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Biomedical subjects

S Wyatt

Publications and source records attributed to S Wyatt.

At least 19 recordsLinked to original sources
PubMed2003

Reduced age-related plasticity of neurotrophin receptor expression in selected sympathetic neurons of the rat.

Selective vulnerability of particular groups of neurons is a characteristic of the aging nervous system. We have studied the role of neurotrophin (NT) signalling in this phenomenon using rat sympathetic (SCG) neurons projecting to cerebral blood vessels (CV) and iris which are, respectively, vulnerable to and protected from atrophic changes during old age. RT-PCR was used to examine NT expression in iris and CV in 3- and 24-month-old rats. NGF and NT3 expression in iris was substantially higher compared to CV; neither target showed any alterations with age. RT-PCR for the principal NT receptors, trkA and p75, in SCG showed increased message during early postnatal life. However, during mature adulthood and old age, trkA expression remained stable while p75 declined significantly over the same period. In situ hybridization was used to examine receptor expression in subpopulations of SCG neurons identified using retrograde tracing. Eighteen to 20 h following local treatment of iris and CV with NGF, NT3 or vehicle, expression of NT receptor protein and mRNA was higher in iris- compared with CV-projecting neurons from both young and old rats. NGF and NT3 treatment had no effect on NT receptor expression in CV-projecting neurons at either age. However, similar treatment up-regulated p75 and trkA expression in iris-projecting neurons from 3-month-old, but not 24-month-old, rats. We conclude that lifelong exposure to low levels of NTs combined with impaired plasticity of NT receptor expression are predictors of neuronal vulnerability to age-related atrophy.

Adrenergic Fibers↗
PubMed2002

A hydrogel material for plastic and reconstructive applications injected into the subcutaneous space of a sheep.

Soft tissue reconstruction using tissue-engineered constructs requires the development of materials that are biocompatible and support cell adhesion and growth. The objective of this study was to evaluate the use of macroporous hydrogel fragments that were formed using either unmodified alginate or alginate covalently linked with the fibronectin cell adhesion peptide RGD (alginate-RGD). These materials were injected into the subcutaneous space of adult, domesticated female sheep and harvested for histological comparisons at 1 and 3 months. In addition, the alginate-RGD porous fragments were seeded with autologous sheep preadipocytes isolated from the omentum, and these cell-based constructs were also implanted. The results from this study indicate that both the alginate and alginate-RGD subcutaneous implants supported tissue and vascular ingrowth. Furthermore, at all time points of the experiment, a minimal inflammatory response and capsule formation surrounding the implant were observed. The implanted materials also maintained their sizes over the 3-month study period. In addition, the alginate-RGD fragments supported the adhesion and proliferation of sheep preadipocytes, and adipose tissue was present within the transplant site of these cellular constructs, which was not present within the biomaterial control sites.

Absorbable Implants↗
PubMed2001

In vivo characterization of a porous hydrogel material for use as a tissue bulking agent.

Tissue engineered biomaterial constructs are needed for plastic and reconstructive applications. To successfully form a space-filling tissue, the construct should induce a minimal inflammatory response, create minimal or no fibrotic capsule, and establish a vascular bed within the first few days after implantation to ensure survival of the implanted cells. In addition, the biomaterial should support cellular adhesion and induce tissue ingrowth. A macroporous hydrogel bead using sodium alginate covalently coupled with an arginine, glycine, and aspartic acid-containing peptide was created. A 6-month subcutaneous rat model study was performed to determine if the implanted material induced tissue ingrowth throughout the implantation area and maintained a three-dimensional vascular bed. The implanted materials produced a vascular bed, minimal inflammation and capsule formation, and good tissue ingrowth throughout the experiment. The material retained its bulking capacity by demonstration of no significant change of the cross-sectional area as measured from the center of the implants after the 2-week time point. In addition, the granulation tissue formed around the implant was loosely organized, and the surrounding tissue had integrated well with the implant. These results indicate that this material has the desired properties for the development of soft-tissue-engineering constructs.

Alginates↗
PubMed2001

Role of STAT3 and PI 3-kinase/Akt in mediating the survival actions of cytokines on sensory neurons.

The binding of cytokines to the gp130 receptor activates the STAT3, MEK/MAPK, and PI3K/Akt signalling pathways. To assess the relative importance of these pathways in promoting the survival of cytokine-dependent neurons, we conditionally inactivated STAT3 in mice and inhibited MEK, PI3K, and Akt in cultured neurons using pharmacological reagents and by expressing specific inhibitory proteins. Inactivation of STAT3 enhanced the death of the cytokine-dependent sensory neurons of the nodose ganglion in vivo and substantially reduced the response of these neurons to CNTF and LIF in vitro. LY294002, an inhibitor of PI3K, but not PD98059, an inhibitor of MEK, markedly reduced the response of these neurons to CNTF, as did dominant-negative PI3K, dominant-negative Akt, and overexpression of Ruk (a natural PI3K inhibitor). These results demonstrate that STAT3 and PI3K/Akt signalling play major roles in mediating the survival response of neurons to cytokines.

Animals↗
PubMed2001

A physician-pharmacist model for the surveillance of blood pressure in the community: a feasibility study.

Hypertension is poorly managed. Hospital-based pharmacists working with physicians have been shown to improve the rate of achievement of "target" blood pressure in selected patients. It is unknown if such schemes can operate in the community and to what extent they would attract volunteers with poorly managed blood pressure. We assessed the feasibility of pharmacists to provide community-based, open-access, blood pressure monitoring. In addition, we describe the blood pressure profile of the group in comparison to that of the 1994 Health Survey of England (HSE). Pharmacists from six pharmacies were trained to deliver the service. Adults living within the postal districts of the pharmacies were invited, through an advertising campaign, to volunteer to have their blood pressure measured. Blood pressure data and information on treatment for hypertension and/or diabetes were collected on 263 registrants. Patients were advised to have their blood pressure managed by the general practitioner immediately (category 1), re-measured within 2-3 months (category 2) or in 12 months time (category 3). The mean (s.d.) blood pressure of patients in categories 1 (n = 16), 2 (n = 117) and 3 (n = 130) was 186(16)/97(29), 151(13)/94(9) and 139(22)/86(13) mm Hg respectively; P < 0.001. Ninety-one patients (35%) were in receipt of antihypertensive therapy. Forty-five percent of the treated group had controlled blood pressure (<160/95 mm Hg) compared with 30% in the HSE dataset. A large proportion of known hypertensive patients with poor blood pressure control who had visited their general practitioner within the previous 6 months were detected by the pharmacist-led service. Pharmacists operating an open-access blood pressure monitoring service may be of value in improving the management of hypertension.

Adult↗
PubMed2001

Measuring the function of children with juvenile arthritis.

OBJECTIVE: Juvenile idiopathic arthritis (JIA) can affect a child's performance across a range of activities necessary to normal childhood development. Although there are now several available measures of disability in JIA, none have been validated for use with children in the UK. Consequently, a study was undertaken to compare and validate four such measures, together with a locally developed function test. METHODS: Fifty-three children between the ages of 5 and 16 yr were recruited into the study. The mean age was 10.4 yr and mean duration of disease 4 yr. Seventy per cent were female. RESULTS: Internal consistency was adequate in three of five measures. Four of five measures showed the expected associations between disease activity and function (P<0.05). The level of reliability was poor for tests that involved direct assessment by therapists. Most showed poor levels of unidimensionality. CONCLUSION: Until new measures become available, the CHAQ appears to be the current 'best buy' for measuring function in children with arthritis.

Adolescent↗
PubMed2001

Understanding the relationship between market competition and students' ratings of the managed care content of their undergraduate medical education.

PURPOSE: The increase in managed care has led to questions about the inadequacy of instruction undergraduate medical students receive in curricular areas related to managed care. This study examined (1) the percentages of graduating medical students who felt they had received inadequate instruction in six curricular content areas (CCAs): primary care, care of ambulatory patients, health promotion and disease prevention, medical care cost control, teamwork with other health professionals, and cost-effective medical practice; and (2) whether the market competitiveness of these students' medical schools affected their reports of inadequacy of instruction in these CCAs. METHOD: Data from the Association of American Medical Colleges' Graduation Questionnaires (GQs) from 1994 to 1997 were analyzed. The GQ asked graduating students to rate the adequacy of instruction they had received in the six CCAs. Students' ratings were collapsed into the dichotomous variables "inadequate" and "not inadequate." The market competitiveness of medical schools was determined using the four-stage Market Evolution Model developed by the University HealthSystem Consortium. Only responses from students graduating from medical schools that could be staged for all four years of the study were analyzed. Statistical analyses were performed to determine trends for each CCA by year, across the entire study period, by market stage, and by market stage across the entire study period. RESULTS: A total of 39,136 respondents from 86 medical schools were used in the study. The percentages of graduating medical students who reported inadequate instruction decreased over the study period for five of the six CCAs: primary care (27.6% in 1994 to 13.7% in 1997), ambulatory care (37.4% to 23. 9%), medical care cost control (62.9% to 52.9%) cost-effectiveness of medical practice (62.7% to 53.9%), and health promotion and disease prevention (44.4% to 23.7%); all at p <0.001. The responses for inadequacy of instruction for teamwork with other health professionals remained steady from 1994 to 1996 (10.2% to 10.6%), then increased 21.8% in 1997. Over the course of the study, students graduating from schools in more competitive markets (Stage 3 or Stage 4) were more likely to report inadequate instruction in three CCAs, primary care, ambulatory care, and health promotion and disease prevention, than were those graduating from schools in less competitive markets (Stage 1 and Stage 2). Conversely, students graduating from schools in the more competitive health care markets were less likely to report inadequate instruction in cost-effectiveness and cost control than were students from schools in less competitive markets. CONCLUSION: Graduating students' reports of inadequacy of instruction decreased over the study period for five of the six CCAs, increasing only for teamwork with other professionals. Findings were mixed with regard to the relationship of medical schools' market competitiveness and graduating students' reports of inadequacy of instruction. More research is needed to confirm graduating students' perceptions of the inadequacy of their instruction in CCAs related to managed care, particularly once they have gained experience treating patients in managed care environments.

Ambulatory Care↗
PubMed2001

Multiple effects of artemin on sympathetic neurone generation, survival and growth.

To define the role of artemin in sympathetic neurone development, we have studied the effect of artemin on the generation, survival and growth of sympathetic neurones in low-density dissociated cultures of mouse cervical and thoracic paravertebral sympathetic ganglia at stages throughout embryonic and postnatal development. Artemin promoted the proliferation of sympathetic neuroblasts and increased the generation of new neurones in cultures established from E12 to E14 ganglia. Artemin also exerted a transient survival-promoting action on newly generated neurones during these early stages of development. Between E16 and P8, artemin exerted no effect on survival, but by P12, as sympathetic neurones begin to acquire neurotrophic factor independent survival, artemin once again enhanced survival, and by P20 it promoted survival as effectively as nerve growth factor (NGF). During this late period of development, artemin also enhanced the growth of neurites from cultured neurones more effectively than NGF. Confirming the physiological relevance of the mitogenic action of artemin on cultured neuroblasts, there was a marked reduction in the rate of neuroblast proliferation in the sympathetic ganglia of mice lacking the GFRalpha3 subunit of the artemin receptor. These results indicate that artemin exerts several distinct effects on the generation, survival and growth of sympathetic neurones at different stages of development.

Animals↗
PubMed2001

Reciprocal developmental changes in the roles of Bcl-w and Bcl-x(L) in regulating sensory neuron survival.

We have compared the roles of two anti-apoptotic members of the Bcl2 family, Bcl-w and Bcl-x(L), in regulating the survival of sensory neurons during development. We used microinjection to introduce expression plasmids containing Bcl-w and Bcl-x(L) cDNAs in the sense and antisense orientations into the nuclei of BDNF-dependent nodose neurons and NGF-dependent trigeminal neurons at stages during and after the period of naturally occurring neuronal death. Whilst overexpression of either protein promoted neuronal survival in the absence of neurotrophins and microinjection of antisense constructs reduced neuronal survival in the presence of neurotrophins, the magnitude of these effects changed with age. Whereas Bcl-w overexpression became more effective in promoting neuronal survival with age, Bcl-x(L) overexpression became less effective, and whereas antisense Bcl-w became much more effective in killing neurotrophin-supplemented neurons with age, antisense Bcl-x(L) became much less effective in killing these neurons. There was a marked increased in Bcl-w mRNA and Bcl-w immunoreactive neurons and a decrease in Bcl-x(L) mRNA and Bcl-x(L) immunoreactive neurons in the trigeminal and nodose ganglia over this period of development. Our results demonstrate that both Bcl-w and Bcl-x(L )play an important anti-apoptotic role in regulating the survival of NGF- and BDNF-dependent neurons, and that reciprocal changes occur in the relative importance of these proteins with age. Whereas Bcl-x(L) plays a more important role during the period of naturally occurring neuronal death, Bcl-w plays a more important role at later stages.

Aging↗
PubMed2000

TrkB expression and early sensory neuron survival are independent of endogenous BDNF.

Sensory neurons initially survive independently of neurotrophins in culture during the stage of development when their axons are growing to their targets. Because mRNAs encoding brain-derived neurotrophic factor (BDNF) and its receptor tyrosine kinase TrkB are detectable in subsets of sensory neurons from the earliest stages of their development, we investigated whether a BDNF autocrine loop is responsible for sustaining the survival of these neurons during this early stage in their development. Low-density dissociated cultures of nodose and dorsal root ganglion neurons were established from wild type and BDNF(-/-) mouse embryos at this stage and were grown in defined medium without added neurotrophins. Wild type and BDNF-deficient neurons survived equally well under these conditions, indicating that a BDNF autocrine loop does not play a role in sustaining the survival of sensory neurons during the earliest stages of their development. As sensory axons approach their targets, TrkB expression increases in a subset of neurons that becomes dependent on BDNF produced by other cells. Because numerous studies have shown that neurotrophins, including BDNF, increase expression of their receptors, we investigated whether endogenous BDNF is required for the increase in TrkB expression observed during stage of development. Quantitative reverse transcriptase-polymerase chain reaction (RT-PCR) showed that the developmental increase in TrkB mRNA expression occurred normally in the sensory ganglia of BDNF(-/-) embryos. Taken together, our studies of sensory neuron development in BDNF-deficient embryos have demonstrated that endogenous BDNF is neither required for the early survival of these neurons nor for the induction of TrkB expression.

Animals↗
PubMed2000

Cytokine-induced nuclear factor kappa B activation promotes the survival of developing neurons.

Ciliary neurotrophic factor (CNTF), leukemia inhibitory factor (LIF), cardiotrophin-1 (CT-1), and interleukin 6 (IL-6) comprise a group of structurally related cytokines that promote the survival of subsets of neurons in the developing peripheral nervous system, but the signaling pathways activated by these cytokines that prevent neuronal apoptosis are unclear. Here, we show that these cytokines activate NF-kappaB in cytokine-dependent developing sensory neurons. Preventing NF-kappaB activation with a super-repressor IkappaB-alpha protein markedly reduces the number of neurons that survive in the presence of cytokines, but has no effect on the survival response of the same neurons to brain-derived neurotrophic factors (BDNF), an unrelated neurotrophic factor that binds to a different class of receptors. Cytokine-dependent sensory neurons cultured from embryos that lack p65, a transcriptionally active subunit of NF-kappaB, have a markedly impaired ability to survive in response to cytokines, but respond normally to BDNF. There is increased apoptosis of cytokine- dependent neurons in p65(-/)- embryos in vivo, resulting in a reduction in the total number of these neurons compared with their numbers in wild-type embryos. These results demonstrate that NF-kappaB plays a key role in mediating the survival response of developing neurons to cytokines.

Apoptosis↗
PubMed2000

In vivo survival requirement of a subset of nodose ganglion neurons for nerve growth factor.

The sensory neurons of the nodose ganglion are the classic example of a population of peripheral nervous system neurons that do not require nerve growth factor (NGF) for survival during development but are dependent on other neurotrophins. We have re-examined this assertion by studying the development of the nodose ganglion of mice that have a null mutation in the NGF gene. Compared with wild-type embryos, the number of neurons undergoing apoptosis was elevated in NGF -/- mice, resulting in a significant reduction in the total number of neurons in the ganglion by the end of embryonic development. TrkA, the NGF receptor tyrosine kinase, was expressed in the nodose ganglion throughout development and there was a marked decrease in TrkA mRNA expression in the nodose ganglion of NGF -/- embryos. Although the in vitro survival of the majority of nodose neurons was promoted by brain-derived neurotrophic factor (BDNF), a minor proportion was supported by NGF in cultures established over a range of embryonic stages. These results clearly demonstrate that a subset of nodose ganglion neurons depends on NGF for survival during development. The finding that the expression of tyrosine hydroxylase (TH) mRNA was unaffected in the nodose ganglia of NGF-deficient embryos indicates that this NGF-dependent subset is distinct from the subset of catacholaminergic neurons in the nodose ganglion.

Animals↗
PubMed2000

Human papilloma virus in melanoma biopsy specimens and its relation to melanoma progression.

OBJECTIVES: To evaluate melanoma biopsy specimens for human papilloma virus (HPV) and determine the relation between the presence of HPV, in vitro growth, and clinical progression of melanoma in the patients from whom the biopsy specimens were derived. SUMMARY BACKGROUND DATA: Ultraviolet radiation from sun exposure appears to be the primary causal agent in the development of cutaneous melanoma. However, other agents, including HPV, as observed in different epithelial carcinomas, may also play a role in melanoma development and progression. METHODS: Twelve melanoma biopsy specimens obtained from 12 patients with AJCC stage III and IV melanoma were stained with antibodies against gp-100 (HMB-45) and S-100 protein to confirm melanoma diagnosis and with a polyclonal HPV antibody. After mechanical dissociation, the melanoma specimen cells' ability to grow in vitro was assessed. Patients were evaluated for melanoma progression with physical examination, complete blood count, and liver function tests every 3 months and a chest radiograph every 6 months. RESULTS: All biopsy specimens were positive for S-100, and nine (75%) were positive for gp-100. Seven of 12 (58%) were positive for HPV by immunohistochemistry. In vitro, none of the HPV-negative tumor cells grew from the tumor biopsies, whereas five of seven (71%) of the HPV-positive melanoma tumor cells grew very well. All patients with HPV-positive tumor cells had recurrences and died of melanoma progression, whereas four of five (80%) patients with HPV-negative tumor cells remained alive and without melanoma recurrence. CONCLUSIONS: The presence of HPV was found in 58% of the biopsy specimens obtained from patients with stage III and IV melanoma and correlated with rapid melanoma progression. HPV may serve as a cofactor in the development of melanoma and may modulate a more aggressive phenotype in HPV-containing melanoma cells.

Biopsy↗
PubMed2000

Depolarisation causes reciprocal changes in GFR(alpha)-1 and GFR(alpha)-2 receptor expression and shifts responsiveness to GDNF and neurturin in developing neurons.

GDNF and neurturin are structurally related neurotrophic factors that promote the survival of many different kinds of neurons and influence axonal and dendritic growth and synaptic function. These diverse effects are mediated via multicomponent receptors consisting of the Ret receptor tyrosine kinase plus one of two structurally related GPI-linked receptors, GFR(alpha)-1 and GFR(alpha)-2. To ascertain how the expression of these receptors is regulated during development, we cultured embryonic neurons under different experimental conditions and used competitive RT/PCR to measure the levels of the mRNAs encoding these receptors. We found that depolarising levels of KCl caused a marked increase in GFR(alpha)-1 mRNA and a marked decrease in GFR(&agr;)-2 mRNA in sympathetic, parasympathetic and sensory neurons. These changes were accompanied by increased responsiveness to GDNF and decreased responsiveness to neurturin, and were inhibited by L-type Ca(2+) channel antagonists, suggesting that they were due to elevated intracellular free-Ca(2+). There was no consistent effect of depolarising levels of KCl on ret mRNA expression, and neither GDNF nor neurturin significantly affected receptor expression. These results show that depolarisation has marked and opposing actions on the expression of GFR(&agr;)-1 and GFR(&agr;)-2, which are translated into corresponding changes in neuronal responsiveness to GDNF and neurturin. This provides evidence for a mechanism of regulating the neurotrophic factor responses of neurons by neural activity that has important implications for structural and functional plasticity in the developing nervous system.

Animals↗
PubMed2000

The burden of cancer in Kentucky: the 1997 Kentucky cancer incidence report.

The purpose of collecting this important disease burden information is of course not simply for reports like this one. The real value lies in use of data for program planning, resource allocation, program design, and evaluation. Data in the annual KCR report and on the website should be a valuable resource for district and county health departments in their assessment of health problems in their area and as critical decisions are made about how to utilize limited intervention resources. The Kentucky Cancer Registry will continue to work very closely with the Community Outreach Division of the Kentucky Cancer Program to make this data available on an annual basis to District Cancer Councils to help guide their assessment and planning process. District and local health departments are encouraged to actively participate in the District Cancer Councils and in the cancer control activities guided by the regional community outreach coordinators.

Adolescent↗
PubMed2000

The burden of cancer in Kentucky. The 1998 Kentucky cancer incidence report.

The purpose of collecting this important disease burden information is just for reports like this. The real value lies in use of data for cancer control research, program planning, resource allocation, program design, and evaluation. Data in the annual KCR report and on the website should be a valuable resource for health agencies, clinicians, policymakers, voluntary organizations, etc in their assessment of health problems in their area and as critical decisions are made about how to utilize limited intervention resources. The Kentucky Cancer Registry will continue to work very closely with the Kentucky Cancer Program, Kentucky Medical Association, and programs and research efforts at the University of Kentucky Cancer Control Program (Mid South Cancer Information Service, Appalachia Cancer Network, Kentucky Prevention Research Center) and the Brown Cancer Center at the University of Louisville to make these data available to partners throughout the Commonwealth to help guide their assessment and planning processes. If you have questions about this data you are encouraged to contact Regional Coordinators for the Kentucky Cancer Program in your Area Development District. The contact information is shown in Appendix I.

Adolescent↗
PubMed1999

Selective regulation of trkC expression by NT3 in the developing peripheral nervous system.

We have studied the influence of neurotrophin-3 (NT3) on the expression of its receptor tyrosine kinase, trkC, in embryonic mice. The expression of trkC transcripts encoding full-length and kinase-deficient receptors was almost entirely restricted to neurons in the trigeminal ganglion and increased markedly throughout development. In NT3(+/-) embryos, the level of trkC mRNA in the trigeminal ganglion was much lower than that in wild-type embryos, although there was no significant reduction in the total number of neurons in the ganglion. This demonstrates that endogenous NT3 regulates trkC expression in trigeminal neurons independently of changes in population size. In NT3(-/-) embryos, the number of neurons in the trigeminal ganglion was much lower than in wild-type embryos, and there was a further reduction in the mean neuronal level of trkC mRNA. Direct regulation of trkC mRNA expression in cultured trigeminal neurons was also observed, although the finding that trkC mRNA levels were sustained better in explant cultures than in dissociated cultures irrespective of the presence of NT3 suggests that trkC mRNA expression is regulated by additional factors within the ganglion. In contrast to trigeminal neurons, the level of trkC mRNA was sustained at normal levels in neurons of the sympathetic chain of NT3(-/-) embryos and was not increased by NT3 in sympathetic neuron cultures. TrkC mRNA expression in developing cutaneous tissues was also unaffected by the NT3 null mutation. In summary, our findings provide the first clear evidence that the expression of a trk receptor, tyrosine kinase, is regulated by physiological levels of its ligand in vivo and show that regulation by NT3 is cell type-specific.

Aging↗