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Biomedical subjects

Mark Harris

Publications and source records attributed to Mark Harris.

53 records · Page 3Linked to original sources
PubMed2003

The di-leucine motif in the cytoplasmic tail of CD4 is not required for binding to human immunodeficiency virus type 1 Nef, but is critical for CD4 down-modulation.

The human immunodeficiency virus type 1 (HIV-1) nef gene encodes a 205 residue, myristoylated phosphoprotein that has been shown to play a critical role in the replication and pathogenesis of the virus. One of the most studied functions of the Nef protein is the down-modulation of cell surface CD4. Nef has been reported to interact with both the cytoplasmic tail of CD4 and proteins that are components of the endocytic machinery, thereby enhancing the endocytosis of CD4 through clathrin-coated pits. A di-leucine motif in the cytoplasmic tail of CD4 (residues 413/414) was reported to be essential both for Nef mediated down-modulation and for Nef binding. In order to further characterize the involvement of this di-leucine motif in CD4 down-modulation we generated a CD4 mutant in which the leucines were substituted by alanines, termed CD4(LL-AA). We demonstrate here that, contrary to previous data obtained with the cytoplasmic tail of CD4 alone, full-length CD4(LL-AA) bound to Nef both in vivo, in recombinant baculovirus-infected Sf9 cells, and in vitro. In contrast the di-leucine motif was required for both Nef-mediated and phorbol ester-induced CD4 down-modulation, suggesting that the essential requirement for the di-leucine motif in CD4 down-modulation reflects the fact that this motif is needed for the interactions of CD4 with the endocytic machinery, not for the interaction with Nef. We have also exploited the observation that CD4(LL-AA) is refractory to Nef-mediated down-modulation to provide the first experimental evidence for a physical interaction between Nef and CD4 in intact mammalian cells.

Amino Acid Motifs↗
PubMed2003

Reversible metaphyseal dysplasia, a novel bone phenotype, in two unrelated children with autoimmunepolyendocrinopathy-candidiasis-ectodermal dystrophy: clinical and molecular studies.

We report the association of an undescribed, reversible metaphyseal dysplasia (RMD) with autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED) in two patients, one homozygous and one heterozygous for a 13-bp deletion in exon 8 of the autoimmune regulator (AIRE) gene. One patient also had a novel deletion in exon 6, resulting in a frameshift mutation and introduction of a STOP codon in exon 10. Their APECED phenotypes differed, but both patients developed progressive skeletal deformities and growth failure from early childhood. Radiological examination suggested a generalized abnormality of endochondral ossification, with irregular, flared, radioopaque regions in the metaphyses, subjacent to the growth plates. Histopathology in patient 1 showed islands of calcified cartilage within bone, consistent with impaired coupling of cartilage resorption with vascular invasion and ossification. Despite discordance for puberty, both patients experienced radiological resolution of their bone disease in their mid-teens, with improvement in histopathology in patient 1. RMD may constitute a rare phenotypic variation of APECED, possibly resulting from autoimmunity directed against skeletal proteins. We also demonstrated AIRE expression in chondrocytes derived from human fetal growth plates, primary culture of human chondrocytes, and two chondrosarcoma cell lines, suggesting a potential role for abnormal AIRE expression in the development of RMD.

Adult↗
PubMed2003

Prostate cancer.

Explore the source record for details and available documents.

Aged↗
PubMed2002

Randomised controlled trial of home based care of patients with chronic obstructive pulmonary disease.

OBJECTIVES: To evaluate usefulness of limited community based care for patients with chronic obstructive pulmonary disease after discharge from hospital. DESIGN: Randomised controlled trial. SETTING: Liverpool Health Service and Macarthur Health Service in outer metropolitan Sydney between September 1999 and July 2000. PARTICIPANTS: 177 patients randomised into an intervention group (84 patients) and a control group (93 patients) which received current usual care. INTERVENTIONS: Home visits by community nurse at one and four weeks after discharge and preventive general practitioner care. MAIN OUTCOME MEASURES: Frequency of patients' presentation and admission to hospital; changes in patients' disease-specific quality of life, measured with St George's respiratory questionnaire, over three months after discharge; patients' knowledge of illness, self management, and satisfaction with care at discharge and three months later; frequency of general practitioner and nurse visits and their satisfaction with care. RESULTS: Intervention and control groups showed no differences in presentation or admission to hospital or in overall functional status. However, the intervention group improved their activity scores and the control group worsened their symptom scores. While intervention group patients received more visits from community nurses and were more satisfied with their care, involvement of general practitioners was much less (with only 31% (22) remembering receiving a care plan). Patients in the intervention group had higher knowledge scores and were more satisfied. There were no differences in general practitioner visits or management. CONCLUSIONS: This brief intervention after acute care improved patients' knowledge and some aspects of quality of life. However, it failed to prevent presentation and readmission to hospital.

Adult↗
PubMed2002

Xtrack - a web-based crystallographic notebook.

Xtrack is a web-based database-backed crystallographic notebook system that allows groups of workers to keep track of crystallographic project data from the crystallization stage through to data bank deposition. A working demonstration version is available from http://xray.bmc.uu.se/xtrack and the code is available for those who wish to set up their own databases.

Crystallography, X-Ray↗
PubMed2002

Age-related differences in vision and proprioception in a lower limb interceptive task: the effects of skill level and practice.

This study examined age-related differences in the role of visual proprioception during a lower limb interceptive action and how this varies as a function of skill and practice. In Experiment 1, skilled and less-skilled 8-, 10-, and 12-year-old boys controlled a soccer ball using their preferred foot under full vision and when sight of the effector was occluded. With the exception of the high-skilled 12-year-olds and low-skilled 8-year-olds, participants showed a decrement in peformance when denied access to visual proprioception. In Experiment 2, the effect of practicing under different informational constraints was examined for 12 year-old boys. Children performed varying amounts of practice under full vision, or in a condition where sight of the foot was occluded, before being transferred to the alternative viewing condition. Participants who practiced under occluded viewing conditions showed greater relative improvement in performance over practice and transfer sessions compared with a full vision control group. Some support is provided for the manipulation of visual informational constraints as an effective pedagogical approach to motor learning.

Age Factors↗
PubMed2002

Australian GPs are satisfied with their job: even more so in rural areas.

BACKGROUND: Australia has seen a constriction of the scope of practice and of professional prerogatives for GPs in the 1990s, which is said to have led to lower job satisfaction, particularly for rural GPs. OBJECTIVE: The aim of this study was to determine levels of job satisfaction and mental health in a rural and an urban sample of GPs, and to correlate population and practice characteristics with lower job satisfaction and morale. METHODS: A postal survey of GP members of two urban and four rural Divisions of General Practice in New South Wales was carried out using the Wall-Cook-Warr scale and the 12-item General Health Questionnaire (GHQ-12). The overall response rate was 74%. RESULTS: Both urban and rural Australian GPs were generally satisfied with their jobs; however, rural GPs had significantly higher job satisfaction scores. The highest levels of satisfaction were recorded for factors denoting autonomy. The lowest ranked factors were hours of work, income and government policy in general practice. GPs without psychological disturbance were significantly more satisfied with their work than those who were disturbed. Lower job satisfaction was significantly associated with urban GPs, GPs who worked full-time and those who used a language other than English during consultations. Poor mental health and working in an urban area were predictive of lower job satisfaction in men, and bulk-billing all patients (i.e. not charging patients a co-payment, but making a consolidated claim to the government funder Medicare) and working full-time were predictive of lower job satisfaction in women. CONCLUSIONS: Both urban and rural GPs derive a large measure of satisfaction from their job. In particular, rural GPs are satisfied, especially so with their autonomy. Poor mental health was the strongest predictor of lower job satisfaction. The high percentage of GPs with psychological disturbances raises the problem of their access to appropriate mental health services, in particular in rural areas.

Female↗
PubMed2002

Efficient delivery and regulable expression of hepatitis C virus full-length and minigenome constructs in hepatocyte-derived cell lines using baculovirus vectors.

Baculovirus vectors have been used as efficient delivery vehicles for constitutive gene expression in a variety of mammalian cells. We have further developed the system to allow for regulable expression by placing the gene of interest under the control of an inducible promoter, and complementing it with a second baculovirus vector providing the control elements necessary for promoter activity. We have used this system to express (a) the lacZ gene, (b) a 'minigenome' derived from hepatitis C virus (HCV) and carrying lacZ or (c) the full-length HCV viral genome, in human hepatocyte cell lines in an inducible fashion. Control systems that rely on either the absence of tetracycline or presence of ponasterone to induce gene expression were tested. Expression of lacZ was controlled by ponasterone, but beta-galactosidase activity was limited to 10-20% of cells. In contrast, the tetracycline-controlled expression system gave a low basal activity and was highly inducible in almost 100% of cells. Inducible expression was also obtained in almost 100% of cells infected with baculoviruses in which an HCV minigenome was placed downstream of the tetracycline-inducible promoter and upstream of either a hammerhead or hepatitis delta virus ribozyme. Northern blot analysis was consistent with accurate cleavage of the minigenome transcript by the hepatitis delta virus ribozyme. Finally, regulable transcript production and viral polypeptide processing could be demonstrated in HepG2 cells infected with baculoviruses bearing the full-length HCV genome. This system thus provides a novel tool for the analysis of HCV replication and host-cell interactions.

Animals↗
PubMed2002

Research capacity in general practice. Opinions from the field.

BACKGROUND: The Primary Health Care Research Evaluation and Development (PHCRED) Strategy includes funding for universities to build research capacity. As part of its implementation, the University of NSW consulted widely with Divisions of General Practice, GPs and representatives from Community Health Services to determine current research capacity. OBJECTIVE: We summarise the results of this consultation, and outline implications for the PHCRED Strategy. DISCUSSION: Divisions reported low research capacity, and welcomed the opportunity to develop it further. GPs with an interest in research were particularly focused on clinical areas, and saw their role in providing patients and collecting data, rather than initiating and developing ideas. Workers in Community Health Services were keen to be involved. There was considerable support and enthusiasm for the concept of capacity building and the activities proposed, despite perceived low levels of research skills. The overall aim of the PHC-RED Strategy may need to be clarified to successfully build on this enthusiasm.

Attitude of Health Personnel↗
PubMed2002

Paget's disease of bone in an Indian patient: genetic and environmental factors.

Epidemiologic data have shown that Paget's disease of bone is common among people of Anglo-Saxon descent, but it is believed to be rare in India and Asia. The worldwide prevalence of the disease shows pronounced geographic and ethnic heterogeneity, and can vary in populations through migration or loss of geographic isolation. The risk to an individual who changes geographic locations, however, is difficult to quantify because the specific genetic or environmental factors responsible for Paget's disease have yet to be completely determined. We describe a case of monostotic Paget's disease in a 59-year-old Asian Indian man, and consider the potential epidemiologic and etiologic influences (moving to an area of higher disease prevalence, role of genetics, viral exposures) that may have increased his risk for the disorder. The patient presented with several months of right anterior leg pain, and was found on examination to have anterior bowing of the tibia as well as warmth and an audible bruit. Radiographs of the tibia demonstrated a V-shaped lucency, enhanced trabecular pattern, and cortical thickening. Whole-body bone scan confirmed monostotic disease with expansile uptake in the tibia, and laboratory data revealed an elevated urinary collagen N-telopeptide that normalized after bisphosphonate treatment, as did his clinical symptoms. In light of the environmental factors that appear significantly to influence the development of Paget's disease, the diagnosis should be considered in patients traditionally considered at low risk for the disorder.

Journal Article↗
PubMed2001

The inhibition of cAMP-dependent protein kinase by full-length hepatitis C virus NS3/4A complex is due to ATP hydrolysis.

Hepatitis C virus (HCV) is an important cause of chronic liver disease, but the molecular mechanisms of viral pathogenesis remain to be established. The HCV non-structural protein NS3 complexes with NS4A and has three enzymatic activities: a proteinase and a helicase/NTPase. Recently, catalytically inactive NS3 fragments containing an arginine-rich motif have been reported to interact with, and inhibit, the catalytic subunit of cAMP-dependent protein kinase (PKA C-subunit). Here we demonstrate that full-length, catalytically active NS3/4A, purified from recombinant baculovirus-infected insect cells, is also able to inhibit PKA C-subunit in vitro. This inhibition was abrogated by mutation of either the arginine-rich motif or the conserved helicase motif II, both of which also abolished NTPase activity. As PKA C-subunit inhibition was also enhanced by poly(U) (an activator of NS3 NTPase activity), we hypothesized that PKA C-subunit inhibition could be due to NS3/4A-mediated ATP hydrolysis. This was confirmed by experiments in which a constant ATP concentration was maintained by addition of an ATP regeneration system--under these conditions PKA C-subunit inhibition was not observed. Interestingly, the mutations also abrogated the ability of wild-type NS3/4A to inhibit the PKA-regulated transcription factor CREB in transiently transfected hepatoma cells. Our data are thus not consistent with the previously proposed model in which the arginine-rich motif of NS3 was suggested to act as a pseudosubstrate inhibitor of PKA C-subunit. However, in vivo effects of NS3/4A suggest that ATPase activity may play a role in viral pathology in the infected liver.

Adenosine Triphosphate↗
PubMedDate not supplied

Identifying soil cleanup criteria for dioxins in urban residential soils: how have 20 years of research and risk assessment experience affected the analysis?

This article reviews the scientific evidence and methodologies that have been used to assess the risks posed by 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) and presents a probabilistic analysis for identifying virtually safe concentrations of TCDD toxicity equivalents (TEQ) in residential soils. Updated data distributions that consider state-of-the-science cancer and noncancer toxicity criteria, child soil ingestion and dermal uptake, bioavailability in soil, and residential exposure duration are incorporated. The probabilistic analysis shows that the most sensitive determinants of dose and risk are childhood soil ingestion, exposure duration, and the selected TCDD cancer potency factor. It also shows that the cancer risk at 1 per 100,000 predicted more conservative (lower) soil criteria values than did the noncancer hazard (e.g., developmental and reproductive effects). In this analysis, acceptable or tolerable soil dioxin concentrations (TCDD TEQ) ranged from 0.4 to 5.5 ppb at the 95th percentile for cancer potency factors from 9600 to 156,000 (mg/kg/d)(-1) with site-specific adjustments not included. Various possible soil guidelines based on cancer and noncancer risks are presented and discussed. In the main, the current toxicology, epidemiology, and exposure assessment data indicate that the historical 1 ppb TEQ soil guidance value remains a reasonable screening value for most residential sites. This analysis provides risk managers with a thorough and transparent methodology, as well as a comprehensive information base, for making informed decisions about selecting soil cleanup values for PCDD/Fs in urban residential settings.

Biological Availability↗
PubMedDate not supplied

Preceptors' perspectives on benefits of precepting student pharmacists to students, preceptors, and the profession.

OBJECTIVES: To educate pharmacists on the shortage of quality preceptors and the benefits received from precepting; present insights from successful preceptors and offer guidance to current and prospective preceptors; and encourage pharmacists to become preceptors and mentor aspiring pharmacy professionals. SETTING: Advanced experiential settings for Nova Southeastern, Ohio Northern, and Creighton Universities. PRACTICE DESCRIPTIONS: Hospital, community, and outpatient clinic settings. PRACTICE INNOVATION: Successful incorporation of student pharmacists and the experiential process into pharmacy practice. MAIN OUTCOME MEASURE: Not applicable. RESULTS: A variety of factors has produced an increased demand for qualified pharmacist preceptors, including workload issues, an increasing number of pharmacy schools, and an increased experiential load in the pharmacy school curricula. Characteristics of quality preceptors include demonstrating enthusiasm in their teaching, being open to questions, and providing constructive feedback. Sites and preceptors can benefit from teaching student pharmacists by receiving assistance in developing and maintaining clinical services, sensing the satisfaction of giving back to the profession, and material rewards provided by schools of pharmacy. In this article, three successful preceptors share their perspectives and insights about precepting, and a professional organization perspective is included to highlight the support for precepting student pharmacists. CONCLUSION: Additional introductory and advanced quality pharmacy experiential practice sites are needed, and pharmacists are encouraged to contact nearby pharmacy schools to become preceptors.

Attitude of Health Personnel↗
PubMedDate not supplied

Health inequalities in general practice.

The higher burden of disease associated with low socioeconomic status is an every day challenge faced in general practice. General practitioners can make an important difference to these inequalities in health by being aware of the importance of patients socioeconomic background, identifying groups of disadvantaged patients in their practice population and targeting efforts to improve preventive care coverage and quality chronic disease management to those groups. Divisions are important to this work. The profession also has an important role in advocating on behalf of disadvantaged communities, and joining with other health workers and professions in doing so.

Australia↗