Characterisation of the growth regulating gene IMP3, a candidate for Silver-Russell syndrome.
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Abnormalities, Multiple↗
Biomedical subjects
J Peters
Publications and source records attributed to J Peters.
The clinical effectiveness and cost-effectiveness of inhaler devices used in the routine management of chronic asthma in older children: a systematic review and economic evaluation.
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Adolescent↗
Cellular expression of CCK-A and CCK-B/gastrin receptors in human gastric mucosa.
Gastrin stimulates gastric acid secretion in various species, but the role of the structurally related CCK for the peripheral regulation of acid secretion in humans remains controversial. Moreover, species differences in CCK receptor function and expression have been reported. We therefore sought to identify the cellular targets of CCK and gastrin within the human gastric mucosa in situ. Gastric biopsies were collected from 15 patients without gastric disease. Expression of CCK receptor subtypes was detected in individual cells of the gastric mucosa by reverse transcription (RT)-PCR in situ, immunohistochemistry and confocal laser scanning microscopy, using antisera against the CCK-A or CCK-B/gastrin receptor subtype. Both CCK-A and CCK-B receptors were detected in antral and oxyntic mucosa at the mRNA and protein level. In fundic mucosa, CCK-A receptor mRNA and protein mapped to D cells (37.4+/-7.7). Besides, individual chief cells, mucous neck cells and parietal cells (12.3+/-4.7%) expressed CCK-A receptors. CCK-B/gastrin receptor mRNA and protein were detected in parietal cells (57.4+/-11.1%) and in neuroendocrine cells (33.2+/-4.4%) expressing chromogranin A. Furthermore, epithelial cells within the neck of the gastric gland were found to express the CCK-B/gastrin receptor. We conclude that (i) identification of CCK-A receptors on somatostatin producing D cells in humans provide the anatomical basis for a receptor-mediated mode of action of CCK on somatostatin release and (ii) detection of either CCK receptor subtype in the putative stem cell compartment implies a role of CCK in the maintenance of tissue homeostasis in human gastric mucosa.
Adult↗
Vascular hypertrophy and increased P70S6 kinase in mice lacking the angiotensin II AT(2) receptor.
BACKGROUND: Angiotensin II activates 2 distinct G protein-coupled receptors, the AT(1) and AT(2) receptors. Most of the known cardiovascular effects of angiotensin II are mediated by the AT(1) receptor subtype. The aim of the present study was to test whether deletion of the AT(2) receptor gene in mice (AT(2)-KO mice) leads to long-term functional or structural alterations in the cardiovascular system. METHODS AND RESULTS: In vivo pressure responses to angiotensin II or the alpha(1)-adrenergic receptor agonist phenylephrine were greatly enhanced in AT(2)-KO mice. Deletion of the angiotensin AT(2) receptor did not lead to a compensatory increase of the activity of the circulating renin-angiotensin system, and arterial blood pressure was identical in wild-type control mice (WT) and AT(2)-KO mice. Cardiac contractility as assessed by LV catheterization and by rapid MRI also did not differ between AT(2)-KO and WT mice. Isolated femoral arteries from AT(2)-KO mice, however, showed enhanced vasoconstriction to angiotensin II, norepinephrine, and K(+) depolarization compared with WT. Morphometric analysis of large and small femoral arteries revealed a significant hypertrophy of media smooth muscle cells. Phospho-P70S6 kinase levels were significantly increased in aortas from AT(2)-KO mice compared with WT mice. Treatment of mice with an ACE inhibitor for 8 weeks abolished the increased pressure responsiveness, vascular hypertrophy, and enhanced P70S6 kinase phosphorylation in AT(2)-KO mice. CONCLUSIONS: These results indicate that vascular AT(2) receptors inhibit the activity and, hence, hypertrophic signaling by the P70S6 kinase in vivo and thus are important regulators of vascular structure and function.
Angiotensin-Converting Enzyme Inhibitors↗
Homozygosity (E140K) in SCO2 causes delayed infantile onset of cardiomyopathy and neuropathy.
OBJECTIVE: To report three unrelated infants with a distinctive phenotype of Leigh-like syndrome, neurogenic muscular atrophy, and hypertrophic obstructive cardiomyopathy. The patients all had a homozygous missense mutation in SCO2. BACKGROUND: SCO2 encodes a mitochondrial inner membrane protein, thought to function as a copper transporter to cytochrome c oxidase (COX), the terminal enzyme of the respiratory chain. Mutations in SCO2 have been described in patients with severe COX deficiency and early onset fatal infantile hypertrophic cardioencephalomyopathy. All patients so far reported are compound heterozygotes for a missense mutation (E140K) near the predicted CxxxC metal binding motif; however, recent functional studies of the homologous mutation in yeast failed to demonstrate an effect on respiration. METHODS: Here we present clinical, biochemical, morphologic, functional, MRI, and MRS data in two infants, and a short report in an additional patient, all carrying a homozygous G1541A transition (E140K). RESULTS: The disease onset and symptoms differed significantly from those in compound heterozygotes. MRI and muscle morphology demonstrated an age-dependent progression of disease with predominant involvement of white matter, late appearance of basal ganglia lesions, and neurogenic muscular atrophy in addition to the relatively late onset of hypertrophic cardiomyopathy. The copper uptake of cultured fibroblasts was significantly increased. CONCLUSIONS: The clinical spectrum of SCO2 deficiency includes the delayed development of hypertrophic obstructive cardiomyopathy and severe neurogenic muscular atrophy. There is increased copper uptake in patients' fibroblasts indicating that the G1541A mutation effects cellular copper metabolism.
Age of Onset↗
Controlled hypertension, a transgenic toggle switch reveals differential mechanisms underlying vascular disease.
A novel inbred rat model with inducible hypertension has been generated using a renin transgene under the transcriptional control of the cytochrome P450, Cyp1a1 promoter. The degree and duration of hypertension are regulated tightly by administration of the natural xenobiotic indole-3 carbinol and can be readily reversed. Induction experiments reveal distinct temporal and mechanistic responses to hypertensive injury in different vascular beds, which is indicative of differential susceptibility of organs to a hypertensive stimulus. The mesentery and heart exhibited the greatest sensitivity to damage, and the kidney showed an adaptive response prior to the development of malignant hypertensive injury. Quantitative analysis of morphological changes induced in mesenteric resistance arteries suggest eutrophic remodeling of the vessels. Kinetic evidence suggests that locally activated plasma prorenin may play a critical role in mediating vascular injury. This model will facilitate studies of the cellular and genetic mechanisms underlying vascular injury and repair and provide a basis for the identification of novel therapeutic targets for vascular disease.
Aldosterone↗
SHIRPA, a protocol for behavioral assessment: validation for longitudinal study of neurological dysfunction in mice.
Mouse models of neurological abnormalities are only valuable if accurately assessed. The three-stage SHIRPA procedure is used for the standardised assessment of mouse phenotype and has been reported in a high throughput experiment in which different mutants were ascertained at one age point using stage 1 of the protocol. In this study we have validated SHIRPA using a large cohort with one single mutation, 'legs at odd angles that causes neurological dysfunction. The cohort aged from 1 to 16 months during this study and this is the first longitudinal SHIRPA analysis.
Animals↗
Chronic mu-opioid receptor stimulation in humans decreases muscle sympathetic nerve activity.
BACKGROUND: Opioid-addicted patients undergoing detoxification provide a unique opportunity to assess the effects of chronic opioid receptor stimulation on the sympathetic nervous system. We tested the hypothesis that chronic oral methadone intake decreases resting efferent sympathetic nerve activity to muscle (MSA). Furthermore, we assessed whether this effect is reversed by mu-opioid receptor blockade during antagonist-supported detoxification under general anesthesia. METHODS AND RESULTS: Fifteen young patients (30+/-1 years old, mean+/-SEM) with a long history of mono-opioid addiction and under oral methadone substitution therapy (65+/-10 mg/d for 21+/-6 months) were selected. Peroneal MSA (microneurography) and catecholamine plasma concentrations (high-performance liquid chromatography) were assessed in the awake state and compared with those of age-matched healthy control subjects. The effects of mu-opioid receptor blockade by naloxone (12.4 mg IV) were determined during propofol anesthesia. Compared with healthy volunteers, resting MSA (4+/-2 versus 22+/-2 bursts/min, P<0.0001) and antecubital venous norepinephrine plasma concentration (100+/-64 versus 256+/-48 pg/mL, P=0.01) were markedly decreased in addicted patients despite similar arterial blood pressure and heart rate. Opioid receptor blockade markedly increased MSA (5+/-2 to 24+/-3 bursts/min) and norepinephrine (49+/-12 to 305+/-48 pg/mL) and epinephrine (13+/-2 to 482+/-67 pg/mL) arterial plasma concentrations as well as mean arterial pressure (82+/-4 to 108+/-3 mm Hg) and heart rate (70+/-3 to 86+/-4 beats/min). CONCLUSIONS: Chronic mu-opioid receptor stimulation by methadone decreases resting MSA in humans.
Adult↗
The pseudomolecule method and the structure of globular proteins. II. The example of ribonuclease F1 and T1.
The pseudomolecule approach to the structure of globular proteins in which a small number of water molecules are incorporated into the "molecule" is tested again by comparing the ribbon of hydrogen bonds in two proteins, ribonuclease F1 and T1. These two molecules are 59% homologous and have the same backbone conformation both globally and locally. The two ribbons of hydrogen bonds that cover the whole of the backbone are conserved with an accuracy of some 95% providing that allowance is made for the intrusion into one of the pair of such extra factors as the presence of adducts or metal ions, the insertions and the absence of a few water molecules from one of the x-ray data sets. Without these corrections, the conservation of the ribbon is some 85%. There are 35 conserved hydrogen-bonding residues, nearly all of which show many unions to the backbone or interactions with the active site. There are 36 point mutations that involve one or two hydrogen-bonding side chains and nearly all of these have either none or one hydrogen bond to the backbone. These are minor contributors to the ribbon of hydrogen bonds. Of the 71 residues involved in these two categories, all but six fit into the pseudomolecular picture of the structure of globular proteins. The remaining 30 residues almost all contain conserved hydrocarbon side chains that may have a second order effect on the structure through their space filling effects.
Amino Acid Sequence↗
Tissue renin-angiotensin systems: new insights from experimental animal models in hypertension research.
Renin was first isolated in the kidney by Tigerstedt and Bergman over 100 years ago. Almost 50 additional years were necessary to isolate the renin substrate angiotensinogen and to show its cleavage to angiotensin (Ang). Further studies were then needed to demonstrate that Ang I is converted via an angiotensin-converting enzyme to Ang II. The circulating renin-angiotensin system, with blood pressure regulatory and aldosterone stimulatory roles, served well for decades. However, more recent information on Ang II and its action in terms of cell proliferation, hypertrophy, and hyperplasia as well as immune-modulatory and even intracellular functions, have focused attention on local Ang II generation and effects. These investigations necessarily began in the kidney, but quickly moved to other organs including the brain, heart, adrenal gland, and vessel wall and formed the basis for the concept of independent tissue renin-angiotensin systems. Both renin and Ang II have even been implicated in intracellular activities. This review presents some selected aspects of the historical development of this concept and summarizes discoveries relying primarily on animal models which demonstrate that Ang II is generated locally and acts in tissues as a local peptidergic system. Comprehensiveness in such an endeavor is not possible. We focus largely on work from our own group, not because the work is necessarily worthy of such scrutiny but rather because of our own familiarity with the contents.
Animals↗
In vitro validation of a metabolic monitor for gas exchange measurements in ventilated neonates.
OBJECTIVE: To evaluate the Datex Deltatrac II for measurements in neonates requiring mechanical ventilation. DESIGN: Prospective laboratory evaluation, using a ventilated lung model and gas injection. During simulation of 79 neonatal respiratory settings, assessment of oxygen consumption (VO2), carbon dioxide production (VCO2) and respiratory quotient (RQ) was compared to a reference method (mass spectrometry, wet gas spirometry) using the statistical method of Bland and Altman. INTERVENTIONS: Respiratory variables, which may influence the accuracy and precision of gas exchange measurements, were varied within the following ranges: inspired oxygen fraction (FIO2): 0.21-0.8, expired carbon dioxide fraction (FECO2) and inspiratory-expiratory oxygen fraction (DFO2): 0.0032-0.0256, expiratory flow rate: 1.0-2.5 l/min, inspiratory pressure: 10-55 mbar, respiratory rate 25-60/min, constant RQ of 1. This resulted in 79 tests with VCO2 and VO2 ranging from 8-64 ml/min. MEASUREMENTS AND RESULTS: The coefficient of repeatability for ten single subsequent Deltatrac measurements was 8.09 ml/min for VO2 and 9.17 ml/min for VCO2 compared to 2.02 ml/min and 0.90 ml/min for VO2 and VCO2 with repeated reference measurements. The coefficient of repeatability of the Deltatrac measurements improved considerably when means of subsequent 5 min intervals were compared: 0.68 ml/min for VO2 and 0.28 ml/ min for VCO2. The difference between the two methods (Deltatrac-reference) was -3.8 % (2 s: 11.4%) for VO2, 13.2% (2s: 7.9%) for VCO2 and 17.6% (2s: 16.7%) for RQ. The agreement between methods deteriorated with smaller (FECO2) or DFO2 and increasing FIO2. CONCLUSIONS: Considering limits of agreement of less than +/- 20% as clinically acceptable, results for VO2 assessment indicate acceptable accuracy and precision whereas VCO2 and RQ assessments exceed this limit. Limited accuracy and precision result from detection of CO2 following dilution of expiratory gases and increased sensitivity to error propagation by Haldane equations due to the small differences between inspiratory and expiratory gas fractions.
Analysis of Variance↗
The importance of the peripheral circulation in critical illnesses.
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Baroreflex↗
Induction of the epithelial Na+ channel via glucocorticoids in mineralocorticoid receptor knockout mice.
Epithelial Na+ channel (ENaC) activity in kidney and colon is stimulated by aldosterone acting on the mineralocorticoid receptor (MR). MR and the glucocorticoid receptor (GR) show high homology in their DNA-binding domain and have similar affinities to mineralo- and glucocorticoids. We therefore asked whether the glucocorticoid-mediated activation of ENaC is restricted to the presence of MR and used the MR knockout mouse model to address this question. Due to their MR deficiency and the consecutive reduction of ENaC activity these mice die as neonates, and even after appropriate substitution therapy adult MR knockout mice suffer from high Na+ loss and hyperkalemia. In the present study, glucocorticoid treatment restored plasma K+ and almost normalized the fractional excretions of Na+ (FENa+) and K+ (FEK+) in adult salt-substituted MR knockout mice, while the effect of amiloride on FENa+ and FEK+ was augmented in these animals. In order to estimate ENaC activity, measurements of transepithelial equivalent short-circuit current (Isc) were performed. Glucocorticoids induced an amiloride-sensitive Na+ absorption in renal cortical collecting duct and distal colon of MR-/- of about 25% and 50% of the currents observed in glucocorticoid-treated wild-type mice, respectively. In the colon glucocorticoid treatment increased the mRNA abundance of all three ENaC subunits, in the kidney only alpha-ENaC was increased. The regulation of ENaC expression was the same in both genotypes and thus irrespective of the presence of MR. These data show that MR is no prerequisite for the activation of ENaC transcription and activity, and that the respective mechanisms can be stimulated via GR.
Amiloride↗
Partial silencing of the NEC1 gene results in early opening of anthers in Petunia hybrida.
The NEC1 gene, previously isolated from Petunia hybrida, is expressed at high levels in nectaries, and in a very localized fashion in stamens, particularly in the anther stomium cells and the upper part of the filament. To elucidate the function of the NEC1 gene, co-suppression was employed for down-regulation of NEC1 expression, and transposon insertion mutagenesis was used to knock out the NEC1 function. Among the transgenic plants and plants carrying dTph1 inserted in the NEC1 gene, an "early open anther" phenotype was observed. In this mutant phenotype, the anthers already open in young flower buds (1.8 cm) that still contain immature pollen, resulting in poor pollen quality and impaired pollen release. The results obtained indicate that NEC1 might be involved in the development of stomium cells, which are ruptured during the normal process of anther dehiscence to release mature pollen. Southern analysis revealed the presence of a highly homologous NEC1-like gene, named NEC2, in the P. hybrida genome. The presence of NEC2 was confirmed by segregation analysis and sequencing of genomic clones. The implications of these results and possible reasons why no visually obvious phenotype in nectaries could be produced by co-suppression or transposon insertion mutagenesis are discussed.
Alleles↗
Exporting a technical skills evaluation technology to other sites.
BACKGROUND: The Objective Structured Assessment of Technical Skill (OSATS) is a multistation performance-based examination that assesses the technical skills of surgery residents. This study explores the implementation issues involved in remote administration of the OSATS focusing on feasibility and the psychometric properties of the examination. METHODS: An eight-station OSATS was administered to surgical residents in Los Angeles and Chicago. The University of Toronto and the local institutions shared responsibility for organization and administration of the examination. RESULTS: There was good reliability for both the checklist (alpha = 0.68 for LA, 0.73 for Chicago) and global rating forms (alpha = 0.82 for both sites). Both iterations also showed evidence of construct validity, with a significant effect of training year for the checklist and global rating forms at both sites (analysis of variance: F = 8.66 to 19.93, P <0.01). Despite some challenges, the model of central organization and peripheral delivery was effective for the administration of the examinations. CONCLUSIONS: Two iterations of the OSATS at remote sites demonstrated psychometric properties that are highly consistent with previously reported data suggesting that the examination is portable. Both faculty and residents indicated satisfaction with the examination experience. A model of central administration with peripheral delivery was feasible and effective.
California↗
The spatial and temporal expression pattern of Nesp and its antisense Nespas, in mid-gestation mouse embryos.
We describe the spatiotemporal expression pattern of Nesp, and its antisense transcript, Nespas. We found non-complementary expression of these two oppositely imprinted transcripts during mouse embryogenesis, in a number of forming embryonic structures. Nesp expression was primarily seen in the somites and vasculature, whereas Nespas was mainly detected in the progress zone, mesenchyme and ectoderm of the limb, and the neural tube.
Animals↗
Probability of acceptable intubation conditions with low dose rocuronium during light sevoflurane anaesthesia in children.
BACKGROUND: To define the rocuronium doses which would provide 50%, 90%, and 95% probability of 'acceptable' intubation conditions during light sevoflurane anaesthesia, we studied 60 children aged 2-7 years in a prospective, randomised, assessor blinded study. METHODS: After mask ventilation with 1 MAC sevoflurane/N2O for 17+/-1 (x+/-SD) min we administered rocuronium (either 0.15, 0.22, 0.3, 0.5, or 1.0 mg. kg(-1)) or placebo, and quantified the evoked force of the adductor pollicis muscle. Intubation conditions were assessed before and 2 min after injection of the test drug. RESULTS: Intubation conditions were improved significantly with rocuronium and scored 'acceptable' in 70%, 90%, and 100% of the children after injection of rocuronium 0.15, 0.22, and 0.3 mg x kg(-1), respectively. In parallel, twitch tension decreased to 53% (6-100), 26% (11-100), and 11% (0-19) of baseline (median (range)). Recovery of train-of-four ratio to 0.8 was achieved 13 (7-19), 16 (8-28), and 27 (23-44) min after injection of the respective rocuronium doses. Higher rocuronium doses did not further improve intubation conditions but only prolonged time of neuromuscular recovery. Logistic regression analysis revealed that rocuronium 0.11 (CI 0.05-0.16), 0.21 (0.14-0.28), and 0.25 (0.15-0.34) mg x kg(-1) provides a 50%, 90%, and 95% probability of 'acceptable' intubation conditions in children during 1 MAC sevoflurane/N2O anaesthesia, respectively. Furthermore, we calculated that force depression of adductor pollicis muscle to 81% (CI 72-90), 58% (42-74), and 50% (29-71) of baseline is associated with 50%, 90%, and 95% probability of 'acceptable' intubation conditions. CONCLUSIONS: Submaximal depression of muscle force with low dose rocuronium improves intubation conditions in children during light sevoflurane anaesthesia while allowing rapid recovery of neuromuscular function. However, when using low dose rocuronium neuromuscular monitoring may be helpful to detect children with inadequate response to the relaxant so as to avoid an unsuccessful intubation attempt.
Androstanols↗