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S A Roberts

Publications and source records attributed to S A Roberts.

At least 55 records · Page 3Linked to original sources
PubMed2001

Ribozyme minigene-mediated RAD51 down-regulation increases radiosensitivity of human prostate cancer cells.

The strand transferase RAD51 is a component of the homologous recombination repair pathway. To examine the contribution of RAD51 to the genotoxic effects of ionising radiation, we have used a novel ribozyme strategy. A reporter gene vector was constructed so that expression of an inserted synthetic double-stranded ribozyme-encoding oligonucleotide would be under the control of the cytomegalovirus immediate-early gene enhancer/promoter system. The prostate tumour cell line LNCaP was transfected with this vector or a control vector, and a neomycin resistance gene on the vector was used to create geneticin-resistant stable cell lines. Three stable cell lines were shown by western blot analysis to have significant down-regulation of RAD51 to 20-50% of the levels expressed in control cell lines. All three cell lines had a similar increased sensitivity to gamma-irradiation by 70 and 40%, respectively, compared to normal and empty vector-transfected cells, corresponding to dose-modifying factors of approximately 2.0 and 1.5 in the mid-range of the dose-response curves. The amount of RAD51 protein in transfected cell lines was shown to strongly correlate with the alpha parameter obtained from fitted survival curves. These results highlight the importance of RAD51 in cellular responses to radiation and are the first to indicate the potential use of RAD51-targeted ribozyme minigenes in tumour radiosensitisation.

Base Sequence↗
PubMed2001

Sensitivity to radiation-induced chromosome damage may be a marker of genetic predisposition in young head and neck cancer patients.

We previously showed that levels of chromosome damage induced by ionizing radiation were, on average, higher in G(2)and G(0)lymphocytes of breast cancer patients than of normal healthy controls, but that there was no correlation between the results in the two assays. We proposed that enhanced sensitivity to G(2)or G(0)irradiation was a marker of low-penetrance predisposition to breast cancer, and have recently demonstrated heritability of sensitivity in families of breast cancer cases. We have now applied these assays to patients with head and neck cancers, for whom there is epidemiological evidence of inherited predisposition in addition to environmental causes. The mean frequency of radiation-induced G(2)aberrations was higher in the 42 patients than in 27 normal controls, but not significantly so. However, cases less than 45 years old were significantly more sensitive than normals of the same age range (P = 0.046), whereas there was no difference between patients and normals of less than 45 years. Also, there was an inverse correlation between G(2)sensitivity and age for patients but not for normals. Radiation-induced micronuclei in G(0)cells were more frequent in 49 patients than in 31 normals (P = 0.056) but, as with the G(2)assay, the greatest difference was seen between early-onset patients and young normals. Again there was an inverse correlation with age for patients but not for normals. Six patients with enhanced toxicity to radiotherapy were G(2)tested and four other such patients were G(0)tested; levels of chromosome damage were not significantly greater than in patients with normal reactions. Both assays were used on 64 individuals (39 patients, 25 normals) and there was no significant correlation between the results. We suggest that a proportion of early-onset head and neck cancer patients are genetically predisposed and that each of the two assays detects a different subset of these cases.

Adult↗
PubMed2001

Infection of orthopedic prostheses after Staphylococcus aureus bacteremia.

We prospectively evaluated 53 patients with prosthetic joints and 27 patients with other orthopedic prosthetic devices who developed Staphylococcus aureus bacteremia (SAB). After exclusion of patients with primary postoperative infections, the risk of a prosthesis becoming infected by means of hematogenous seeding after SAB was 34% (15 of 44 patients) for prosthetic joints and 7% (1 of 15 patients) for other orthopedic prostheses.

Adult↗
PubMed2001

Normal tissue radiobiology: from the laboratory to the clinic.

This manuscript is in four parts, presenting the four talks given in a symposium on normal tissue radiobiology. The first part addresses the general concept of the role of parenchymal cell radiosensitivity vs. other factors, highlighting research over the last decade that has altered our understanding of factors underlying normal tissue response. The other three parts expand on specific themes raised in the first part dealing in particular with (1) modifications of fibroblast response to irradiation in relation to the induction of tissue fibrosis, (2) the use of the linear-quadratic equation to model the potential benefits of using different means (both physical and biologic) of modifying normal tissue response, and (3) the specific role of the growth factor TFG-beta1 in normal tissue response to irradiation. The symposium highlights the complexities of the radiobiology of late normal tissue responses, yet provides evidence and ideas about how the clinical problem of such responses may be modified or alleviated.

Animals↗
PubMed2001

The required number of treatment imaging days for an effective off-line correction of systematic errors in conformal radiotherapy of prostate cancer--a radiobiological analysis.

BACKGROUND AND PURPOSE: To use radiobiological modelling to estimate the number of initial days of treatment imaging required to gain most of the benefit from off-line correction of systematic errors in the conformal radiation therapy of prostate cancer. MATERIALS AND METHODS: Treatment plans based on the anatomical information of a representative patient were generated assuming that the patient is treated with a multi leaf collimator (MLC) four-field technique and a total isocentre dose of 72 Gy delivered in 36 daily fractions. Target position variations between fractions were simulated from standard deviations of measured data found in the literature. Off-line correction of systematic errors was assumed to be performed only once based on the measured errors during the initial days of treatment. The tumour control probability (TCP) was calculated using the Webb and Nahum model. RESULTS: Simulation of daily variations in the target position predicted a marked reduction in TCP if the planning target volume (PTV) margin was smaller than 4 mm (TCP decreased by 3.4% for 2 mm margin). The systematic components of target position variations had greater effect on the TCP than the random components. Off-line correction of estimated systematic errors reduced the decrease in TCP due to target daily displacements, nevertheless, the resulting TCP levels for small margins were still less than the TCP level obtained with the use of an adequate PTV margin of approximately 10 mm. The magnitude of gain in TCP expected from the correction depended on the number of treatment imaging days used for the correction and the PTV margin applied. Gains of 2.5% in TCP were estimated from correction of systematic errors performed after 6 initial days of treatment imaging for a 2 mm PTV margin. The effect of various possible magnitudes of systematic and random components on the gain in TCP expected from correction and on the number of imaging days required was also investigated. CONCLUSIONS: Daily variations of target position markedly reduced the TCP if small margins were used. Off-line correction of systematic errors can only partly compensate for these TCP reductions. The adequate number of treatment imaging days required for systematic error correction depends on the magnitude of the random component compared with the systematic component, and on the size of PTV margin used. For random components equal to or smaller than the systematic component, 3 consecutive treatment imaging days are estimated to be sufficient to gain most of the benefit from correction for current clinically used margins (6-10 mm); otherwise more days are required.

Humans↗
PubMed2001

Reasons for increased postnatal length of stay & women's perceptions of length of stay.

A quality improvement project was conducted by a major maternity provider (3000 births per year) in the western suburbs of Melbourne. The first part of the project explored the reasons for increased length of stay (LOS), beyond the average timeframe for women receiving postnatal care. The perceptions of 100 women on their length of stay was also measured in the second part of the project. Two information audits were conducted to explore reasons for increased LOS. These reasons were varied, and by the time of the second audit, there was a demonstrated reduction in LOS. A Length of Stay Questionnaire was used to investigate women's perceptions of their LOS on discharge from hospital, and by telephone follow-up 14 days post-discharge. Perceptions varied between women and related to issues such as individual health complications, models of care, postnatal education, and degree of support at home. This project has implications for postnatal midwifery care in relation to discharge planning and women's expectations of care following birth.

Female↗
PubMed2001

Experience with laparoscopic ultrasonography for defining tumour resectability in carcinoma of the pancreatic head and periampullary region.

BACKGROUND: Computed tomography (CT) is currently the most widely available staging investigation for pancreatic tumours. However, the accuracy of CT for determining tumour resectability is variable and can be poor. Laparoscopic ultrasonography (LUS) is potentially a more accurate method for disease staging. The authors' experience of LUS for staging carcinoma of the pancreatic head and periampullary region is described. METHODS: Fifty-one patients with potentially resectable pancreatic tumours defined at CT underwent further investigation with LUS. Twenty-seven patients subsequently had an open laparotomy. The evaluations of tumour resectability at CT and LUS were compared with the operative findings. RESULTS: At LUS, 24 patients were considered to have resectable tumours, 21 non-resectable tumours and six patients were shown to have no pancreatic tumour mass. Twenty-two patients deemed to have a resectable tumour at LUS underwent surgery. Twenty patients were confirmed to have resectable disease and two patients had non-resectable disease. A further five patients underwent surgery. In all five the ultrasonographic diagnosis was confirmed at surgery (four patients with non-resectable disease and no pancreatic tumour in one patient). LUS prevented unnecessary extensive surgery in 53 per cent of patients. For the 22 patients who underwent surgery for potentially resectable disease, the positive predictive value of LUS for defining tumour resectability was 91 per cent. CONCLUSION: LUS is an accurate additional investigation for defining tumour resectability and directing management in patients with potentially resectable carcinoma of the pancreatic head or periampullary region.

Adult↗
PubMed2001

Investigation of an outbreak of multi-drug resistant Acinetobacter baumannii in an intensive care burns unit.

Over a three month period there was an outbreak of infection, due to a multi-drug resistant Acinetobacter baumannii in the intensive care burns unit with spread of infection to other patients, both within the unit and elsewhere in the hospital. Microbiological sampling of the environment and of the healthcare workers' (HCWs) hands were carried out. Strain relatedness of the isolates was confirmed by pulsed field gel electrophoresis. Fifteen patients were involved in the outbreak, whose infections were all hospital-acquired. The burns room environment was contaminated with the A. baumannii, as was the door handle of the door leading from the ante-chamber between both rooms. This allowed the hands of HCWs to be contaminated by A. baumannii despite appropriate handwashing procedures prior to leaving the rooms. Two staff members were colonized with A. baumannii. One HCW who was directly involved in patient care was found to be "heavily" colonized, the other, with less patient contact, was only "lightly" colonized. Review of handwashing practices revealed that chlorhexidine/alcohol hand wash solution was not used by the HCW whose hands were heavily colonized.A combination of a review of handwashing practice, education about the spread of bacteria via hands and contaminated environment, and the revision of infection control procedures in the unit contributed to a prompt termination of the outbreak.

Acinetobacter↗
PubMed2001

Tyrosine requirement of healthy men receiving a fixed phenylalanine intake determined by using indicator amino acid oxidation.

BACKGROUND: The currently accepted total aromatic amino acid requirement for adults is based on nitrogen balance measurements in individuals who received their intake of aromatic amino acids solely as phenylalanine. OBJECTIVE: The objective of this study was to determine the requirement for the amino acid tyrosine in healthy men receiving an adequate, but not excessive, intake of phenylalanine (9 mg x kg(-1) x d(-1)). DESIGN: The effect of a graded intake of tyrosine was determined in 6 healthy men consuming energy-sufficient diets containing 1 g protein x kg(-1) x d(-1). The tyrosine requirement was determined by using indicator amino acid oxidation methodology with L-[1-13C]lysine as the indicator. Subjects were studied at each of 7 tyrosine intakes. RESULTS: A graded intake of tyrosine had no effect on lysine flux. The mean tyrosine requirement was determined from the response of the oxidation of L-[1-13C]lysine to breath 13CO2. A 2-phase linear regression crossover analysis of breath 13CO2 identified the breakpoint and upper 95% confidence limit, which represents the mean and safe intakes, to be 6.0 and 7.0 mg x kg(-1) x d(-1), respectively. CONCLUSIONS: The safe intake of total aromatic amino acids calculated from the present results for tyrosine and our previous estimate for phenylalanine is estimated to be 21 mg x kg(-1) x d(-1). This intake is 1.5 times the currently recommended total aromatic amino acid intake of the FAO/WHO/UNU (1985), 14 mg x kg(-1) x d(-1). Furthermore, the absolute aromatic amino acid requirement may be dependent on the proportional balance of these amino acids in the diet.

Adult↗
PubMed2001

A new MMPI-derived indicator of liability to develop schizophrenia: evidence from the New York High-Risk Project.

A large body of research indicates that the liability to develop schizophrenia is largely genetically mediated, although phenotypic expression requires environmental triggers/insults and/or epigenetic and/or stochastic factors. In an effort to identify the precise environmental factors that precipitate a predisposition to schizophrenia, researchers have implemented a high-risk model-the prospective study of offspring born to schizophrenic parents. As it is difficult to ascertain exactly which of the "high-risk" participants will actually develop the disorder, we examined the validity of an experimental MMPI scale, Schizophrenia Proneness (SzP), and the Moldin-Gottesman psychometric index to identify such individuals. Results suggest that the SzP scale can be an effective predictor of schizophrenia-related psychoses. A revised psychometric index is offered for further study.

Adolescent↗
PubMed2001

The effect of graded intake of glycyl-L-tyrosine on phenylalanine and tyrosine metabolism in parenterally fed neonates with an estimation of tyrosine requirement.

Although tyrosine is considered indispensable during the neonatal period, its poor solubility has limited its inclusion in parenteral amino acid solutions to less than 1% of total amino acids. Dipeptides of tyrosine are highly soluble, have been shown to be well used and safe in animal models and humans, and, therefore, may be used as an effective means of providing tyrosine in the parenterally fed neonate. The goal of the present study was to determine the tyrosine requirement of the parenterally fed neonate receiving graded intakes of glycyl-L-tyrosine as a source of tyrosine. Thirteen infants receiving adequate energy (340 +/- 38 kJ. kg(-1).d(-1)) and protein (2.4 +/- 0.4 g.kg(-1).d(-1)) were randomized to receive parenteral nutrition with one of five graded levels of glycyl-L-tyrosine. The mean requirement and safe level of intake were estimated using a 1-(13)C-phenylalanine tracer and linear regression cross-over analysis that identified a break point in the response of label appearance in breath CO(2) (F(13)CO(2)) and phenylalanine oxidation to graded tyrosine intake. Based on the mean estimates of whole-body phenylalanine oxidation, the tyrosine mean requirement and safe level of intake were found to be 74 mg.kg(-1). d(-1) and 94 mg.kg(-1).d(-1), respectively. This represents 3.1 and 3.9% of total amino acids, respectively, considerably higher than levels found in present commercially available pediatric amino acid solutions. These data raise concern regarding the adequacy of aromatic amino acid intake in the parenterally fed neonate.

Amino Acids↗
PubMed2001

Prospective study of 424 cases of Staphylococcus aureus bacteraemia: determination of factors affecting incidence and mortality.

BACKGROUND: Staphylococcus aureus bacteraemia (SAB) is a common complication of S. aureus infection and is associated with a high mortality. AIMS: To document prospectively the pattern of illness associated with SAB in New Zealand and, by recording patient demographic factors and clinical features, to identify risk factors associated with a poor outcome. METHODS: From 1 July 1996 to 31 December 1997, adults with SAB were prospectively studied in six tertiary care hospitals. All information obtained from patients' records was recorded on worksheets and transferred to a computerized spreadsheet for analysis. RESULTS: There were 424 patients with SAB. Maori (relative risk (RR)= 1.8, 95% confidence interval (CI) = 1.3-2.6) and Pacific Island people (RR = 4.0, 95% CI = 3.1-5.3) were significantly more likely than people of European descent to acquire SAB, but not to die from the infection. Fifty per cent of cases were community acquired. A source was identified for 85%: intravenous catheter (31%), primarily hospital acquired, and skin/soft tissue (22%), primarily community acquired, were the most common foci. The 30-day mortality was 19%, 83% of whom died within 2 weeks. Risk factors for a poor outcome were: increasing age above 60, female sex (RR = 1.4, 95% CI = 1.0-2.1), diabetes mellitus (RR = 1.5, 95% CI = 1.0-2.4), immunosuppression (RR = 1.5, 95% CI = 1.0-2.4), pre-existing renal impairment (RR = 1.8, 95% CI = 1.2-2.7), malignancy (RR= 2.2, 95% CI = 1.4-3.5), lung as a source (RR = 2.8, 95% CI = 1.9-4.2) and unknown source (RR = 2.3, 95% CI = 1.5-3.3). Mortality was also accurately predicted by two multifactor scoring systems. There was a low rate of methicillin resistance (5%). CONCLUSIONS: Staphylococcus aureus bacteraemia is more likely to occur in certain ethnic groups, while mortality is associated with other identifiable risk factors and continues to be high. Intravenous catheters remain the most common and most preventable cause of SAB.

Adolescent↗
PubMed2000

Nocardia infection in heart-lung transplant recipients at Alfred Hospital, Melbourne, Australia, 1989-1998.

Nocardia infections are uncommon in recipients of heart, lung, or heart-lung transplants, but such infections are well described. Frequent episodes of rejection, high-dose prednisolone treatment, renal impairment, and prolonged respiratory support have all been shown to increase the risk of Nocardia infection in this group. In this retrospective review of 540 recipients of heart, lung, or heart-lung transplants, 10 patients developed Nocardia infection (frequency, 1.85%). Infection occurred at a mean +/- standard deviation of 13+/-14.5 months after transplantation. All patients had pulmonary disease with no evidence of extrapulmonary disease. The Nocardia infection did not contribute directly to patient deaths. Coinfection with other pathogens was present in 6 patients, and 2 patients had sequential infections. Radiological findings varied. All isolates were susceptible to trimethoprim-sulfamethoxazole, amikacin, and imipenem. Treatment regimens varied. Two (30%) of 6 patients treated with trimethoprim-sulfamethoxazole developed adverse reactions, which necessitated a change in antibiotic therapy. The optimal treatment regimen, which comprises both the antimicrobial agent and the length of treatment, is unclear.

Adult↗
PubMed2000

Effect of tyrosine intake on the rate of phenylalanine hydroxylation in adult males.

This study evaluated the effect of varying levels of tyrosine intake on the estimation of phenylalanine hydroxylation. Healthy men were fed 1 g protein kg(-1) x d(-1) for a 2-day period. On the third day, subjects consumed a formula diet containing 1 g protein kg(-1) x d(-1) hourly over 10 hours, and primed hourly oral doses of L-[15N]phenylalanine and L-[3,3-2H2]tyrosine for the last 6 hours. Each subject was studied at 7 levels of tyrosine intake (3.0, 4.5, 6.0, 7.5, 9.0, 10.5, and 12.0 mg x kg(-1) x d(-1)) at a constant intake of phenylalanine (9 mg x kg(-1) x d(-1), 4.55 micromol x kg(-1) x h(-1)). Phenylalanine hydroxylation was estimated from the ratio of plasma amino acid isotope enrichment of [15N]phenylalanine and [15N]tyrosine and the tyrosine flux estimated from [2H2]tyrosine enrichment. Phenylalanine and tyrosine fluxes showed no significant response to alterations in the intake of tyrosine. Linear regression analysis showed a significant response such that the rate of phenylalanine hydroxylation decreased as tyrosine intake increased (R2 = .21; P = .003). The mean rates of phenylalanine hydroxylation were 3.89 to 8.06 micromol x kg(-1) x h(-1). Given model uncertainties, the apparent protein breakdown observed at tyrosine intake levels less than 10.5 mg x kg(-1) x d(-1), and the significant differences observed between the present data and our prior data, we cannot estimate the tyrosine requirement with any degree of certainty with the present hydroxylation results.

Adult↗
PubMed2000

Relationship between in vitro chromosomal radiosensitivity of peripheral blood lymphocytes and the expression of normal tissue damage following radiotherapy for breast cancer.

BACKGROUND AND PURPOSE: There is a need for rapid and reliable tests for the prediction of normal tissue responses to radiotherapy, as this could lead to individualization of patient radiotherapy schedules and thus improvements in the therapeutic ratio. Because the use of cultured fibroblasts is too slow to be practicable in a clinical setting, we evaluated the predictive role of assays of lymphocyte chromosomal radiosensitivity in patients having radiotherapy for breast cancer. MATERIALS AND METHODS: Radiosensitivity was assessed using a micronucleus (MN) assay at high dose rate (HDR) and low dose rate (LDR) on lymphocytes irradiated in the G(0) phase of the cell cycle (Scott D, Barber JB, Levine EL, Burril W, Roberts SA. Radiation-induced micronucleus induction in lymphocytes identifies a frequency of radiosensitive cases among breast cancer patients: a test for predispostion? Br. J. Cancer 1998;77;614-620) and an assay of G(2) phase chromatid radiosensitivity ('G(2) assay') (Scott D, Spreadborough A, Levine E, Roberts SA. Genetic predisposition in breast cancer. Lancet 1994; 344: 1444). In a study of acute reactions, blood samples were taken from breast cancer patients before the start of radiotherapy, and the skin reaction documented. 116 patients were tested with the HDR MN assay, 73 with the LDR MN assay and 123 with the G(2) assay. In a study of late reactions, samples were taken from a series of breast cancer patients 8-14 years after radiotherapy and the patients assessed for the severity of late effects according to the'LENT SOMA' scales. 47 were tested with the HDR assay, 26 with the LDR assay and 19 with the G(2) assay. For each clinical endpoint, patients were classified as being normal reactors or 'highly radiosensitive patients' (HR patients (Burnet NG. Johansen J, Turesson I, Nyman J. Describing patients' normal tissue reactions: Concerning the possiblity of individualising radiotherapy dose presciptions based on potential predictive assays of normal tissue radiosensitivity. Int. J. Cancer 1998;79:606-613)). RESULTS: The HR patients could be identified in some of the assays. For example, for acute skin reactions, 9/123 patients were judged as HR; they had significantly higher G(2) scores than normal reactors (P=0.004). For the late reactions, the mean HDR MN scores were higher for the 4/47 patients who had severe telangiectasia (P=0.042) and the 8/47 patients had severe fibrosis (P=0.055). However, there were no trends towards increased chromosomal radiosensitivity with the micronucleus scores at HDR or LDR, or with G(2) chromosomal radiosensitivity. CONCLUSIONS: While these results support the concept of using lymphocytes to detect elevated sensitivity to radiotherapy (as an alternative to fibroblasts), these assays are unlikely to be of assistance for the prediction of normal tissue effects in the clinic in their present form.

Adult↗
PubMed2000

Nitric oxide binding to nitrophorin 4 induces complete distal pocket burial.

The nitrophorins comprise an unusual family of proteins that use ferric (Fe(III)) heme to transport highly reactive nitric oxide (NO) from the salivary gland of a blood sucking bug to the victim, resulting in vasodilation and reduced blood coagulation. We have determined structures of nitrophorin 4 in complexes with H2O, cyanide and nitric oxide. These structures reveal a remarkable feature: the nitrophorins have a broadly open distal pocket in the absence of NO, but upon NO binding, three or more water molecules are expelled and two loops fold into the distal pocket, resulting in the packing of hydrophobic groups around the NO molecule and increased distortion of the heme. In this way, the protein apparently forms a 'hydrophobic trap' for the NO molecule. The structures are very accurate, ranging between 1.6 and 1.4 A resolutions.

Animals↗