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Biomedical subjects

M Sutherland

Publications and source records attributed to M Sutherland.

At least 37 records · Page 2Linked to original sources
PubMed2000

Primary spontaneous pneumothorax: treatment practices in Australia.

OBJECTIVE: The aim of the present study was to determine treatment practices for spontaneous pneumothorax (PTX) in Australia. METHODOLOGY: A questionnaire regarding treatment of PTX was posted to all medically qualified members of the Thoracic Society of Australia and New Zealand resident in Australia. RESULTS: Fifty-three per cent (n = 226) of questionnaires were returned. Twenty-one responses were judged to be informal and rejected from analysis. The results indicate a general agreement in the treatment of small and large PTX but a wide variation in PTX of intermediate size. CONCLUSION: Opinion regarding the optimal treatment for PTX of intermediate size was found to vary considerably. There is a need for evidence-based development and publication of best practice guidelines for PTX.

Australia↗
PubMed2000

Intramedullary nailing of tibial fractures: how often are post-operative radiographs needed?

A series of 53 closed tibial fractures were treated with interlocking intramedullary nailing. Excluding the routine postoperative radiographs at the time of surgery, a median number of seven radiographs were taken per patient (range 2-13). In total, 343 radiographs were taken after the postoperative film. Of these 343 radiographs, only nine (3%) radiographs led to a decision for clinical intervention. No radiograph in the first 10 weeks after surgery changed management. A reduction in the use of post-operative radiography after tibial nailing is recommended.

Adolescent↗
PubMed1999

Metabolic suppression of platelet-type 12-lipoxygenase in human uterine cervix with invasive carcinoma.

Several types of lipoxygenases with various functions occur in mammalian cells. Although the presence of 12-lipoxygenase activity has been reported in uterine tissues, neither its type nor its biological functions have yet been established. Moreover, the putative role of uterine 12-lipoxygenase in cervical cancer has not been addressed before. Homogenates of uterine tissues from women without cancer and from patients with invasive cervical carcinoma were incubated with (1-(14)C)-arachidonic acid under various conditions and the labelled reaction products were analyzed both by thin-layer chromatography and by high-pressure liquid chromatography. 12-Lipoxygenase protein was estimated by Western blot using anti-serum against recombinant human platelet-type 12-lipoxygenase. Highest concentrations and activities of 12-lipoxygenase were found in the exocervix. The formation of 12S-hydroxy-5Z,8Z,10E, 14Z-eicosatetraenoic acid (12-HETE) was stimulated by micromolar concentrations of 13S-hydroperoxy-9Z,11E-octadecadienoic acid, suggesting metabolic control of the 12-lipoxygenase activity via the hydroperoxide tone. Immunohistochemical investigation revealed that the enzyme is mainly located in the squamous epithelium, and is of platelet-type. Significantly lower values for the 12-HETE formation were found in samples from patients with invasive cervical carcinoma, whereas the amount of immunochemically detectable 12-lipoxygenase protein was unaltered. At the same time the expression levels of the bcl-2 gene were enhanced. Thus, it is concluded that during carcinogenesis the hydroperoxide-reducing capacity of the uterine cervix tissue is enhanced, possibly mediated by bcl-2 protein, and in turn metabolically suppresses the 12-lipoxygenase activity. Furthermore, the data suggest an anti-carcinogenic action of 12-lipoxygenase in human cervix, in contrast to its reported pro-carcinogenic action in breast cancer.

12-Hydroxy-5,8,10,14-eicosatetraenoic Acid↗
PubMed1999

Hepoxilin signaling in intact human neutrophils: biphasic elevation of intracellular calcium by unesterified hepoxilin A3.

We have previously shown that the methyl ester of hepoxilin A3 causes a receptor-induced rise in intracellular calcium through the release from intracellular stores in suspended human neutrophils. The corresponding free acid was devoid of activity. We now report that the action of the free acid form of hepoxilin A3 is dependent on the type of vehicle used, i.e. it is active in releasing calcium when used in an ethanol vehicle but not in DMSO. The methyl ester is equally active in either vehicle. The pattern of calcium release between the free acid and the methyl ester is qualitatively different. Both compounds show a biphasic pattern, i.e. an initial rapid phase followed by a slow decline in calcium levels but never reaching pre-hepoxilin A3 baseline levels. The methyl ester appears slightly more potent in the initial phase of calcium release than the free acid (methyl = 188+/-14 S.D., free acid = 135+/-11 S.D. nM, P < 0.0005). Both compounds appear to reach the same calcium levels at the plateau of the second prolonged phase (methyl = 88+/-8 S.D., free acid = 107+/-15 S.D. nM, not significant). Lanthanum chloride (an inhibitor of calcium influx) interfered with the second phase of the curve causing calcium levels to return to normal pre-hepoxilin levels for both compounds. Addition of lanthanum chloride prior to the hepoxilin addition or carrying out the experiments in calcium-free medium, eliminated the second phase completely, with the calcium peak returning rapidly to normal baseline levels, suggesting that the second phase is due to calcium influx. Again the methyl ester is more active than the free acid (methyl, 189+/-12; free acid, 145+/-6 S.D. nM, P<0.005). Additional experiments with tritium-labelled methyl ester of hepoxilin A3 demonstrated that the compound is hydrolyzed into the free acid intracellularly. These experiments demonstrate that DMSO interacts with hepoxilin free acid, interfering with its entry into the cell while ethanol does not. Once inside the cell, hepoxilin interacts with its own receptor to release calcium rapidly from stores, but it also causes a more prolonged influx of calcium from the extracellular milieu.

8,11,14-Eicosatrienoic Acid↗
PubMed1998

15-Lipoxygenation of phospholipids may precede the sn-2 cleavage by phospholipases A2: reaction specificities of secretory and cytosolic phospholipases A2 towards native and 15-lipoxygenated arachidonoyl phospholipids.

Reticulocyte-type 15-lipoxygenase is known to dioxygenate phospholipids without preceding action of phospholipases A2 (PLA2). Therefore we studied the reaction of the secretory PLA2s (sPLA2) from pancreas and snake venom, and of the human cytosolic PLA2 (cPLA2) with 1-palmitoyl-2-arachidonoyl phosphatidylcholine (PAPC) and their 15-lipoxygenated species (PAPC-OOH and PAPC-OH) either alone or as equimolar mixtures. These PLA2s cleaved PAPC-O(O)H with higher (sPLA2) or similar rates (cPLA2) as compared with native PAPC. In mixtures, however, PAPC proved to be the preferred, albeit not exclusive substrate for all three PLA2s. Thus, partial 15-lipoxygenation of phospholipids may also trigger liberation of arachidonic acid.

Arachidonate 15-Lipoxygenase↗
PubMed1998

Phase II study of suramin plus aminoglutethimide in two cohorts of patients with androgen-independent prostate cancer: simultaneous antiandrogen withdrawal and prior antiandrogen withdrawal.

Management of prostate cancer progression after failure of initial hormonal therapy is controversial. Recently, the activity of the simple discontinuation of antiandrogen therapy has been established by several groups, as well as the enhanced activity when combined with adrenal suppression (i.e., aminoglutethimide and hydrocortisone). Furthermore, suramin has generated considerable interest following reports of response rates ranging from 17 to 70%. More recently, suramin response rates of 18 and 22% have been reported when the potential confounding variables of flutamide withdrawal and hydrocortisone were prospectively controlled. On the basis of the activity of combining aminoglutethimide with flutamide withdrawal, we designed a protocol in which suramin was combined with aminoglutethimide in two cohorts of patients (those with simultaneous antiandrogen withdrawal compared to those who had previously discontinued antiandrogen therapy). Eighty-one evaluable patients were enrolled in this study between June 1992 and November 1994. Patients were a priori divided into two cohorts, those receiving prior antiandrogen withdrawal (n = 56) and those receiving simultaneous antiandrogen withdrawal (n = 25) at the time the patients were enrolled into the trial. For the group that discontinued antiandrogen prior to enrolling in therapy, the partial response rate (> 50% decline in PSA for > 4 weeks) was 14.2%, whereas the partial response was 44% for those patients who discontinued their antiandrogen at the time of starting suramin and aminoglutethimide. The median time to progression was 3.9 months in patients failing prior antiandrogen withdrawal and 5.5 months in those patients having concomitant antiandrogen withdrawal (P = 0.36 for the overall difference). The progression-free survival estimate at 1 year for patients having prior antiandrogen withdrawal was 19.8% [95% confidence interval (CI), 11-32.9%]. For those patients who experienced antiandrogen withdrawal simultaneous with the treatment, the progression-free survival estimates at 1 and 2 years were 27.1 (95% CI, 13.2-47.6%) and 4.5% (95% CI, 0.8-21.6%). The median survival time for those patients having prior antiandrogen withdrawal was 14.2 months, whereas the median survival was 21.9 months for those having concomitant antiandrogen withdrawal (P = 0.029 for the overall difference). In conclusion, the partial response rate of 44% for those who had concomitant flutamide withdrawal with adrenal suppression was consistent with that of other reports using a similar maneuver. Although this study was not randomized and thus we should not over-interpret the results, flutamide withdrawal plus adrenal suppression appears to have greater activity than flutamide withdrawal alone. Furthermore, these data suggest that suramin adds little to the response rate observed for other adrenal suppressive agents in the presence of antiandrogen withdrawal. This interpretation is in agreement with those studies controlling for adrenal suppression and flutamide withdrawal prior to suramin administration, which noted modest activity of short duration. Given that antiandrogen withdrawal is now accepted as an active maneuver for a subset of patients progressing after maximum androgen blockade, we propose that future trials attempting to maximize response rates incorporate this maneuver whenever possible into prospectively designed regimens.

Adult↗
PubMed1998

Allergy in the airway.

BACKGROUND: Airway disease is responsible for significant morbidity worldwide and the role of allergies in the cause and persistence of airway symptoms is becoming increasingly appreciated. OBJECTIVE: The exposure of the airway to allergens depends on the size of inhaled particles. Common allergens encountered in Australia include grass pollens, house dust mites and animal danders and sensitivity to each leads to a different clinical pattern of disease. The diagnosis of allergy requires a history of symptoms related to exposure to an allergen, together with detection of allergen-specific IgE. The evidence for the role of allergens in contributing to allergic airway disease is extensive. DISCUSSION: Airway allergies are an important factor in the genesis of asthma and allergic rhinitis. There is increasing evidence that modification of exposure to allergens can improve allergic symptoms and may prevent allergic diseases. Methods of allergen avoidance are discussed.

Allergens↗
PubMed1997

Predictors of attendance at a relocatable mammography service for rural women.

This study aimed to identify factors that predicted attendance at a relocatable screening mammography service in a rural centre in Victoria. A cohort design was used whereby 180 women from the target population were interviewed by telephone two weeks before the service moved to the area for a 10-week period of operation. Attendance data were ascertained from service records. Fifty per cent of the sample attended the service. Significant predictors of attendance were: mammographic history, with women who reported previous screening mammography being less likely to attend than women who had not had a previous mammogram (odds ratio (OR) 0.38, 95% confidence interval (CI) 0.17 to 0.83); perception of personal risk for breast cancer, with women who perceived at least some risk being more likely to attend than women who perceived no risk (OR 2.73, CI 1.07 to 6.99); stated intention of attending (OR 2.01, CI 1.49 to 2.71); knowing the correct location of the service (OR 3.08, CI 1.37 to 6.89); and education, with higher education being associated with a lower likelihood of attending (OR 0.65, CI 0.44 to 0.96). Our study raised some issues, including the high prevalence of rural women who reported a previous screening mammogram, although BreastScreen services had not previously been available in their area; factors underlying perceptions of personal risk for breast cancer; and the generalisability of our finding of an inverse relationship between higher education and attendance for screening.

Aged↗
PubMed1996

Comparison of angiotensin II type 1 receptor blockade and angiotensin-converting enzyme inhibition in pregnant sheep during late gestation.

1. The effects of antagonism of the maternal renin-angiotensin system (RAS) with either an angiotensin II type 1-(AT1) specific receptor blocker (GR138950) or an angiotensin-converting enzyme (ACE) inhibitor (captopril) were compared in chronically-catheterised ewes and their foetuses during late gestation. 2. Daily from 127 +/- 1 days of gestation until parturition at 145 +/- 2 days, each ewe received i.v. either GR138950 (3 mg kg-1; n = 10), captopril (3 mg kg-1; n = 6) or an equivalent volume of vehicle solution (0.9% w/v saline; n = 10). 3. Within 2 h of drug administration, GR138950 abolished the maternal, but not the foetal, pressor responses to angiotensin II (AII; 100-188 ng kg-1, i.v.; P < 0.05), whereas captopril abolished both the maternal and foetal pressor responses to angiotensin I (AI; 400-750 ng kg-1, i.v.; P < 0.05). 4. On the first day of treatment, maternal blood pressure decreased in all GR138950-treated (-21 +/- 4 mmHg; P < 0.05) and captopril-treated (-13 +/- 5 mmHg; P > 0.05) ewes at 2 h after drug administration. Captopril also significantly decreased foetal blood pressure by 5 +/- 1 mmHg (P < 0.05). However, foetal blood pressure in the GR138950-treated animals remained unchanged. Maternal and foetal heart rates were unaffected by any treatment. Uterine blood flow was significantly reduced within 2 h of both GR138950 (-130 +/- 20 ml min-1; P < 0.05) and captopril (-72 +/- 16 ml min-1; P < 0.05) administration. 5. On the first day of treatment, maternal arterial haemoglobin (Hb) concentration and oxygen (O2) content increased at 2 h in all GR138950-treated and captopril-treated ewes. Foetal arterial pH and oxygenation (O2 content, O2 saturation and Pao2) were reduced by a similar extent in both groups of drug-treated ewes. 6. After one week of daily GR138950 administration, maternal blood pressure decreased from a pretreatment value of 96 +/- 5 mmHg on day 1 to 79 +/- 2 mmHg by day 7 (P < 0.05). Captopril treatment had no long-term effect on maternal blood pressure. Although foetal blood pressure increased by 3 +/- 1 mmHg over a week of vehicle treatment (P < 0.05), no significant differences were observed between the long-term changes in foetal blood pressure in all three groups of animals. 7. There were no long-term effects of drug administration on maternal Hb concentration or oxygenation, or on the foetal haematological parameters. However, changes in maternal PaCo2 observed in the GR138950-treated (+1.4 +/- 0.5 mmHg; P < 0.05) and captopril-treated (+3.3 +/- 1.1 mmHg; P > 0.05) ewes were significantly different from those seen in the vehicle-treated animals (P < 0.05). 8. There were no apparent adverse effects of maternal GR138950 or captopril treatment on foetal viability. 9. The present study demonstrated that administration of either GR138950 or captopril to pregnant ewes effectively blocked the maternal RAS, and caused hypotension and a decrease in uterine blood flow. However, only captopril appeared to cross the placenta to influence directly the RAS of the sheep foetus. This suggests that the fall in foetal oxygenation observed after AT1-specific receptor blockade and ACE inhibition originates primarily from changes in the maternal and/or placental vasculature. Despite these changes, neither GR138950 nor captopril were detrimental to the outcome of pregnancy when foetal blood loss was kept to a minimum.

Angiotensin Receptor Antagonists↗
PubMed1996

Defective thrombin-induced calcium changes and aggregation of Bernard-Soulier platelets are not associated with deficient moderate-affinity receptors.

Cloning of the moderate-affinity, serpentine thrombin receptor has helped clarify the mechanism of thrombin-induced platelet activation. Proteolytic cleavage by thrombin generates a new amino terminal that autostimulates the receptor, leading to activation of multiple signaling pathways and the platelet response. The function of other thrombin receptors, such as high-affinity glycoprotein Ib (GPIb), on platelets and their relationships to the moderate-affinity receptor remain unclear. The present study examined the role of the moderate-affinity thrombin receptor in Bernard-Soulier syndrome (BSS) platelets, which contain low amounts of GPIb. Platelets from four BSS subjects displayed normal aggregation profiles and cytosolic calcium changes in response to moderate or high concentrations of thrombin. In contrast, the BSS platelet aggregation response was delayed and calcium changes were absent in response to low thrombin concentrations. Platelets from an asymptomatic BSS heterozygote displayed an activation profile similar to those of control individuals. Specific activation of the moderate-affinity receptor by a synthetic peptide caused similar aggregation in platelets from all individuals. The synthetic peptide also elicited calcium responses in BSS platelets. Platelets from the BSS subjects and from an individual with the May-Hegglin anomaly showed increased expression of the moderate-affinity thrombin receptor by flow-cytometric analyses. These results suggest that BSS platelets possess high levels of a functional moderate-affinity thrombin receptor, probably due to large platelet size, and provide indirect evidence that a high-affinity thrombin receptor is associated with GPIb.

Bernard-Soulier Syndrome↗
PubMed1995

Vav and Ras induce fibroblast transformation by overlapping signaling pathways which require c-Myc function.

Recent evidence has suggested that the Vav oncoprotein may function as a hematopoietic-specific GTP exchange factor for the Ras superfamily of proteins. However, transformation of NIH3T3 fibroblast cells by Vav is morphologically distinct from that induced by activated Ras oncogenes, suggesting that the two oncoproteins induce separate signal transduction pathways which promote transformation. To address this issue, the effects of dominant negative mutants of H-ras and proto-Vav (proto-VavR695L, a mutation in the VavSH2 domain) were tested on Vav- and Ras-induced transformation. These mutants partially inhibited both Vav- and Ras-induced transformation, suggesting that they may induce a common downstream signaling pathway which potentiates transformation. As an independent measure of Vav function we also tested the ability of the purified protein encoded by VavSH2 to influence Germinal Vesicle Breakdown (GVBD) during Xenopus oocyte maturation. Microinjection of the VavSH2 protein alone, but not mutant VavR695L SH2 protein, was sufficient to induce GVBD and accelerated maturation induced by normal Ras, suggesting that in this system as well Vav and Ras signals overlap through a common effector. A key target of multiple signalling pathways is c-Myc. Dominant negative versions of c-Myc totally abolished morphologic transformation of NIH3T3 cells by both Vav and Ras oncogenes. These results suggest that distinct, but overlapping, signalling pathways are induced by Vav and Ras and that fibroblast cell transformation by either oncogene requires c-Myc functions.

3T3 Cells↗
PubMed1994

The protein tyrosine kinase ZAP-70 can associate with the SH2 domain of proto-Vav.

Stimulation of the T cell antigen receptor (TCR) leads to tyrosine phosphorylation of a number of cellular proteins, including the vav proto-oncogene product. We now report the detection of several phosphotyrosine proteins (80, 74, and 70 kDa) from TCR-stimulated T cells that bind to the Src homology 2 (SH2) domain of proto-Vav (Vav-SH2) and co-immunoprecipitate with the proto-Vav product. Their binding to Vav-SH2 differs from that observed with SH2 domains from other proteins. None of the Vav-SH2-associated phosphoproteins bind to either of the Src homology 3 (SH3) domains of proto-Vav or to mutant Vav-SH2 proteins. The association of the phosphoproteins with Vav-SH2 requires induction of tyrosine phosphorylation of cellular proteins since proteins from lysates of herbimycin A-treated TCR-activated T cells fail to associate with Vav-SH2. Among the proteins from T cells that co-immunoprecipitate with the proto-Vav product and bind to its SH2 domain, specific antibodies identified the 70-kDa tyrosine phosphoprotein as ZAP-70, a protein tyrosine kinase (PTK) involved in TCR signal transduction. Binding of this PTK to Vav-SH2 is inhibited by a ZAP-70-specific synthetic tyrosine phosphopeptide. We suggest that ZAP-70 may function as a PTK for proto-Vav.

3T3 Cells↗
PubMed1994

Cloning, sequence and in vitro transcription/translation analysis of a 3.2-kb EcoRI-HindIII fragment of Leuconostoc oenos bacteriophage L10.

A 3.2-kb EcoRI-HindIII DNA fragment of Leuconostoc oenos bacteriophage L10 was cloned and sequenced. Computer-assisted analysis of the sequence identified eleven possible open reading frames (ORFs) that were all on the same strand. In vitro transcription/translation analysis of the full-length DNA fragment yielded five prominent proteins that were correlated with ORFs by their sizes and expression from deleted clones. Only those ORFs containing recognizable Shine-Dalgarno sequences coded for proteins. Neither the nucleotide sequence, nor deduced amino-acid sequences showed significant homology with other known sequences.

Amino Acid Sequence↗