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Biomedical subjects

P Ryan

Publications and source records attributed to P Ryan.

At least 19 recordsLinked to original sources
PubMed1997

p53 mediated sensitization of squamous cell carcinoma of the head and neck to radiotherapy.

Radiation resistant squamous cell carcinoma of the head and neck cell line JSQ-3 carries a mutant form of tumor suppressor gene p53. Treatment of these cells with an adenoviral vector containing wild-type p53 (Av1p53) was able to inhibit their growth in vitro and in vivo while having no effect on normal cells. More significantly, introduction of wtp53 also reduced the radiation-resistance level of this cell line in vitro, in a viral dose-dependent manner. Furthermore, this radiosensitization also carried over to the in vivo situation where the response of JSQ-3 cell-induced mouse xenografts to radiotherapy was markedly enhanced after treatment with Av1p53. Complete, long-term regression of the tumors for up to 162 days was observed when a single dose of Av1p53 was administered in combination with ionizing radiation, demonstrating the effectiveness of this combination of gene therapy and conventional radiotherapy. This sensitization of tumors to radiation therapy by replacement of wtp53 could significantly decrease the rate of recurrence after radiation treatment. Since radiation is one of the most prevalent forms of adjunctive therapy for a variety of cancers, these results have great relevance in moving toward an improved cancer therapy.

Adenoviridae↗
PubMed1997

Restoration of the G1 checkpoint and the apoptotic pathway mediated by wild-type p53 sensitizes squamous cell carcinoma of the head and neck to radiotherapy.

BACKGROUND: A significant number of squamous cell carcinomas of the head and neck (SCCHN) resist radiation treatment, the most common form of adjuvant therapy for this disease. The presence of a mutant form of the tumor suppressor gene p53 has been correlated with disruption of programmed cell death (apoptosis) and reduced cell cycle arrest, resulting in increased radiation resistance and survival. METHODS AND RESULTS: We introduced by means of an adenoviral vector a functional p53 gene into a radiation-resistant SCCHN cell line that harbors mutant p53. Replacement of wild-type p53 restored the G1 block and apoptosis in these cells in vitro. Moreover, introduction of wild-type p53 sensitized SCCHN-induced mouse xenografts to radiotherapy in vivo. CONCLUSION: The combination of p53 replacement gene therapy with conventional radiotherapy may treat SCCHN more effectively.

Animals↗
PubMed1997

Registration bone scan in the evaluation of wrist pain.

We assessed the value of bone scintigraphy combined with X-ray registration for the diagnosis and management of wrist pain in 65 patients. Studies were reported independently by two observers before and after registration. Registration improved localization of scan abnormalities in 53% (observer 1) and 61% (observer 2). In these patients, the bone scan contributed to the diagnosis independently of the X-ray in 37% and the management was altered in 31%. The value of the bone scan in the early diagnosis and management of wrist pain is increased when it is registered with X-rays.

Adult↗
PubMed1997

Feasibility of conducting cardiovascular outcome research in Australian general practice: results from the ANBP2 pilot study. Australian National Blood Pressure Study.

1. The present study aimed to determine the feasibility of conducting a 5 year cardiovascular outcome trial of the treatment of 6000 elderly hypertensive patients in Australian general practices. 2. General practitioners (GPs) were invited to participate by mail and personal follow-up. Patient records were reviewed to identify subjects for a blood pressure (BP) screening programme. Blood pressure was measured on three occasions and eligible subjects were included if the average BP was > or = 160 mmHg systolic or > or = 90 mmHg diastolic if systolic BP was > or = 140 mmHg. 3. Seven hundred and forty-one GPs were approached and 89 were enrolled in the study (12% of mail invites and 75% of those receiving a personal contact). In 16 practices where screening was completed, 82,000 records were reviewed to identify 4% patients eligible for screening. Twenty-two per cent of eligible subjects attended screening. Of 1938 subjects screened, 180 (9%) had BP > or = 160/90 mmHg. Forty-seven per cent of subjects (n = 916) were receiving antihypertensive therapy and 184 (20%) were withdrawn from therapy. One hundred and sixteen (63%) of these subjects had BP return to study entry levels within 6 weeks. Fifty-seven newly diagnosed and 81 previously treated subjects were randomized (7% of the screened population). 4. Based on the high participation rate of GPs, the response rate of patients to attend a BP screening programme and the 7% randomization to screening ratio for entry into the study, the ANBP2 pilot study has demonstrated that it is feasible to recruit subjects from Australian general practices to a cardiovascular outcome trial.

Aged↗
PubMed1997

Dosing implications of a clinical interaction between grapefruit juice and cyclosporine and metabolite concentrations in patients with autoimmune diseases.

OBJECTIVE: To determine the effect of chronic grapefruit juice administration on steady state blood concentrations of cyclosporine and metabolites in patients with autoimmune diseases. METHODS: 9 patients stabilized on administration of cyclosporine (range 0.7-6.7 mg/kg/day) were given either grapefruit juice or water using randomized crossover design. Whole blood samples were collected before the morning cyclosporine dose and during the 12 h interdose interval. Cyclosporine concentrations were measured using a relatively specific assay (Emit) and total metabolite concentrations were estimated using a nonspecific assay (polyclonal Abbott-TDx). RESULTS: Exposure to grapefruit juice produced significant increases in predose cyclosporine concentrations (p < 0.01) and total metabolite concentrations (p = 0.03) and the area under the cyclosporine and metabolite blood concentration-time curves (p = 0.005, p = 0.001, respectively). One patient developed significant neurological side effects associated with a 68.9 and 214% increase in predose cyclosporine and metabolite concentrations, respectively, during grapefruit juice co-administration. CONCLUSION: Grapefruit juice causes an increase in both parent and metabolite profiles, indicating an alteration in the disposition of cyclosporine and metabolites. This interaction is of potential clinical importance in terms of mechanism, side effects, and dosing.

Adult↗
PubMed1996

Diet, acetylator phenotype, and risk of colorectal neoplasia.

BACKGROUND: Inherited or acquired differences in metabolic pathways that activate or inactivate dietary carcinogens may influence the risk of developing cancer. A polymorphism in N-acetyltransferase classified people into fast and slow acetylators. This enzyme catalyses the formation of mutagenic products from foodstuffs, especially cooked meat and fish. Some data suggest that fast acetylators are at higher risk of colorectal cancer. We have studied the adenoma and cancer risk in relation to meat intake and acetylator status. METHODS: In a case-control study, we compared 110 patients with colorectal cancer, 89 patients with colorectal adenomatous polyps, and 110 controls. Acetylator status was assessed by the rate of acetylation of sulphamethazine given orally. FINDINGS: The fast-acetylator phenotype was associated with odds ratios of 1.1 (95% Cl 0.6-2.1) and 1.8 (1.0-3.3) for adenoma and colorectal cancer, respectively. The highest risk occurred in the youngest tertile (< 64 years) of cases (2.5 [0.7-9.4] and 8.9 [2.6-30.4], respectively). There was no difference between the sexes. The risk of adenoma or cancer increased with increasing intake of meat in fast but not in slow acetylators: covariate-adjusted odds of disease over three levels of meat consumption were 2.1 (0.9-4.7) for adenoma, 1.7 (0.9-3.5) for cancer, and 1.9 (1.0-3.7) for all tumours. INTERPRETATION: Our findings indicate that acetylator status modulates the risk of colorectal neoplasia associated with meat intake.

Acetylation↗
PubMed1996

Mode of interaction between pseudorabies virus and heparan sulfate/heparin.

It has been demonstrated that the efficient attachment of pseudorabies virus (PrV) is mediated by an interaction between glycoprotein C (gC) and a cellular heparin-like substance (T. C. Mettenleiter, L. Zsak, F. Zuckermann, N. Sugg, H. Kern, and t. Ben-Porat, J. Virol. 64, 278-286, 1990). According to the prevalent concept, this interaction is likely to occur between clusters of basic residues of PrV gC and the negatively charged sulfate esters and carboxylate groups of heparan sulfate/heparin. To elucidate which of the three major types of sulfate groups of heparan sulfate/heparin are involved in the interaction with PrV, we used selectively N-, 2-O-, and 6-O-desulfated samples and other modified heparins as competitors in virus-attachment assays. PrV exhibited limited preference for the specific sulfate groups of heparan sulfate/heparin in accordance with a hierarchy of 6-O- > 2-O- > N-sulfates. In addition, since selective removal of any of the specific sulfates had only a slight effect on the competition capacity of heparin, it is likely that the combination of any two of three types of sulfate groups could contribute to an interaction with PrV with an efficiency nearly equal to native, fully sulfated heparin. When tested on different cell lines the pattern of PrV requirement for the specific O-sulfate groups, i.e., 6-O-sulfates > 2-O-sulfates, remained the same. However, different minimum lengths of heparin fragments were required to inhibit PrV attachment to different cell lines, suggesting a relative virus flexibility in accommodation to different forms of heparan sulfate.

Animals↗
PubMed1996

First experimental sutureless laser anastomosis of the large bowel: long-term study.

UNLABELLED: Large bowel anastomoses were successfully performed without sutures on New Zealand white rabbits using 1,064 nm, 0.4-W power pulsating Nd:YAG laser to create tissue welding. PURPOSE: The aim of this study was to assess long-term results of our experimental data and summarize our experimental work on laser colon anastomosis. METHODS: This experimental study investigated long-term integrity, degree of narrowing, animal body weight change, visual findings, microscopic appearance, and collagen concentration of laser colon anastomoses, compared with those of conventional sutured anastomoses at thirty and ninety postoperative days. RESULTS: Two animals in the laser group died without leakage. Postsurgical course in all remaining rabbits studied was uneventful. Bursting pressures in the two groups were equivalent, but the laser group exhibited a consistent narrowing tendency. However, laser anastomoses demonstrated fewer and milder adhesions, and animals showed a better recovery of body weight. Histologically, laser anastomoses showed better layer-to-layer reconstitution without foreign body response and with less fibrosis. Difference in collagen (hydroxyproline) concentration did not reach statistical significance. CONCLUSION: The nature of tissue welding via laser remains undefined, but there is definitely a future for laser bowel anastomosis.

Anastomosis, Surgical↗
PubMed1996

Differential recognition by CD28 of its cognate counter receptors CD80 (B7.1) and B70 (B7.2): analysis by site directed mutagenesis.

CD28, which is a member of the immunoglobulin superfamily of molecules (IgSF), is a homodimer of two polypeptides containing a single V-like domain with short transmembrane and cytoplasmic regions. It serves as a co-signalling molecule for T cell activation through binding to its cognate counter-receptors CD80 and B70, expressed on antigen presenting cells. In the current study, we investigated the regions of CD28 which are involved in its interactions with CD80 and B70, using site directed mutagenesis, CD28 mAb epitope mapping, receptor based adhesion assays and direct binding of Ig-fusion proteins to cell surface receptors. Truncation or substitution of a stretch of a proline rich "hallmark" sequence, "MYPPPY", abrogates binding to CD80 or B70, while retaining CD28 mAb epitopes and cell surface expression. On an Ig-fold model of the CD28 V-domain, this fully conserved motif localizes to a CDR3-like region. Mutations introduced into other loops, including the CDRI-like and CDR2-like regions, had very little effect on CD80 or B70 binding. Mutations introduced within the predicted beta-strand regions caused loss of receptor expression. Conservative substitution of both the flanking tyrosine residues within the "MYPPPY" motif with phenylalanine, caused loss of binding to B70 but not to CD80. These results show that, although the same overall region on CD28 may be involved in the interactions with CD80 and B70, subtle but important differences distinguish recognition by the two molecules. These finding, along with previous observations on the differential pattern of expression and tissue distribution of CD80 and B70, support the contention that these molecules play distinct roles in the regulation of immune responses in vivo.

Abatacept↗
PubMed1996

A double-strand break in a herpesvirus genome stimulates targeted homologous recombination with exogenous, cloned viral sequences.

A method is described for the highly efficient recovery of recombinant pseudorabies virions; the approach should be applicable to other herpesviruses. Pseudorabies virus (PRV) strain PRV509 contains a unique EcoRI site in its genome, largely replacing the glycoprotein gC gene. By digesting PRV509 DNA with EcoRI prior to cotransfection with plasmid DNA that harbored a cloned copy of gC, we isolated recombinant viruses containing the cloned gC allele at a frequency exceeding 75%. This represented u to a 37-fold increase over the use of intact viral DNA in cotransfection experiments, and may eliminate the need for phenotypic screening of recombinants. Closer analysis of the recombinant viruses revealed that genetic markers up to 1 kilobase pair apart could be recombined into the genome using the EcoRI-digested DNA. Overall, the increased frequency of recombinant viruses can be explained if homologous recombination at sites of double-strand breakage is a more efficient repair mechanism than the re-annealing and ligation of the break itself.

Animals↗
PubMed1996

Cognitive gender differences in very young children parallel biologically based cognitive gender differences in monkeys.

Infant humans were trained on 2 cognitive tests that have previously revealed, in infant monkeys, a double dissociation that was reversible by perinatal manipulations of androgens and ablations of specific brain sites. Children showed the same sex-linked behavior found with infant monkeys: young boys were superior on the object reversal task and young girls were superior on the concurrent discrimination task. As happened previously with infant monkeys, the gender difference was not apparent in older human subjects. Thus, early in ontogeny, cognitive gender differences have now been discovered in both humans and monkeys, probably a result of gender differences in androgens that influence the maturation rate of specific brain systems.

Adolescent↗
PubMed1996

Extra-articular features of benign joint hypermobility syndrome.

To define the phenotype of patients with benign joint hypermobility syndrome (BJHS), we studied 58 consecutive patients (mean age 37 yr) presenting to a rheumatology clinic and 30 controls. Patients underwent rheumatological and ophthalmic examination, hypermobility scoring, echocardiography, measurement of bone mineral density (BMD), and skin thickness, elasticity and light transmissibility. The median hypermobility score was 5/9 Beighton and 31/56 Contompasis. Eighteen (31%) patients complained of significant arthralgia. Six (10%) patients and two (7%) controls had mitral valve prolapse (MVP) (chi(2) = 0.27, P = NS). Neither MVP nor aortic diameters showed a correlation with hypermobility score. There was no significant reduction in BMD. There was a significant correlation between hypermobility and light transmissibility of the skin (r = 0.71, P < 0.0001 Contompasis; r = 0.47, P < 0.05 Beighton) and skin stretchiness (r = 0.49, P < 0.05 Contompasis; r = 0.39, P < 0.05 Beighton). On ophthalmic examination, 14 (41%) patients had upper eyelid laxity. Thus, patients with BJHS do not have an increased prevalence of significant cardiac, bone, skin or eye abnormalities, helping differentiate BJHS from other more serious hereditary disorders of connective tissue.

Adolescent↗
PubMed1996

Anal pathology in patients with Crohn's disease.

BACKGROUND: A distinctive feature of patients suffering from Crohn's disease is a predisposition to develop a variety of anal complications. The aetiology of such conditions is unclear, and the reported incidence of anal involvement in Crohn's disease varies party due to the various criteria used for classification. This study aims to review the management of patients with symptomatic anal pathology associated with Crohn's disease at St Vincent's Hospital, Melbourne. METHODS: A database of 306 patients with Crohn's disease referred to the department between January 1978 and October 1994 was reviewed to identify those patients with symptomatic anal disease. The anal pathology was recorded and classified. Demographic data and the clinical and surgery history of the patient were recorded. RESULTS: Of the 306 patients with Crohn's disease, 129 (42.4%) were identified as having symptomatic anal pathology. Patients were likely to present with anal symptoms after they had been diagnosed as having intestinal Crohn's disease (46.1%). The commonest presentations were perianal abscess (29.5%), anal fissure (27.6%), and low anal fistula (26.7%). A minority of patients presented with high/complex anal fistulae (3.8%), or recto-vaginal fistulae (5.2%). Five per cent of patients had Crohn's disease localized to the anal area. The pattern of intestinal disease in the remaining patients was small bowel 21.1%. small bowel and colon 31.9%, and colon 43.0%. A total of 244 local anal and surgical procedures were performed on these patients; the commonest of these were drainage of an abscess (38.5%), examination under anaesthetic (29.1%), and laying open of a low anal fistula (22.5%). Following surgical treatment, the recurrence rate for perianal abscesses was 13%, and for low anal fistulae 6%. CONCLUSIONS: The majority of patients with Crohn's disease who develop anal pathology have an excellent prognosis. A minority of patients develop complex anal complex anal fistulae and these remain a therapeutic challenge.

Adult↗
PubMed1996

Epidemiological study of angioedema and ACE inhibitors.

BACKGROUND: Angioedema is an uncommon and poorly recognised adverse reaction to angiotensin converting enzyme inhibitors (ACE-Is). The epidemiology of this association has not been described. AIMS: To examine the epidemiology of angioedema and its relation to ACE inhibitor prescribing. To examine the characteristics of angioedema occurring in patients taking ACE inhibitors. METHODS: A retrospective case control study and a case note audit were conducted of 40 patients who presented to a teaching hospital Accident and Emergency Department with angioedema on 48 occasions. One hundred and sixty control subjects presenting to the same Accident and Emergency Department but without angioedema were matched to cases by age, sex and presentation date. An ecological study comparing the numbers of angioedema admissions by age cohorts to South Australian (SA) public hospitals with the prescription volumes of ACE-Is in Australia was also undertaken. RESULTS: Case control study: In patients presenting with angioedema compared with controls, the exposure odds ratio for ACE-Is was 5.1 (95% CI 2.03-12.89) and for non-steroidal anti-inflammatory drugs (NSAIDs) was 4.13 (95% CI 1.28-13.39). CASE NOTE AUDIT: 15/40 (38%) patients presenting with angioedema on 19/48 (40%) occasions were taking an ACE-I. These patients were older and less likely to have an atopic history than those not taking an ACE-I. The onset of angioedema after starting an ACE-I was delayed for greater than six months in nine patients. ACE-I therapy was continued after 53% of presentations. ECOLOGICAL STUDY: The number of admissions with angioedema to SA public hospitals increased between 1985-86 and 1994-95, predominantly in older patients, and paralleled the increasing prescription volumes of ACE-Is. CONCLUSIONS: A considerable proportion of patients presenting with angioedema will be taking an ACE-I or a NSAID. The association of ACE-Is and angioedema is not well recognised, partly because the onset of angioedema may be delayed for months or years after commencement of an ACE-I. A persisting risk of angioedema is present in patients who have initially commenced an ACE-I uneventfully. The epidemiology of angioedema is now changing in parallel with the increasing use of ACE-Is.

Adolescent↗
PubMed1996

The receptor-binding domain of pseudorabies virus glycoprotein gC is composed of multiple discrete units that are functionally redundant.

Many herpesviruses attach to cells in a two-step process, using the glycoprotein gC family of homologs to bind the primary receptor, heparan sulfate (HS) proteoglycan, and glycoprotein gD homologs to bind an unknown secondary receptor. We have previously shown by deletion analysis that the amino-terminal one-third of gC from pseudorabies virus (PRV), a swine herpesvirus, includes at least the principal HS receptor-binding domain. This portion of PRV gC contains three discrete clusters of basic residues that exactly or nearly match proposed consensus sequences for heparin-binding domains (HBDs); four additional potential HBDs lie in the distal two-thirds of the glycoprotein. We now specifically implicate each of the three amino-terminal HBDs in virus attachment. Mutational analysis demonstrated that any one of the three HBDs could mediate efficient virus infectivity; HS-dependent PRV attachment to cells was eliminated only after all three amino-terminal HBDs were altered. Furthermore, the binding dysfunction was due to a disruption of the specific HBDs and not to total charge loss. Thus, unlike previously described viral receptor-binding domains, the PRV gC receptor-binding domain is composed of multiple, discrete units that can function independently of one another. These units may function redundantly either to increase binding affinity or perhaps to effectively increase the virus's host range.

Amino Acid Sequence↗
PubMed1995

Systematic introduction of proline in a eukaryotic signal sequence suggests asymmetry within the hydrophobic core.

The hydrophobic core or h region of both prokaryotic and eukaryotic signal sequences is the predominant structural domain that controls the efficiency of protein translocation across membranes. Characteristically, hydrophobic cores appear to assume alpha-helical conformations, and studies in prokaryotes have indicated that this conformation is necessary for efficient signal sequence function. To address the conformational constraints of a eukaryotic signal sequence, we have introduced a single proline in almost each position of the signal sequence hydrophobic core of glycoprotein C (gC) of the swine herpesvirus, pseudorabies virus. When the resulting mutant virus strains were used to infect cells, we found that substitution of proline at certain positions affected gC translocation greater than its introduction at other sites within the hydrophobic core. The observed positional effects did not completely correlate with reductions in overall hydrophobicity or linear position within the hydrophobic core. Rather, it appeared that one face of the gC signal sequence alpha-helix is far more sensitive to proline disruption than the other, potentially indicating a functional asymmetry.

Amino Acid Sequence↗