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Biomedical subjects

J Cooke

Publications and source records attributed to J Cooke.

At least 55 records · Page 3Linked to original sources
PubMed1997

Evolutionary origins and maintenance of redundant gene expression during metazoan development.

Various levels of redundancy in developmental gene function appear common in complex metazoans. There might be no apparent phenotype at many, or even any, of a gene's specific expression sites in homozygous null mutant embryos. Here we ask what underlies the origin of such arrangements. The generation of families of genes by duplication has clearly been important. Additionally, however, selection might have driven molecularly unrelated genes, which encode proteins of similar physiological function, to become expressed during the same sets of developmental events (times and places), even though each such gene might initially have evolved in connection with just one of these events.

Animals↗
PubMed1997

Economic evaluation under managed competition: evidence from the U.K.

Although economic evaluation in health care has a long-standing tradition in the United Kingdom, very little is known about its impact on decision making, particularly following the introduction of the internal market. Since managed competition appears to be growing in popularity worldwide, the U.K. is an interesting case study, as the reforms are well underway and there have been a number of efforts to conduct and disseminate economic evaluations. In this paper the potential for using economic evaluation in health care decision making in the U.K. is discussed. Then its actual impact is assessed in two ways. First, two case studies are discussed, on heart transplantation and the use of pharmaceuticals in the management of labour in pregnancy. Second, new data from a recent survey of potential users of economic evaluations are presented, with the emphasis on exploring the reasons for the impact, or lack of impact, of economic results. It is concluded that the NHS reforms increase the potential for the use of economic evaluation. However, there is a need to increase decision makers' awareness of economic studies and to help them interpret study methodology and results. Although worries about validity of economic studies are one of the major barriers to their use, other important barriers relate to the multiple objectives being pursued, of which increased efficiency is just one, and the difficulties of freeing resources from existing services in order to divert them to more cost-effective treatments and programmes.

Cost-Benefit Analysis↗
PubMed1997

Noggin acts downstream of Wnt and Sonic Hedgehog to antagonize BMP4 in avian somite patterning.

In the vertebrate embryo, the lateral compartment of the somite gives rise to muscles of the limb and body wall and is patterned in response to lateral-plate-derived BMP4. Activation of the myogenic program distinctive to the medial somite, i.e. relatively immediate development of the epaxial muscle lineage, requires neutralization of this lateral signal. We have analyzed the properties of molecules likely to play a role in opposing lateral somite specification by BMP4. We propose that the BMP4 antagonist Noggin plays an important role in promoting medial somite patterning in vivo. We demonstrate that Noggin expression in the somite is under the control of a neural-tube-derived factor, whose effect can be mimicked experimentally by Wnt1. Wnt1 is appropriately expressed in the neural tube. Furthermore, we show that Sonic Hedgehog is able to activate ectopic expression of Noggin resulting in the blocking of BMP4 specification of the lateral somite. Our results are consistent with a model in which Noggin activation lies downstream of the SHH and Wnt signaling pathways.

Animals↗
PubMed1997

Effect of automatic kV selection on dose and contrast for a mammographic X-ray system.

The effect of automatic tube potential (kV) selection on breast dose and contrast has been assessed using a Philips MammoDiagnost 3000 mammography X-ray set. The performance of the X-ray set using automatic kV selection has been compared with that found using a fixed kV of 28. The AUTOKV mode selected 25 kV for breasts with thickness up to about 50 mm, which increased the contrast by 5-10%, and increased the mean glandular dose (MGD) per film by, on average, 30-40%. For large breasts with a compressed thickness of 70 mm and above, kVs up to 30 were selected so that the average MGD per film was reduced by 19% from 3.62 to 2.94 mGy, with an estimated loss in contrast of about 4-8%. For all breasts the mean MGD per film was 1.85 +/- 0.05 mGy where AUTOKV was used, and 1.74 +/- 0.08 mGy per film when 28 kV was used. The overall image quality of the mammograms was found to be higher when AUTOKV was used. Overall, the AUTOKV facility on this X-ray set generally worked well and resulted in slightly higher contrast and slightly better image quality at the price of a small increase in the average dose for this patient group when compared with the usual UK procedure of using a fixed 28 kV.

Breast Neoplasms↗
PubMed1997

Chick noggin is expressed in the organizer and neural plate during axial development, but offers no evidence of involvement in primary axis formation.

We have cloned and examined the early developmental expression of the chick homolog of noggin, a gene originally isolated in Xenopus that can dorsalize gastrular mesoderm and induce anterior neural tissue from gastrular ectoderm when expressed experimentally. Chick noggin is expressed at relatively low levels, but at sites equivalent to those seen in amphibian development, namely Hensen's node and the endo- and mesodermal head process. There is also diffuse expression in the early CNS, centered on the ventral midline, and later hindbrain-associated expression. Since the earlier of these expression sites are consistent with endogenous organizer functions suggested by the properties of the protein in Xenopus experiments, we have used recombinant mammalian Noggin protein secreted by CHO cells in tests for developmental disturbance on the early gastrula-staged chick blastoderm. Comparable tests sensitively detect effects, on chick, of various other secreted proteins that simulate or replicate early developmental signals in Xenopus. We have been unable to observe such effects with a range of Noggin concentrations including those that dramatically dorsalize Xenopus ventral marginal zones. To illustrate effects observed in such tests with secreted proteins active on early stages, we show results with the known Xenopus ventralizer Bone Morphogenetic Protein 4 (BMP-4).

Amino Acid Sequence↗
PubMed1997

Pharmacoeconomic aspects of antibacterial treatment with cefotaxime.

Pharmacoeconomics is a relatively new discipline, which is becoming increasingly useful in the current climate of medical advances that continue despite limited access to healthcare resources. Pharmacoeconomics may be used as a tool, assisting healthcare decision makers to select clinically beneficial therapies and weigh clinical gain against expenditure. Cefotaxime has been shown in many studies to be a cost-effective antibiotic agent, its monetary value being augmented by its use in low dose, low frequency regimens. This cost-effectiveness, combined with a maintained broad spectrum of antibiotic activity, low propensity for selecting resistant bacterial strains and high therapeutic index, makes cefotaxime a suitable antibiotic agent in many indications involving mild-to-moderate infections by susceptible organisms.

Cefotaxime↗
PubMed1997

Pharmacoeconomics of haemophilia.

Pharmacoeconomic analysis is one method of providing health-care decision-makers with information to assist them in assigning priorities for the allocation of resources, both within a particular disease area and between different diseases. Conducted well, such analyses can provide a valuable contribution to the published literature which can contribute to improving clinical outcomes through the endorsement of evidence-based medicine. The treatment of haemophilia with replacement therapy is an area which could benefit from such an approach, both by modelling pharmacoeconomic analyses on published clinical studies and by incorporating pharmacoeconomic analysis and quality of life measurements alongside existing clinical trials.

Drug Costs↗
PubMed1996

Early developmental expression and experimental axis determination by the chicken Vg1 gene.

BACKGROUND: Genes of the transforming growth factor beta (TGF beta) superfamily have been implicated in the earliest steps of developmental patterning in vertebrates. In Xenopus, the Vg1 gene is a candidate for the initiator of axis formation: its RNA and protein are broadly but appropriately localized at the start of development, and processed Vg1 protein is a powerful inducer of organized axial tissue in blastular animal caps in vitro and when locally produced in vivo after injection of Vg1 mRNA into blastomeres. Site-specific proteolytic processing occurs ubiquitously for most TGF beta members, producing the active peptide ligand, but is tightly restricted, by unknown mechanisms, for endogenous Vg protein in Xenopus and zebrafish embryos. This restriction may be involved in the spatial localization of activity required for an organizing role. RESULTS: We have characterized an amniote (chick) orthologue of Vg1, cVg1, and examined its developmental expression. The early expression of cVg1 includes a phase broadly related to the known time and site of axis (primitive streak) initiation; the initial transcription of cVg1 is centred in the posterior marginal zone (PMZ), a region of the blastoderm known to contain the axial organizing activity at this stage. We also observed later neural and paraxial mesodermal expression of cVg1, which has not been described previously for Vg homologues in other vertebrates. We have grafted transfected COS cells, producing processed cVg1 protein, to peripheral positions around the chick early blastoderm. Such grafts initiate formation of morphologically complete primitive streaks, simulating the properties of grafts from the PMZ. CONCLUSIONS: In vertebrate development, Vg genes may be required for an evolutionarily conserved early step in positioning or induction of the axis.

Amino Acid Sequence↗
PubMed1996

Cloning and early dorsal axial expression of Flik, a chick follistatin-related gene: evidence for involvement in dorsalization/neural induction.

We have cloned and sequenced a chick gene, Flik (follistatin-like) that appears to be the homolog of the mammalian TSC36. The ORF encodes a secreted protein of approx 38 kDa, containing a single cysteine-rich domain that shows a strong relationship with the second of the four from which Follistatin is constructed. The remainder of the Flik protein shows no strong family affinities. We describe here the normal expression pattern of the gene during primitive streak and neurula stages. We also give revised data for early neurectodermal expression of chick follistatin (Connolly et al., 1995, Developmental Genetics 17(1), 65-77) and follow the new ectopic expression of both genes during the induction of a second neural axis, after grafting of Hensen's node into a peripheral position in a host blastoderm. Both genes mark the organizer (node and/or mesodermal head process) and early neural plate, and could thus be involved in intercellular signaling during mesodermal dorsalization and neural induction. Flik expression appears earlier than that of follistatin however, and unlike that of follistatin, it is maintained strongly in the dorsal midline with intensity smoothly declining into presumptive lateral regions. We show that both genes are upregulated in host tissue in the neighborhood of node grafts, but whereas follistatin is transcribed after 8-10 hr in host epiblast that has formed new neural plate, Flik is expressed within 4 hr in this region, sometimes detectable before the first structural changes (columnarization) of neuralization. Thus, although ectodermal Flik expression is later confined within neural plate, and mesodermal expression concentrated in dorsal axial tissue, its early distribution is consistent with the idea that the encoded protein may first be involved in generating a graded system that positions the boundaries of both neural and dorsal axial mesodermal territories. The results are discussed in relation to this hypothesis and to other recent findings regarding control of vertebrate dorsoventral patterning.

Amino Acid Sequence↗
PubMed1996

The expression and regulation of follistatin and a follistatin-like gene during avian somite compartmentalization and myogenesis.

We report on the normal and experimentally altered expression of two structurally related genes, Follistatin and Follistatin-like (Flik), in the somites of avian embryos. In normal chick embryos, Follistatin expression can first be seen in the cells of the dorsolateral somite quarter. During somite maturation, the cells of the dorsomedial quarter also express this gene. Within the dermomyotome it seems that only the muscle precursors are Follistatin-positive. The migrating precursors of limb and tongue muscle as well as the myotome cells show Follistatin expression. The manipulation experiments reveal that the expression of Follistatin in the somites can be inhibited by notochord signals. This effect can be mimicked by sonic hedgehog protein. Flik is expressed in the dorsomedial compartment of the somite and later on in the myotome. Unlike Follistatin, Flik expression requires signals emanating from the neural tube. Notochordal influences do not alter Flik expression. The expression of both genes does not depend on signals of intermediate or lateral mesoderm. Since the products of both genes are proposed to antagonize TGF-beta superfamily proteins during gastrulation and neuralization, we postulate that during myogenesis follistatin and flik counteract inhibiting effects of related molecules on muscle differentiation.

Animals↗
PubMed1996

Expression of interleukin-6 in osteoarthritic chondrocytes and effects of fluid-induced shear on this expression in normal human chondrocytes in vitro.

This study tested the effect of fluid-induced shear on interleukin-6 expression in normal human articular chondrocytes in vitro. As determined by Northern blot analysis, interleukin-6 mRNA expression occurs in chondrocytes from osteoarthritic cartilage but not in normal chondrocytes. Applying fluid-induced shear stress to primary high density cultures of chondrocytes increased interleukin-6 mRNA signal 4-fold at 1 hour and 10 to 15-fold at 48 hours compared with unsheared control cultures. At 48 hours, fluid-induced shear stress increased interleukin-6 protein levels in the culture medium 9 to 10-fold compared with unsheared controls. mRNA signals for interleukin-1alpha, interleukin-1beta, and tumor necrosis factor-alpha in RNA from sheared or control chondrocytes were not detected by Northern blotting. Transforming growth factor-beta mRNA signal was detectable but was not affected by shear. In contrast, human lung fibroblasts (WI-38) responded to fluid-induced shear with increased signal for transforming growth factor-beta, but not interleukin-6, mRNA. Both cell types did respond to interleukin-1alpha with increased interleukin-6 mRNA signal. These data demonstrated that distortional forces, such as fluid-induced shear stress, alter interleukin-6 levels in normal chondrocytes in vitro and suggest that increased interleukin-6 expression in osteoarthritic cartilage may result, in part, from alterations in the mechanical loading of the tissue.

Adult↗
PubMed1996

Comparison of radiographer/radiologist double film reading with single reading in breast cancer screening.

OBJECTIVES - To assess the efficacy of dual film reading in screening mammography with a suitably trained radiographer as the second reader and to determine a suitable decision model for radiographer/radiologist double reading. SETTING - Three breast screening centres in South Thames (West) region. METHODS - Seven radiographers with prior film reading training double read 17 202 screening mammograms with a radiologist. Screening performance of radiographers and radiologists was assessed taking into account interval cancers. The efficacy of radiographer/radiologist double reading was assessed in terms of changes in sensitivity and specificity compared with radiologist single reading. RESULTS - Radiographers yielded equivalent sensitivity but lower specificity than radiologist film readers. The effect of double reading between radiographer/radiologist pairs was an increase in sensitivity of 6-4%, which was achieved at the cost of a 0-6% decrease in specificity. This was reached by a decision system involving radiologists' review of radiographer queries and recall classifications. If all radiographer queries were recalled a large increase in sensitivity would be counterbalanced by an equally large decrease in specificity. CONCLUSIONS - Radiographer/radiologist double reading resulted in similar increases in sensitivity as those previously reported in radiologist double reading studies. Radiologist review of radiographer reported abnormalities is a suitable means by which to limit excess recall.

Adult↗
PubMed1996

Radiographers as film readers in screening mammography: an assessment of competence under test and screening conditions.

The aim of this study was to investigate the potential of radiographers as film readers in screening mammography. Seven radiographers received training in mammogram interpretation at a National Health Service (NHS) Breast Screening Training Centre. Film reading performance was assessed over a period of 1 year after training with test sets of selected screening mammograms. Actual screening performance on contemporary screening mammograms was monitored after training in relation to radiologist decisions and screening outcome. It was found that trained radiographers read mammograms to a standard comparable with that of radiologists. Film reading skills were maintained consistently over the period of this study and transferred to actual screening performance. It was concluded that radiographers could play a useful role as second readers in screening mammography. Training needs have to be assessed in relation to the role the film reading radiographer is to adopt.

Adult↗
PubMed1995

Morphogens in vertebrate development: how do they work?

The idea that concentration gradients of crucial substances might control the pattern of development, even in the embryos of complex organisms, has been around for a long time, but mostly in obscure forms. Twenty five years ago clear, experimentally testable ideas about how such gradients might work were enunciated, and more recently the morphogen gradient principle was shown to underlie the beginnings of patterning in Drosophila. Is it also central to vertebrate development? Four recent papers raise experimentation to a new level, while showing how difficult it might be to pin down the precise form of the mechanism.

Animals↗
PubMed1995

Cloning, sequencing, and expressional analysis of the chick homologue of follistatin.

Follistatin, a secreted glycoprotein, has been shown to act as a potent neural inducer during early amphibian development. The function of this protein during embryogenesis in higher vertebrates is unclear, and to further our understanding of its role we have cloned, sequenced, and performed an in-depth expressional analysis of the chick homologue of follistatin. In addition we also describe the expression pattern of activin beta A and activin beta B, proteins that have previously been shown to be able to interact with follistatin. In this study we show that the expression of follistatin and the activins do not always overlap. Follistatin was first detected in Hensen's node and subsequently in the region described by Spratt [1952] as the neuralising area. In older embryos it was also expressed in a highly dynamic manner in the hindbrain as well as in the somites. We also present evidence that follistatin may have a later role in the resegmentation of the somites. We were unable to detect the expression of activin beta A during early embryogenesis, whereas activin beta B was first expressed in the extending primitive streak and subsequently in the neural folds. The results from this study are consistent with a role for follistatin in neural induction but suggest it has additional functions unrelated to its inhibitory actions on activins.

Activins↗