Biomedical subjects
Publications and source records attributed to I Mason.
Preliminary results indicate that no evidence has been found to support the spread of FMD virus from the burning of animal carcases on open pyres. This finding is subject to a number of assumptions, and is based on a limited number of case studies.
The cells of the mesencephalic trigeminal nucleus (MTN) are the proprioceptive sensory neurons that innervate the jaw muscles. Interestingly, their evolution is generally thought to have been concomitant with that of the jaws. They are also the first born neurons of the mesencephalon, and their axons pioneer some of the major tracts within the brain. The cells of the MTN are also paradoxical in being the only group of intramedullary primary sensory neurons in amniotes. However, we know little about the early development of these important neurons, and we have analysed this here. To study the earliest stages of MTN development, we have used a battery of neural crest markers to try and pinpoint the progenitors of the MTN. We find that, contrary to current perceptions, the progenitors of the MTN are not highlighted by these markers, suggesting that they are not neural crest derived. However, the cells of the MTN are marked by means of their expression of Brn-3a. This gene labels cells that arise either side of the dorsal midline, extending rostrally from the isthmus across the roof of the mesencephalon. We have further demonstrated that the MTN develops under the influence of the Fgf-8 secreted by the isthmus. Ectopic Fgf-8 application promotes MTN development, whereas inhibiting Fgf-8 function in vivo drastically affects MTN development.
AIM: To investigate gastric pacemaker activity in gastro-oesophageal reflux disease using the electrogastrogram. PATIENTS: Forty patients with gastro-oesophageal reflux disease (20 with acid reflux, 20 with the additional symptom of food regurgitation) and 30 asymptomatic controls. METHODS: Patients were studied using an electrogastrogram, oesophageal manometry, and 24 hour ambulatory oesophageal pH analysis. RESULTS: An abnormal electrogastrogram was recorded in two (7%) controls, two (10%) patients with acid reflux, and 10 (50%) patients with food regurgitation. Food regurgitators had significantly more gastric dysrhythmias (tachygastrias) both before (p<0.02) and after (p<0.01) a test meal. Gastric pacemaker activity was also significantly less stable following the test meal in food regurgitators (p<0.003). Patients with food regurgitation and an abnormal electrogastrogram had higher oesophageal acid exposure than those with a normal electrogastrogram (p<0.05). CONCLUSIONS: The electrogastrogram is usually normal in gastro-oesophageal reflux disease but an abnormal rhythm occurred in half of our patients with the additional symptom of food regurgitation. Furthermore, an abnormal electrogastrogram is associated with increased oesophageal acid exposure.
In this article we consider some of the implications of the UK Human Rights Act 1998 for nurses in practice. The Act has implications for all aspects of social life in Britain, particularly for health care. We provide an introduction to the discourse of rights in health care and discuss some aspects of four articles from the Act. The reciprocal relationship between rights and obligations prompted us to consider also the relationship between guidelines in the United Kingdom Central Council's Code of professional conduct and the requirements of the Human Rights Act 1998. We conclude with the recommendation that the new legislation should be welcomed for its potential to support good practice and to urge critical and reflective practice rather than as yet another burdensome bureaucratic imposition.
Neural stem cells (NSCs) are self-renewable, multipotential cells capable of differentiating into the three major neural cell types, but the mechanisms which regulate their development are not fully understood. Both basic fibroblast growth factor (bFGF) and epidermal growth factor (EGF) promote the proliferation of NSCs. However, studies on the role of FGFs in the differentiation of EGF-expanded NSCs are still incomplete. We have studied the expression of distinct FGF receptors (FGFRs) in the progeny of EGF-expanded NSCs isolated from E15 rat striatum. In situ hybridization analysis and immunocytochemistry showed a developmentally related expression pattern and a cell lineage-specific distribution of these receptors. FGFR1 and FGFR2 were identified in many early precursors and in the oligodendrocyte lineage. The latter receptor was also present in a subpopulation of astrocytes. FGFR3 was detected in a restricted population of early precursors, in oligodendroglial progenitors, and in neurons and protoplasmic astrocytes of late-term cultures. Basic FGF treatment of the progeny of NSCs increased the proliferative rate of precursors and the number of oligodendrocytes generated, whereas the number of differentiating neurons was significantly reduced. Together these data provide evidence that FGFs modulate the development of EGF-expanded NSCs, and that this is at least partly determined by a cell lineage-specific expression of multiple FGFRs.
Aromatase activity may be detected using in vitro and in vivo techniques in most breast cancers and mammary adipose tissue. This activity makes a variable contribution to endogenous estrogens within the breast and in many cases represents the major source of these hormones. Such local biosynthesis may maintain the growth of some hormone-dependent tumors. The factors which regulate aromatase activity within the breast are not defined but are likely to include growth factors and cytokines which may be produced by breast tissues so that autocrine and paracrine loops may exist. Estrogen biosynthesis within the breast, like other peripheral systems, appears sensitive to classical aromatase inhibitors and the new generation of drugs are capable of profoundly blocking the activity and markedly reducing endogenous estrogen levels; in turn these endocrine effects are translated in dramatic anti-tumor influences in hormone-dependent breast cancer.
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Fibroblast growth factors (FGFs) transmit their signals through four transmembrane receptors that are designated FGFR1-4. Alternative splicing in the extracellular region of FGFR1-3 generates receptor variants with different ligand binding affinities. Thus two types of transmembrane receptors (IIIb and IIIc isoforms) have been identified for FGFR2 and FGFR3, and the existence of analogous variants has been postulated for FGFR1 based on its genomic structure. However, only a single full-length transmembrane FGFR1 variant (FGFR1-IIIc) has been identified so far. Here we describe the cloning of a full-length cDNA encoding FGFR1-IIIb from a mouse skin wound cDNA library. This receptor isoform was expressed at the highest levels in a subset of sebaceous glands of the skin and in neurons of the hippocampus and the cerebellum. FGFR1-IIIb was expressed in L6 rat skeletal muscle myoblasts and used in cross-linking and receptor binding studies. FGF-1 was found to bind the receptor with high affinity, whereas FGF-2, -10, and -7 bound with significantly lower affinities. Despite their apparently similar but low affinities, FGF-10 but not FGF-7 induced the activation of p44/42 mitogen-activated protein kinase in FGFR1-IIIb-expressing L6 myoblasts and stimulated mitogenesis in these cells, demonstrating that this new receptor variant is a functional transmembrane receptor for FGF-10.
The Drosophila sprouty protein is a recently-identified intracellular modulator of FGF and EGF receptor tyrosine kinase activity which antagonises ras/MAP kinase signalling. In a differential display analysis to identify genes involved in patterning the mid/hindbrain region of the chick neural tube, we have identified a sprouty orthologue, sprouty2. Here we report expression of sprouty2 transcripts in the developing chick embryo. We find a close correlation with known sites of FGF activity but little correlation with expression patterns of members of the EGF family. Initially, transcripts are associated with the primitive streak. During the period of neural tube patterning expression is detected in the anterior neuropore, in the isthmic region and in neural plate and posterior spinal cord. Transcripts are also detected in the otic placode, tail bud, mesoderm of the branchial arches, somitic myotome, retina, limb buds and gut mesenchyme; all known sites of FGF action.
Specification and polarization of the midbrain and anterior hindbrain involve planar signals originating from the isthmus. Current evidence suggests that FGF8, expressed at the isthmus, provides this patterning influence. In this study, we have sought to identify novel genes which are involved in the process by which regional identity is imparted to midbrain and anterior hindbrain (rhombomere 1). An enhanced differential display reverse transcription method was used to clone cDNAs derived from transcripts expressed specifically in either rhombomere 1 or midbrain during the period of isthmic patterning activity. This gene expression screen identified 28 differentially expressed cDNAs. A clone upregulated in cDNA derived from rhombomere 1 tissue showed a 91% identity at the nucleotide level to the putative human receptor tyrosine kinase antagonist: sprouty2. In situ hybridization on whole chick embryos showed chick sprouty2 to be expressed initially within the isthmus and rhombomere 1, spatially and temporally coincident with Fgf8 expression. However, at later stages this domain was more extensive than that of Fgf8. Introduction of ligand-coated beads into either midbrain or hindbrain region revealed that sprouty2 could be rapidly induced by FGF8. These data suggest that sprouty2 participates in a negative feedback regulatory loop to modulate the patterning activity of FGF8 at the isthmus.
The RET receptor tyrosine kinase was first identified in a screen for human oncogenes and has subsequently been linked to several human syndromes: Hirschprung's disease, multiple endocrine neoplasia types 2A and 2B and familial thyroid carcinoma. Interestingly, all of the tissues affected by mutations in RET are derived from the neural crest during development. RET transduces a signal following activation by ligands of the glial cell line-derived neurotrophic factor (GDNF) family of neurotrophins which currently comprises GDNF, neuturin (NTN), artemin (ART) and persephin (PSP). To activate RET they form a tripartite complex with RET and a member of a family of four extracellular, GPI-linked alpha receptors (GFR alpha 1-4). Specificity is achieved by each GFR alpha binding only one member of the GDNF family with high affinity. Current evidence indicates that signal transduction by RET activates several second messenger systems including the PLC gamma, Ras, JNK and inositol phosphate pathways. Targeted mutagenesis in transgenic mice has shown that Ret, GFR alpha 1 and GDNF are required for multiple developmental events including development of the enteric nervous system (ENS) affected in Hirschsprung's disease. We describe experiments in chick neural crest cells which provide evidence for the normal function of RET and the basis of the defect in Hirschsprung's disease.
Studies in Drosophila suggest that receptor-tyrosine phosphatases are key regulators of neural development, however little is known about their expression or function in the nervous system of vertebrate embryos. In this report, we describe the expression pattern of RPTPgamma during early chick embryogenesis. Transcripts are largely restricted to the developing nervous system including oculomotor, trochlear and branchiomotor populations but are absent from spinal motor neurones. RPTPgamma is also detected in cells in the positions of hindbrain reticulospinal neurones, spinal commisural neurones and in cells with neuronal morphology in the ventral diencephalon. Within the peripheral nervous system transcripts are found in neuroblasts delaminating from epibranchial placodes and subsequently in placode-derived cranial ganglia. Outside the nervous system expression is detected in somites and transiently in the second branchial arch and the cranial mesenchyme.
Studies involving chick embryos have implicated FGFs in neural induction and patterning as well as in other developmental events. Detailed analyses of FGF receptor expression at early stages of neural development have not been reported for the chick embryo and are incomplete for other vertebrate classes. Here we show the expression patterns of three FGF receptors, (FGFR1, FGFR2 and FGFR3) in embryonic stages between gastrulation and limb bud formation, focussing particularly on neural tissues. Between neural induction and neurulation, all three receptors are expressed in the neural plate albeit with distinct and overlapping distributions. During early neuromere formation FGFR1 transcripts are present throughout the neural tube, while transcripts for FGFR2 and FGFR3 become restricted to regions of the diencephalon and spinal cord. A little later, FGFR2 and FGFR3 are additionally expressed in the anterior midbrain and within the hindbrain. During later neuromere development, FGFR1 transcripts become localised to the telencephalon, anterior dorsal diencephalon and throughout the midbrain and hindbrain, whereas FGFR2 mRNA is restricted to dorsal telencephalon, dorsoanterior midbrain and hindbrain. FGFR3 is also expressed in anterior midbrain and hindbrain during this developmental period, and is additionally expressed in the posterior telencephalon, in the pretectum, and at the zona limitans intrathalamica. The observed expression patterns of all three receptors within the hindbrain, including rhombomere boundaries, are complex and dynamic. Expression patterns within the somites, eye, head mesenchyme, branchial arches, limb buds, nephric kidney and pharynx are also described.
During differentiation of sympathetic neurons in chick embryos, tyrosine hydroxylase (TH) and dopamine beta-hydroxylase (DBH) mRNAs become detectable during the same developmental period and are both induced by BMP 4. Later during sympathetic ganglion development, DBH is detectable in TH-positive and -negative cells. Moreover, BMPs reduce DBH mRNA in cultures of sympathetic neurons while leaving TH unaffected. The data provide evidence for a common regulation of TH and DBH early during sympathetic neuron differentiation and indicate that BMPs promote their initial expression but not the maintenance during later development. The time course of Phox2a and 2b expression suggests an evolutionary conserved role in noradrenergic induction. In addition, Phox2a, Phox2b, and c-ret may be involved in the differentiation of cholinergic sympathetic neurons.
Current evidence suggests that the anterior segment of the vertebrate hindbrain, rhombomere 1, gives rise to the entire cerebellum. It is situated where two distinct developmental patterning mechanisms converge: graded signalling from an organising centre (the isthmus) located at the midbrain/hindbrain boundary confronts segmentation of the hindbrain. The unique developmental fate of rhombomere 1 is reflected by it being the only hindbrain segment in which no Hox genes are expressed. In this study we show that ectopic FGF8 protein, a candidate for the isthmic organising activity, is able to induce and repress gene expression within the hindbrain in a manner appropriate to rhombomere 1. Using a heterotopic, heterospecific grafting strategy we demonstrate that rhombomere 1 is able to express Hox genes but that both isthmic tissue and FGF8 inhibit their expression. Inhibition of FGF8 function in vivo shows that it is responsible for defining the anterior limit of Hox gene expression within the developing brain and thereby specifies the extent of the rl territory. Previous studies have suggested that a retinoid morphogen gradient determines the axial limit of expression of individual Hox genes within the hindbrain. We propose a model whereby activation by retinoids is antagonised by inhibition by FGF8 in the anterior hindbrain to set aside the territory from which the cerebellum will develop.
In this article, an adjunct to a platform presentation at the Winternational 2000 Symposium, we summarize the recent findings of this group concerning the regulation and functions of FGF8 expressed at the isthmus of the developing brain. We show that several different FGF8 isoforms, ectopically expressed in midbrain or posterior forebrain, are able to mimic the proliferative and patterning functions previously attributed to the isthmus in tissue grafting studies. Moreover, we also show that FGF8 protein is sufficient to induce an ectopic isthmic organiser (Fgf-8+, Gbx2+) in anterior midbrain. We also provide evidence that isthmic FGF8 patterns anterior hindbrain, repressing Hox-a2 expression and setting aside a territory of the brain that includes the cerebellar anlage. We show that these effects of FGF8 are likely to be mediated via FGFR1 and be modulated by the putative FGF antagonist, Sprouty2, identified using a differential display screen. Finally, we provide evidence that the onset of Fgf8 expression is regulated by En1 and that its expression at the isthmus is subsequently maintained by a specific and direct interaction between rhombomere 1 and midbrain.
Receptor tyrosine kinases and receptor protein tyrosine phosphatases (RPTPs) appear to coordinate many aspects of neural development, including axon growth and guidance. Here, we focus on the possible roles of RPTPs in the developing avian retinotectal system. Using both in situ hybridization analysis and immunohistochemistry, we show for the first time that five RPTP genes--CRYPalpha, CRYP-2, PTPmu, PTPgamma, and PTPalpha--have different but overlapping expression patterns throughout the retina and the tectum. PTPalpha is restricted to Muller glia cells and radial glia of the tectum, indicating a possible function in controlling neuronal migration. PTPgamma expression is restricted to amacrine neurons. CRYPalpha and CRYP-2 mRNAs in contrast are expressed throughout the retinal ganglion cell layer from where axons grow out to their tectal targets. PTPmu is expressed in a subset of these ganglion cells. CRYPalpha, CRYP-2, and PTPmu proteins are also localized in growth cones of retinal ganglion cell axons and are present in defined laminae of the tectum. Thus, the spatial and temporal expression of three distinct RPTP subtypes--CRYPalpha, CRYP-2, and PTPmu--are consistent with the possibility of their involvement in axon growth and guidance of the retinotectal projection.
Fibroblast growth factor 4 (Fgf4) has been implicated as a regulator of mesoderm formation, posteriorisation, neural induction and neural patterning. Much of the evidence for this derives from studies in which exogenous FGF4 is applied to avian embryos. We have therefore examined expression of endogenous Fgf4 mRNA in the developing chick embryo at stages when these processes are occurring. Expression was detected in the primitive streak from the onset of gastrulation. Notably, transient expression of transcripts was found in head process cells at the onset of neural plate formation and regionalisation. Later, mRNA was detected in the presumptive posterior hindbrain and within the ventral midbrain. Fgf4 mRNA was also found in paraxial mesoderm underlying the posterior hindbrain, somites, branchial arches, limb buds and the tail bud.