PubMed Health⌕ Search

Biomedical subjects

N H de Klerk

Publications and source records attributed to N H de Klerk.

At least 19 recordsLinked to original sources
PubMed2006

Authenticity and drug resistance in a panel of acute lymphoblastic leukaemia cell lines.

Cell lines are important models for drug resistance in acute lymphoblastic leukaemia (ALL), but are often criticised as being unrepresentative of primary disease. There are also doubts regarding the authenticity of many lines. We have characterised a panel of ALL cell lines for growth and drug resistance and compared data with that published for primary patient specimens. In contrast to the convention that cell lines are highly proliferative, those established in our laboratory grow at rates similar to estimates of leukaemic cells in vivo (doubling time 53-442 h). Authenticity was confirmed by genetic fingerprinting, which also demonstrated the potential stability of long-term cultures. In vitro glucocorticoid resistance correlated well with that measured ex vivo, but all lines were significantly more sensitive to vincristine than primary specimens. Sensitivity to methotrexate was inversely correlated to that of glucocorticoids and L-asparaginase, indicating possible reciprocity in resistance mechanisms. A cell line identified as highly methotrexate resistant (IC50 > 8000-fold higher than other lines) was derived from a patient receiving escalating doses of the drug, indicating in vivo selection of resistance as a cause of relapse. Many of these lines are suitable as models to study naturally occurring resistance phenotypes in paediatric ALL.

Antineoplastic Agents↗
PubMed2006

Altered glucose metabolism in childhood pre-B acute lymphoblastic leukaemia.

The cells of solid tumours are known to have an altered metabolism, with high rates of glucose uptake and glycolysis, which results in the excessive production of lactate. To date there has been no definitive research documenting metabolic changes in acute lymphoblastic leukaemia (ALL) cells. In order to investigate whether ALL cells have an altered metabolism, we initially compared the transcriptional profiles of 22 specimens from paediatric patients diagnosed with ALL to five CD34+ specimens isolated from bone marrow, which was verified in an independent cohort of 101 specimens. Profiling revealed the upregulation of genes facilitating glycolysis in the ALL specimens compared to the CD34+ specimens, while those involved in the tricarboxylic acid cycle were downregulated. Functional studies supported the microarray findings threefold: (1) higher expression of the glucose transport protein glucose transporter 1 in ALL compared to CD34+ specimens, (2) the excessive production of lactate in ALL cell lines and (3) sensitivity of ALL cell lines to the glycolysis inhibitor 2-deoxy-D-glucose. While metabolic alterations have been well documented in solid tumours, this is the first study to provide direct evidence for the existence of metabolic changes in the leukaemic cells of ALL patients. The finding offers new options for targeted therapy for ALL patients.

Antigens, CD34↗
PubMed2006

The risk of lung cancer with increasing time since ceasing exposure to asbestos and quitting smoking.

OBJECTIVES: To examine if the risk of lung cancer declines with increasing time since ceasing exposure to asbestos and quitting smoking, and to determine the relative asbestos effect between non-smokers and current smokers. METHODS: A cohort study of 2935 former workers of the crocidolite mine and mill at Wittenoom, who responded to a questionnaire on smoking first issued in 1979 and on whom quantitative estimates of asbestos exposure are known. Conditional logistic regression was used to relate asbestos exposure, smoking category, and risk of lung cancer. RESULTS: Eighteen per cent of the cohort reported never smoking; 66% of cases and 50% of non-cases were current smokers. Past smokers who ceased smoking within six years of the survey (OR = 22.1, 95% CI 5.6 to 87.0), those who ceased smoking 20 or more years before the survey (OR = 1.9, 95% CI 0.50 to 7.2), and current smokers (<20 cigarettes per day (OR = 6.8, 95% CI 2.0 to 22.7) or >20 cigarettes per day (OR = 13.2, 95% CI 4.1 to 42.5)) had higher risks of lung cancer compared to never smokers after adjusting for asbestos exposure and age. The asbestos effect between non-smokers and current smokers was 1.23 (95% CI 0.35 to 4.32). CONCLUSION: Persons exposed to asbestos and tobacco but who subsequently quit, remain at an increased risk for lung cancer up to 20 years after smoking cessation, compared to never smokers. Although the relative risk of lung cancer appears higher in never and ex-smokers than in current smokers, those who both smoke and have been exposed to asbestos have the highest risk; this study emphasises the importance of smoking prevention and smoking cessation programmes within this high risk cohort.

Asbestos, Crocidolite↗
PubMed2005

Interpretation of recent sudden infant death syndrome rates in Western Australia.

The diagnosis of sudden infant death syndrome (SIDS) has undergone several changes in definition since first being recognised as a cause of death. Linked total population data from Western Australia enable investigations to determine changes in classifications of mortality for the infants of Aboriginal and non-Aboriginal mothers (Aboriginal and Torres Strait Islander people are referred to throughout this report as 'Aboriginal'). Data for recent years show a shift away from a classification of 'SIDS' towards a classification of 'unascertainable', particularly for Aboriginal infants. This has implications for the accurate translation of data into policy and practice.

Cause of Death↗
PubMed2004

Ratio of omega-6 to omega-3 fatty acids and childhood asthma.

UNLABELLED: Asthma is a leading cause of morbidity for children and is a major public health problem in Australia. Ecological and temporal data suggest that dietary factors may have a role in recent increases in the prevalence of asthma. AIM: The aim of conducting this study was to investigate whether childhood asthma was associated with the ratio of omega 6 (n-6) to omega 3 (n-3) fatty acids in the diet (n-6:n-3). METHOD: The Western Australian Pregnancy Cohort Study is a prospective birth cohort of 2602 children. Using a nested case-control cross-sectional study design within this cohort, a group of children were identified as cases with current asthma at 6 or at 8 years of age or as controls with no asthma at 6 or at 8 years. Dietary details including n-6 and n-3 fatty acid intake data were collected by parent response to a questionnaire when the children were 8 years old. Logistical regression was used to compare quartiles of n-6:n-3 intake in cases and controls. Adjustment was made for covariates: gender, gestational age, breastfeeding, older siblings, maternal smoking during pregnancy, maternal age, maternal asthma, child's current age in months, body mass index, total energy intake, and antioxidant intake (vitamins A, C, E, and zinc). RESULTS: A response rate of 83% was achieved by providing complete data from 335 children [49% cases with current asthma (n = 166), 51% controls (n = 169)]. Following adjustment for covariates the association between the ratio of n-6:n-3 fatty acids and risk for current asthma was statistically significant (p = 0.022). CONCLUSION: We found evidence for a modulatory effect of the dietary n-6:n-3 fatty acid ratio on the presence of asthma in children. Our results provide evidence that promotion of a diet with increased n-3 fatty acids and reduced n-6 fatty acids to protect children against symptoms of asthma is warranted.

Asthma↗
PubMed2004

Malignant pleural and peritoneal mesotheliomas in former miners and millers of crocidolite at Wittenoom, Western Australia.

AIMS: To report the number of malignant pleural and peritoneal mesotheliomas that have occurred in former Wittenoom crocidolite workers to the end of 2000, and to compare this with earlier predictions. METHODS: A group of 6493 men and 415 women who had worked at the former Wittenoom crocidolite mine and mill at some time between 1943 and 1966 have been followed up throughout Australia and Italy to the end of 2000. RESULTS: The cumulative number of mesotheliomas up to 2000 was 235 in men (202 pleural, 33 peritoneal) and seven (all pleural) in women. There had been 231 deaths with mesothelioma (9% of known deaths). CONCLUSIONS: The number of deaths in men with mesothelioma between 1987 and 2000 was at the low end of the predictions made earlier based on the number of cases to 1986. If this trend continues, it is predicted that about another 110 deaths with mesothelioma will occur in men by 2020.

Adult↗
PubMed2004

Effects of asbestos and smoking on the levels and rates of change of lung function in a crocidolite exposed cohort in Western Australia.

BACKGROUND: Increased rates of death from asbestos related diseases have been reported in former workers and residents exposed to crocidolite (blue asbestos) at Wittenoom, Western Australia. Exposure to asbestos is associated with reduced static lung volumes, gas transfer and lung compliance, and a restrictive ventilatory abnormality. METHODS: The effects of crocidolite exposure and smoking history on levels and rates of change of lung function were evaluated using a linear mixed model. Lung function was measured as forced expiratory volume in 1 second (FEV1), forced vital capacity (FVC), and FEV1/FVC. RESULTS: Cumulative doses of asbestos and the presence of radiographic asbestosis were associated with lower levels of FEV1 and FVC and a steeper decline during the period of observation. Subjects exposed to asbestos at a younger age had lower levels of FEV1 and FVC. Current smokers had lower levels and a steeper decline in lung function than never smokers. No significant interactions between crocidolite exposure and smoking on the levels or rates of change of lung function were found. CONCLUSIONS: The deleterious effects of crocidolite exposure on lung function persist in this population, despite asbestos exposure having ceased more than 30 years ago. No significant interactions were found in this population between asbestos and smoking at the first visit or longitudinally.

Asbestos, Crocidolite↗
PubMed2003

Association between antenatal cytokine production and the development of atopy and asthma at age 6 years.

BACKGROUND: Various lines of evidence suggest that antenatal factors are important in determining susceptibility to atopy and asthma. One possible mechanism is cytokines, production of which in the placenta is high throughout gestation and which protect placental integrity via control of local immunological homoeostasis. We investigated antenatal cytokine concentrations in a prospective birth cohort, intensively monitored for atopy and asthma outcomes at age 6 years. METHODS: Cryopreserved cord-blood serum samples from 407 children were assayed for interleukins 4, 5, 6, 10, 12, and 13, interferon gamma, and tumour necrosis factor alpha (TNFalpha). Associations between family, antenatal, and perinatal factors, cord-blood cytokine concentrations, and atopy or asthma outcomes were analysed by logistic regression. Causal effects of cytokines on outcomes were estimated by propensity scores based on family, antenatal, and perinatal factors. FINDINGS: Detectable cord-blood concentrations of interleukin 4 and interferon gamma were each associated with lower risk of physician-diagnosed asthma (adjusted odds ratios 0.60 [95% CI 0.37-0.99] and 0.60 [0.37-0.97] respectively), current asthma (0.59 [0.33-1.00] and 0.39 [0.22-0.71]), and current wheeze (0.55 [0.32-0.93] and 0.52 [0.31-0.90]) and atopy (sensitisation to some inhalant allergens) outcomes at 6 years. High concentrations of TNFalpha were associated with lower risk of atopy but not with asthma risk. These associations were broadly unaltered by propensity-score adjustment. Maternal smoking was associated with higher risk of both wheeze at 6 years and lower concentrations of interleukin 4 and interferon gamma in cord blood. INTERPRETATION: The mechanism underlying attenuated T-helper-1/T-helper-2 cytokine production in high-risk children also apparently operates in control of cytokine production in the fetoplacental unit. The finding that this mechanism is dysregulated by maternal smoking suggests it is a target for antenatal environmental factors relevant to asthma aetiology.

Asthma↗
PubMed2003

Comparison of an Australian food-frequency questionnaire with diet records: implications for nutrition surveillance.

OBJECTIVES: To compare a widely used Australian food-frequency questionnaire (FFQ) with diet records and consider the results in relation to its use in nutrition surveillance. DESIGN: Inter-method reliability study. SETTING: A randomised trial in subjects with past asbestos exposure. SUBJECTS: Seventy-two adults living in Western Australia. METHODS: A semi-quantitative FFQ developed by the Commonwealth Scientific Industrial Research Organisation in South Australia was administered after the completion of four 7-day diet records (DRs). RESULTS: Mean agreement between methods was not significantly different from 100% for many nutrients, but the limits of agreement indicated that, at the individual level, the FFQ over- or underestimated the DR by at least 50%. Mean agreement between methods decreased significantly with increasing intakes for the majority of nutrients. Pearson's correlation coefficients were less informative indicators of agreement compared with the limits of agreement. CONCLUSIONS: These results indicate poor agreement between the FFQ and DR when estimating absolute intakes. Therefore, comparing intakes collected using this FFQ with specific cut-off points such as Recommended Dietary Intakes for nutrition surveillance may lead to seriously flawed conclusions about population intakes.

Australia↗
PubMed2003

Breast feeding and respiratory morbidity in infancy: a birth cohort study.

AIM: To examine the relation between the duration of breast feeding and morbidity as a result of respiratory illness and infection in the first year of life. METHODS: Prospective birth cohort study of 2602 live born children ascertained through antenatal clinics at the major tertiary obstetric hospital in Perth, Western Australia. Main outcome measures were hospital, doctor, or clinic visits, and hospital admissions for respiratory illness and infection in the first year of life. Main exposure measures were the duration of predominant breast feeding (defined as the age other milk was introduced) and partial (any) breast feeding (defined as the age breast feeding was stopped). Main confounders were gender, gestational age less than 37 weeks, smoking in pregnancy, older siblings, maternal education, and maternal age. RESULTS: Hospital, doctor, or clinic visits for four or more upper respiratory tract infections were significantly greater if predominant breast feeding was stopped before 2 months or partial breast feeding was stopped before 6 months. Predominant breast feeding for less than six months was associated with an increased risk for two or more hospital, doctor, or clinic visits and hospital admission for wheezing lower respiratory illness. Breast feeding for less than eight months was associated with a significantly increased risk for two or more hospital, doctor, or clinic visits or hospital admissions because of wheezing lower respiratory illnesses. CONCLUSIONS: Predominant breast feeding for at least six months and partial breast feeding for up to one year may reduce the prevalence and subsequent morbidity of respiratory illness and infection in infancy.

Bottle Feeding↗
PubMed2003

Radiographic (ILO) readings predict arterial oxygen desaturation during exercise in subjects with asbestosis.

BACKGROUND: Exercise impairment is common in subjects with asbestosis. Arterial oxygen desaturation during exercise is an important contributor to exercise limitation. The International Labour Office (ILO) classification of plain chest radiographs correlates with resting pulmonary function, but its value in predicting abnormal ventilatory responses to exercise, including desaturation, has not been explored. AIMS: To determine in subjects with asbestosis (1) if radiographic profusion scores and the extent of small irregular shadows on plain chest radiographs correlate with resting lung function and abnormal ventilatory responses to exercise; and (2) if radiographic scores add value to resting lung function tests in predicting abnormal ventilatory responses to exercise. METHODS: Thirty eight male subjects with asbestosis were included. Plain chest radiographs were read according to the ILO classification independently by three observers. All subjects underwent assessment of lung function and an incremental exercise test. RESULTS: Profusion scores and number of affected zones correlated significantly with the percentage predicted values of single breath diffusing capacity (DLCO), forced vital capacity (FVC), and total lung capacity (TLC). Arterial oxygen desaturation occurred in 29% of the subjects. The severity of desaturation correlated significantly with profusion and the number of affected zones. The combined use of number of affected zones, FEV(1)/FVC ratio and DLCO predicted desaturation during exercise with an explained variance of 41%. VO(2)max was significantly related only to DLCO but was not predicted by the ILO score. CONCLUSION: Arterial oxygen desaturation correlated with the profusion and extent of parenchymal abnormality on chest radiographs. The addition of morphological indices to physiological measurements is valuable for predicting oxygen desaturation during exercise but not for VO(2)max. Refinement of the radiographic scoring system and the addition of more sophisticated imaging techniques may further improve the predictive power.

Aged↗
PubMed2002

The effects of respiratory infections, atopy, and breastfeeding on childhood asthma.

The objectives of the present study were to quantify the association of atopy and respiratory infections with asthma, and exclusive breastfeeding with respiratory illness, atopy and asthma in children. A cohort study of 2,602 children enrolled prior to birth and followed prospectively, provided data on respiratory illness, the method of feeding in the first year of life, as reported on a prospective diary card, and current asthma at the age of 6 yrs (defined as doctor-diagnosed asthma with wheeze in the last year or cough without a cold, and currently taking either preventer or reliever asthma medication), as reported by parental questionnaire. Atopy was defined by a positive skin-prick test assessed at the age of 6 yrs. Wheezing lower respiratory illness (LRI) in the first year of life, particularly multiple episodes of wheezing LRI, increased the risk for current asthma in both nonatopic (odds ratio (OR) 4.10, p< or =0.0005) and atopic children (OR 9.00, p< or =0.0005), but did not increase the risk for atopy. In contrast, up to three upper respiratory tract infections demonstrated a negative association and four or more a positive risk for current asthma in unadjusted (p=0.006) and adjusted (p=0.057) analysis. Following adjustment, exclusive breastfeeding for <4 months was associated with an increased risk for current asthma (OR 1.36, 95% confidence interval 1.00-1.85, p=0.047). Wheezing lower respiratory illness in the first year of life and atopy are independently associated with increased risk for current asthma at the age of 6 yrs, suggesting that their effects are mediated via different causal pathways and that these risk factors are multiplicative when they operate concomitantly within individual children. Exclusive breastfeeding protects against asthma via effects on both these pathways, as well as through other as yet undefined mechanisms.

Asthma↗
PubMed2001

Increased body mass index is related to apparent circumscribed pleural thickening on plain chest radiographs.

BACKGROUND: Diffuse pleural thickening and pleural plaques are the commonest radiological manifestations of asbestos exposure. Differentiation between subpleural fat and non-calcified pleural plaques is important clinically and medico-legally. This study aims to determine if apparent circumscribed pleural thickening on chest radiographs is related with obesity. METHODS: Surveillance chest x-rays of 693 former asbestos workers were read with the ILO classification. Subjects with costophrenic angle obliteration (n = 57) were analyzed separately. The remaining subjects were subdivided according to their body mass index (BMI): Group 1 < 26 kg/m(2); Group 2 26-30 kg/m(2); Group 3 > 30 kg/m(2). RESULTS: Baseline characteristics, asbestos exposure, and profusion scores were evenly distributed. BMI of > 30 kg/m(2) was associated with a higher prevalence of pleural thickening on CXR (Gp1 = 8.5%; Gp2 = 9.3%; Gp3 = 18.3%). This relationship was strongest in the subgroups with 25-50% of the lateral chest wall involved and pleural thickness of < 10 mm. CONCLUSIONS: Obesity (BMI > 30 kg/m(2)) is related to apparent circumscribed pleural thickening on CXR, especially thin (< 1 cm) shadows covering 25-50% of the lateral chest wall.

Adipose Tissue↗
PubMed2001

Respiratory symptoms and lung function in bauxite miners.

OBJECTIVES: To determine whether cumulative bauxite exposure is associated with respiratory symptoms or changes in lung function in a group of bauxite miners. METHODS: Current employees at three bauxite mines in Australia were invited to participate in a survey comprising: questionnaire on demographic details, respiratory symptoms, and work history; skin prick tests for four common aeroallergens; and spirometry. A task exposure matrix was constructed for bauxite exposure in all tasks in all jobs based on monitoring data. Data were examined for associations between cumulative bauxite exposure, and respiratory symptoms and lung function, by regression analyses. RESULTS: The participation rate was 86%. Self-reported work-related respiratory symptoms were reported by relatively few subjects (1.5%-11.8%). After adjustment for age and smoking no significant differences in the prevalence of respiratory symptoms were identified between subjects, in the quartiles of cumulative bauxite exposure distribution. The forced expiratory volume in I s (FEV1) of the exposed group was found to be significantly lower than that for the unexposed group. After adjustment for age, height, and smoking there were no statistically significant differences between quartiles in FEVI, forced vital capacity (FVC) and FEVl/FVC ratio. CONCLUSIONS: These data provide little evidence of a serious adverse effect on respiratory health associated with exposure to bauxite in an open-cut bauxite mine in present day conditions.

Adult↗
PubMed2001

Agreement between a brief food frequency questionnaire and diet records using two statistical methods.

OBJECTIVE: To compare intra- and inter-method reliability of a semi-quantitative food frequency questionnaire (FFQ) designed specifically to measure beta carotene (BC) and retinol intake, using two methods - the limits of agreement (LOA) and the correlation coefficient. DESIGN: A cross-sectional study of dietary intake. SETTING: A randomized trial of vitamin A supplements in 2769 subjects with past asbestos exposure. SUBJECTS: Data from 57 men and 26 women, aged 28-72 years, living in Western Australia. METHODS: The FFQ was administered at baseline (FFQ1) and repeated 1 year later (FFQ2). Four 1-week diet records (DRs) were completed during the year. RESULTS: Mean agreement between FFQ2 and FFQ1 was 120% for BC and 98% for retinol. LOA were 47-306% and 21-459%, respectively. Mean agreement between FFQ2 and the DR was 149% for BC and 63% for retinol; LOA were 50-447% and 11-349%, respectively. Mean agreement and LOA varied across energy intakes. Between the DR and FFQ2, correlation coefficients were 0.36 for BC and 0.51 for retinol. These varied considerably across age, gender and energy intakes and were not in accordance with limits of agreement findings. CONCLUSION: Although correlation coefficients were positive and significant, there was less than ideal intra-method and inter-method reliability shown by the limits of agreement method. Bias was uneven across the range of intakes, the LOA were wide and, compared with the DR, the FFQ significantly over-estimated BC and under-estimated retinol. This shows the limitations of calculating correlation coefficients alone, for assessing reliability and validity.

Adult↗