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Biomedical subjects

M Freeman

Publications and source records attributed to M Freeman.

At least 55 records · Page 3Linked to original sources
PubMed1999

No genetic association between polymorphisms in the Tau gene and Alzheimer's disease in clinic or population based samples.

Mutations in the tau protein gene have recently been found to cause familial fronto-temporal dementia in a number of kindreds demonstrating linkage to chromosome 17. Given that tau pathology is a hallmark of Alzheimer's disease (AD), this raises the possibility that mutations in tau may also be associated with AD. We have investigated the allelic frequencies of polymorphisms in the Tau gene for a possible allelic distortion in Alzheimer's cases, which might suggest a conferred genetic risk. We have genotyped 65 community-based and 200 clinic-based AD cases, and 142 community-based controls at the Tau exon 6 AflIII and BslI polymorphisms and find no independent association with risk for AD in these samples. Further analysis including APOE genotypes from the same samples demonstrated no interaction between either of these polymorphisms and APOE in conferring risk for AD. In addition, haplotype analysis across both sites revealed no difference in haplotype frequencies between cases and controls, nor any interaction with APOE. Therefore our data do not suggest any association between these variations in the Tau gene and Alzheimer's disease.

Age of Onset↗
PubMed1999

Sprouty, an intracellular inhibitor of Ras signaling.

Sprouty was identified in a genetic screen as an inhibitor of Drosophila EGF receptor signaling. The Egfr triggers cell recruitment in the eye, and sprouty- eyes have excess photoreceptors, cone cells, and pigment cells. Sprouty's function is, however, more widespread. We show that it also interacts genetically with the receptor tyrosine kinases Torso and Sevenless, and it was first discovered through its effect on FGF receptor signaling. In contrast to an earlier proposal that Sprouty is extracellular, we show by biochemical analysis that Sprouty is an intracellular protein, associated with the inner surface of the plasma membrane. Sprouty binds to two intracellular components of the Ras pathway, Drk and Gap1. Our results indicate that Sprouty is a widespread inhibitor of Ras pathway signal transduction.

Animals↗
PubMed1999

Control of EGF receptor signalling: lessons from fruitflies.

The EGF receptor, and the related ErbB family of receptor tyrosine kinases, have been much implicated in human cancer. Hyperactive receptor signalling promotes deregulated growth control and the onset of malignancy, as well as the disruption of developmental programmes. Very little, however, is known about ErbB physiological regulation in humans. The fruitfly, Drosophila melanogaster, has a single receptor homologous to the four ErbB receptors and in this review we discuss how a genetic approach has led to significant insights into how the fly receptor is regulated. As signalling mechanisms have been well conserved between flies and mammals, these results of experiments in flies are relevant to the study of the human receptors in development and disease. Two areas of recent progress are emphasised. First, a number of signal modulators have been identified, including three EGF receptor inhibitors, several of which have human homologues. Second, we describe how the signalling molecules are integrated into regulatory networks that specify the elaborate activation profiles needed in development--positive and negative feedback control of EGF receptor signalling emerges as a central theme. Although the study of the Drosophila EGF receptor has no direct clinical application, the mechanistic insight it provides suggests new avenues of more applied research, including potential therapeutic targets.

Animals↗
PubMed1999

Costs of care associated with high-dose therapy and autologous transplantation for non-Hodgkin's lymphoma: results from the University of Nebraska Medical Center 1989 to 1995.

The purpose of this paper was to (1) comprehensively analyze transplant-related costs for predicted temporal cost shifting and (2) to evaluate whether previous findings of decreasing costs of care persisted using a cost analysis of 353 NHL patients who received autologous stem cell transplantation (SCT) at the University of Nebraska Medical Center. All transplant-related costs between the patient's initial consult and program dismissal were obtained and inflated to constant 1995 dollars. Homogeneous resources were categorized into six cost-drivers and subdivided into outpatient, transplant, and additional inpatient time periods in order to evaluate resource utilization and cost shifting patterns. Between 1989 and 1991 both the average length of stay and comprehensive costs decreased 4.9 days and 14%, respectively. By 1995 additional decreases of 25.7 days and 51% led to an overall 7 year cost decline of 65%. Percent contributions of the six cost-drivers remained similar demonstrating uniformed suppression in transplant-related resource consumption. In contrast, the timing of resource utilization changed dramatically, with transplant hospitalization costs accounting for 83% of the overall costs in 1989, 71% by 1992, and only 45% in 1995, while total outpatient's contribution was 14%, 26% and 49%. Before 1991 ebbing costs were likely related to the development of new technologies such as hematopoietic growth factors and peripheral SCT, while the three-fold larger improvement in costs reported by 1995 are presumably associated with learning curve effects such as organizational changes, increased use of coordinated outpatient facilities, and the more cost-effective use of laboratory tests and pharmaceuticals.

Adolescent↗
PubMed1999

Validity of reported age and centenarian prevalence in New England.

INTRODUCTION: the age reported by or on behalf of centenarians may be suspect unless proven correct. We report the validity of age reports in a population-based sample of centenarians living in New England and the prevalence of centenarians in an area within the North Eastern USA. METHODS: cohort study. All centenarians in a population-based sample detected by local censuses. Ages were confirmed by birth certificate. Type of residence and whether the subject was living independently were also recorded. RESULTS: from a population of about 450,000 people, 289 potential centenarians were reported by the censuses of the eight towns participating in the study. Of these, 186 (64%) had died at the time centenarian prevalence was determined. Of the 80 still alive, 13 (16%) had incorrect birth years recorded by the censuses. The specificity of the censuses for stating the number of centenarians alive and living in the sample was 28-31%. Using additional sources, only four more centenarians were located, indicating that the sensitivity of the censuses approached 100%. We had an 83% success rate in obtaining proof of age in those families we interviewed. In all instances, age and birth order of children were an important source of corroborative evidence and in no case did we detect inconsistencies with the families' reported ages of the centenarian subjects. Therefore, there were at least 46 centenarians or approximately 1 centenarian per 10,000 people. CONCLUSIONS: age validation can be performed for most centenarians in the North Eastern USA. Self or family reports of those between the ages of 100 and 107 years were dependable.

Age Distribution↗
PubMed1999

Pediatricians' and social workers' knowledge and opinions of Florida's religious immunity laws.

BACKGROUND: Florida laws grant exemption from prosecution to parents who choose spiritual healing rather than conventional medical therapy for their children. Despite the American Academy of Pediatrics' policy statement supporting repeal of such laws, we believe pediatricians are not aware of existing statutes. METHODS: A survey to assess understanding of Florida's religious exemption laws was distributed to pediatric house staff, faculty, and clinical social workers at a large teaching hospital and to community pediatricians in private practice. RESULTS: Eighty-four percent of respondents were unaware of Florida statutes, and physicians were significantly less knowledgeable than social workers. Of those who understood the statutes, 92% believed physicians should overrule parents' decisions. Significantly more social workers than physicians believed that parents should be prosecuted for child abuse or neglect when medical treatment is withheld for religious reasons. CONCLUSIONS: Further education of pediatric health care workers is required before repeal of these laws will become a priority for legislators.

Adolescent↗
PubMed1999

Role of the EGF receptor pathway in growth and patterning of the Drosophila wing through the regulation of vestigial.

Growth and patterning of the Drosophila wing disc depends on the coordinated expression of the key regulatory gene vestigial both in the Dorsal-Ventral (D/V) boundary cells and in the wing pouch. We propose that a short-range signal originating from the core of the D/V boundary cells is responsible for activating EGFR in a zone of organizing cells on the edges of the D/V boundary. Using loss-of-function mutations and ectopic expression studies, we show that EGFR signaling is essential for vestigial transcription in these cells and for making them competent to undergo subsequent vestigial-mediated proliferation within the wing pouch.

Animals↗
PubMed1999

Pooling talents.

Explore the source record for details and available documents.

Cooperative Behavior↗
PubMed1998

An autoregulatory cascade of EGF receptor signaling patterns the Drosophila egg.

Intercellular signaling through the EGF receptor (EGFR) patterns the Drosophila egg. The TGF alpha-like ligand Gurken signals from the oocyte to the receptor in the overlying somatic follicle cells. We show that in the dorsal follicle cells this initial paracrine signaling event triggers an autocrine amplification by two other EGFR ligands, Spitz and Vein. Spitz only becomes an effective ligand in the presence of the multitransmembrane domain protein Rhomboid. Consequent high-level EGFR activation leads to localized expression of the diffusible inhibitor Argos, which alters the profile of signaling. This sequential activation, amplification, and local inhibition of the EGFR forms an autoregulatory cascade that leads to the splitting of an initial single peak of signaling into two, thereby patterning the egg.

Animals↗
PubMed1998

Multiple functions of the EGF receptor in Drosophila eye development.

BACKGROUND: During animal development, cells need to make spatially and temporally regulated fate decisions. These decisions are largely controlled by intercellular signalling, often through receptor tyrosine kinases. One of these, the epidermal growth factor receptor (EGFR), regulates multiple cell fate decisions. Its importance in the recruitment of photoreceptors in the developing fly eye, a useful model for neural development, has already been reported. Other EGFR functions in the eye have not been characterised. RESULTS: We have examined the consequences of removing or activating the EGFR at different stages of eye development. The earliest stages of assembly occurred normally within EGFR- clones--the morphogenetic furrow was unimpeded and the R8 photoreceptor was specified. All subsequent photoreceptor recruitment was blocked. EGFR- clones had a characteristic shape indicating that they had undergone substantial cell death posterior to the furrow, where the differentiation program is normally activated; consistent with this, excess apoptosis was detected. We found that the receptor also regulates cell proliferation in the disc, has an early function at the disc margin (where the morphogenetic furrow initiates) and contributes to the regulation of spacing of the R8 precursors. Finally, we found that activation of the receptor is sufficient to trigger non-R8 photoreceptor development, even in cells in front of the furrow or in the absence of the proneural gene atonal. CONCLUSION: At least five distinct functions of EGFR signalling need to be integrated during fly eye development. These include roles in cell proliferation, survival and differentiation.

Animals↗
PubMed1998

In vivo analysis of Argos structure-function. Sequence requirements for inhibition of the Drosophila epidermal growth factor receptor.

The Drosophila Argos protein is the only known extracellular inhibitor of the epidermal growth factor receptor (EGFR). It is structurally related to the activating ligands, in that it is a secreted protein with a single epidermal growth factor (EGF) domain. To understand the mechanism of Argos inhibition, we have investigated which regions of the protein are essential. A series of deletions were made and tested in vivo; furthermore, by analyzing chimeric proteins between Argos and the activating ligand, Spitz (a transforming growth factor-alpha-like factor), we have examined what makes one inhibitory and the other activating. Our results reveal that Argos has structural requirements that differ from all known EGFR activating ligands; domains flanking the EGF domain are essential for its function. We have also defined the important regions of the atypical Argos EGF domain. The extended B-loop is necessary, whereas the C-loop can be replaced with the equivalent Spitz region without substantially affecting Argos function. Comparison of the argos genes from Drosophila melanogaster and the housefly, Musca domestica, supports our structure-function analysis. These studies are a prerequisite for understanding how Argos inhibits the Drosophila EGFR and provide a basis for designing mammalian EGFR inhibitors.

Amino Acid Sequence↗
PubMed1998

Complexity of EGF receptor signalling revealed in Drosophila.

The multiple roles of the Drosophila epidermal growth factor receptor (EGFR) require that its activation is regulated precisely. Recent work has highlighted two important control mechanisms: the existence of multiple ligands with distinct properties and the interaction between EGFR pathway and other signalling pathways. The integration of signalling pathways into networks is beginning to be understood.

Animals↗
PubMed1998

Rural palliative care volunteer education and support program.

The present paper looks at the challenges of palliative care delivery in rural and remote areas and proposes the establishment, education and coordination of a network of palliative care volunteers to assist in the delivery of non-clinical services. The development of a rural palliative care volunteer education and support training package is documented, together with details of the trailing of the package and its evaluation. Possible benefits of the program and some key issues to be considered when establishing a volunteer network are raised.

Attitude of Health Personnel↗
PubMed1998

Characterisation and molecular typing of Burkholderia pseudomallei: are disease presentations of melioidosis clonally related?

Eighteen cases of culture positive melioidosis caused by Burkholderia pseudomallei, were seen in four geographically separate communities in North Queensland, Australia. The genetic inter-relatedness of the clinical isolates were compared utilising random amplification of polymorphic DNA (RAPD) and multilocus enzyme electrophoresis (MEE). The isolates segregated into two groups that correlated with clinical presentation rather than geographical location. This is the first described association between the varied clinical presentations of this condition and specific molecular type. If proven on larger studies, this may further our understanding of the pathogenesis of this important condition.

Adolescent↗
PubMed1997

Modulation of plasminogen activator inhibitor-1 in vivo: a new mechanism for the anti-fibrotic effect of renin-angiotensin inhibition.

We examined the potential of in vivo linkage of plasminogen activator inhibitor-1 (PAI-1) and angiotensin II (Ang II) in the setting of endothelial injury and sclerosis following radiation injury in the rat. PAI-1 is a major physiological inhibitor of the plasminogen activator (PA)/plasmin system, a key regulator of fibrinolysis and extracellular matrix (ECM) turnover. PAI-1 mRNA expression in the kidney was markedly increased (9-fold) at 12 weeks after irradiation (P < 1.001 vs. normal control). In situ hybridization revealed significant association of PAI-1 expression with sites of glomerular injury (signal intensity in injured vs. intact glomeruli, P < 0.001). Angiotensin converting enzyme inhibitors (ACEI, captopril or enalapril) or angiotensin II receptor antagonist (AIIRA, L158,809) markedly reduced glomerular lesions (thrombosis, mesangiolysis, and sclerosis; sclerosis index, 0 to 4+ scale, 0.49 +/- 0.20 in untreated vs. 0.05 +/- 0.02, 0.02 +/- 0.01, 0.04 +/- 0.02 in captopril, enalapril and AIIRA, respectively, all P < 0.01 vs untreated). Further, ACEI and AIIRA markedly attenuated increased PAI-1 mRNA expression in the irradiated kidney (36, 19 and 20% expression, respectively, for captopril, enalapril and AIIRA, compared to untreated irradiated kidney, P < 0.05, < 0.01, < 0.01). This effect was selective in that neither tissue-type nor urokinase-type PA mRNA expression was affected by these interventions. Thus, we speculate that inhibition of the renin-angiotensin system may ameliorate injury following radiation by accelerating fibrinolysis and ECM degradation, at least in part, via suppression of PAI-1 expression. In summary, inhibition of Ang II, in addition to its known effects on vascular sclerosis, may also by its novel effect to inhibit PAI-1, lessen fibrosis following endothelial/thrombotic injury.

Angiotensin II↗
PubMed1997

Antagonism between EGFR and Wingless signalling in the larval cuticle of Drosophila.

Signalling by the epidermal growth factor receptor (EGFR) plays a critical role in the segmental patterning of the ventral larval cuticle in Drosophila: by expressing a dominant-negative EGFR molecule or Spitz, an activating ligand of EGFR, we show that EGFR signalling specifies the anterior denticles in each segment of the larval abdomen. We provide evidence that these denticles derive from a segmental zone of embryonic cells in which EGFR signalling activity is maximal. Within each segment, there is a competition between the denticle fate specified by EGFR signalling and the naked cuticle fate specified by Wingless signalling. The final pattern of the denticle belts is the product of this antagonism between the two signalling pathways. Finally, we show that the segmental zones of high EGFR signalling activity depend on bithorax gene function and that they account for the main difference in shape between abdominal and thoracic denticle belts.

Abdomen↗