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Biomedical subjects

T Dawson

Publications and source records attributed to T Dawson.

At least 19 recordsLinked to original sources
PubMed2004

Impaired regulation of neuronal nitric oxide synthase and heart rate during exercise in mice lacking one nNOS allele.

We tested the hypothesis that a single allele deletion of neuronal nitric oxide synthase (nNOS) would impair the neural control of heart rate following physical training, and that this phenotype could be restored following targeted gene transfer of nNOS. Voluntary wheel-running (+EX) in heterozygous nNOS knockout mice (nNOS(+/-), +EX; n= 52; peak performance 9.1 +/- 1.8 km day(-1)) was undertaken and compared to wild-type mice (n= 38; 9.5 +/- 0.8 km day(-1)). In anaesthetized wild-type mice, exercise increased phenylephrine-induced bradycardia by 67% (measured as heart rate change, in beats per minute, divided by the change in arterial blood pressure, in mmHg) or pulse interval response to phenylephrine by 52% (measured as interbeat interval change, in milliseconds, divided by the change in blood pressure). Heart rate changes or interbeat interval changes in response to right vagal nerve stimulation were also enhanced by exercise in wild-type atria (P < 0.05), whereas both in vivo and in vitro responses to exercise were absent in nNOS(+/-) mice. nNOS inhibition attenuated heart rate responses to vagal nerve stimulation in all atria (P < 0.05) and normalized the responses in wild-type, +EX with respect to wild-type with no exercise (-EX) atria. Atrial nNOS mRNA and protein were increased in wild-type, +EX compared to wild-type, -EX (P < 0.05), although exercise failed to have any effect in nNOS(+/-) atria. In vivo nNOS gene transfer using adenoviruses targeted to atrial ganglia enhanced choline acetyltransferase-nNOS co-localization (P < 0.05) and increased phenylephrine-induced bradycardia in vivo and heart rate responses to vagal nerve stimulation in vitro compared to gene transfer of enhanced green fluorescent protein (eGFP, P < 0.01). This difference was abolished by nNOS inhibition (P < 0.05). In conclusion, genomic regulation of NO bioavailability from nNOS in cardiac autonomic ganglia in response to training is dependent on both alleles of the gene. Although basal expression of nNOS is normal, polymorphisms of nNOS may interfere with neural regulation of heart rate following training. Targeted gene transfer of nNOS can restore this impairment.

Alleles↗
PubMed2003

Cancer-related fatigue--a difference of opinion? Results of a multicentre survey of healthcare professionals, patients and caregivers.

UNLABELLED: The objective of this study was to investigate the perceptions of patients with cancer, their caregivers and healthcare professionals (HCPs) about fatigue and its impact on quality of life. It was a cross-sectional survey, the respondents were patients with cancer attending three UK regional cancer centres (n = 1,370), their informal caregivers (n = 1,370) and a random selection of HCPs (oncologists/nurses/radiographers/haematologists; n = 1,098). The response rates for patients, caregivers and HCPs were 42%, 33% and 34% respectively. Fatigue was reported to affect 56% of patients and to have a considerable impact on quality of life. Caregivers also recognized that fatigue was a common problem, with significant effects on patients' quality of life and impact on themselves. Healthcare professionals recognized that fatigue was a common problem for their patients but overestimated its impact on some aspects of patients' daily lives. Although most HCPs reported that they prescribed/recommended treatment for over half of their patients, only 14% of patients reported receiving any such treatment. The most common advice was to take more rest and relaxation. CONCLUSIONS: patients with cancer report that fatigue is a common and distressing symptom and the importance of this symptom is generally recognized by both HCPs and lay-carers. Healthcare professionals need more information about the effectiveness of existing interventions for cancer-related fatigue and further research is required to improve the current management of this debilitating symptom.

Attitude of Health Personnel↗
PubMed2001

Reduction of functional N-methyl-D-aspartate receptors in neurons by RNase P-mediated cleavage of the NR1 mRNA.

One approach to studying the functional role of individual NMDA receptor subunits involves the reduction in the abundance of the protein subunit in neurons. We have pursued a strategy to achieve this goal that involves the use of a small guide RNA which can lead to the destruction of the mRNA for a specific receptor subunit. We designed a small RNA molecule, termed 'external guide sequence' (EGS), which binds to the NR1 mRNA and directs the endonuclease RNase P to cleave the target message. This EGS has exquisite specificity and directed the RNase P-dependent cleavage at the targeted location within the NR1 mRNA. To improve the efficiency of this EGS, an in vitro evolution strategy was employed which led to a second generation EGS that was 10 times more potent than the parent molecule. We constructed an expression cassette by flanking the EGS with self-cleaving ribozymes and this permitted generation of the specified EGS RNA sequence from any promoter. Using a recombinant Herpes simplex virus (HSV), we expressed the EGS in neurons and showed the potency of the EGS to reduce NR1 protein within neurons. In an excitotoxicity assay, we showed that expression of the EGS in cortical neurons is neuroprotective. Our results demonstrate the utility of EGSs to reduce the expression of any gene (and potentially any splice variant) in neurons.

Animals↗
PubMed2000

Mice with a selective deletion of the CC chemokine receptors 5 or 2 are protected from dextran sodium sulfate-mediated colitis: lack of CC chemokine receptor 5 expression results in a NK1.1+ lymphocyte-associated Th2-type immune response in the intestine.

The chemokine receptors CCR2 and CCR5 and their respective ligands regulate leukocyte chemotaxis and activation. To determine the role of these chemokine receptors in the regulation of the intestinal immune response, we induced colitis in CCR2- and CCR5-deficient mice by continuous oral administration of dextran sodium sulfate (DSS). Both CCR2- and CCR5-deficient mice were susceptible to DSS-induced intestinal inflammation. The lack of CCR2 or CCR5 did not reduce the DSS-induced migration of macrophages into the colonic lamina propria. However, both CCR5-deficient mice and, to a lesser degree, CCR2-deficient mice were protected from DSS-induced intestinal adhesions and mucosal ulcerations. CCR5-deficient mice were characterized by a greater relative infiltration of CD4+ and NK1.1+ lymphocyte in the colonic lamina propria when compared to wild-type and CCR2-deficient mice. In CCR5-deficient mice, mucosal mRNA expression of IL-4, IL-5, and IL-10 was increased, whereas that of IFN-gamma was decreased, corresponding to a Th2 pattern of T cell activation. In CCR2-deficient mice, the infiltration of Th2-type T cells in the lamina propria was absent, but increased levels of IL-10 and decreased levels of IFN-gamma may have down regulated mucosal inflammation. Our data indicate that CCR5 may be critical for the promotion of intestinal Th1-type immune responses in mice.

Animals↗
PubMed2000

Acetabular morphology and resurfacing design.

The bony surfaces of 18 archaeological hemipelves were scanned using a 3D laser surface scanner and CyDir software on a Silicon Graphics workstation. The acetabular area was selected and point data from the approximately spherical bone surface saved. These data were input to a MATLAB routine that calculated the radius and centre of the best-fit sphere. The goodness of fit was estimated using the mean and standard deviation of the distance of the bone surface points from the sphere surface. Eight points, at approximately equal distances around the acetabular rim, were selected with reference to bony landmarks. A plane containing three of these points served as an orientation reference plane. The vectors joining the eight rim points to the centre of the best-fit sphere were found. The angles between these vectors and the normal to the reference plane were calculated. Paired angles were summed to give the angle subtended by the acetabular rim in four directions. The overall mean angle was 158 degrees (range of mean angles 145 degrees -173 degrees ). The largest individual angles, some exceeding 180 degrees, were in the superior-inferior direction, while the mean angle in the anterior-posterior direction, i.e. that controlling flexion-extension, was 152 degrees. Males had larger subtended angles than females, although the difference was not statistically significant. Simulated reaming increased all angles by approximately 10 degrees. The subtended angles are important parameters in the design of the acetabular component of a hip replacement and particularly important in resurfacing hip replacement when the volume available is tightly constrained.

Acetabulum↗
PubMed2000

The Orpheus complex.

This paper examines the possible psychological implications of two adaptations of the myth of Orpheus and Eurydice, both of which were completed in 1997. The first is by a man: 'Deconstructing Harry', a film by Woody Allen. The second is by a woman: 'Eurydice in the Underworld', a short story written by Kathy Acker in the last year of her life. The paper argues that there are only four 'necessary events' in the myth of Orpheus and Eurydice. It defines the sequence of these events as a 'mythic pattern' that represents the experience of loss, unconscious yearning, depression, and psychological inflation. The film is examined as an expression of an 'Orpheus complex', the short story as an expression of an 'Eurydice complex'. The paper suggests a possible reason for the persistence of interest in the myth throughout the twentieth century. Although it notes that women appear to find it easier to free themselves from identification with the mythic pattern, it also provides reasons for thinking that men may be about to do the same.

Depressive Disorder↗
PubMed2000

An education programme for people with cancer.

Evidence suggests that cancer patients want support, information and to be involved in treatment decisions. A course designed in the USA aims to help cancer patients learn more about the disease and become an informed part of the therapeutic team. The introduction of a similar course at one UK centre suggested that it is an effective way of informing and supporting people.

Humans↗
PubMed1999

Pituitary apoplexy following metastasis of bronchogenic adenocarcinoma to a prolactinoma.

A 42-year-old house wife presented with worsening headaches over 6 months in the absence of visual symptoms or symptoms suggestive of focal neurology. She was a life-long smoker. Systems review was unremarkable apart from secondary amenorrhoea and galactorrhoea of 6 months duration. Her serum prolactin was found to be 620 mU/l (60-400), FT4 12.6 nmol/l (9.8-23.1), TSH 1.38 mU/l (0.35-5.5), oestradiol < 73 pmol/l, LH and FSH of 4.4 and 12.6 mIU/l, respectively. She was on bromocriptine. A presumptive diagnosis of pneumonia, based on pyrexia and CXR findings, was made and she was started on IV antibiotics. Two days later she developed meningism and deterioration of conscious level. (Lumbar puncture results: no organisms, 312 neutrophils and 164 lymphocytes). CT scan revealed a 2.5-cm pituitary adenoma, with suprasellar extension. A repeat hormonal profile revealed FSH 1.4, LH < 0.3 mU/l, oestradiol < 73 pmol/l, prolactin 488 mU/l (60-400), and low random cortisol at 29 nmol/l. T1-weighted MRI revealed a large pituitary mass with evidence of haemorrhage. The patient subsequently underwent a transsphenoidal exploration with resection of the pituitary lesion. Whilst awaiting the histopathology results, CT of chest revealed a 1. 5-cm diameter rounded well defined density in the right lower lobe associated with hilar, pre- and right para-tracheal lymphadenopathy. The histopathology of the pituitary lesion, obtained piecemeal, revealed fragments of fibrous tissue infiltrated by sheets of acidophilic prolactin-positive cells, in keeping with a prolactinoma. In addition, other fragments with blood clot included highly atypical epithelial cells with mitotic figures. These were negative for prolactin but showed HMFG-and CEA-positivity, excluding them from a pituitary lineage. Transbronchial biopsy revealed moderately differentiated adenocarcinoma, with evidence of lymphatic spread. The overall conclusion was of bronchogenic adenocarcinoma, metastasizing to a prolactinoma and complicated by apoplexy.

Adult↗
PubMed1996

The prevalence of genetic disorders, birth defects and syndromes in central and eastern Kentucky.

Without an operative Birth Defects Registry, the state of Kentucky does not have a means of determining which of the nearly 6,000 syndromes and birth defects are the most common or the most rare, nor is there an ability to compare and contrast these data with data from other states. The authors reviewed 4,212 charts of patients evaluated between July 1981 and February 1995 by the Division of Genetics and Dysmorphology at the University of Kentucky Chandler Medical Center. Each patient's chart was categorized by diagnosis, and tables were generated to determine the most common diagnoses in the following groups: (1) multiple congenital anomaly syndromes, (2) teratogenic embryopathies, (3) chromosome anomalies, (4) isolated malformations, and (5) bone dysplasias. The most common multiple congenital anomaly syndromes were Down syndrome, Marfan syndrome, and trisomy 18. Fetal alcohol syndrome and infants of diabetic mothers were the most common embryopathies. Spina bifida (meningocele and myelomeningocele) was by far the most common isolated birth defect, followed by cleft lip/ palate and microcephaly. Achondroplasia was the most common bone dysplasia. These data support a number of previous assumptions including the universally high frequency of syndromes like Down syndrome and trisomy 18. The data also give credence to what was previously thought, but unproven, to be a high incidence of diabetic and alcohol embryopathies. The latter (fetal alcohol syndrome) has increased in frequency tremendously over the past 7 years. This is undoubtedly due in part to the overall increased awareness of the diagnosis in the medical community. However, it may also be due to the increased use of alcohol among Kentucky women. Other "rare" disorders, like diastrophic dysplasia, seem to be unusually the diagnosis in the medical community. However, it may also be due to the increased use of alcohol among Kentucky women. Other "rare" disorders, like diastrophic dysplasia, seem to be unusually the diagnosis in the medical community. However, it may also be due to the increased use of alcohol among Kentucky women. Other "rare" disorders, like diastrophic dysplasia, seem to be unusually

Chromosome Aberrations↗
PubMed1995

Does autocrine growth factor secretion form part of a mechanism which paradoxically protects against tumour development?

Autocrine growth factor secretion has classically been considered as a mechanism by which tumour cells achieve autonomous growth. However, there is now considerable evidence that autocrine circuits operate in the growth regulation of normal adult tissues. Here we consider the possible advantages to the normal epithelial cell of utilising such an external growth factor circuit and suggest that autocrine growth factor secretion, when viewed in a multicellular context, could paradoxically form part of a mechanism for preventing tumour development.

Adult↗
PubMed1993

Direct growth stimulation of normal human epithelial cells by mutant p53.

We developed a high-titer amphotropic retroviral vector that expresses mutant (Ala143) human p53 to test directly the response of genetically normal human epithelial cells to p53 mutation. Contrary to our prediction, we found that in pancreatic epithelium (whose tumors display a high frequency of p53 mutation) but not in thyroid (whose tumors show an exceptionally low mutation frequency), expression of mutant p53 induced a dramatic, though self-limiting, proliferative response. This result questions the assumption that p53 mutation is relevant only to the later stages of tumorigenesis.

Cell Division↗
PubMed1993

Toxicity of phorbol esters for human epithelial cells expressing a mutant ras oncogene.

Phorbol esters and related compounds provide a promising source of potential anticancer agents. The mechanism of their toxicity, however, is unclear, and interpretation has been complicated by the conflicting responses exhibited by different transformed cell lines. Previously we showed that in primary thyroid follicular cells, expression of mutant p21ras conferred a striking sensitivity to the toxic effects of phorbol esters. We have now extended this work using a thyroid cell line with an inducible mutant ras gene to exclude the possibility that this result was a trivial consequence of the marked growth stimulation induced in these cells by mutant p21ras. Furthermore, by assessing the action of a panel of phorbol esters and a potential chemotherapeutic agent, bryostatin, we demonstrated that this phenomenon was only a function of biologically active phorbol esters. These results provide a molecular rationale for the development of phorbol ester analogues as chemotherapeutic agents.

Antineoplastic Agents↗
PubMed1993

A variant epithelial sub-population in normal thyroid with high proliferative capacity in vitro.

We describe the existence in normal human primary thyroid cultures of a hitherto unrecognised sub-population of epithelial cells. This variant phenotype is characterised by squamoid morphology, absence of thyroglobulin, and an altered profile of intermediate filament expression. We suggest that these cells are derived from scattered foci of squamous metaplasia present in the normal gland. Although they are initially present at a frequency of less than 10(-4), their very high proliferative capacity enables them to outgrow the 'classical' follicular cells and confers a much increased capacity for gene transduction. Recognition of these cells is therefore crucial in the interpretation of long-term thyroid culture experiments and those involving in vitro gene transfer.

Biomarkers↗
PubMed1993

Construction of an ecotropic retroviral vector expressing human insulin-like growth factor-I.

There is increasing evidence that IGF-I plays an autocrine role in a wide range of human tumours, including, in particular, adenomas of the thyroid epithelium. To investigate this further, we set out to generate a retrovirus vector which would permit experimental manipulation of the expression of IGF-I in normal and neoplastic epithelial cells. We describe here the construction and validation of a high-titre ecotropic vector which transduces stable expression and secretion of human IGF-IA, as shown by analysis of mRNA and conditioned medium from rodent epithelial target cells. This vector should be a useful tool for assessing the contribution of abnormal IGF-I expression to the neoplastic phenotype.

3T3 Cells↗
PubMed1992

A phenotypically and karyotypically stable human thyroid epithelial line conditionally immortalized by SV40 large T antigen.

Primary cultures of normal human neonatal thyroid follicular cells were transfected with a plasmid expressing a temperature-sensitive (tsA58) mutant of SV40 large T antigen. An epithelial cell line, designated B-thy-ts.1, was obtained which showed tight temperature-dependent growth. In sharp contrast to previous such lines, which were derived from adult thyroid, B-thy-ts.1 has retained a well-differentiated phenotype as reflected in its morphology and cytokeratin expression pattern. In addition to phenotypic stability the line also displays an unusually stable karyotype, lacking the usual clastogenic effects of SV40, which we speculate to result from a greater DNA repair capacity of its cell of origin. B-thy-ts.1 should be a particularly useful tool with which to study the effects of activated oncogenes on epithelial growth and differentiation.

Antigens, Polyomavirus Transforming↗
PubMed1992

Effect of serum growth factors and phorbol ester on growth and survival of human thyroid epithelial cells expressing mutant ras.

We previously demonstrated a high incidence of ras mutation in thyroid follicular (epithelial) cell neoplasms and showed that expression of mutant ras is a potent mitogenic stimulus for normal human follicular cells in culture. Here we show that induction of cell proliferation in primary follicular cells by a mutant human Ha-ras (val 12) expressed from a retroviral vector was absolutely dependent on the presence of serum growth factors. Induction of DNA synthesis showed partial dependence. Mutant ras-induced growth was also inhibited by exposure to phorbol ester at concentrations sufficient to downregulate protein kinase C. More importantly, we observed an unexpected toxic effect of phorbol ester in this system that was specific to cells expressing mutant ras. This has potential significance both for elucidating the basic mechanism of ras action in epithelial cells and also as a pointer to a novel therapeutic strategy.

Animals↗