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Biomedical subjects

J Briscoe

Publications and source records attributed to J Briscoe.

At least 19 recordsLinked to original sources
PubMed2002

Everyday ethics in an acute psychiatric unit.

The paper begins with a brief statement about the centrality of autonomy or self governance as a core ethical value in the interaction between health care worker and patient. Then there are three stories describing everyday interactions in an acute psychiatric unit. These are used to help unravel ethical issues relating to patient autonomy. Each story is analysed for its ethical components by describing the protagonists' different perspectives, and their reactions to the events. Attention is also paid to institutional policy. Suggestions are made for small changes in both staff behaviour and institutional procedures. Such changes could enhance rather than diminish patient autonomy.

Anecdotes as Topic↗
PubMed2001

Morphogens.

Explore the source record for details and available documents.

Bone Morphogenetic Protein 2↗
PubMed2001

Specification of neuronal fates in the ventral neural tube.

The generation of distinct classes of neurons at defined positions is a fundamental step in the development of the vertebrate central nervous system. Recent work has begun to reveal the extracellular signals and transcriptional mediators that direct the pattern of generation of distinct neuronal subtypes in the neural tube. This work has provided a framework to understand the patterning of the ventral neural tube and is permitting molecular analyses of the assembly of functional neuronal circuits.

Animals↗
PubMed2001

A hedgehog-insensitive form of patched provides evidence for direct long-range morphogen activity of sonic hedgehog in the neural tube.

Cell pattern in the ventral neural tube is organized by Sonic hedgehog (Shh) secreted by floor plate cells. To assay the range of direct Shh action, we developed a general method for blocking transduction of Hedgehog (Hh) signals through ectopic expression of a deleted form of the Hh receptor Patched (Ptc), termed Ptc(Deltaloop2). We validated this method in Drosophila and used mouse Ptc1(Deltaloop2) (mPtc1(Deltaloop2)) to block Shh transduction in the chick neural tube. mPtc1(Deltaloop2) expression caused cell-autonomous ventral-to-dorsal switches in progenitor identity and neuronal fate throughout the ventral neural tube, supporting a gradient mechanism whereby Shh acts directly and at long range. mPtc1(Deltaloop2) expression also caused the abnormal spread of Shh to more dorsal cells, indicating that Shh in the neural tube, like Hh in Drosophila, induces a feedback mechanism that limits its range of action.

Animals↗
PubMed2001

Production of English finite verb morphology: a comparison of SLI and mild-moderate hearing impairment.

The performance on production of finite verb morphology of 19 children (ages 5;9-10;7) with mild-moderate sensorineural hearing impairment (SNH) was compared with that of 14 children with specific language impairment (SLI) (ages 7;2-10;9) and age-matched and language-matched control groups. On average, the SNH group outperformed the SLI group and was comparable to controls. However, a subset of the SNH group (n = 6) was impaired on one or both of these tasks. Degree of hearing loss or age of receiving hearing aids was not directly related to performance, but other language measures were. The subset was also significantly younger than the rest of the SNH group, suggesting that acquisition of finite verb morphology may be delayed in children with hearing impairments. Verb regularity had no effect on performance of any group, but word frequency and phonological complexity did exert an influence. The findings are discussed in relation to causative theories of SLI.

Auditory Threshold↗
PubMed2001

Everyday memory and cognitive ability in children born very prematurely.

In light of recent reports of episodic memory difficulties linked to early childhood hypoxia (Isaacs et al., 2000; Vargha-Khadem et al., 1997), preliminary findings of everyday memory function are reported for 20 children born at or before 32 weeks gestation, compared to 20 children born at term. Memory skills were assessed using the Rivermead Behavioural Memory Test for Children (Wilson, Ivani-Chalian, & Aldrich, 1991) at 5 years of age. Everyday memory problems were not found to be a general feature of children born prematurely, and performance was closely linked to receptive language ability but not general cognitive ability in both groups of children. Three children in the preterm group did obtain scores in the impaired range of the RBMT, and in two of these children memory impairment could not be predicted from their receptive language ability. This suggests an increased risk of everyday memory difficulties in populations of preterm children that may be enhanced in further studies by sampling children with greater risk of hypoxic insult.

Child, Preschool↗
PubMed2001

Phonological processing, language, and literacy: a comparison of children with mild-to-moderate sensorineural hearing loss and those with specific language impairment.

Phonological skills, language ability, and literacy scores were compared for four groups: 19 children with mild-to-moderate sensorineural hearing loss (SNH), 20 children with specific language impairment (SLI), 20 controls matched on chronological age to the SNH group (CA), and 15 controls matched on receptive vocabulary level to a subset of the SLI group (CB). In common with the SLI group, mean scores of children with mild-to-moderate hearing loss were significantly poorer on tests of phonological short-term memory, phonological discrimination, and phonological awareness than CA controls. No differences between group means were observed in SNH and CA control groups on vocabulary, digit and sentence recall, sentence comprehension, and literacy scores. However, there was considerable individual variation within the SNH group. Nearly 50% of the SNH group showed phonological impairment associated with poorer expressive and receptive vocabulary and higher hearing thresholds than remaining children without phonological impairment. Nonword repetition deficits were observed in SNH subgroups with and without phonological impairment and were of a similar magnitude to those observed in children with SLI. Indeed, poorer repetition in children with SLI could only be differentiated from children with SNH on phonologically complex nonwords. Overall, findings suggested major problems in nonword repetition and phonological impairment occurred without clinically significant deficits in wider language and literacy abilities in children with mild-to-moderate sensorineural hearing loss. Implications for theories of SLI are discussed.

Auditory Threshold↗
PubMed2000

Ventral neural patterning by Nkx homeobox genes: Nkx6.1 controls somatic motor neuron and ventral interneuron fates.

There is growing evidence that sonic hedgehog (Shh) signaling regulates ventral neuronal fate in the vertebrate central nervous system through Nkx-class homeodomain proteins. We have examined the patterns of neurogenesis in mice carrying a targeted mutation in Nkx6.1. These mutants show a dorsal-to-ventral switch in the identity of progenitors and in the fate of postmitotic neurons. At many axial levels there is a complete block in the generation of V2 interneurons and motor neurons and a compensatory ventral expansion in the domain of generation of V1 neurons, demonstrating the essential functions of Nkx6.1 in regional patterning and neuronal fate determination.

Animals↗
PubMed2000

A homeodomain protein code specifies progenitor cell identity and neuronal fate in the ventral neural tube.

Distinct classes of neurons are generated at defined positions in the ventral neural tube in response to a gradient of Sonic Hedgehog (Shh) activity. A set of homeodomain transcription factors expressed by neural progenitors act as intermediaries in Shh-dependent neural patterning. These homeodomain factors fall into two classes: class I proteins are repressed by Shh and class II proteins require Shh signaling for their expression. The profile of class I and class II protein expression defines five progenitor domains, each of which generates a distinct class of postmitotic neurons. Cross-repressive interactions between class I and class II proteins appear to refine and maintain these progenitor domains. The combinatorial expression of three of these proteins--Nkx6.1, Nkx2.2, and Irx3--specifies the identity of three classes of neurons generated in the ventral third of the neural tube.

Animals↗
PubMed2000

Regulation of the neural patterning activity of sonic hedgehog by secreted BMP inhibitors expressed by notochord and somites.

The secretion of Sonic hedgehog (Shh) from the notochord and floor plate appears to generate a ventral-to-dorsal gradient of Shh activity that directs progenitor cell identity and neuronal fate in the ventral neural tube. In principle, the establishment of this Shh activity gradient could be achieved through the graded distribution of the Shh protein itself, or could depend on additional cell surface or secreted proteins that modify the response of neural cells to Shh. Cells of the neural plate differentiate from a region of the ectoderm that has recently expressed high levels of BMPs, raising the possibility that prospective ventral neural cells are exposed to residual levels of BMP activity. We have examined whether modulation of the level of BMP signaling regulates neural cell responses to Shh, and thus might contribute to the patterning of cell types in the ventral neural tube. Using an in vitro assay of neural cell differentiation we show that BMP signaling markedly alters neural cell responses to Shh signals, eliciting a ventral-to-dorsal switch in progenitor cell identity and neuronal fate. BMP signaling is regulated by secreted inhibitory factors, including noggin and follistatin, both of which are expressed in or adjacent to the neural plate. Conversely, follistatin but not noggin produces a dorsal-to-ventral switch in progenitor cell identity and neuronal fate in response to Shh both in vitro and in vivo. These results suggest that the specification of ventral neural cell types depends on the integration of Shh and BMP signaling activities. The net level of BMP signaling within neural tissue may be regulated by follistatin and perhaps other BMP inhibitors secreted by mesodermal cell types that flank the ventral neural tube.

Animals↗
PubMed1999

Homeobox gene Nkx2.2 and specification of neuronal identity by graded Sonic hedgehog signalling.

During vertebrate development, the specification of distinct cell types is thought to be controlled by inductive signals acting at different concentration thresholds. The degree of receptor activation in response to these signals is a known determinant of cell fate, but the later steps at which graded signals are converted into all-or-none distinctions in cell identity remain poorly resolved. In the ventral neural tube, motor neuron and interneuron generation depends on the graded activity of the signalling protein Sonic hedgehog (Shh). These neuronal subtypes derive from distinct progenitor cell populations that express the homeodomain proteins Nkx2.2 or Pax6 in response to graded Shh signalling. In mice lacking Pax6, progenitor cells generate neurons characteristic of exposure to greater Shh activity. However, Nkx2.2 expression expands dosally in Pax6 mutants, raising the possibility that Pax6 controls neuronal pattern indirectly. Here we provide evidence that Nkx2.2 has a primary role in ventral neuronal patterning. In Nkx2.2 mutants, Pax6 expression is unchanged but cells undergo a ventral-to-dorsal transformation in fate and generate motor neurons rather than interneurons. Thus, Nkx2.2 has an essential role in interpreting graded Shh signals and selecting neuronal identity.

Animals↗
PubMed1999

The specification of neuronal identity by graded Sonic Hedgehog signalling.

During the development of vertebrate nervous system, distinct classes of motor neurons and interneurons are generated at distinct dorsoventral positions in the ventral neural tube. The differentiation of these neuronal subtypes is directed by the secreted protein Sonic Hedgehog (Shh). Shh acts in a graded manner to establish different neural progenitor cell populations, defined by the expression of homeodomain transcription factors. These factors are critical for the interpretation of graded Shh signalling and act initially both to refine progenitor domain boundaries and to maintain their integrity. Subsequently, these factors direct the expression of genes that confer neuronal subtype identity to post-mitotic neurons.

Animals↗
PubMed1999

The transcription factor GATA3 is a downstream effector of Hoxb1 specification in rhombomere 4.

In this paper, we show that the transcription factor GATA3 is dynamically expressed during hindbrain development. Function of GATA3 in ventral rhombomere (r) 4 is dependent on functional GATA2, which in turn is under the control of Hoxb1. In particular, the absence of Hoxb1 results in the loss of GATA2 expression in r4 and the absence of GATA2 results in the loss of GATA3 expression. The lack of GATA3 expression in r4 inhibits the projection of contralateral vestibuloacoustic efferent neurons and the migration of facial branchiomotor neurons similar to Hoxb1-deficient mice. Ubiquitous expression of Hoxb1 in the hindbrain induces ectopic expression of GATA2 and GATA3 in ventral r2 and r3. These findings demonstrate that GATA2 and GATA3 lie downstream of Hoxb1 and provide the first example of Hox pathway transcription factors within a defined population of vertebrate motor neurons.

Animals↗
PubMed1998

Short-term memory and language outcomes after extreme prematurity at birth.

The performance of 26 children (3;0-4;0 years) who were born before 32 weeks gestation was compared with the performance of 26 full-term children on a range of short-term memory and language measures. The measures tested vocabulary, expressive language, phonological short-term memory, and general nonverbal ability. Preterm children scored more poorly across the full range of measures. The mildly depressed performance of the preterm group on the short-term memory and language measures was attributable to the large deficits on these tests shown by a subgroup of approximately one third of preterm children identified as being "at risk" for persisting language difficulties using the Bus Story Test (Bishop & Edmundson, 1987). The findings indicate that preterm birth and associated hazards may constitute a significant risk factor for specific language impairment in a sizable minority of children.

Apgar Score↗
PubMed1997

Pax6 controls progenitor cell identity and neuronal fate in response to graded Shh signaling.

Distinct classes of motor neurons and ventral interneurons are generated by the graded signaling activity of Sonic hedgehog (Shh). Shh controls neuronal fate by establishing different progenitor cell populations in the ventral neural tube that are defined by the expression of Pax6 and Nkx2.2. Pax6 establishes distinct ventral progenitor cell populations and controls the identity of motor neurons and ventral interneurons, mediating graded Shh signaling in the ventral spinal cord and hindbrain.

Animals↗
PubMed1997

A JAK1/JAK2 chimera can sustain alpha and gamma interferon responses.

Cell lines that are mutated in interferon (IFN) responses have been critical in establishing an essential role for the JAK family of nonreceptor tyrosine kinases in interferon signalling. Mutant gamma1A cells have previously been shown to be complemented by overexpression of JAK2. Here, it is shown that these cells carry a defect in, and can also be complemented by, the beta-subunit of the IFN-gamma receptor, consistent with the hypothesis that the mutation in these cells affects JAK2-receptor association. In contrast, mutant gamma2A cells lack detectable JAK2 mRNA and protein. By using gamma2A cells, the role of various domains and conserved tyrosine residues of JAK2 in IFN-gamma signalling was examined. Individual mutation of six conserved tyrosine residues, mutation of a potential phosphatase binding site, or mutation of the arginine residue in the proposed SH2-like domain had no apparent effect on signalling in response to IFN-gamma. Results with deletion mutants, however, indicated that association of JAK2 with the IFN-gammaR2 subunit requires the amino-terminal region but not the pseudokinase domain. Consistent with this, in chimeras with JAK1, the JAK2 amino-terminal region was required for receptor association and STAT1 activation. Conversely, a JAK1-JAK2 chimera with the amino-terminal domains of JAK1 linked to the pseudokinase and kinase domains of JAK2 is capable of reconstituting JAK-STAT signalling in response to IFN-alpha and -gamma in mutant U4C cells lacking JAK1. The specificity of the JAKs may therefore lie mainly in their structural interaction with different receptor and signalling proteins rather than in the substrate specificity of their kinase domains.

Amino Acid Sequence↗