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Biomedical subjects

P Fitzgerald

Publications and source records attributed to P Fitzgerald.

At least 55 records · Page 3Linked to original sources
PubMed1998

New developments in intravascular ultrasound.

Intravascular ultrasound (IVUS) is a dynamic imaging modality that provides real-time in vivo visualization of atherosclerosis and other vascular pathology. The tomographic image presentation of IVUS permits detailed assessment of plaque morphology and its corresponding responses to interventional therapy. IVUS studies have confirmed vascular remodeling in vivo, have proposed a high-pressure stent implantation strategy and have shown two key mechanisms of restenosis after angioplasty: plaque proliferation and vessel shrinkage (negative remodeling). IVUS also provides accurate quantitative information regarding lumen size, vessel size and plaque burden. These observations, essential to achieving improved outcomes, have drastically changed the understanding of atherosclerotic artery disease and interventional procedures. IVUS has matured into an essential complement to daily peripheral and coronary interventional practice and is routinely incorporated as part of the interventional arsenal in the catheterization laboratory. A variety of new imaging techniques are currently being designed and tested. These include combined therapeutic devices, further miniaturization, 3-D applications and tissue characterization. These techniques may evolve to provide increased favorable clinical outcomes and more accurate information of vessel geometry and plaque composition.

Angioplasty, Balloon, Coronary↗
PubMed1998

Home-oriented management programme for people with early psychosis.

BACKGROUND: The HOMES (Home-Oriented Management of Early Psychosis) programme is a new home-based management programme for people presenting for the first time with psychotic illnesses. The present paper aims to present preliminary data as to the efficacy of this programme and factors identified as being associated with successful prevention of hospital admission. METHOD: The programme applied to all the people presenting to the Dandenong Hospital Department of Psychiatry with first-episode psychosis who are considered suitable at first assessment for home-based management. A programme description is included in the paper. Prospective evaluation data on the first 31 people managed within the programme is presented. RESULTS: Twenty-two out of 31 people were managed without the necessity for hospital admission. Illness severity was not related to the ability to manage this group of people outside of hospital. The level of social support and duration of untreated psychosis prior to treatment, may be most closely related to home-based treatment success. CONCLUSIONS: Home-based management of people with first-episode psychosis is feasible and offers a viable alternative to admission for this group. Home-based treatment is dependent on the degree of social support but is independent of the degree of illness severity.

Adolescent↗
PubMed1997

Retinoic acid receptor alpha expression correlates with retinoid-induced growth inhibition of human breast cancer cells regardless of estrogen receptor status.

Retinoic acid receptor (RAR) alpha has been shown to play a role in retinoid-induced growth inhibition of human breast cancer cell lines that express the estrogen receptor (ER). The dogma in the field has been that ER-positive breast cancer cell lines respond to retinoid treatment because they express RAR alpha, whereas ER-negative breast cancer cell lines are refractory to retinoid treatment and have been thought to express little or no RAR alpha. We set out to test several ER-negative breast cancer cell lines for expression of RAR alpha protein and responsiveness to retinoids in growth inhibition assays. Of six ER-negative breast cancer cell lines that were tested, one (SK-BR-3) had high levels of RAR alpha protein as measured by ligand-binding immunoprecipitation (approximately 55 fmol/mg protein) and also displayed sensitivity to growth inhibition by retinoids (9-cis-retinoic acid; EC50, approximately 3 nM). These cells were more sensitive than an ER-positive cell line, T-47D, which expressed approximately 35 fmol RAR alpha/mg total protein (9-cis retinoic acid; EC50, approximately 50-100 nM). Another ER-negative cell line, Hs578T, also expressed RAR alpha (approximately 23 fmol/mg) and was sensitive to retinoid-induced growth inhibition, albeit to a lesser extent than SK-BR-3 or T-47D cells. In contrast, the other ER-negative cell lines tested expressed low (<10 fmol/mg) or no detectable levels of RAR alpha protein and also did not respond to retinoids in growth inhibition assays. A RAR alpha agonist displayed 100 times greater potency than a RARgamma agonist in growth inhibition of both T-47D and SK-BR-3 cells, suggesting RAR alpha involvement in the process. Furthermore, a RAR alpha antagonist completely abolished the growth inhibition induced by RAR agonists, implying that the activity of the agonists is exerted solely through RAR alpha, not RARgamma, which is also expressed in both cell lines. Additionally, although retinoid X receptor (RXR) compounds are weakly active in growth inhibition of the RAR alpha-positive cell lines, they markedly increased the growth-inhibitory activity of RAR ligands. RXR compounds also potentiated the action of the antiestrogen 4-hydroxytamoxifen to inhibit the growth of T-47D cells. These findings have clinical ramifications in that patients with ER-negative tumors that are RAR alpha positive may be candidates for retinoid therapy. Additionally, combinations of RXR ligands with RAR ligands (especially RAR alpha agonists) and/or antiestrogens may have utility in the treatment of breast cancer.

Alitretinoin↗
PubMed1997

Assessment of the postoperative visit after routine inguinal hernia repair: a prospective randomized trial.

Treatment of pediatric patients undergoing routine inguinal hernia repair usually includes a postoperative clinic visit. We prospectively assessed the necessity for the traditional postoperative visit. One hundred patients undergoing a routine inguinal hernia repair were randomly selected to receive either a follow-up visit at 4 weeks or a detailed instruction sheet and no follow-up visit. Parents were given a telephone questionnaire to determine overall satisfaction with their child's care and the usefulness of the follow-up visit or instruction sheet. Forty-seven of 50 parents of patients randomly assigned to a follow-up clinic visit (FU) and all 50 parents in the no follow-up group (NFU) completed the questionnaire. Sixty-eight percent of the FU group found the follow-up visit "helpful" and 59% found it "necessary." Fifty-six percent would have been satisfied with a telephone call instead of a visit. In the NFU group only 4% thought a follow-up visit would have been "helpful" and 4% thought a visit was "necessary." Ninety-six percent found the postoperative instruction sheet "helpful." There was no difference between groups in overall satisfaction with the care received as assessed on a 5-point scale (4.7 FU group v 4.7 NFU group). Accurate postoperative instruction and open access to follow-up when required is as effective as the traditional postoperative clinic visit for patients who have undergone routine inguinal hernia repair.

Appointments and Schedules↗
PubMed1996

Role for cyclin A-dependent kinase in DNA replication in human S phase cell extracts.

Cell cycle progression is regulated by cyclin-dependent kinases. Using in vitro replication of SV40 origin containing DNA as a model system, we have performed a detailed analysis of the dependence on cyclin-associated kinases of mammalian DNA replication. Complete immunodepletion of cyclin A from human S phase cell extracts decreases replication, and replication activity of cyclin A-depleted S phase extracts can subsequently be restored by the addition of purified CDK2-cyclin A kinase. Addition of cyclin A alone reconstitutes both kinase activity and DNA replication, whereas addition of cyclin E or cyclin B reconstitutes neither. We therefore conclude that reconstitution of DNA replication specifically correlates with an increase in kinase activity. By comparison, depletion of cyclin E from S phase cell extracts does not have any significant inhibitory effect on DNA replication. Moreover, specific p21(Waf1) mutants that bind to CDK2-cyclin and inhibit both cyclin A and cyclin E kinase activities, but do not bind to proliferating cell nuclear antigen, inhibit DNA replication to the same extent as cyclin A depletion. Together, these results show that the kinase activity associated with cyclin A, but not with cyclin E, is primarily responsible for activating SV40 plasmid replication in mammalian S phase cell extracts. Finally, we present evidence that the cyclin-dependent kinase does not influence the assembly of initiation complexes but acts at a stage prior to elongation.

Cyclin-Dependent Kinase Inhibitor p21↗
PubMed1996

A conserved domain of the large subunit of replication factor C binds PCNA and acts like a dominant negative inhibitor of DNA replication in mammalian cells.

Replication factor C (RF-C), a complex of five polypeptides, is essential for cell-free SV40 origin-dependent DNA replication and viability in yeast. The cDNA encoding the large subunit of human RF-C (RF-Cp145) was cloned in a Southwestern screen. Using deletion mutants of RF-Cp145 we have mapped the DNA binding domain of RF-Cp145 to amino acid residues 369-480. This domain is conserved among both prokaryotic DNA ligases and eukaryotic poly(ADP-ribose) polymerases and is absent in other subunits of RF-C. The PCNA binding domain maps to amino acid residues 481-728 and is conserved in all five subunits of RF-C. The PCNA binding domain of RF-Cp145 inhibits several functions of RF-C, such as: (i) in vitro DNA replication of SV40 origin-containing DNA; (ii) RF-C-dependent loading of PCNA onto DNA; and (iii) RF-C-dependent DNA elongation. The PCNA binding domain of RF-Cp145 localizes to the nucleus and inhibits DNA synthesis in transfected mammalian cells. In contrast, the DNA binding domain of RF-Cp145 does not inhibit DNA synthesis in vitro or in vivo. We therefore conclude that amino acid residues 481-728 of human RF-Cp145 are critical and act as a dominant negative mutant of RF-C function in DNA replication in vivo.

Amino Acid Sequence↗
PubMed1996

p21 contains independent binding sites for cyclin and cdk2: both sites are required to inhibit cdk2 kinase activity.

Cyclin dependent kinases regulate the progression of eukaryotic cells through the cell cycle. p21Cip1/Waf1/Sdi1 is an inhibitor of cdk-cyclin kinase activity, and has been shown to form complexes with cdk-cyclins and with PCNA, an accessory protein of DNA polymerase delta. The kinase inhibitory domain maps to the N-terminus (1-82) and contains the cdk2 binding site (28-82). We have generated a panel of deletion mutants of p21. A functional characterization of p21 mutants in the N-terminal domain reveals that cyclins bind to this domain independently of cdk2. Correlating with these results we find that p21 can associate with cyclin-cdk kinases in two functionally distinct forms, one in which the kinase activity is inhibited and the other in which the kinase is still active. The cdk2 and cyclin binding sites on p21 are both required to inhibit kinase activity. The second type of interaction, in which an active cyclin-cdk complex only interacts with p21 either via the cyclin or the cdk2 binding site but not through both, does not lead to inhibition of cyclin kinase activity. These results thus provide a basis for understanding the mechanism by which p21, and perhaps other cdk-cyclin kinase inhibitory proteins, suppress kinase activity.

Amino Acid Sequence↗
PubMed1996

The cytotoxic cell protease granzyme B initiates apoptosis in a cell-free system by proteolytic processing and activation of the ICE/CED-3 family protease, CPP32, via a novel two-step mechanism.

The major mechanism of cytotoxic lymphocyte killing involves the directed release of granules containing perforin and a number of proteases onto the target cell membrane. One of these proteases, granzyme B, has an unusual substrate site preference for Asp residues, a property that it shares with members of the emerging interleukin-1beta-converting enzyme (ICE)/CED-3 family of proteases. Here we show that granzyme B is sufficient to reproduce rapidly all of the key features of apoptosis, including the degradation of several protein substrates, when introduced into Jurkat cell-free extracts. Granzyme B-induced apoptosis was neutralized by a tetrapeptide inhibitor of the ICE/CED-3 family protease, CPP32, whereas a similar inhibitor of ICE had no effect. Granzyme B was found to convert CPP32, but not ICE, to its active form by cleaving between the large and small subunits of the CPP32 proenzyme, resulting in removal of the prodomain via an autocatalytic step. The cowpox virus protein CrmA, a known inhibitor of ICE family proteases as well as granzyme B, inhibited granzyme B-mediated CPP32 processing and apoptosis. These data demonstrate that CPP32 activation is a key event during apoptosis initiated by granzyme B.

Apoptosis↗
PubMed1996

BCR gene recombines with genomically distinct sites on band 11Q13 in complex BCR-ABL translocations of chronic myeloid leukemia.

We have analysed a cloned 11q13/3'BCR junction fragment, one recombination product of a complex t(9;11;22) translocation in a patient with chronic myeloid leukemia. 3'M-Bcr recombined with chromosome band 11q13 at a specific point between two Alu elements lying in opposite orientation. We present new molecular data comparing the genomic location of the 11q13 breakpoint in our patient with that of one other recently reported to lie within the GSTP1 gene. This is the first time that specific breakpoint sites within a chromosomal region highly involved in complex Ph translocations have been relatively mapped. These early results argue against a precise site in 11q13 with which M-Bcr preferentially recombines and favour instead a larger recombination-prone domain. Both of the 11q13 breakpoint regions show Alu repeat elements in close proximity to the site of recombination.

Base Sequence↗
PubMed1995

Fragile X mental retardation syndrome: DNA diagnosis and carrier detection in New Zealand families.

AIMS: To establish a DNA-based test for the diagnosis and carrier detection of fragile X syndrome, and to investigate the nature of the mutation and patterns of inheritance in New Zealand families. METHODS: A probe for the FRAXA region was generated by polymerase chain reaction, cloned in a plasmid vector, and its structure was confirmed by DNA sequencing. This probe was used in a Southern blot assay to detect full mutations or premutations associated with fragile X syndrome in DNA from peripheral blood samples submitted to our laboratory for routine testing. RESULTS: We tested 379 individuals from throughout New Zealand. Full mutations were found in 29 males, leading to a fragile X diagnosis, or confirmation of an earlier cytogenetic diagnosis. Premutations were detected in 45 females and 11 males, all of whom are asymptomatic carriers of the disease. CONCLUSIONS: The DNA test is rapid and accurate, in contrast to the cytogenetic test. It allows unequivocal detection of carriers, enabling effective counselling, prenatal testing, and more generalised screening of at-risk populations. Our discovery of one large pedigree with many carriers and no prior history of X-linked mental retardation demonstrates that the DNA test is appropriate even in apparently sporadic cases of mental retardation.

Blotting, Southern↗
PubMed1995

Abdominal aortic aneurysm in the Irish population: a familial screening study.

A pilot screening programme was undertaken in Ireland to determine the incidence of abdominal aortic aneurysm (AAA) (diameter 3 cm or greater) in the siblings of 120 patients known to have AAA. There were 621 siblings; 270 of them were dead, 32 were over 80 years old and 85 lived outside Ireland, leaving 234 under 80 years of age still living in Ireland who were invited to attend for ultrasonographic screening. Of the 270 siblings who had died, 102 were women and 168 men; eight men (4.8 per cent) had died from ruptured AAA. Only 125 (53.4 percent) of the 234 siblings agreed to participate in the screening programme, 60 brothers from 31 families and 65 sisters from 35 families. Fifteen (12.0 per cent) of the 125 siblings had an AAA (median size 4.2 (range 3.1-6.8) cm), 13 (22 per cent) of the 60 male siblings and two (3 per cent) of the 65 female siblings. The prevalence of AAA among siblings was not affected by the age or sex of the patient with aneurysm. Seven of the 14 male siblings with hypertension had an AAA, compared with only six of the 46 who were normotensive (P = 0.01). The high incidence of AAA in brothers of affected patients highlights the need to counsel this group on their risk of aneurysm. The relatively low participation rate by siblings in this screening programme indicates that a hospital-based unit is unlikely to be effective in recruiting all patient siblings at risk from an AAA.

Adult↗
PubMed1995

Button-pexy fixation for repair of ileostomy and colostomy prolapse.

Intestinal stomas are used in the surgical management of a number of congenital and acquired gastrointestinal conditions. Minor stomal complications are relatively common and are often well managed with nonoperative measures. Stomal prolapse may not represent a serious problem, but occasionally it requires surgical correction because of severe skin excoriation, bleeding, or incarceration of the bowel. The authors describe the treatment of stomal prolapse with the technique of button-pexy fixation, as originally described by C.W. Mayo.

Colostomy↗
PubMed1995

Activation-induced T-cell death is cell cycle dependent and regulated by cyclin B.

Developing thymocytes and some T-cell hybridomas undergo activation-dependent programmed cell death. Although recent studies have identified some critical regulators in programmed cell death, the role of cell cycle regulation in activation-induced cell death in T cells has not been addressed. We demonstrate that synchronized T-cell hybridomas, irrespective of the point in the cell cycle at which they are activated, stop cycling shortly after they reach G2/M. These cells exhibit the diagnostic characteristics of apoptotic cell death. Although p34cdc2 levels are not perturbed after activation of synchronously cycling T cells, cyclin B- and p34cdc2-associated histone H1 kinase activity is persistently elevated. This activation-dependent induction of H1 kinase activity in T cells is associated with a decrease in the phosphotyrosine content of p34cdc2. We also demonstrate that transient inappropriate coexpression of cyclin B with p34cdc2 induces DNA fragmentation in a heterologous cell type. Finally, in T cells, cyclin B-specific antisense oligonucleotides suppress activation-induced cell death but not cell death induced by exposure to dexamethasone. We therefore conclude that a persistent elevation of the level of cyclin B kinase is required for activation-induced programmed T-cell death.

Amino Acid Sequence↗
PubMed1994

Cutaneous malignant melanoma in Australia, 1989.

OBJECTIVE: To describe the characteristics of cutaneous malignant melanoma in Australians in 1989. DESIGN AND DATA: Descriptive analysis of all invasive melanomas reported to State or Territory cancer registries in 1989. MAIN OUTCOME MEASURES: The age, sex and State or Territory of residence of affected individuals, and the topography, morphology and thickness of the melanoma. RESULTS: The age-standardised incidence rates of melanoma were 30.2 and 23.9 per 100,000 males and females respectively; the highest rates were observed for the male trunk (11.7 per 100,000) and female lower limbs (8.8 per 100,000); the most commonly specified morphology was superficial spreading melanoma, followed by nodular melanoma and lentigo malignant melanoma. Fifty-two per cent of melanomas of known thickness were thinner than 0.76 mm, with females having proportionally more thin melanomas than males, and males having twice the rate of melanomas thicker than 3 mm. Melanoma rates in northern latitudes were approximately double those further south. CONCLUSIONS: Distinct patterns of melanoma incidence by latitude and body site confirm the role of sunlight exposure in melanoma aetiology. Females often have thinner melanomas than males, which is reflected in their better prognosis. People living closer to the equator more often have level 1 (in situ) and thin invasive melanoma, probably related to increased awareness of melanoma risk with decreasing latitude. The collection of melanoma data would be improved if pathologists' reports routinely included melanoma site, morphology, level and thickness. All registries should collect data on level 1 melanomas to help evaluate early melanoma detection programs and to continue surveillance of the Australian skin cancer epidemic.

Adolescent↗
PubMed1994

Massive chylothorax associated with lymphangiomatosis of the bone.

Chylothorax in the absence of tumor or trauma is uncommon. Lymphangiomatosis of the bone, although extremely rare, has been associated with chylothorax. The authors describe the case of a 12-year-old boy who presented with a symptomatic left chylothorax associated with lymphangiomatosis of the ribs, scapula, and clavicle. Despite tube thoracostomies and the initiation of total parenteral nutrition, massive losses of chyle persisted, resulting in hypoproteinemia and severe lymphopenia. Control of the chylothorax was achieved by a parietal pleurectomy and application of fibrin glue (Tisseel). In the literature there are 16 cases of chylothorax associated with lymphangiomatosis of the bone. Their presentation, treatment, and outcome are reviewed. Conservative treatments such as dietary manipulations or thoracenteses were rarely successful. Thoracotomy with parietal pleurectomy on the side of the effusion is usually effective in controlling the chylothorax. Lymphangiomatosis should be considered a diagnostic possibility for any child who presents with a chylothorax.

Biopsy↗