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P Worley

Publications and source records attributed to P Worley.

At least 19 recordsLinked to original sources
PubMed2006

Glomerular expression of neuronal activity-regulated pentraxin precedes the development of anti-Thy-1-induced progressive glomerulosclerosis.

Although it is clear that genetic predispositions play a role in progressive glomerulosclerosis, identification of specific genes is difficult because of natural genetic heterogeneity among individuals. We have reported a differential susceptibility to progressive glomerulosclerosis after induction of experimental glomerulonephritis anti-Thy-1 nephritis in Lewis rat substrains. Glomerular lesions in Lewis/Møllegard rats resolve spontaneously, whereas Lewis/Maastricht (Lew/Maa) rats develop progressive glomerulosclerosis. This predisposition for progressive glomerulosclerosis is governed by unknown genes that are expressed by renal cells. Here, differential gene expression analysis using a rat complementary DNA micro array revealed neuronal activity-regulated pentraxin (Narp) as a candidate gene involved in the remodeling or progression of damaged glomeruli. Glomerular Narp mRNA expression was monitored during disease in both Lewis sub strains. Immunohistochemistry revealed that Narp protein is exclusively expressed in Lew/Maa glomeruli 7 and 14 days after induction of anti-Thy-1 nephritis. Double-immunofluorescent staining showed that proliferating mesangial cells and parietal epithelial cells (PECs) at sites of adhesion to podocytes are partially Narp-positive, whereas podocytes fail to express Narp. Immunohistochemistry in nephritic Wistar, unilaterally nephrectomized Wistar and Sprague-Dawley rats showed that Narp protein is present only in strains that develop progressive glomerulosclerosis but never in strains that show remodeling. We conclude that Narp is a predictor for anti-Thy-1 nephritis-induced glomerulosclerosis and its expression by PECs may be involved in the progression to glomerulosclerosis.

Animals↗
PubMed2004

Can medical students learn specialist disciplines based in rural practice: lessons from students' self reported experience and competence.

INTRODUCTION: Medical schools in Australia are being funded by the Commonwealth Government Department of Health and Aging to move a considerable amount of undergraduate clinical education into rural and remote settings. There are concerns that these students may be disadvantaged in terms of exposure to appropriate clinical learning opportunities. This study compared learning opportunities for students undertaking an entire clinical year based in a rural primary care setting, a remote secondary hospital, or a traditional urban tertiary teaching hospital. METHODS: Twenty-nine students, six from rural primary care, eight from the remote secondary hospital, and 15 from the urban tertiary teaching hospital, completed a retrospective survey of their experience and perceived competence to manage 78 common procedural skills and 62 common conditions. RESULTS: Students in rural primary care reported a pattern of increased clinical exposure to common clinical conditions and procedures in comparison with their hospital-based peers. In comparing the two hospital-based programs, the students in the remote secondary care hospital reported increased exposure to common conditions and no significant difference in the opportunity to undertake common procedures. The data also demonstrated that there was a positive correlation between reported experience and self-perceived competence, and that this was greater for procedural skills than competence in managing common conditions. CONCLUSIONS: This study provides further evidence that rural primary care is an excellent setting for high quality clinical and educational experiences. These findings should serve to encourage students and staff involved with the new Rural Clinical School programs.

Journal Article↗
PubMed2004

Activity-regulated cytoskeletal-associated protein is localized to recently activated excitatory synapses.

Activity-regulated, cytoskeletal-associated protein (Arc) is an immediate early gene induced in excitatory circuits following behavioral episodes. Arc mRNA is targeted to activated regions of the dendrite after long-term potentiation (LTP) of the dentate gyrus, a process dependent on NMDA receptor activation. We used post-embedding immunogold electron microscopy (EM) to test whether synaptic Arc expression patterns are selectively modified by plasticity. Consistent with previous light microscopic observations, Arc protein was rapidly induced in the dentate gyrus following LTP-producing stimulation of the perforant path and was detectable in granule cell nuclei, somata and dendrites after two hours of high frequency stimulation. Post-embedding EM revealed Arc immunogold labeling in three times as many spines in the middle molecular layer of the stimulated dentate gyrus than in either the ipsilateral outer molecular layer or the contralateral middle and outer molecular layers. This upregulation did not occur with low frequency stimulation of the perforant path. Therefore Arc protein localization may be a powerful tool to isolate recently activated dendritic spines.

Animals↗
PubMed2001

The scaffold protein, Homer1b/c, regulates axon pathfinding in the central nervous system in vivo.

Homer proteins are a family of multidomain cytosolic proteins that have been postulated to serve as scaffold proteins that affect responses to extracellular signals by regulating protein-protein interactions. We tested whether Homer proteins are involved in axon pathfinding in vivo, by expressing both wild-type and mutant isoforms of Homer in Xenopus optic tectal neurons. Time-lapse imaging demonstrated that interfering with the ability of endogenous Homer to form protein-protein interactions resulted in axon pathfinding errors at stereotypical choice points. These data demonstrate a function for scaffold proteins such as Homer in axon guidance. Homer may facilitate signal transduction from cell-surface receptors to intracellular proteins that govern the establishment of axon trajectories.

Animals↗
PubMed2001

Country report: Australia.

The last 10 years has been an interesting time for Australian medical education despite reduced funding. WORKFORCE: There are five main workforce trends: a rural/urban maldistribution, a need for more specialists, public hospital staffing difficulties, increasing female practitioners and under-representation of indigenous practitioners. ISSUES FACING THE DEANS: Lack of resources is a problem facing Deans, with pressure for clinical service in teaching hospitals. Entrepreneurial activities have been undertaken including the enrollment of overseas students. Medical schools have also responded to important government initiatives. DEVELOPMENTS IN MEDICAL EDUCATION: Australia's 11 medical schools have undergone significant reform in the last decade. There is a mix of four (graduate), five and six year courses. AUSTRALIA'S NEW MEDICAL SCHOOL: James Cook University opened the first medical school in northern Australia in 2000. The School admits students from rural, northern Australian and indigenous backgrounds. It has a strong regional mission. RURAL AND COMMUNITY-BASED EDUCATION: Government funding to address the maldistribution of the workforce has led to the establishment of rural clubs, Departments of Rural Health and community-based programs. THE FIRST TWO POSTGRADUATE YEARS: There have been recent moves to improve education in the two years following graduation. This includes the initiation of national projects in curriculum and assessment. POSTGRADUATE AND CONTINUING MEDICAL EDUCATION: Postgraduate programs in Australia are being reformed to build on the changes in undergraduate education. CME is also under review. CONCLUSION: Australian medical educators should build on the recent reforms and take on some of the new directions in medical education.

Australia↗
PubMed2001

General practice research. Problems and solutions in participant recruitment and retention.

BACKGROUND: Increasing interest in general practice research, especially postal surveys, has been met with decreasing response rates. Prospective, longitudinal surveys pose additional concerns for general practice researchers, one of the major problems being sample attrition after project commencement. OBJECTIVE: This article draws on the authors' experiences from seven studies conducted by them to identify useful strategies for researchers who need to recruit general practitioners and/or their patients, with particular reference to retaining participants across time. A list of issues, lessons learned and possible strategies was developed which, although not exhaustive, probably reflects those commonly encountered in many general practice studies. DISCUSSION: The issues identified here are not necessarily new, but it is useful to revisit such issues and to review and reiterate methods and processes, as even experienced researchers encounter problems from time to time. Studies involving prolonged participation especially, require diligent consideration of likely recruitment/retention problems.

Australia↗
PubMed2000

Presynaptic clustering of mGluR7a requires the PICK1 PDZ domain binding site.

Aggregation of neurotransmitter receptors at pre- and postsynaptic structures is crucial for efficient neuronal communication. In contrast to the wealth of information about postsynaptic specializations, little is known about the molecular organization of presynaptic membrane proteins. We show here that the metabotropic glutamate receptor mGluR7a, which localizes specifically to presynaptic active zones, interacts in vitro and in vivo with PICK1. Coexpression in heterologous systems induces coclustering dependent upon the extreme C terminus of mGluR7a and the PDZ domain of PICK1. mGluR7a and PICK1 localize to excitatory synapses in hippocampal neurons. Furthermore, whereas transfected mGluR7a clusters at presynaptic sites, mGluR7adelta3 lacking the PICK1 binding site targets to axons but does not cluster. These results suggest that PICK1 is a component of the presynaptic machinery involved in mGluR7a aggregation and in modulation of glutamate neurotransmission.

Animals↗
PubMed2000

The parallel rural community curriculum: an integrated clinical curriculum based in rural general practice.

INTRODUCTION: In an attempt to address the rural medical workforce maldistribution and the concurrent inappropriate caseload at the urban tertiary teaching hospitals, Flinders University and the Riverland Division of General Practice decided to pilot, in 1997, an entire year of undergraduate clinical curriculum in Australian rural general practice. This program is called the Parallel Rural Community Curriculum (PRCC). This paper is a discussion of the aims of the programme; student selection; practice recruitment; curriculum structure, and academic content, together with lessons learnt from the evaluation of the first cohort of students' experience of the course. METHODS: Independent external evaluators undertook a thematic analysis of a series of structured interviews of students and faculty involved in both the PRCC and the traditional curriculum. The mean examination results were determined and a rank order comparison of student academic performance was undertaken. RESULTS: The eight selected volunteer students reported greater access to patients and clinical learning opportunities than their mainstream counterparts and learned clinical decision making in the context of the whole patient, their family, and the available community resources. They identified patients with 'core' clinical conditions and had a longitudinal exposure to common diseases, whereas hospital-based peers had a cross-sectional exposure to highly filtered illness. The PRCC students' academic performance improved in comparison with that of their tertiary hospital peers' and in comparison to their own results in previous years. CONCLUSION: The PRCC curriculum has cut across the traditional clinical discipline boundaries by teaching in an integrated way in rural general practice. It has affirmed the potential role of true generalist physicians in undergraduate medical education.

Community Medicine↗
PubMed2000

The activity-regulated cytoskeletal-associated protein arc is expressed in different striosome-matrix patterns following exposure to amphetamine and cocaine.

The activity-regulated, cytoskeletal-associated gene, arc, is a brain-enriched immediate-early gene whose expression is rapidly induced in the striatum by dopamine receptor agonists. This rapid induction of arc in the striatum is similar to that of other early response genes such as c-fos, junB, deltafosB, fra, and NGFI-A, which code for transcription factors. Unlike these proteins, however, Arc is a cytoskeletal protein expressed not only in the nucleus of neurons but also in their dendrites. We investigated the patterns of Arc expression evoked in the rat striatum by acute exposures to two psychomotor stimulants, cocaine and amphetamine. Cocaine induced arc in striatal neurons that were broadly distributed within both striosome and matrix compartments of the caudoputamen. Amphetamine also evoked Arc expression in striatal projection neurons, but these were heavily concentrated in the striosomal compartment and only sparsely in the matrix compartment in the rostral striatum. The contrasting patterns of Arc expression evoked by cocaine and amphetamine parallel those of c-Fos, JunB, FRA, and NGFI-A expression induced by these two psychomotor stimulants. This difference in the action of cocaine and amphetamine at the level of protein expression may be linked to the different effects of these psychomotor stimulants on behavior.

Amphetamine↗
PubMed1999

Importance of AMPA receptors for hippocampal synaptic plasticity but not for spatial learning.

Gene-targeted mice lacking the L-alpha-amino-3-hydroxy-5-methylisoxazole-4-propionate (AMPA) receptor subunit GluR-A exhibited normal development, life expectancy, and fine structure of neuronal dendrites and synapses. In hippocampal CA1 pyramidal neurons, GluR-A-/- mice showed a reduction in functional AMPA receptors, with the remaining receptors preferentially targeted to synapses. Thus, the CA1 soma-patch currents were strongly reduced, but glutamatergic synaptic currents were unaltered; and evoked dendritic and spinous Ca2+ transients, Ca2+-dependent gene activation, and hippocampal field potentials were as in the wild type. In adult GluR-A-/- mice, associative long-term potentiation (LTP) was absent in CA3 to CA1 synapses, but spatial learning in the water maze was not impaired. The results suggest that CA1 hippocampal LTP is controlled by the number or subunit composition of AMPA receptors and show a dichotomy between LTP in CA1 and acquisition of spatial memory.

Action Potentials↗
PubMed1999

Synaptic clustering of AMPA receptors by the extracellular immediate-early gene product Narp.

Narp (neuronal activity-regulated pentraxin) is a secreted immediate-early gene (IEG) regulated by synaptic activity in brain. In this study, we demonstrate that Narp possesses several properties that make it likely to play a key role in excitatory synaptogenesis. Narp is shown to be selectively enriched at excitatory synapses on neurons from both the hippocampus and spinal cord. Overexpression of recombinant Narp increases the number of excitatory but not inhibitory synapses in cultured spinal neurons. In transfected HEK 293T cells, Narp interacts with itself, forming large surface clusters that coaggregate AMPA receptor subunits. Moreover, Narp-expressing HEK 293T cells can induce the aggregation of neuronal AMPA receptors. These studies support a model in which Narp functions as an extracellular aggregating factor for AMPA receptors.

Animals↗
PubMed1998

Identification of a Torpedo homolog of Sam68 that interacts with the synapse organizing protein rapsyn.

Nicotinic acetylcholine receptors (nAChRs) are initially expressed diffusely on the surface of myotubes and, in response to neuronally derived factors, cluster at the endplate to a final concentration of approximately 10000/microm2. The synaptic peripheral membrane protein rapsyn has been shown to mediate clustering of nAChRs in several systems. Here we describe the use of the yeast two-hybrid system to identify proteins that can interact with rapsyn. One of the clones we have identified is a Torpedo californica homolog of the Src-associated in mitosis protein (Sam68). We further show that Sam68, like rapsyn, is localized at the neuromuscular junction.

Amino Acid Sequence↗
PubMed1998

Undergraduate education in anaesthesia: the influence of role models on skills learnt and career choice.

Undergraduate teaching of anaesthesia occurs in about two-thirds of Australian departments of anaesthesia: however, student contact hours are limited compared with those of other disciplines. Seventy-five directors of anaesthesia were surveyed by written questionnaire concerning the time devoted in their department to undergraduate study and teaching of practice/skills to undergraduate students (40 responded). One hundred and sixty final year students were surveyed regarding career choice, anaesthesia skills taught them and role models identified during their training (101 responded). Most final year students had been taught and had learnt the basic skills of life support such as bag and mask ventilation, cardiopulmonary resuscitation and intravenous cannulation. However, fewer were taught more specialized skills such as induction of anaesthesia and spinal anaesthesia. Positive role models in teaching anaesthetists were identified by 66% of students, more commonly if they were taught advanced skills, and were significantly associated with satisfaction with theoretical and practical training. For those students intending a career in anaesthesia (18%), 94% identified a positive role model compared to 65% who did not (P = 0.03).

Anesthesiology↗
PubMed1997

Huntingtin-associated protein 1 (HAP1) interacts with the p150Glued subunit of dynactin.

Huntington's disease (HD) is an inherited neurodegenerative disease caused by expansion of a polyglutamine repeat in the HD protein huntingtin. Huntingtin's localization within the cell includes an association with cytoskeletal elements and vesicles. We previously identified a protein (HAP1) which binds to huntingtin in a glutamine repeat length-dependent manner. We now report that HAP1 interacts with cytoskeletal proteins, namely the p150 Glued subunit of dynactin and the pericentriolar protein PCM-1. Structural predictions indicate that both HAP1 and the interacting proteins have a high probability of forming coiled coils. We examined the interaction of HAP1 with p150 Glued . Binding of HAP1 to p150 Glued (amino acids 879-1150) was confirmed in vitro by binding of p150 Glued to a HAP1-GST fusion protein immobilized on glutathione-Sepharose beads. Also, HAP1 co-immunoprecipitated with p150 Glued from brain extracts, indicating that the interaction occurs in vivo . Like HAP1, p150 Glued is highly expressed in neurons in brain and both proteins are enriched in a nerve terminal vesicle-rich fraction. Double label immunofluorescence experiments in NGF-treated PC12 cells using confocal microscopy revealed that HAP1 and p150 Glued partially co-localize. These results suggest that HAP1 might function as an adaptor protein using coiled coils to mediate interactions among cytoskeletal, vesicular and motor proteins. Thus, HAP1 and huntingtin may play a role in vesicle trafficking within the cell and disruption of this function could contribute to the neuronal dysfunction and death seen in HD.

Animals↗
PubMed1997

Huntingtin-associated protein 1 (HAP1) binds to a Trio-like polypeptide, with a rac1 guanine nucleotide exchange factor domain.

Huntington's disease (HD) occurs when the widely expressed protein huntingtin contains an expanded glutamine repeat. The selective degeneration and neuronal morphologic abnormalities of HD may involve interactions with proteins that bind to huntingtin, such as HAP1. The biological significance of this interaction is unclear because neither HAP1 nor huntingtin have significant homology to known proteins. Therefore, we sought to identify HAP1-binding proteins. Using the yeast two-hybrid system, we isolated a rat cDNA encoding part of a protein that interacts with HAP1, and we confirmed the specificity of this interaction using an in vitro protein-binding assay. We called the protein Duo because it is closely related to the human protein Trio but is shorter. Northern blot analysis indicates brain-specific expression of Duo. Human Duo contains a guanine nucleotide exchange factor (GEF) domain that is likely to be rac1-specific, a pleckstrin homology (PH) domain and spectrin-like repeat units. These data support the hypothesis that huntingtin is involved in vesicle trafficking and cytoskeletal functions, and raise the possibility of a role for huntingtin in the regulation of a ras-related signaling pathway.

Amino Acid Sequence↗
PubMed1997

Secretory leukocyte protease inhibitor (SLPI) in mucosal fluids inhibits HIV-I.

Despite the presence of HIV-1 in the oral cavity, transmission of the virus through saliva has not been proven. Consistent with these observations, we recently identified an endogenous 12 kD protein, secretory leukocyte protease inhibitor (SLPI), in saliva which blocks HIV-1 infection in vitro. Whereas other salivary proteins tested were inactive, purified native or recombinant SLPI inhibited HIV-1 infection of human monocytes at 100 ng ml-1. Levels of SLPI quantitated by ELISA in saliva from control and HIV-1 infected individuals exceeded this level, consistent with in vivo antiviral activity. As in saliva, levels of SLPI mRNA determined by Northern hybridization, and protein as assessed by immunohistochemistry in the salivary glands of control and infected populations were comparable. In contrast to adults, oral transmission occurs in infants, possibly due to their lack of fully developed salivary glands. To determine whether the inadequate antiviral protection might be compensated for by maternal sources, we evaluated breast milk samples obtained 6 months postpartum. Levels of SLPI were significantly lower than in saliva and not sufficient to provide antiviral protection in contrast to colostrum samples in which SLPI levels were equivalent to those in saliva and able to inhibit HIV-1 infection when tested in vitro. These data suggest that breast milk may provide transient antiviral activity in the newborn, but that this maternal source of SLPI is of insufficient duration to maintain protection against mucosal transmission of the virus over time. The high functional levels of SLPI in saliva and the low levels in mature breast milk correlate with negligible rates of HIV-1 transmission by saliva and higher rates by breast feeding.

Adult↗