Search PubMed⌕ Search

Biomedical subjects

N R Dunn

Publications and source records attributed to N R Dunn.

At least 19 recordsLinked to original sources
PubMed2001

Bone morphogenetic protein 4 in the extraembryonic mesoderm is required for allantois development and the localization and survival of primordial germ cells in the mouse.

Evidence suggests that the specification of primordial germ cells (PGCs) in the mammalian embryo does not depend on maternal determinants. Rather, previous genetic analysis in the mouse has shown that bone morphogenetic protein 4 (Bmp4) is required for the formation of both PGCs and allantois. Bmp4 is expressed in both the trophoblast-derived extraembryonic ectoderm (ExE) and in the epiblast-derived extraembryonic mesoderm (ExM), in which the PGCs, allantois primordium, and angioblasts are first detected. We have shown that Bmp4 made in the ExE functions to induce precursors of PGCs and allantois in the adjacent epiblast, resulting in complete lack of both cell types in homozygous null mutants. However, the function of Bmp4 in the ExM is totally unknown. To address this question, we generated tetraploid (4N) chimeras by aggregating Bmp4 null ES cells with wild-type tetraploid embryos. In this combination, wild-type tetraploid cells contribute to the extraembryonic trophoblast and primitive endoderm lineages but are excluded from the epiblast and its derivatives, including the ExM. Our results clearly demonstrate that Bmp4 made in the ExM does not affect the establishment of either PGC or allantois lineages, but is required for PGC localization and survival and for the differentiation of the allantois. These findings suggest that Bmp4 expressed in epiblast-derived tissues plays vital roles in reproduction by regulating both the development of the germ line and the vascular connection between the embryo and the placenta.

Allantois↗
PubMed2001

Distinct mesodermal signals, including BMPs from the septum transversum mesenchyme, are required in combination for hepatogenesis from the endoderm.

Mesodermal signaling is critical for patterning the embryonic endoderm into different tissue domains. Classical tissue transplant experiments in the chick and recent studies in the mouse indicated that interactions with the cardiogenic mesoderm are necessary and sufficient to induce the liver in the ventral foregut endoderm. Using molecular markers and functional assays, we now show that septum transversum mesenchyme cells, a distinct mesoderm cell type, are closely apposed to the ventral endoderm and contribute to hepatic induction. Specifically, using a mouse Bmp4 null mutation and an inhibitor of BMPs, we find that BMP signaling from the septum transversum mesenchyme is necessary to induce liver genes in the endoderm and to exclude a pancreatic fate. BMPs apparently function, in part, by affecting the levels of the GATA4 transcription factor, and work in parallel to FGF signaling from the cardiac mesoderm. BMP signaling also appears critical for morphogenetic growth of the hepatic endoderm into a liver bud. Thus, the endodermal domain for the liver is specified by simultaneous signaling from distinct mesodermal sources.

Animals↗
PubMed2001

The relationship between use of oral contraceptives and myocardial infarction in young women with fatal outcome, compared to those who survive: results from the MICA case-control study.

To examine the relationship between use of oral contraceptives and the risk of dying from myocardial infarction, we made a comparison of deceased patients and live patients (women aged less than 45) identified for the Myocardial Infarction Causality case-control study, using data obtained from general practice medical notes. There were 422 live patients and 110 deceased patients of women with a myocardial infarction with data available. The adjusted odds ratio for exposure to second generation oral contraceptives and risk of death within 28 days of a myocardial infarction compared with no oral contraceptive use was raised (2.88, 95% confidence interval 1.22-6.77), and this effect was not seen for other types of oral contraceptives including third generation oral contraceptive formulations. In absolute terms, between 47,000 and 71,000 women would have to be exposed to a second generation pill for one year to result in one extra death from myocardial infarction, and this risk applies mainly to smokers. The results suggest a slightly increased relative risk of death among those having a myocardial infarction associated with exposure to second generation oral contraceptives, but this represents a small absolute risk. Further work is required before any change in contraceptive practice should be advocated.

Adult↗
PubMed2001

Mouse embryos lacking Smad1 signals display defects in extra-embryonic tissues and germ cell formation.

The Smad proteins are important intracellular mediators of the transforming growth factor beta (TGFbeta) family of secreted growth factors. Smad1 is an effector of signals provided by the bone morphogenetic protein (BMP) sub-group of TGFbeta molecules. To understand the role of Smad1 in mouse development, we have generated a Smad1 loss-of-function allele using homologous recombination in ES cells. Smad1-/- embryos die by 10.5 dpc because they fail to connect to the placenta. Mutant embryos are first recognizable by 7.0 dpc, owing to a characteristic localized outpocketing of the visceral endoderm at the posterior embryonic/extra-embryonic junction, accompanied by a dramatic twisting of the epiblast and nascent mesoderm. Chimera analysis reveals that these two defects are attributable to a requirement for Smad1 in the extra-embryonic tissues. By 7.5 dpc, Smad1-deficient embryos show a marked impairment in allantois formation. By contrast, the chorion overproliferates, is erratically folded within the extra-embryonic space and is impeded in proximal migration. BMP signals are known to be essential for the specification and proliferation of primordial germ cells. We find a drastic reduction of primordial germ cells in Smad1-deficient embryos, suggesting an essential role for Smad1-dependent signals in primordial germ cell specification. Surprisingly, despite the key involvement of BMP signaling in tissues of the embryo proper, Smad1-deficient embryos develop remarkably normally. An examination of the expression domains of Smad1, Smad5 and Smad8 in early mouse embryos show that, while Smad1 is uniquely expressed in the visceral endoderm at 6.5 dpc, in other tissues Smad1 is co-expressed with Smad5 and/or Smad8. Collectively, these data have uncovered a unique function for Smad1 signaling in coordinating the growth of extra-embryonic structures necessary to support development within the uterine environment.

Animals↗
PubMed2000

The rates of common adverse events reported during treatment with proton pump inhibitors used in general practice in England: cohort studies.

AIMS: To estimate the rates of common adverse events in patients treated with the proton pump inhibitors omeprazole, lansoprazole and pantoprazole in general practice in England. METHODS: In prescription-event monitoring cohort studies, data on dispensed prescriptions prescribed by general practitioners in England soon after each drug was launched were linked to subsequent clinical events recorded by the prescriber. 16 205 patients prescribed omeprazole between June 1989 and June 1990, 17 329 patients prescribed lansoprazole between May and November 1994, and 11 541 patients prescribed pantoprazole between December 1996 and June 1997 were studied. RESULTS: The commonest adverse events in the omeprazole, lansoprazole and pantoprazole cohorts were diarrhoea (incidence: 0. 18, 0.39 and 0.23 per 1000 days of exposure, respectively); nausea/vomiting (incidence: 0.16, 0.22 and 0.18 per 1000 days of exposure, respectively); abdominal pain (incidence: 0.17, 0.21 and 0. 17 per 1000 days of exposure, respectively); and headache (incidence rates: 0.10, 0.17 and 0.15 per 1000 days of exposure, respectively). The remaining adverse events occurred at rates of less than 0.11 per 1000 days of exposure. There were little absolute differences in the rates of most events between the three proton pump inhibitors. However, diarrhoea was more commonly associated with lansoprazole compared with omeprazole (rate difference: 0.21 per 1000 days of exposure; 95% CI 0.17, 0.25; rate ratio: 2.11; 1.78, 2.51), and there was a clear age-response relationship. CONCLUSIONS: Adverse events occurred relatively infrequently in all three cohorts. There were only small absolute differences in event rates between the three drugs, although these data suggest the hypothesis that lansoprazole is associated with more frequent occurrence of diarrhoea, particularly in the elderly.

2-Pyridinylmethylsulfinylbenzimidazoles↗
PubMed2000

Regional variation in incidence and case fatality of myocardial infarction among young women in England, Scotland and Wales.

OBJECTIVES: To examine the regional variation in incidence and case fatality of myocardial infarction among young women. DESIGN: Cross sectional survey, using population based incidence data. SETTING: England, Scotland and Wales. SUBJECTS: Subjects were women aged 16-44 with a diagnosis of myocardial infarction between 1 October 1993 and 15 October 1995. OUTCOME MEASURES: Incidence of myocardial infarction per 100,000 women years, with case fatality as a percentage of total cases. RESULTS: Incidence of myocardial infarction rose steeply from age 33 upwards, (maximum = 20.2 cases per 100,000 women years at age 44). The adjusted incidence rate for myocardial infarction was 3.7 (95% CI 3.2, 4.2) times greater in Scotland than in southern England. In contrast, case fatality was significantly lower in Scotland: 18.5% (95% CI 13.1%, 25.0%), compared with 31.0% (95% CI 25.9%, 36.0%) in southern England. CONCLUSIONS: The incidence of myocardial infarction varied widely within the United Kingdom. Case fatality variation may reflect differences in ambulance response, or in diagnostic acumen, within the regions.

Adolescent↗
PubMed2000

Costs of seeking ethics approval before and after the introduction of multicentre research ethics committees.

With the advent of multicentre research ethics committees in the UK, local research ethics committees (LRECs) are required to advise only on issues relating to the local acceptability of a project. We looked at the handling of two commercially sponsored studies, one initiated before the change and one after, confining the analysis to 21 LRECs approached in both. As judged by the amount of paper per application, the new system for LRECs is simpler and should be less costly. However, there was an increasing tendency for LRECs to charge for their services (30% study 1, 47% study 2) and these charges varied by more than 400%. If such fees must be levied, a common scale is desirable.

Case-Control Studies↗
PubMed2000

Adverse effects associated with the use of donepezil in general practice in England.

Donepezil is an acetylcholinesterase inhibitor indicated for the symptomatic treatment of mild to moderate Alzheimer's disease. It is reported to have a relatively favourable side-effect profile. We report here on a pharmacovigilance study carried out post-marketing in England. An observational cohort study using the technique of Prescription-Event Monitoring was carried out. Some 1762 patients (mean age 72.9 years; 42% male) were followed up for 6 months minimum. The commonest adverse events were nausea, diarrhoea, malaise, dizziness and insomnia. Aggression, agitation and abnormal dreams were uncommonly associated with the drug. There were no cardiac rhythm disturbances or liver disorders causally associated. The commonest adverse drug reactions are already reported in the product information. Given the relatively small size of this cohort, the signals of abnormal dreams and psychiatric disturbance as possible adverse drug reactions need further investigation in carefully planned studies.

Aged↗
PubMed2000

Bmp4 and Fgf10 play opposing roles during lung bud morphogenesis.

Morphogenesis of the mouse lung involves reciprocal interactions between the epithelial endoderm and the surrounding mesenchyme, leading to an invariant early pattern of branching that forms the basis of the respiratory tree. There is evidence that Fibroblast growth factor 10 (Fgf10) and Bone Morphogenetic Protein 4 (Bmp4), expressed in the distal mesenchyme and endoderm, respectively, play important roles in branching morphogenesis. To examine these roles in more detail, we have exploited an in vitro culture system in which isolated endoderm is incubated in Matrigel(TM) substratum with Fgf-loaded beads. In addition, we have used a Bmp4(lacZ) line of mice in which lacZ faithfully reports Bmp4 expression. Analysis of lung endoderm in vivo shows a dynamic pattern of Bmp4(lacZ) expression during bud outgrowth, extension and branching. In vitro, Fgf10 induces both proliferation and chemotaxis of isolated endoderm, whether it is derived from the distal or proximal lung. Moreover, after 48 hours, Bmp4(lacZ) expression is upregulated in the endoderm closest to the bead. Addition of 30-50 ng/ml of exogenous purified Bmp4 to the culture medium inhibits Fgf-induced budding or chemotaxis, and inhibits overall proliferation. By contrast, the Bmp-binding protein Noggin enhances Fgf-induced morphogenesis. Based on these and other results, we propose a model for the combinatorial roles of Fgf10 and Bmp4 in branching morphogenesis of the lung.

Animals↗
PubMed1999

Bmp4 is required for the generation of primordial germ cells in the mouse embryo.

In many organisms the allocation of primordial germ cells (PGCs) is determined by the inheritance of maternal factors deposited in the egg. However, in mammals, inductive cell interactions are required around gastrulation to establish the germ line. Here, we show that Bmp4 homozygous null embryos contain no PGCs. They also lack an allantois, an extraembryonic mesodermal tissue derived, like the PGCs, from precursors in the proximal epiblast. Heterozygotes have fewer PGCs than normal, due to a reduction in the size of the founding population and not to an effect on its subsequent expansion. Analysis of beta-galactosidase activity in Bmp4(lacZneo) embryos reveals that prior to gastrulation, Bmp4 is expressed in the extraembryonic ectoderm. Later, Bmp4 is expressed in the extraembryonic mesoderm, but not in PGCs. Chimera analysis indicates that it is the Bmp4 expression in the extraembryonic ectoderm that regulates the formation of allantois and primordial germ cell precursors, and the size of the founding population of PGCs. The initiation of the germ line in the mouse therefore depends on a secreted signal from the previously segregated, extraembryonic, trophectoderm lineage.

Allantois↗
PubMed1999

Case and control recruitment, and validation of cases for the MICA case-control study in England, Scotland and Wales.

OBJECTIVES: To describe the processes involved in the selection of cases and controls, and the validation of case diagnosis, in a large case-control study on the association between myocardial infarction (MI) and oral contraceptives. DESIGN: Community case-control study in England, Scotland and Wales. SUBJECTS: Cases were women aged 16-44 with a diagnosis of MI. Controls were age and general practice matched women without a diagnosis of MI. RESULTS: The proportion of interviewed cases per number eligible was 19% (95% CI 12-26%) lower in England and Wales than in Scotland. The kappa score for agreement between three cardiologists on diagnostic categories of the potential cases was 0.52 overall ('moderate' agreement). For the 35 cases resubmitted for categorization, the kappa scores for agreement between the first and second classification for the two national committee cardiologists were 0.32 and 0.23 ('fair' agreement). Age matching of controls was better in Scotland than England and Wales, the proportion of the first choice controls being 14% (95% CI 8-19%) higher in Scotland. The mean time to complete a cluster of interviews (one case and four controls) was 36 days in Scotland and 63 days in England and Wales. CONCLUSIONS: Very close age-matching was achieved overall, although the process was more efficient in Scotland than in England and Wales. Some suggestions for improvement in the case validation process are made.

Journal Article↗
PubMed1999

Cohort study on calcium channel blockers, other cardiovascular agents, and the prevalence of depression.

AIMS: Some reports have suggested that calcium channel blockers may be associated with an increased incidence of depression or suicide. There is a paucity of evidence from large scale studies. The aim of this study was to assess rates of depression with calcium channel antagonists using data from prescription event monitoring studies. METHODS: Observational studies on large cohorts of patients using lisinopril, enalapril (ACE inhibitors), nicardipine (type 2 calcium channel blocker) and diltiazem (type 3 calcium channel blocker) were conducted, using prescription-event monitoring. Rates of depression in the different drugs and rate ratios (95% CI) were computed. RESULTS: The crude overall rates of depression during treatment were 1.89, 1.92 and 1.62 per 1000 patient months for the ACE inhibitors, diltiazem and nicardipine, respectively. Using the ACE inhibitors as the reference group, the rate ratios for depression were 1.07 (0. 82-1.40) and 0.86 (0.69-1.08) for diltiazem and nicardipine, respectively. CONCLUSIONS: This study does not support the hypothesis that calcium channel blockers are associated with depression, when considering patients treated in general practice in the UK.

Angiotensin-Converting Enzyme Inhibitors↗
PubMed1999

Risk of myocardial infarction in young female smokers.

OBJECTIVES: To determine the extent of risk of myocardial infarction from cigarette smoking in young women, and to examine the relation of smoking with other putative risk factors. DESIGN: Community based case control study. SETTING: England, Scotland, and Wales. PATIENTS: Women (n = 448) between 16 and 44 years old with a diagnosis of incident myocardial infarction between 1 October 1993 and 16 October 1995. Controls (n = 1728) were age and general practice matched women without a diagnosis of myocardial infarction. OUTCOMES MEASURES: Odds ratios for risk of myocardial infarction associated with smoking and other risk factors. RESULTS: Odds ratios for myocardial infarction in smokers versus non-smokers showed a strong dose response, from 2.47 (95% confidence interval (CI) 1.12 to 5.45) in smokers of 1-5 cigarettes per day to 74.6 (95% CI 33.0 to 169) in smokers of >/= 40 cigarettes per day. There was no interaction of smoking with use of oral contraceptives, but there were additive risks with other clinical risk factors such as hypertension and diabetes. It is estimated that if all women aged 16-44 years were able to stop smoking, 400 cases of myocardial infarction per annum (of whom 112 would die) would be prevented. CONCLUSIONS: In young women the risk of myocardial infarction from smoking was considerable, and heavy smokers with other risk factors were especially at risk.

Adolescent↗
PubMed1999

Bmp signaling regulates proximal-distal differentiation of endoderm in mouse lung development.

In the mature mouse lung, the proximal-distal (P-D) axis is delineated by two distinct epithelial subpopulations: the proximal bronchiolar epithelium and the distal respiratory epithelium. Little is known about the signaling molecules that pattern the lung along the P-D axis. One candidate is Bone Morphogenetic Protein 4 (Bmp4), which is expressed in a dynamic pattern in the epithelial cells in the tips of growing lung buds. Previous studies in which Bmp4 was overexpressed in the lung endoderm (Bellusci, S., Henderson, R., Winnier, G., Oikawa, T. and Hogan, B. L. M. (1996) Development 122, 1693-1702) suggested that this factor plays an important role in lung morphogenesis. To further investigate this question, two complementary approaches were utilized to inhibit Bmp signaling in vivo. The Bmp antagonist Xnoggin and, independently, a dominant negative Bmp receptor (dnAlk6), were overexpressed using the surfactant protein C (Sp-C) promoter/enhancer. Inhibiting Bmp signaling results in a severe reduction in distal epithelial cell types and a concurrent increase in proximal cell types, as indicated by morphology and expression of marker genes, including the proximally expressed hepatocyte nuclear factor/forkhead homologue 4 (Hfh4) and Clara cell marker CC10, and the distal marker Sp-C. In addition, electron microscopy demonstrates the presence of ciliated cells, a proximal cell type, in the most peripheral regions of the transgenic lungs. We propose a model in which Bmp4 is a component of an apical signaling center controlling P-D patterning. Endodermal cells at the periphery of the lung, which are exposed to high levels of Bmp4, maintain or adopt a distal character, while cells receiving little or no Bmp4 signal initiate a proximal differentiation program.

Animals↗