Deafness and goiter: molecular genetic considerations.
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Deafness↗
Biomedical subjects
D Forrest
Publications and source records attributed to D Forrest.
Genetic analysis of thyroid hormone receptors in development and disease.
Thyroid hormone (T3) fulfills diverse functions in vertebrate development and physiology. These functions are thought to be mediated by two genes encoding the related T3 receptors. TR alpha and TR beta. The use of homologous recombination in embryonic stem cells to generate defined, single-gene mutations provides a powerful means to investigate the individual functions of TR alpha and TR beta in mice. We have shown that targeted inactivation of the TR beta gene results in goiter and elevated levels of thyroid hormone. Thyroid stimulating hormone (TSH), which is released by pituitary thyrotropes and is normally suppressed by increased levels of thyroid hormone, was present at elevated levels in homozygous mutant (Thrb-/-) mice. These findings suggest a unique role for TR beta that cannot be substituted by TR alpha in the T3-dependent feedback regulation of TSH transcription. Thrb-/- mice provide a recessive model for the human syndrome of resistance to thyroid hormone (RTH). Typically, RTH is associated with dominant mutations in TR beta. It is unknown whether TR alpha, TR beta, or other receptors are targets for inhibition in dominant RTH; however, the analysis of Thrb-/- mice suggests that antagonism of TR beta-mediated pathways underlies the disorder of the pituitary-thyroid axis. Thrb-/- mice also display defective maturation of auditory function, demonstrating that TR beta is essential for the development of hearing. Interestingly, hearing defects are generally absent in dominant RTH, indicating that in the auditory system, a dominant TR beta mutant cannot mimic the defect caused by loss of TR beta. This suggests the existence of tissue-specific mechanisms that modulate the activity of TR beta. These results define in vivo functions for TR beta and indicate that specificity in T3 signaling is conferred by distinct receptor genes.
Animals↗
A guide to writing medical reports on survivors of torture.
Based on a number of years' experience by volunteer doctors engaged in the examination and welfare of refugees and asylum-seekers who have claimed that they have suffered torture a scheme of history-taking and physical examination is offered. The role of the medical expert in the investigation of abuse of human rights is discussed, as is the need for the presentation and format of the interpretation to be carefully considered.
Guidelines as Topic↗
The physical after-effects of torture.
Descriptions and differentiating factors in post-torture lesions are described and discussed, from the point of view of the medical examination of persons alleging physical abuse of human rights. The lesions caused by various methods of torture are described. The material and expertise is drawn from a long experience both in clinical practice and in the examination of refugees and asylum-seekers who claim to have been tortured.
Humans↗
Patterns of abuse in Sikh asylum-seekers.
Many states practise or condone torture to control dissident groups in their population. Most techniques used and the resulting injuries are common to all cultures. 31 male Sikh asylum-seekers, examined between December, 1991, and May, 1994, showed a pattern of abuse that included features particular to their region of origin. All gave a persuasive history of serious abuse and all showed long-term mental and physical effects that could be convincingly attributed to their experiences.
Adult↗
Factors relating to smoking and pregnancy in the North Western Region.
BACKGROUND: One of the targets for the Health of the nation is to increase the proportion of women smokers who give up smoking at the start of their pregnancy, from a quarter to at least one-third, by the year 2000. This study uses a regional lifestyle survey to look at the characteristics of pregnant women who smoke. METHODS: The lifestyle survey was based on a structured questionnaire which was sent by post to a systematic random sample of 60,000 adults across the North Western Region. A total of 513 respondents were pregnant; of these, 150 (29 per cent) reported that they smoked. The responses of pregnant smokers and non-smokers were compared to identify differences in age, demographic and social characteristics, mental distress and attitudes to lifestyle variables. RESULTS: Women in the North Western Region who smoked tended not to give up during pregnancy, but they did tend to smoke less. Smokers were more likely to be under 25 than non-smokers, less likely to be home-owners, and less likely to be living with a husband or partner. There was no difference in mental distress between smokers and ex-smokers, but they both experienced significantly greater mental distress than those who had never smoked. The difference between smokers and ex-smokers was in their type of occupation, housing tenure and whether they were living with a partner, ex-smokers being much more similar to non-smokers. CONCLUSIONS: More work needs to be done to improve the design of smoking cessation programmes, to make them more culturally appropriate for pregnant women who appear to be socially disadvantaged, have poor housing and lack a stable relationship.
Adaptation, Psychological↗
N-terminal variants of thyroid hormone receptor beta: differential function and potential contribution to syndrome of resistance to thyroid hormone.
The human syndrome of resistance to thyroid hormone (RTH) is associated with dominant mutations in the thyroid hormone receptor beta (TR beta) gene that generate mutant receptors with impaired binding for T3. Although the TR beta gene differentially expresses two N-terminal variant receptors, TR beta 1 and TR beta 2, functional analyses of RTH mutants have focused exclusively on TR beta 1. Since TR beta 2 is expressed in tissues that are malfunctional in RTH, the role of mutations in the context of TR beta 2 was examined. We compared the functional properties of corresponding RTH mutations in the common C-terminal domain of both TR beta 1 and TR beta 2. Wild type TR beta 1 and TR beta 2 bound similarly as homodimers and as heterodimers with retinoid X receptors to T3-responsive elements consisting of a direct repeat with 4-base pair spacing or an everted repeat. Homodimers, but not monomers or heterodimers, of both receptor subtypes were dissociated by the addition of T3. However, TR beta 2 formed at least 10-fold more stable homodimers than TR beta 1 on a palindromic repeat element, indicating that the N termini of TR beta 1 and TR beta 2 differentially influence dimerization on DNA. The RTH-like mutants of both TR beta 1 and TR beta 2 were equally insensitive to T3. They were defective in T3 binding but still bound DNA like their wild type counterparts except that the T3-dependent dissociation of homodimers from DNA was severely reduced. Wild type TR beta 1 and TR beta 2 mediated T3-inducible transactivation in cotransfection assays; this, however, was abolished in both mutants. TR beta 1 mediated more sensitive T3-dependent transcriptional suppression than TR beta 2 through the negative T3 response region of the TSH beta gene. Again, the mutation abolished T3-dependent suppression by both mutants. Furthermore, both mutants inhibited T3-inducible transcriptional activation by different wild type TR alpha and beta variants. These results indicate that both mutants have the potential to contribute to the pathogenesis of RTH and suggest that a reassessment of previous models of RTH is required to take into account the inhibitory activity of both TR beta 2 and TR beta 1 mutants.
3T3 Cells↗
Human rights and medical education.
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Education, Medical↗
Targeted disruption of NMDA receptor 1 gene abolishes NMDA response and results in neonatal death.
In vitro studies have suggested that the NMDA receptor consists of an essential subunit, NR1, and various modulatory NR2 subunits. To test this hypothesis directly in vivo, we generated mice carrying a disrupted NR1 allele. NMDA-inducible increases in intracellular calcium and membrane currents were abolished in neurons from homozygous null mutants (NR1-/-). Thus, NR1 has a unique role, which cannot be substituted by any other subunit, in determining the activity of the endogenous NMDA receptor. A concomitant reduction in levels of NR2B but not NR2A occurred in NR1-/- mice, demonstrating that there is an interdependence of subunit expression. NR1-/- mice died 8-15 hr after birth, indicating a vital neonatal function for the NMDA receptor. Although the NMDA receptor has been implicated in several aspects of neurodevelopment, overall neuroanatomy of NR1-/- mice appeared normal. Pathological evidence suggested that respiratory failure was the ultimate cause of death.
Animals↗
What about the health of ancillary staff? A management audit.
Health at Work in the NHS was launched at the same time as Health of the Nations, in July 1992. There is good national and local evidence identifying ancillary staff as a priority for health promotion. Despite the evidence, and a regional drive to make work with ancillary staff a priority, a recent audit made clear that very little has happened. Market testing seems to have excluded ancillary staff health from senior management responsibility. discusses possible reasons and the implications.
Allied Health Personnel↗
The erbA/thyroid hormone receptor genes in development of the central nervous system.
It has long been established that thyroid hormones are essential for correct development and differentiation in the central nervous system (CNS). More recent identification of a family of receptors for thyroid hormone as the products of cellular erbA genes has provided the opportunity to understand the mechanisms by which the hormone elicits its complex responses in the CNS. These receptors belong to the family of nuclear hormone receptors and act as ligand-responsive transcription factors. This suggests models of developmental control in the CNS in which thyroid hormone receptors convert the extracellular hormonal signal into specific cellular responses by regulation of transcription of networks of target genes.
Animals↗
Differential roles for Fos and Jun in DNA-binding: redox-dependent and independent functions.
The Fos and Jun family of transcription factors contain an invariant sequence motif lysine-cysteine-arginine (KCR) in the highly conserved DNA-binding region. Reduction of the cysteine residue is necessary to facilitate DNA-binding. Here, we examined the potential dual roles of the flanking lysine and arginine residues in influencing the redox reactivity of the cysteine and the DNA-binding activity of Fos and Jun. Two sets of Fos and Jun mutants were generated: the KCR and KSR series representing proteins capable of redox-dependent and redox-independent DNA-binding activity, respectively. Mutation of the lysine in Fos-Jun heterodimers had no obvious effect on the redox reactivity of the cysteine, suggesting that lysine is not essential in this respect. However, mutation of the arginine but not lysine, in both the KCR and the KSR series abolished DNA-binding activity. Thus, the arginine but not the lysine residue in the KCR motif is critical for both redox-dependent and redox-independent functions in DNA-binding. Surprisingly, the triple substitution, ISI, exhibited high levels of DNA-binding activity. This demonstrates that the effects of amino acid substitutions can be highly dependent on context and that non-basic amino acids can function efficiently in DNA-binding. Analysis of combinations of wild-type and mutant Fos and Jun proteins indicated that Fos was dominant in dictating the DNA-binding ability of Fos-Jun heterodimers. This suggests that the lysine and arginine residues in the KCR region of Fos are not equivalent to those in Jun and that they interact with DNA differently.
Animals↗
Conserved regulatory elements in the promoter region of the N-CAM gene.
Genomic clones containing 5'-flanking sequences, the first exon, and the entire first intron from the chicken N-CAM gene were characterized by restriction mapping and DNA sequencing. A > 600-bp segment that includes the first exon is very G + C-rich and contains a large proportion of CpG dinucleotides, suggesting that it represents a CpG island. SP-1 and AP-1 consensus elements are present, but no TATA- or CCAAT-like elements were found within 300 bp upstream of the first exon. Comparison of the chicken promoter region sequence with similar regions of the human, rat, and mouse N-CAM genes revealed that some potential regulatory elements including a "purine box" seen in mouse and rat N-CAM genes, one of two homeodomain binding regions seen in mammalian N-CAM genes, and several potential SP-1 sites are not conserved within this region. In contrast, high CpG content, a homeodomain binding sequence, an SP-1 element, an octomer element, and an AP-1 element are conserved in all four genes. The first intron of the chicken gene is 38 kb, substantially smaller than the corresponding intron from mammalian N-CAM genes. Together with previous studies, this work completes the cloning of the chicken N-CAM gene, which contains at least 26 exons distributed over 85 kb.
Animals↗
Crossed signals: oncogenic transcription factors.
Transcription factors operate at key regulatory junctions in the cell's responses to diverse extracellular stimuli. We discuss how the transforming activity of mutated transcription factors encoded by several oncogenes (v-erbA, v-fos, v-jun and v-rel) may result in part from a loss of the integrated response to the signalling network.
Genes, fos↗
Thyroid hormone receptors in chick retinal development: differential expression of mRNAs for alpha and N-terminal variant beta receptors.
Thyroid-hormone-dependent development of the neuroretina has principally been described in amphibia. Here, we show by in situ hybridisation that mRNAs coding for three distinct thyroid hormone receptors (TRs), TR alpha and two TR beta variants, are differentially expressed during chick retinal development. We isolated a cDNA for a novel N-terminal variant of chick TR beta (cTR beta 2) that is predominantly expressed in retinal development. Interestingly, in its N-terminal A/B domain cTR beta 2 is 70% homologous to the rat pituitary-specific TR beta 2. Expression of cTR beta 2 mRNA was high at embryonic day 6 (E6) in the retinal outer nuclear layer (ONL) and decreased to low levels at hatching. mRNA for the previously described chick beta receptor, cTR beta 0, was expressed at low levels in both the ONL and the inner nuclear layer (INL) after E10. In contrast, cTR alpha expression occurred in the ONL, INL and ganglion cell layer at intermediate and later stages. Finally, cTR beta 2 confers a stronger trans-activation of reporter gene transcription than cTR beta 0. The distinctive kinetics and localisation of TR alpha and beta gene expression suggest cell- and stage-specific functions for TRs, both individually and in combinations, in chick neuroretinal development.
Amino Acid Sequence↗
Detention in the UK of tortured refugees.
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Adult↗
Distinct functions for thyroid hormone receptors alpha and beta in brain development indicated by differential expression of receptor genes.
Thyroid hormones are essential for correct brain development, and since vertebrates express two thyroid hormone receptor genes (TR alpha and beta), we investigated TR gene expression during chick brain ontogenesis. In situ hybridization analyses showed that TR alpha mRNA was widely expressed from early embryonic stages, whereas TR beta was sharply induced after embryonic day 19 (E19), coinciding with the known hormone-sensitive period. Differential expression of TR mRNAs was striking in the cerebellum: TR beta mRNA was induced in white matter and granule cells after the migratory phase, suggesting a main TR beta function in late, hormone-dependent glial and neuronal maturation. In contrast, TR alpha mRNA was expressed in the earlier proliferating and migrating granule cells, and in the more mature granular and Purkinje cell layers after hatching, indicating a role for TR alpha in both immature and mature neural cells. Surprisingly, both TR genes were expressed in early cerebellar outgrowth at E9, before known hormone requirements, with TR beta mRNA restricted to the ventricular epithelium of the metencephalon and TR alpha expressed in migrating cells and the early granular layer. The results implicate TRs with distinct functions in the early embryonic brain as well as in the late phase of hormone requirement.
Animals↗
The South West Thames Regional Health Authority approach to the method of audit in public health medicine.
Following the Faculty Training Conference on Audit in March 1990, South West Thames Region set up a Working Group to develop a framework for audit in Public Health Medicine that could be adopted across the Region. This paper outlines the methodology used by the Working Group, introducing the concept of an 'Audit Tree', and describes how audit in Public Health Medicine can be approached using such a model.
England↗