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Biomedical subjects

Andrew Campbell

Publications and source records attributed to Andrew Campbell.

16 recordsLinked to original sources
PubMed2007

Perceptions and behaviour of access of the Internet: a study of women attending a breast screening service in Sydney, Australia.

OBJECTIVES: To describe the perceptions and behaviour in accessing health information from the Internet by women attending a BreastScreen, New South Wales (NSW) Service in Northern Sydney. DESIGN: Cross-sectional study. SETTING: A BreastScreen NSW Service in Northern Sydney. MAIN OUTCOME MEASURES: Behaviour and perceptions of accessing of the Internet for breast health and screening information and other related health information. PARTICIPANTS: Four hundred and fifteen women aged > or =40 years who had a screening mammogram at a BreastScreen NSW Service in Northern Sydney. Data were collected from 1 October to 22 December 2004 (study interval). RESULTS: Four hundred and sixty-one eligible women were invited to participate in the study and of these 415 women agreed to participate in the study (participation rate=90%). Of the 415 women enrolled in the cohort, 80% (333/415) of women accessed the Internet in general and 62% (205/333) of the women who accessed the Internet also accessed health related information from the Internet, but only 7% of the total women accessed breast health and screening information from the Internet. Two hundred and eighty (70%) women in the cohort expressed their intention to access the Internet if they were diagnosed with breast cancer. Age (OR=0.94; 95% CI=0.91-0.97), marital status (OR=2.65; 95% CI=1.45-4.83), educational status (OR=3.26; 95% CI=1.77-6.02) and behavioural intention of accessing the Internet if diagnosed with breast cancer (OR=3.31; 95% CI=1.83-5.98) were found to be associated with access of Internet for general information. Furthermore, behavioural intention (OR=2.43; 95% CI=1.30-4.55), rating of computer skills as 'average' (OR=0.42; 95% CI=0.22-0.79) and 'not good to poor' (OR=0.23; 95% CI=0.11-0.49) were found to be associated with access of health related information from the Internet. CONCLUSIONS: Information searching from the Internet is common among women having a screening mammogram. There is potential to provide guidance to women regarding accessing the BreastScreen NSW website and other reliable sources of Internet information on breast health, breast screening and cancer-related information.

Aged↗
PubMed2006

Characterization of a monoclonal antibody with specificity for holo-transcobalamin.

BACKGROUND: Holotranscobalamin, cobalamin-saturated transcobalamin, is the minor fraction of circulating cobalamin (vitamin B12), which is available for cellular uptake and hence is physiologically relevant. Currently, no method allows simple, direct quantification of holotranscobalamin. We now report on the identification and characterization of a monoclonal antibody with a unique specificity for holotranscobalamin. METHODS: The specificity and affinity of the monoclonal antibodies were determined using surface plasmon resonance and recombinant transcobalamin as well as by immobilizing the antibodies on magnetic microspheres and using native transcobalamin in serum. The epitope of the holotranscobalamin specific antibody was identified using phage display and comparison to a de novo generated three-dimensional model of transcobalamin using the program Rosetta. A direct assay for holotrnscobalamin in the ELISA format was developed using the specific antibody and compared to the commercial assay HoloTC RIA. RESULTS: An antibody exhibiting >100-fold specificity for holotranscobalamin over apotranscobalamin was identified. The affinity but not the specificity varied inversely with ionic strength and pH, indicating importance of electrostatic interactions. The epitope was discontinuous and epitope mapping of the antibody by phage display identified two similar motifs with no direct sequence similarity to transcobalamin. A comparison of the motifs with a de novo generated three-dimensional model of transcobalamin identified two structures in the N-terminal part of transcobalamin that resembled the motif. Using this antibody an ELISA based prototype assay was developed and compared to the only available commercial assay for measuring holotranscobalamin, HoloTC RIA. CONCLUSION: The identified antibody possesses a unique specificity for holotranscobalamin and can be used to develop a direct assay for the quantification of holotranscobalamin.

Journal Article↗
PubMed2006

Can the semiempirical PM3 scheme describe iron-containing bioinorganic molecules?

A set of iron parameters for use in the semiempirical PM3 method have been developed to allow the structure and redox properties of the active sites of iron-containing proteins to be accurately modeled, focussing on iron-sulfur, iron-heme, and iron-only hydrogenases. Data computed at the B3LYP/6-31G* level for a training set of 60 representative complexes have been employed. A gradient-based optimization algorithm has been used, and important modifications of the core repulsion function have been highlighted. The derived parameters lead in general to good predictions of the structure and energetics of molecules both within and outside the training set, and overcome the extensive deficiencies of a B3LYP/STO-3G model. Particularly encouraging is the success of the parameters in describing [4Fe-4S] cubanes. The derived parameter set provides a starting point should greater accuracy for a more restricted range of compounds be required.

Hydrogenase↗
PubMed2005

Combined use of the JAK3 inhibitor CP-690,550 with mycophenolate mofetil to prevent kidney allograft rejection in nonhuman primates.

BACKGROUND: Immunosuppression via Janus kinase (JAK) 3 inhibition affords significant prolongation of allograft survival. We investigated the effects of an immunosuppressive regimen combining the JAK3 inhibitor CP-690,550 with mycophenolate mofetil (MMF) in nonhuman primates (NHPs). METHODS: Life-supporting kidney transplantations were performed between ABO-compatible, MLR-mismatched NHPs. Animals were treated orally twice a day with CP-690,550 and MMF (n=8) or MMF alone (n=2) and were euthanized at day 90 or earlier due to allograft rejection. RESULTS: Mean survival time (+/-SEM) in animals treated with MMF alone (23+/-1 days) was significantly extended in animals that concurrently received CP-690,550 (59.5+/-9.8 days, P=0.02). Combination animals exposed to higher levels of CP-690,550 had a significantly better survival (75.2+/-8.7 days) than animals that received less CP-690,550 (33.3+/-12.6 days, P=0.02). Three combination therapy animals were euthanized at day 90 with a subnormal renal function and early-stage acute graft rejection. Rejection, delayed by treatment, ultimately developed in other animals. Anemia and gastrointestinal intolerance was seen in combination therapy animals that otherwise did not show evidence of viral or bacterial infection besides signs consistent with subclinical pyelonephritis (n=3). One incidental lymphosarcoma was noted. CONCLUSIONS: Addition of CP-690,550 to MMF significantly improved allograft survival. The observed side effects appear amenable to improvements upon alteration of dosing strategies. Efficacy of this combination regimen suggests that it could become the backbone of calcineurin inhibitor-free regimens.

Animals↗
PubMed2005

Allogeneic and syngeneic hematopoietic cell transplantation in patients with amyloid light-chain amyloidosis: a report from the European Group for Blood and Marrow Transplantation.

Using the European Group for Blood and Marrow Transplantation (EBMT) registry, we retrospectively studied 19 patients with AL (amyloid light-chain) amyloidosis who underwent allogeneic (allo; n = 15) or syngeneic (syn; n = 4) hematopoietic stem cell transplantation (SCT) between 1991 and 2003. For allo-SCT, full-intensity conditioning was used in 7 patients and reduced-intensity conditioning (RIC) in 8 patients. Engraftment was durable in 12 of those 15 patients. The median follow-up time is 19 months. Kaplan-Meier probabilities of overall and progression-free survival were 60% and 53% at 1 year, respectively. Overall, 40% of patients died of transplant-related mortality (TRM). Best hematologic response after SCT was complete remission (CR) and partial remission (PR) in 8 and 2 patients, respectively, leading to an organ response in 8 of these patients. Seven of the 10 patients in remission are long-term survivors. In 5 of 7 evaluable patients in CR, chronic graft-versus-host disease (GvHD) was observed, indicating the contribution of immune effects to disease control. The main clinical problem was cardiac failure in patients with poor performance status due to amyloidosis or in combination with severe infections. These data suggest that allo-SCT might be a promising and potentially curative treatment modality for selected patients with AL amyloidosis.

Adult↗
PubMed2005

Effects of JAK3 inhibition with CP-690,550 on immune cell populations and their functions in nonhuman primate recipients of kidney allografts.

BACKGROUND: Janus Kinase (JAK) 3 is a tyrosine kinase essential for proper signal transduction downstream of selected cytokine receptors and for robust T-cell and natural killer cells activation and function. JAK3 inhibition with CP-690,550 prevents acute allograft rejection. To provide further insight into the mechanisms of efficacy, we investigated the immunomodulatory effects of CP-690,550 in vitro and in vivo in nonhuman primates. METHODS: Pharmacodynamic assessments of lymphocyte activation, function, proliferation and phenotype were performed in three settings: in vitro in whole blood isolated from untransplanted cynomolgus monkeys (cynos), in vivo in blood from untransplanted cynos dosed with CP-690,550 for 8 days, and in vivo in blood from transplanted cynos immunosuppressed with CP-690,550. Cell surface activation markers expression, IL-2- enhanced IFN-gamma production, lymphocyte proliferation and immune cell phenotype analyzes were performed with multiparametric flow cytometry. RESULTS: In vitro exposure to CP-690,550 resulted in significant reduction of IL-2-enhanced IFN-gamma production by T-cells (maximum inhibition of 55-63%), T-cell surface expression of CD25 (50% inhibitory concentration (IC50); 0.18 microM) and CD71 (IC50; 1.6 microM), and T-cell proliferative capacities measured by proliferating cell nuclear antigen expression (IC50; 0.87 microM). Similar results were observed in animals dosed with CP-690,550. In addition, transplanted animals displayed significant reduction of NK cell (90% from baseline) and T-cell numbers whereas CD8 effector memory T-cell populations were unaffected. CONCLUSIONS: Potent in vitro and in vivo immunomodulatory effects of the JAK3 inhibitor CP-690,550 likely contribute to its efficacy in the prevention of organ allograft rejection.

Animals↗
PubMed2005

Immunosuppression by the JAK3 inhibitor CP-690,550 delays rejection and significantly prolongs kidney allograft survival in nonhuman primates.

BACKGROUND: Janus kinase 3 (JAK3) mediates signal transduction from cytokine receptors using the common chain (gammac). Because mutations in genes encoding gammac or JAK3 result in immunodeficiency, we investigated the potential of a rationally designed inhibitor of JAK3, CP-690,550, to prevent renal allograft rejection in nonhuman primates. METHODS: Life-supporting kidney transplantations were performed between mixed leukocyte reaction-mismatched, ABO blood group-matched cynomolgus monkeys. Animals were treated with CP-690,550 (n = 18) or its vehicle (controls, n = 3) and were euthanized at day 90 or earlier if there was allograft rejection. RESULTS: Mean survival time (+/- standard error of mean) in animals treated with CP-690,550 (53 +/- 7 days) was significantly longer than in control animals (7 +/- 1 days, P=0.0003) and was positively correlated with exposure to the drug (r = 0.79, P < 0.01). Four treated animals were euthanized at 90 days with a normal renal function and low-grade rejection at final pathology. Occurrence of rejection was significantly delayed in treated animals (46 +/- 7 days from transplantation vs. 7 +/- 1 days in controls, P = 0.0003). Persistent anemia, polyoma virus-like nephritis (n = 2), and urinary calcium carbonate accretions (n = 3) were seen in animals with high exposure. Natural killer cell and CD4 and CD8 T-cell numbers were significantly reduced in treated animals. Blood glucose, serum lipid levels, and arterial blood pressure were within normal range in treated animals, and no cancers were demonstrated. CONCLUSIONS: CP-690,550 is the first reported JAK3 inhibitor combining efficacy and good tolerability in a preclinical model of allotransplantation in nonhuman primates and thus has interesting potential for immunosuppression in humans.

Administration, Oral↗
PubMed2005

Quantitative analysis of the immunosuppressant CP-690,550 in whole blood by column-switching high-performance liquid chromatography and mass spectrometry detection.

A fast and accurate method to quantify the new immunosuppressive JAK3 inhibitor CP-690,550 in whole blood using a dual-pump liquid chromatography-liquid chromatography-mass spectrometry (LC/LC-MS) system was developed and validated in nonhuman primate blood. Before injection, blood samples were prepared by precipitation with a reagent that included methanol and acetonitrile (30:70, vol/vol) along with the internal standard (CP-istd). Column-switching LC/LC-MS analysis used online extraction followed by separation on a C8 analytic column and MS detection of the [M + H] CP-690,550 (m/z = 313.1) and CP internal standard (m/z = 288.1). Linearity was always better than r = 0.99 (n = 7) for CP-690,550 (range 2.5-750 ng/mL), with a lower limit of quantification (LLOQ) of 2.5 ng/mL. The intrarun accuracy and precision ranged from 103.0% to 105.4% and 2.7% to 4.3%, respectively (n = 5), and the interday precision ranged from 8.7% to 11.1%, and the interday accuracy ranged from 98.1% to 103.8% of nominal values (n = 14). The injection repeatability for the method was 1.3% (n = 7). Except for the LLOQ, the intraday accuracy and precision in human blood were also within 15% (n = 5). The combination of simple sample preparation and short analytic run time of this sensitive procedure makes it effective for monitoring the concentration of CP-690,550 in whole blood in organ-transplant recipients.

Animals↗
PubMed2005

Effect of 99mTc-MDP administration on dual-energy X-ray absorptiometry bone mineral density measurements.

The effect of a diagnostic dose of (99m)Tc-MDP on bone mineral density (BMD) estimations in the lumbar spine and the neck of femur was assessed in 20 patients using a Hologic QDR4500 scanner. Each patient underwent a DXA assessment prior to and 1 h following injection of (99m)Tc-MDP (mean dose-910 MBq). For comparative purposes, the precision of BMD estimation without the presence of a radioisotope was assessed by performing two sequential DXA studies on 30 volunteers and was found to be less than 0.01 g/cm(2). No significant change in BMD reading was detected following (99m)Tc-MDP injection for either measurement site and the precision of the readings was similar to that observed for the 30 volunteers. This study has shown that any effect produced by a typical bone scan dose of (99m)Tc-MDP is small in comparison with the intrasubject variance when estimating BMD using a Hologic QDR4500 scanner.

Absorptiometry, Photon↗
PubMed2004

Preparation of aqueous gel beads coated by lipid bilayers.

Novel giant liposome microcapsules have been fabricated based on aqueous gel cores encapsulated with a lipid bilayer. The method involves templating of lipid-stabilised water-in-oil emulsions after gelling the aqueous phase with a suitable hydrocolloid.

Capsules↗
PubMed2003

Low molecular weight heparin and unfractionated heparin are both effective at accelerating pulmonary vascular maturation in neonatal rabbits.

BACKGROUND: Creation of a bi-directional cavopulmonary shunt after the Norwood procedure for hypoplastic left heart syndrome is delayed to allow pulmonary vascular resistance to fall with maturation of the pulmonary vascular bed. We hypothesized that unfractionated heparin (UFH) and low molecular weight heparin (LMWH), which promote angiogenesis and inhibit smooth muscle cell growth, could accelerate this process. METHODS AND RESULTS: Fifty-six newborn rabbits were randomly selected to receive UFH 225U/kg (n=12), LMWH 1 mg/kg (n=14), LMWH 10 mg/kg (n=16), or saline (n=14) by subcutaneous injection every 12 hours for 14 days. Treatment with heparin reduced mean pulmonary artery (PA) pressure by 12% to 16% relative to controls [9.0+/-0.2 (UFH), 9.4+/-0.1 (LMWH 1 mg/kg), 9.2+/-0.2 (LMWH 10 mg/kg) versus 10.7+/-0.2 mm Hg (saline), P=0.0001]. Lower PA pressures were associated with reduced alveolar:arterial ratio consistent with enhanced pulmonary angiogenesis in heparin treated animals [8+/-1 (UFH), 13+/-2 (LMWH 1 mg/kg), 12+/-2 (LMWH 10 mg/kg) versus 23+/-5 (saline), P<0.03]. Reduced PA medial wall thickness and muscularization, two additional features of pulmonary vascular maturation, were also more evident in heparin treated animals. Mean PA pressures in 14-day-old rabbits treated with heparin were lower than those measured in control rabbits less than 7 weeks of age suggesting that heparin shortens the pulmonary vascular maturation process by over 60%. CONCLUSIONS: These results indicate that both UFH and LMWH are effective at accelerating pulmonary vascular maturation in newborn rabbits. This raises the possibility that administration of heparin to children after the Norwood procedure might allow for earlier conversion to a bi-directional cavopulmonary shunt.

Animals↗
PubMed2003

Retroaortic innominate vein with coarctation of the aorta: surgical repair and embryology review.

A newborn girl with a retroaortic innominate vein, coarctation of the aorta, ventricular septal defect, and subaortic stenosis underwent a complete repair at 8 days of age. The ascending aorta was transected and the innominate vein was brought in front of it. We review the anatomy and embryology of this rare entity and describe the surgical technique to avoid recoarctation and innomante vein compression.

Anastomosis, Surgical↗
PubMed2003

Translocation (11;15;19): a highly specific chromosome rearrangement associated with poorly differentiated thymic carcinoma in young patients.

Thymic carcinoma is a rare epithelial neoplasm of the thymus. The presence of a specific chromosomal abnormality may augment diagnosis and therapeutic stratification. We report a 15-year-old boy diagnosed with thymic carcinoma who presented with a large anterior mediastinal mass, pleural effusion, and bone metastasis. The pleural fluid, cytology, bony lesions, and bone marrow were examined and chromosomal studies were performed. Histologic and immunohistochemical studies confirmed a poorly differentiated squamous cell type of thymic carcinoma. The karyotype of the pleural fluid at the time of diagnosis revealed a complex three-way translocation t(11;15;19)(p15;q12;p13.3). The constitutional karyotype was 46,XY. Five months after diagnosis, a bone marrow aspirate demonstrated tetraploidy with all translocation chromosomes in duplicate, as well as an unbalanced rearrangement involving chromosome 1: 92,XXYY,t(11;15;19)(p15;q12;p13.3)x2[15]/92,XXYY,idem,add(1)(qter)[5]. Despite aggressive multiagent chemotherapy, the patient's condition progressed with bone marrow disease and he died 6 months after diagnosis. Several case reports of a similar chromosomal abnormality have been reported for thymic carcinoma in young patients with poor outcome. This karyotypic abnormality appears to mark a cohort of patients with thymic carcinoma who have a poor prognosis despite aggressive chemotherapy.

Adolescent↗
PubMed2002

Do you have a well-designed organization?

For most companies, organization design is neither a science nor an art; it's an oxymoron. Organizational structures evolve in fits and starts, shaped more by politics than by policies. Although most executives can sense when their organization designs are not working well, few take meaningful action, partly because they lack a practical framework to guide them. The authors of this article provide just such a framework; they present nine tests that can be used to either evaluate an existing organization design or create a new one. Four "fit" tests offer an initial screen: The market advantage test asks whether a design directs sufficient management attention to the company's sources of competitive advantage; the parenting advantage test determines whether the design gives enough attention to the corporate-level activities that provide real value to the company; the people test shows whether the design reflects the employees' strengths; and the feasibility test looks at constraints that may impede implementation. Five "good design" tests can help a company refine its prospective design. The specialist cultures test ensures that there's sufficient insulation for units that need to be different from the prevailing culture; the difficult-links test determines whether a design offers solutions for potentially problematic unit-to-unit links; the redundant-hierarchy test asks whether the design has too many parent levels; the accountability test looks at whether every unit has suitable controls; and the flexibility test ensures that the design lets the company adapt to change. Once a design is altered, the tests should be repeated. Organizational decisions are inevitably complex, and tweaking one part of the design may produce unanticipated consequences elsewhere.

Commerce↗