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Biomedical subjects

T O'Brien

Publications and source records attributed to T O'Brien.

At least 19 recordsLinked to original sources
PubMed2006

Effect of gene delivery of NOS isoforms on intimal hyperplasia and endothelial regeneration after balloon injury.

Endothelial cell loss is a critical event in the pathological repair of the injured blood vessel. Impaired endothelial function results in reduced production of key vascular mediators such as nitric oxide (NO) within the vessel wall leading to enhanced smooth muscle cell proliferation and migration and ultimately intimal hyperplasia. The aim of the present study was to directly compare the effects of adenoviral-mediated gene delivery of two nitric oxide synthase (NOS) isoforms, eNOS and iNOS on endothelial regeneration and intimal hyperplasia following endothelial injury in the rabbit carotid artery. The right carotid arteries of male New Zealand white rabbits were denuded by passing a 3French Fogarty balloon catheter along the artery three times. In all, 1 x 10(9) PFU of adenoviral(Ad)eNOS, AdiNOS or Adbeta-galactosidase (Adbeta-Gal) was then delivered intraluminally and allowed to dwell for 20 min. Transgene expression was sought after 3 days by immunohistochemistry and at 7 days by quantitative reverse transcriptase PCR. The effect on intimal hyperplasia was sought using histological staining after 14 days. Evans blue staining was used to determine the effect on endothelial regeneration. eNOS and iNOS expression was detected in transduced arteries. Neointima/media ratios were significantly reduced in eNOS (0.07+/-0.044) and iNOS (0.087+/-0.086) transduced arteries compared with Adbeta-Gal (0.332+/-0.14) transduced arteries (n=7). In addition, AdeNOS treatment (4.21+/-3.12% de-endothelialized area) enhanced endothelial regeneration compared to Adbeta-Gal treatment (10.05+/-4.98), while treatment with AdiNOS (25.17+/-11.92) inhibited endothelial regeneration in the injured rabbit carotid artery (n=7-8). These results highlight the potential of NOS gene therapy, in particular, eNOS gene therapy as a potential therapeutic strategy for the prevention of restenosis after vascular injury.

Adenoviridae↗
PubMed2006

Factors associated with pelvic retraction during gait in cerebral palsy.

Clinical and dynamic (gait-related) measures thought to be associated with pelvic retraction were investigated in patients with cerebral palsy. Gait laboratory data of 233 patients with cerebral palsy were studied retrospectively. Two groups were selected; those who demonstrated pelvic retraction during gait <-6.85 degrees (mean - 2 standard deviations from normal (n=88) and those with >-4.83 degrees (mean - 1 standard deviation from normal) (n=101). About 37.8% of the total population reviewed showed pelvic retraction of <-6.85 degrees . There was a higher prevalence of retraction among hemiplegics (46.3%) compared to diplegics (30.4%). Differences were also found between hemiplegic and diplegic subjects in terms of factors associated with pelvic retraction. Clinical and dynamic tightness of the gastro-soleus were the most significant features associated with pelvic retraction among hemiplegic subjects. Clinical and dynamic flexion and internal rotation of the hip were the most significant features associated with retraction in the diplegic population. This study suggests that pelvic retraction is multifactorial in origin and secondary to both static clinical measures as well as dynamic features during gait.

Adolescent↗
PubMed2006

Vitamin D insufficiency in older female community-dwelling acute hospital admissions and the response to supplementation.

OBJECTIVES: A significant proportion of the older population may exhibit vitamin D insufficiency. We sought to establish the proportion of 25-hydroxyvitamin D (25OHD) insufficient individuals in an older female cohort presenting for acute medical admission and how they responded to supplementation. DESIGN: A prospective cohort study. SETTING: Hospital admissions followed up as a population-based study. SUBJECTS: A total of 114 consecutive female acute medical admissions aged over 65 years from November 2003 to January 2004 were enrolled. All admissions with hypercalcaemia, metabolic bone disease (other than osteoporosis/osteomalacia) and creatinine > 150 micromol/l were excluded. INTERVENTIONS: iPTH, calcium and 25OHD levels were measured in each patient. Of the total, 22 were already receiving calcium and vitamin D supplementation at enrolment. The remaining 92 were commenced on 800 IU of vitamin D and 1 g calcium, and levels were reassessed after supplementation for 3 months. RESULTS: 25-Hydroxyvitamin D insufficiency, as defined by a 25OHD concentration of < 50 nmol/l, was present in 86 (75.4%) patients at initial assessment (mean 35.8 nmol/l, s.d. 23.3). Secondary hyperparathyroidism was present in only 36.7% of those with 25OHD deficiency at baseline. Of the total, 51 (44.7%) patients presented for follow-up. 25-Hydroxyvitamin D concentration increased in this group from 42.1 nmol/l (s.d. 26.6) to 59.5 nmol/l (s.d. 27.4) after supplementation, P < 0.001, but 18(35.3%) still remained deficient. There was no significant change in iPTH or calcium following supplementation. Assessment of compliance revealed 6 (11.7%) admitted to partial or non-compliance. CONCLUSIONS: Insufficiency of 25OHD was very common in this cohort. Despite calcium and vitamin D supplementation, 25OHD concentrations failed to reach normality in a significant proportion. Maintaining vitamin D and calcium intake at the level of current recommended doses may not be sufficient to ensure adequate 25OHD stores.

Aged↗
PubMed2006

Gene transfer into rat mesenchymal stem cells: a comparative study of viral and nonviral vectors.

Mesenchymal stem cells (MSCs) have been proposed for use in combinatorial gene and cell therapy protocols for the treatment of disease and promotion of repair. The efficacy of such a therapeutic approach depends on determination of which vectors give maximal transgene expression with minimal cell death. The study was carried out on bone-marrow derived rat MSCs, and a range of vectors was tested on the same stem cell preparation. Adenovirus, adeno-associated virus (AAV; serotypes 1, 2, 4, 5, and 6), lentivirus, and nonviral vectors were compared. Lentivirus proved to be most effective with transduction efficiencies of up to 95%, concurrent with low levels of cell toxicity. Adenovirus also proved effective, but a significant increase in cell death was seen with increasing viral titer. Rat MSCs remained refractory to transduction by all AAV serotypes, in contrast to rabbit MSCs tested at the same time. Lipofection of plasmid DNA gave moderate transfection levels but was also accompanied by cell death. Electroporative gene transfer proved ineffective at the parameters tested and resulted in high cell death. High and moderate levels of cell transduction using lentivirus vectors did not affect the ability of the cells to differentiate down the adipogenic pathway.

Adenoviridae↗
PubMed2006

Adolescent and young adult cancer: a revolution in evolution?

The optimal management of adolescent and young adult cancer has been the subject of vigorous debate in paediatric and adult cancer community for many years. This debate is rapidly coming to the boil. There is international recognition that not only is cancer in young people on the rise but also that improvements in outcomes of cancer in young people lag well behind the advances that have been achieved for both children and older adults in the past 30 years. The underlying problems appear to relate to a complex set of interactions between the health-care system and the prevalence of cancer in this age group and the unique psychosocial and educational needs of this population. This article explores why we should be concerned about Australian health outcomes in this group and considers how best we might respond to these concerns.

Adolescent↗
PubMed2005

Altering end-to-side anastomosis junction hemodynamics: the effects of flow-splitting.

The long-term patency rate of peripheral artery bypass grafts remains low. Several theories exist which attempt to explain the disease forming mechanisms at the disease prone distal junction of the bypass graft. Common to these theories is that abnormal hemodynamics and wall mechanics contribute to the development of disease at the junction. This study describes a means by which the hemodynamics in the end-to-side anastomosis can be altered by inserting a flow-split into the junction, the function of which is to divert the flow away from the artery bed and toward the sidewalls. Velocity vectors through the junction are significantly altered, and artery centreline WSS magnitudes decrease by up to 36% during the deceleration phase of the flow pulse. Corresponding wall shear stress gradients are found to decrease by 49%. However, locations along the artery sidewall have been identified with increased WSS. It is possible to significantly alter junction hemodynamics using a flow-splitter.

Anastomosis, Surgical↗
PubMed2005

Purification of adenovirus and adeno-associated virus: comparison of novel membrane-based technology to conventional techniques.

Adenovirus (Ad) and Adeno-associated virus (AAV) are efficient gene delivery systems; manipulation of the wild-type genome allows their use as vectors for the overexpression of desirable transgenes. Generation and purification of such viral vectors can be labour intensive, costly and require specialized equipment, but a new generation of membrane-mediated ion exchange kits for purification of recombinant virus may facilitate this process. Here, we examine the yields, transgene expression and purity of preparations of Ad and AAV purified using commercially available kits in comparison to other established techniques for purification of recombinant viral vectors. We demonstrate comparable results for Ad and AAV respectively in all parameters investigated, with a substantial reduction in purification time for the kit-based technology. Such approaches are attractive methods for small-scale purification of recombinant Ad and AAV viral vectors.

Adenoviridae↗
PubMed2005

Injection-moulded models of major and minor arteries: the variability of model wall thickness owing to casting technique.

Cardiovascular disease of major and minor arteries is a common cause of death in Western society. The wall mechanics and haemodynamics within the arteries are considered to be important factors in the disease formation process. This paper is concerned with the development of an efficient computer-integrated technique to manufacture idealized and realistic models of diseased major and minor arteries from radiological images and to address the issue of model wall thickness variability. Variations in wall thickness from the original computer models to the final castings are quantified using a CCD camera. The results found that wall thickness variation from the major and minor idealized artery models to design specification were insignificant, up to a maximum of 16 per cent. In realistic models, however, differences were up to 23 per cent in the major arterial models and 58 per cent in the minor arterial models, but the wall thickness variability remained within the limits of previously reported wall thickness results. It is concluded that the described injection moulding procedure yields idealized and realistic castings suitable for use in experimental investigations, with idealized models giving better agreement with design. Wall thickness is variable and should be assessed after the models are manufactured.

Anatomy, Cross-Sectional↗
PubMed2004

Current status of catheter- and stent-based gene therapy.

Significant progress has been made in the field of cardiovascular gene therapy over the past decade. Animal models of human disease have helped in identifying potential therapeutic genes and have also assisted in the evaluation of an ideal vector. A number of percutaneous catheter systems have been used in animal models with limited success. Stents represent an attractive alternative for localized gene delivery, as they provide a platform for prolonged gene elution and efficient transduction of opposed arterial walls. This gene delivery strategy has the potential to decrease the systemic spread of the viral vectors and hence a reduced host immune response. Both synthetic and naturally occurring stent coatings have shown potential to allow prolonged gene elution with no significant adverse reaction. However, further animal studies are required to evaluate the compatibility of stent coatings, vector solutions, and the arterial wall as well as assessment of the feasibility of this approach to achieve the full potential of gene therapy.

Animals↗
PubMed2004

Kinematics of the toe touching test: an investigation using motion analysis.

We describe a technique for measuring dynamic motion at the low back along with the major lower limb joints during the toe touching maneuver. This type of motion analysis was carried out on eight normal volunteers. Flexion during the toe touching maneuver involves not only low back and hip movement but also ankle plantar flexion and a varying degree of knee movement. The low back and ankle movements were highly correlated within each subject to an extent that suggests a functional connection between the lower limb and low back movements. The significance of our work is two-fold. First, we emphasize that the toe touching test represents a combined movement of the low back, the hips, the knees, and the ankles and it is reasonable to suggest that abnormalities of these joints may affect the clinical relevance of the test as an indicator of back movement. Second, we point out that the guidelines of the American Medical Association in using the test to determine hip movement are incorrect as they do not take into account the effect of knee and ankle movements on the estimation of hip movement.

Adult↗
PubMed2004

Movements at the low back during normal walking.

We present a technique for measuring the kinematics of the functional low back during normal gait. We have used a similar technique previously to measure low back movement simultaneously with hip, knee, and ankle movement during the toe-touching manoeuvre. We noted that movements at the low back were biphasic. The greatest low back movements were found to occur in the transverse plane (mean = 23 degrees), whereas a mean of 17 degrees movement occurred in the coronal plane and only 5 degrees movement in the sagittal plane. These findings confirm, using a non-invasive technique, that there are significant ranges of movement at the low back during walking and lend some support to the theory that rotational movement at the low back is a major component of human locomotion.

Adult↗
PubMed2004

Characterisation of three novel canine osteosarcoma cell lines producing high levels of matrix metalloproteinases.

Three canine osteosarcoma cell lines were established from spontaneous pelvic and radial osteosarcomas. The cell populations cultured exhibited characteristics of malignancy and consisted of adherent, pleomorphic, mostly large spindle-shaped or polyhedral cells, characterised by the presence of numerous cytoplasmic granules and vacuoles. The main ultrastructural features included the presence of abundant rough endoplasmic reticulum and numerous cytoplasmic vesicles, deposit vacuoles and small cytoplasmic protrusions. Zymography showed that the cell lines produce high levels of MMP-2 and MMP-9, enzymes directly involved in crucial aspects of the metastatic process. Consistent with their osteoblastic lineage and malignant phenotype, all cell lines were immunoreactive to vimentin, osteopontin, PCNA, p53, MMP-2 and MMP-9, while they were negative for cytokeratin, desmin, SMA, Factor VIII, NSE, GFAP, Rb and p21 protein. No retroviral particles or RNA were detected ultrastructurally or with RT-PCR, although the possibility of viral involvement in osteosarcoma cannot be excluded. The new cell lines provide excellent in vitro models that may allow further studies on the pathobiology of canine osteosarcoma to be undertaken.

Alkaline Phosphatase↗
PubMed2003

On the existence of an optimum end-to-side junctional geometry in peripheral bypass surgery--a computer generated study.

BACKGROUND: To investigate hemodynamic flow changes associated with vein cuffs and patches that may be responsible for improved patency of prosthetic infrainguinal grafts. METHODS: The role of the graft-artery junction angle was examined by computational fluid dynamics to assess the influence of anastomotic geometry on wall shear stress (WSS) distributions. Three geometrically different junction configurations were studied and the WSS and WSS gradient (WSSG) values were compared. RESULTS: The inclusion of a patch or a cuff moves the bed stagnation point (BSP) distally, increasing the area on the bed of the junction which experiences a BSP and reducing the strength of the recirculation region opposite the heel of the junction by 54.8 and 50.8%, respectively. The patched geometry promotes earlier recovery of the flow in the distal outflow segment (DOS) than for the unpatched model. Also, the helical flow patterns in the DOS associated with the cuffed geometry are stronger. The net effect of these changes are that peak WSSG values for the patched and cuffed geometries are three times lower than those for the uncuffed geometry. CONCLUSION: This study provides some additional insights into the hemodynamics of graft-artery junction geometry which may influence future clinical practice.

Anastomosis, Surgical↗