed the titles and abstracts of 4717 papers but found only 4 relevant papers. Three of the papers had consulted with parents of children who had been on PIC but only one study had spoken directly to a child themselves. The studies had used a number of different methods to invite people to take part but there did not appear to be one solution. All of the studies thought PPI was good for the development of their research but none of them had tried to measure what had changed as a result. There are difficulties associated with carrying out PPI in the PIC setting. Researchers need to share more of their experiences, positive and negative, so we can try to identify the best ways of carrying out PPI in PIC studies. This will help ensure that research studies are designed which address the needs and concerns of children and their parents. ABSTRACT: Introduction Involving the public in health care research is reported to enhance the quality, appropriateness, acceptability and relevance to patients and the public (INVOLVE, Briefing notes for researchers, 2012; Staniszewska et al., Int J Technol Assess Health Care 274:391-9, 2011). Conducting research with children and young people is regarded as challenging and this makes it even more important that the research is well designed and understands the perspective of the child and family. We conducted a narrative literature review of the Patient and Public Involvement (PPI) literature, in the context of Paediatric Intensive Care (PIC). Our aims were to identify what PPI activity has taken place, with whom researchers engaged and what outcomes they reported. Method Electronic databases Medline, CINAHL and Embase (January 2000- June 2016) were searched using the search terms patient and public involvement and consultation. Participants were defined as child, parent, paediatric or pediatric and the context as intensive or critical care. Papers were excluded where activity reflected 'participants' as research subjects. Included papers were reviewed using the GRIPP checklist to appraise the quality of reporting. Results The search strategy identified 4717 abstracts. Seventeen papers were reviewed in full and four papers were included, all of which are case studies, describing a consultation approach. None of the papers described PPI as a multi-stage process. Only one study engaged with a former PIC patient and the majority of those consulted did not have any PIC experience. Activity was reported as being of benefit but there was no measurement of the impact of PPI. Conclusion There are numerous challenges associated with the conduct of research in PIC. It is therefore essential that the perspective of children, young people and their parents have been considered in the design of trials. However, there are few published accounts of PPI within the PIC context and the accounts that exist highlight issues about who to approach and when, and a lack of clarity about the best ways to engage with them. Research Ethics Committees and funding bodies expect to see evidence of PPI in research applications and we need to develop our understanding of what contributes towards successful PPI in this context.

The complications of hypertension in pregnancy.

The hypertensive disorders of pregnancy remain a leading cause of maternal and perinatal morbidity and mortality in Europe and North America. Pre-eclampsia, which is proteinuric gestational hypertension, accounts for the majority of the excess risks and is defined by the maternal syndrome. The maternal syndrome of pre-eclampsia is characterised by a systemic inflammatory response and its sequelae. Systematic multisystem evaluation of pre-eclampsia, evidence-based antihypertensive therapy, and the use of MgSO4 to prevent and treat the seizures of eclampsia can reduce maternal risks. For mild-to-moderate pregnancy hypertension, maternal risks are small, and there may be adverse perinatal consequences of blood pressure normalisation. Early-onset and severe pre-eclampsia predict an excess risk of later cardiovascular morbidity and mortality. Both Chlamydophila pneumoniae and cytomegalovirus have bee associated with pre-eclampsia and atherosclerosis, and may provide a mechanistic link between pre-eclampsia and the recognised cardiovascular risk. Women with a history of either early-onset and/or severe pre-eclampsia should be considered to be at increased risk for later cardiovascular disease, and it may be prudent for them to have regular lipid profiles and tests for urinary microalbumin excretion.

Increased basal expression of hepatic Cyp1a1 and Cyp1a2 genes in inbred mice selected for susceptibility to acetaminophen-induced hepatotoxicity.

Susceptibility to acetaminophen-induced hepatotoxicity was found to vary widely in an outbred colony of Swiss Webster mice. Some acetaminophen-treated male mice showed a significant elevation in serum levels of the hepatic enzyme alanine aminotransferase at a normally non-hepatotoxic oral dose. A selective breeding program over 17 generations produced inbred mice which were either susceptible or nonsusceptible to the hepatotoxic effects of acetaminophen. Liver microsomes from the susceptible group showed a statistically significant increase in the ability to metabolize acetaminophen to a reactive intermediate which covalently binds N-acetylcysteine. Microsomal cytochrome P450 activities associated with CYP1A2 (acetanilide 4-hydroxylation and methoxyresorufin O-demethylase) were significantly increased in the susceptible group. Ethoxyresorufin O-deethylase activity, associated with both CYP1A1 and CYP1A2, was also significantly elevated in this group. Further examination of both CYP1A isoforms revealed that hepatic CYP1A1 and CYP1A2 mRNA and protein levels were significantly elevated in animals from the susceptible group. In vivo caffeine 3-demethylation, which is associated with CYP1A2 activity, co-segregated with acetaminophen susceptibility and showed a significant positive correlation (r = 0.626, p < 0.005) with CYP1A2 mRNA expression in animals from both the susceptible and nonsusceptible groups. The co-segregation of elevated basal Cyp1a1 and CYP1a2 gene expression levels in animals selected for susceptibility to acetaminophen-induced hepatotoxicity suggested a common heritable basis for regulation of basal expression of both of these CYP1A isoforms. This was supported by the correlated expression of both CYP1A mRNAs within individual mice (r = 0.644, p < 0.02).

Release of a soluble ATPase from the rabbit isolated vas deferens during nerve stimulation.

The properties of the ATPase released during electrical field stimulation (EFS) (8 Hz, 25 s) of the sympathetic nerves of the superfused rabbit isolated vas deferens were investigated. Superfusate collected during EFS rapidly metabolised exogenous ATP (100 microM) and 50% was broken down in 5.67+/-0.65 min. The main metabolite was ADP, virtually no AMP was produced and adenosine was absent. No enzyme activity was seen in samples collected in the absence of EFS. Lineweaver-Burke analysis of the initial rates of ATP hydrolysis gave a K(M) of 40 microM and V(max) of 20.3 nmol ATP metabolized min(-1) ml(-1) superfusate. ATPase activity was unaffected by storage at room temperature for 24 h, but was abolished at pH4 or by heating at 80 degrees C for 10 min. ARL 67156 inhibited ATP breakdown in a concentration-dependent manner (IC(50)=25 microM (95% confidence limits=22-27 microM), Hill slope=-1.06+/-0.04). When EFS was applied three times at 30 min intervals, ATP metabolism was 20-30% less in superfusate collected during the second and third stimulation periods compared with the first. ATPase activity was released in a frequency-dependent manner, with significantly greater activity seen after stimulation at 4 and 8 Hz than at 2 Hz. In conclusion, EFS of the sympathetic nerves in the rabbit vas deferens causes release of substantial ATPase, but little ADPase activity into the extracellular space. This contrasts with the guinea-pig vas deferens, which releases enzymes that degrade ATP to adenosine. Thus, the complement of enzymes released by nerve stimulation is species-dependent.

Differential alterations in tachykinin NK2 receptors in isolated colonic circular smooth muscle in inflammatory bowel disease and idiopathic chronic constipation.

Inflammatory bowel disease (IBD) and idiopathic chronic constipation (ICC) are intestinal disorders which disrupt normal colonic motility. Enteric tachykinins are well-recognised to play a role in the motor control of the gut, and increased colonic levels of substance P are seen in IBD, whereas decreased levels have been reported in ICC. In this investigation, we have characterised the tachykinin receptor population of normal human colonic circular smooth muscle and examined any changes that occur in IBD and ICC. The selective tachykinin NK2 receptor agonist, [beta-Ala8]neurokinin A(4-10), caused concentration-dependent contractions in healthy tissues; neither NK1 receptor-selective nor NK3 receptor-selective agonists were contractile. In diseased preparations also, only [beta-Ala8]neurokinin A(4-10) caused contractions with EC50 values similar to health. The maximum contractile responses (Emax), however, were significantly decreased in both forms of IBD but significantly increased in ICC. The muscarinic acetylcholine receptor agonist, carbachol, also caused contractions in diseased tissues, but EC50 and Emax values were not significantly different from health. The differential changes in contractility found in IBD and ICC are specific to NK2 receptors, and may reflect the altered levels of substance P or other tachykinins found in these intestinal disorders.

Electronmicroscopy of the surface of Pasteurella haemolytica.

The surfaces of Pasteurella haemolytica, biotype A, serotypes 1, 2, 6, 7 and 9 and of P. haemolytica, biotype T serotypes 3, 4, 10 and 15 were examined by transmission electronmicroscopy with ruthenium red staining and polycationic ferritin labelling, by scanning electronmicroscopy, and by light microscopy. Electronmicroscopy showed that the surface of strains of P. haemolytica biotype A was covered by irregular protrusions which were probably capsular material. The surface and general morphology of P. haemolytica biotype T were distinct from those of biotype A.

Nociceptin inhibits tonic nitric oxide release in the mouse isolated proximal colon.

Nociceptin/orphanin FQ, the endogenous ligand of the opioid receptor-like (ORL1) receptor, caused contractions in the isolated colon of the mouse. Tetrodotoxin and the nitric oxide (NO) synthase inhibitor Nomega-nitro-L-arginine also produced contractions which were quantitatively similar to those seen in response to nociceptin. In the presence of either tetrodotoxin or Nomega-nitro-L-arginine, nociceptin was unable to cause a further contraction, whereas the muscarinic receptor agonist carbachol elicited a contractile response. Nociceptin had no contractile activity in colonic preparations contracted by Nomega-nitro-L-arginine then relaxed by addition of the NO donor sodium nitroprusside. These data suggest that nociceptin causes contractions of the mouse proximal colon by inhibiting the tonic, neuronal release of NO.

Opioid activity of alkaloids extracted from Picralima nitida (fam. Apocynaceae).

Extracts of the seeds of Picralima nitida (fam. Apocynaceae) have been reported to have opioid analgesic activity. In this investigation, isolated tissue bioassays and radioligand binding assays have been used to determine the opioid activity of five alkaloids--akuammidine, akuammine, akuammicine, akuammigine and pseudoakuammigine--extracted from the seeds of P. nitida. Akuammidine showed a preference for mu-opioid binding sites with Ki values of 0.6, 2.4 and 8.6 microM at mu-, delta- and kappa-opioid binding sites, respectively. The agonist actions of akuammidine in the mouse-isolated vas deferens were antagonised by naloxone and the mu-opioid receptor selective antagonist D-Phe-Cys-Tyr-D-Trp-Orn-Thr-Pen-Thr-NH2 (CTOP) confirming an action at mu-opioid receptors. In contrast, akuammine also showed highest affinity for mu-opioid binding sites (Ki 0.5 microM) but was an antagonist at mu-opioid receptors with a pK(B) of 5.7 against the selective mu-opioid receptor agonist [D-Ala2,MePhe4,Gly-ol5]enkephalin (DAMGO). Akuammicine has the highest affinity for kappa-opioid binding sites (Ki 0.2 microM) and was a full agonist at kappa-opioid receptors in the guinea pig ileum preparation but a partial kappa-opioid receptor agonist in the vasa deferentia of the mouse and the rabbit. Akuammigine and pseudoakuammigine showed little or no efficacy in the opioid bioassays. None of the alkaloids had significant activity for opioid receptor-like binding sites (ORL1-binding sites) with Ki values >> 10 microM. These data show that some alkaloids extracted from the medicinal plant P. nitida possess varying degrees of agonist and antagonist activity at opioid receptors but possess neither high affinity nor selectivity for mu-, delta- or kappa-opioid receptors or the ORL1-receptor.

In vitro agonist effects of nociceptin and [Phe(1)psi(CH(2)-NH)Gly(2)]nociceptin(1-13)NH(2) in the mouse and rat colon and the mouse vas deferens.

Nociceptin is an endogenous ligand of the opioid receptor-like (ORL1) receptor, a G-protein coupled receptor with sequence similarities to the opioid receptors. ORL1 receptors are present at both central and peripheral sites in several mammalian species but their functions are as yet poorly understood. The main aim of this investigation was to study the effects of nociceptin and the putative ORL1 receptor antagonist [Phe(1)psi(CH(2)-NH)Gly(2)]nociceptin(1-13)NH(2) in two peripheral tissues, the isolated proximal colon of the mouse and the distal colon of the rat. Nociceptin, [D-Ala(2), MePhe(4), Gly-ol(5)]enkephalin (DAMGO; mu-opioid receptor selective) and [D-Pen(2), D-Pen(5)]enkephalin (DPDPE; delta-opioid receptor selective) caused concentration-dependent contractions of mouse and rat isolated colon preparations (nociceptin EC(50)=1.20 and 0.28 nM in the mouse and rat, respectively). Des[Phe(1)]nociceptin (250 nM) had no contractile effect. Naloxone (300 nM) antagonised the effects of DAMGO and DPDPE but had no effect in either preparation on contractions seen in response to nociceptin. [Phe(1)psi(CH(2)-NH)Gly(2)]nociceptin(1-13)NH(2) also caused contractions in the colonic preparations (EC(50)=6.0 and 3.1 nM in the mouse and rat, respectively); there was no evidence of any antagonist activity. Tetrodotoxin (1 microM) abolished the contractile effects of nociceptin in the mouse colon but had no effect in the rat. In the vas deferens preparation isolated from DBA/2 mice, nociceptin caused concentration-dependent inhibitions of electrically-evoked contractions which were antagonised by [Phe(1)psi(CH(2)-NH)Gly(2)]nociceptin(1-13)NH(2) (apparent pK(B)=6. 31). However, [Phe(1)psi(CH(2)-NH)Gly(2)]nociceptin(1-13)NH(2) (0.3-10 microM) also possessed agonist activity in this preparation, as it inhibited the electrically-evoked contractions in a concentration-dependent manner. These observations do not support the proposal that [Phe(1)psi(CH(2)-NH)Gly(2)]nociceptin(1-13)NH(2) has agonist activity at central ORL1 receptors but is an antagonist in the periphery and that these differences in efficacy point to differences in the receptors. Rather, these data along with those of others suggest that [Phe(1)psi(CH(2)-NH)Gly(2)]nociceptin(1-13)NH(2) is a partial agonist and that differences in receptor reserve can account for the varied pharmacological actions of this pseudopeptide at central and peripheral sites.

Biliary metabolites of estriol in the rat.

Following the subcutaneous administration of estriol-6,7-3H to rats, biliary metabolites were identified and quantitated. Approximately 70% of the metabolites were excreted in the form of "glucosiduronate" conjugates. 3,17beta-Dihydroxy-2-methoxy-1,3,5(10)-estratrien-16-one was the major metabolite in this conjugate fraction. Significant amounts of 3,17beta-dihydroxy-1,3,5(10)-estratrien-16-one and 2,3,17beta-trihydroxy-1,3,5(10)-estratrien-16-one, as well as smaller quantities of 1,3,5(10)-estratriene-2,316alpha,17beta, tetrol and 2-methoxy-1,3,5(10)-estratriene-3, 16alpha, 17beta-triol, were also found. In 17alpha-ethinylestradiol-treated animals, the rate of excretion of radioactivity and the proportion of 16-oxo-17beta-ol metabolites found in the "glucosiduronate" fraction were reduced.

PIP: The biliary metabolites of tritiated-6,7-estriol were identified following the administration of the estrogen to rats. Glucosiduronate conjugate fraction constituted approximately 70% of the excreted metabolites. The primary metabolite found in this conjugate fraction was 3,17beta-dihydroxy-2-methoxy-1,3,5(10)-estratrien-16-one. There were also significant amounts of 3,17beta-dihydroxy-1,3,5,(10-estratrien-16-one and 2,3,17beta-trihydroxy-1,3,5(10)-estratrien-16-one. Smaller amounts of 1,3,5(10)-estratriene-2,3,16alpha,17beta-terol and 2-methoxy-1,3,5(10)-estratriene-3,16alpha,17beta-triol were also present. The administration of 17alpha-ethinyl estradiol reduced the rate of excretion of radioactivity and the proportion of 16-oxo-17-beta-ol metabolites in the glucosiduronate fraction.

HPLC-RIA of a metabolite of norethindrone in human plasma, 17 alpha-ethinyl-5 beta-estrane-3 alpha, 17 beta-diol, following conjugate hydrolysis.

An HPLC-RIA method for the assay of a reduced metabolite of norethindrone, 17 alpha-ethinyl-5 beta-estrane-3 alpha, 17 beta-diol, is described. Conjugated metabolites were extracted from human plasma and subjected to hydrolysis prior to analysis. With a daily dose of 2 mg of norethindrone, the mean plasma level of the metabolite was 24.8 ng/ml with a range of 22.8 ng/ml to 33.9 ng/ml.

Cytological Evidence of an Active Role of Silicon in Wheat Resistance to Powdery Mildew (Blumeria graminis f. sp. tritici).

ABSTRACT Silicon (Si) amendments in the form of exogenously supplied nutrient solution or calcium silicate slag protect wheat plants from powdery mildew disease caused by the fungus Blumeria graminis f. sp. tritici. The most striking difference between Si- and Si+ plants challenged with B. graminis f. sp. tritici was the extent of epidermal cell infection and colonization by B. graminis f. sp. tritici. Histological and ultrastructural analyses revealed that epidermal cells of Si+ plants reacted to B. graminis f. sp. tritici attack with specific defense reactions including papilla formation, production of callose, and release of electron-dense osmiophilic material identified by cytochemical labeling as glycosilated phenolics. Phenolic material not only accumulated along the cell wall but also was associated with altered integrity of haustoria in a manner similar to localized phytoalexins as reported from other pathosystems. These results strongly suggest that Si mediates active localized cell defenses against B. graminis f. sp. tritici attack.