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Biomedical subjects

R Luben

Publications and source records attributed to R Luben.

At least 37 records · Page 2Linked to original sources

Relation between plasma ascorbic acid and mortality in men and women in EPIC-Norfolk prospective study: a prospective population study. European Prospective Investigation into Cancer and Nutrition.

BACKGROUND: Ascorbic acid (vitamin C) might be protective for several chronic diseases. However, findings from prospective studies that relate ascorbic acid to cardiovascular disease or cancer are not consistent. We aimed to assess the relation between plasma ascorbic acid and subsequent mortality due to all causes, cardiovascular disease, ischaemic heart disease, and cancer. METHODS: We prospectively examined for 4 years the relation between plasma ascorbic acid concentrations and mortality due to all causes, and to cardiovascular disease, ischaemic heart disease, and cancer in 19 496 men and women aged 45-79 years. We recruited individuals by post using age-sex registers of general practices. Participants completed a health and lifestyle questionnaire and were examined at a clinic visit. They were followed-up for causes of death for about 4 years. Individuals were divided into sex-specific quintiles of plasma ascorbic acid. We used the Cox proportional hazard model to determine the effect of ascorbic acid and other risk factors on mortality. FINDINGS: Plasma ascorbic acid concentration was inversely related to mortality from all-causes, and from cardiovascular disease, and ischaemic heart disease in men and women. Risk of mortality in the top ascorbic acid quintile was about half the risk in the lowest quintile (p<0.0001). The relation with mortality was continuous through the whole distribution of ascorbic acid concentrations. 20 micromol/L rise in plasma ascorbic acid concentration, equivalent to about 50 g per day increase in fruit and vegetable intake, was associated with about a 20% reduction in risk of all-cause mortality (p<0.0001), independent of age, systolic blood pressure, blood cholesterol, cigarette smoking habit, diabetes, and supplement use. Ascorbic acid was inversely related to cancer mortality in men but not women. INTERPRETATION: Small increases in fruit and vegetable intake of about one serving daily has encouraging prospects for possible prevention of disease.

Age Distribution↗

Patterns of physical activity and ultrasound attenuation by heel bone among Norfolk cohort of European Prospective Investigation of Cancer (EPIC Norfolk): population based study.

OBJECTIVES: To study associations between patterns of physical activity and ultrasound attenuation by the heel bone in men and women. DESIGN: Cross sectional, population based study. SETTING: Norfolk. PARTICIPANTS: 2296 men and 2914 women aged 45-74 registered with general practices participating in European Prospective Investigation into Cancer (EPIC Norfolk). RESULTS: Self reported time spent in high impact physical activity was strongly and positively associated with ultrasound attenuation by the heel bone, independently of age, weight, and other confounding factors. Men who reported participating in >/=2 hours/week of high impact activity had 8.44 dB/MHz (95% confidence interval 4.49 to 12.40) or 9.5%, higher ultrasound attenuation than men who reported no activity of this type. In women, the difference in ultrasound attenuation between those reporting any high impact activity and those reporting none was 2.41 dB/MHz (0.45 to 4.37) or 3.4% higher. In women this effect was similar in size to that of an age difference of four years. Moderate impact activity had no effect. However, climbing stairs was strongly independently associated with ultrasound attenuation in women (0.64 dB/MHz (0.19 to 1.09) for each additional five flights of stairs). There was a significant negative association in women between time spent watching television or video and heel bone ultrasound attenuation, which decreased by 0.08 dB/MHz (0.02 to 0.14) for each additional hour of viewing a week. CONCLUSIONS: High impact physical activity is independently associated with ultrasound attenuation by the heel bone in men and women. As low ultrasound attenuation has been shown to predict increased risk of hip fracture, interventions to promote participation in high impact activities may help preserve bone density and reduce the risk of fracture. However, in older people such interventions may be inappropriate as they could increase the likelihood of falls.

Age Factors↗

Glycated haemoglobin, diabetes, and mortality in men in Norfolk cohort of european prospective investigation of cancer and nutrition (EPIC-Norfolk).

OBJECTIVE: To examine the value of glycated haemoglobin (HbA(1c)) concentration, a marker of blood glucose concentration, as a predictor of death from cardiovascular and all causes in men. DESIGN: Prospective population study. SETTING: Norfolk cohort of European Prospective Investigation into Cancer and Nutrition (EPIC-Norfolk). SUBJECTS: 4662 men aged 45-79 years who had had glycated haemoglobin measured at the baseline survey in 1995-7 who were followed up to December 1999. MAIN OUTCOME MEASURES: Mortality from all causes, cardiovascular disease, ischaemic heart disease, and other causes. RESULTS: Men with known diabetes had increased mortality from all causes, cardiovascular disease, and ischaemic disease (relative risks 2.2, 3.3, and 4.2, respectively, P <0.001 independent of age and other risk factors) compared with men without known diabetes. The increased risk of death among men with diabetes was largely explained by HbA(1c) concentration. HbA(1c) was continuously related to subsequent all cause, cardiovascular, and ischaemic heart disease mortality through the whole population distribution, with lowest rates in those with HbA(1c) concentrations below 5%. An increase of 1% in HbA(1c) was associated with a 28% (P<0.002) increase in risk of death independent of age, blood pressure, serum cholesterol, body mass index, and cigarette smoking habit; this effect remained (relative risk 1.46, P=0.05 adjusted for age and risk factors) after men with known diabetes, a HbA(1c) concentration >/=7%, or history of myocardial infarction or stroke were excluded. 18% of the population excess mortality risk associated with a HbA(1c) concentration >/=5% occurred in men with diabetes, but 82% occurred in men with concentrations of 5%-6.9% (the majority of the population). CONCLUSIONS: Glycated haemoglobin concentration seems to explain most of the excess mortality risk of diabetes in men and to be a continuous risk factor through the whole population distribution. Preventive efforts need to consider not just those with established diabetes but whether it is possible to reduce the population distribution of HbA(1c) through behavioural means.

Aged↗

Nutritional methods in the European Prospective Investigation of Cancer in Norfolk.

OBJECTIVE: To describe methods and dietary habits of a large population cohort. DESIGN: Prospective assessment of diet using diet diaries and food-frequency questionnaires, and biomarkers of diet in 24-h urine collections and blood samples. SETTING: Free living individuals aged 45 to 75 years living in Norfolk, UK. SUBJECTS: Food and nutrient intake from a food-frequency questionnaire on 23 003 men and women, and from a 7-day diet diary from 2117 men and women. Nitrogen, sodium and potassium excretion was obtained from single 24-h urine samples from 300 individuals in the EPIC cohort. Plasma vitamin C was measured for 20 846 men and women. RESULTS: The food-frequency questionnaire (FFQ) and the food diary were able to determine differences in foods and nutrients between the sexes and were reliable as judged by repeated administrations of each method. Plasma vitamin C was significantly higher in women than men. There were significant differences in mean intake of all nutrients measured by the two different methods in women but less so in men. The questionnaire overestimated dairy products and vegetables in both men and women when compared with intakes derived from the diary, but underestimated cereal and meat intake in men. There were some consistent trends with age in food and nutrient intakes assessed by both methods, particularly in men. Correlation coefficients between dietary intake assessed from the diary and excretion of nitrogen and potassium in a single 24-h urine sample ranged from 0.36 to 0.47. Those comparing urine excretion and intake assessed from the FFQ were 0.09 to 0.26. The correlations between plasma vitamin C and dietary intake from the first FFQ, 24-h recall or diary were 0.28, 0.35 and 0.40. CONCLUSIONS: EPIC Norfolk is one of the largest epidemiological studies of nutrition in the UK and the largest on which plasma vitamin C has been obtained. Methods for obtaining food and nutrient intake are described in detail. The results shown here for food and nutrient intakes can be compared with results from other population studies utilising different methods of assessing dietary intake. The utility of different methods used in different settings within the main EPIC cohort is described. The FFQ is to be used particularly in pooled analyses of risk from diet in relation to cancer incidence within the larger European EPIC study, where measurement error is more likely to be overcome by large dietary heterogeneity on an international basis. Findings in the UK, where dietary variation between individuals is smaller and hence the need to use a more accurate individual method greater, will be derived from the 7-day diary information on a nested case-control basis. 24-h recalls can be used in the event that diary information should not be forthcoming from some eventual cases. Combinations of results utilising all dietary methods and biomarkers may also be possible.

Aged↗

DINER (Data Into Nutrients for Epidemiological Research) - a new data-entry program for nutritional analysis in the EPIC-Norfolk cohort and the 7-day diary method.

BACKGROUND AND OBJECTIVE: A new data-entry system (DINER - Data Into Nutrients for Epidemiological Research) for food record methods has been devised for the European Prospective Investigation into Cancer (EPIC) cohort study of 25,000 men and women in Norfolk. DINER has been developed to address the problems of efficiency and consistency of data entry, comparability of data, maximising information and future flexibility in large long-term population studies of diet and disease that use record methods to assess dietary intakes. DINER captures more detail than traditional systems and enables provision of new variables for specific food types or groups. The system has been designed to be fully flexible and easy to update. Analysis of consistency of data entry was tested in a group of 3525 participants entered by 25 coders. RESULTS: A food list of 9000 food items and values for 24,000 portion sizes have been incorporated into the database, using information from the 5979 diaries coded since 1995. Analysis of consistency of entry indicated that this has largely been achieved. The effect of coders in a multivariate regression model was significant only if the three coders involved in early use of the program were included (P < 0.013). CONCLUSIONS: The development of DINER has facilitated the use of more accurate record methods in large-scale epidemiological studies of diet and disease. Furthermore, the retention of original information as an extensive food list allows greater flexibility in later analyses of data of multiple dietary hypotheses.

Cohort Studies↗

Mammographic parenchymal patterns and breast cancer natural history--a case-control study.

The relationship between tumour size, malignancy grade and dense mammographic parenchymal patterns was evaluated by using a nested case-control design with 875 breast cancer cases and 2 601 matched controls. Wolfe's classification was used to assess mammographic parenchymal patterns. The dense P2/DY mammographic parenchymal patterns were significantly associated with invasive ductal grade 3 carcinoma (OR = 2.03; 95%, CI 1.13-3.62, p = 0.016). Stratified by tumour size, we found that the odds ratio for grade 3 invasive ductal NOS breast cancer measuring 15-19 mm associated with P2/DY mammographic parenchymal patterns was 3.46 (95% CI 1.12-10.68). For tumours larger than 30 mm, the odds ratio was 10.09 (95% CI 1.27-79.93). The highest risk of grade 3 cancers being in tumours measuring 30 mm + may be due to dedifferentiation of missed cancers, but there is some excess even in the < 20 mm tumours, suggesting an increased risk in association with dense mammographic patterns of some aggressive cancers which are grade 3 at inception. Our results are consistent with the model that breast cancer is a progressive disease, whose development can be arrested by screening, and that the point at which individual tumour progression is stopped is crucial for prognosis not simply in terms of stage of disease, but also of histological grade.

Breast↗

Estimation of disease progression parameters from case-control data: application to mammographic patterns and breast cancer natural history.

BACKGROUND: Estimations of mean sojourn time (MST) and sensitivity (S) in disease screening have been previously calculated from case-control data, using simple models which did not include covariates. Many studies have shown an effect of mammographic parenchymal pattern (MPP) on breast-cancer risk and tumour histology. We have expanded previous models on these to estimate MST and S with the effects of MPP as a covariate. METHODS: Data were from a nested case-control study within the East Anglian screening programme, with 875 cases and 2,601 controls. Estimates of disease progression and screening parameters were based on conditional likelihood calculation, using a Markov process model. Ninety-five per cent confidence intervals (CI) were calculated using the profile likelihood wherever possible and using a numerical estimate of the information matrix or the area under the likelihood curve where necessary. RESULTS: We obtained estimates of the incidence of preclinical disease, rate of transition from preclinical to clinical and screening sensitivity, and evaluated the association of these parameters with mammographic parenchymal pattern. A higher incidence of preclinical disease was found for high-risk MPP [relative incidence = 1.62 (95% CI: 0.89; 2.73)]. However, no difference in progression rate from preclinical to clinical disease between different MPP was found. Dense MPPs were associated with decreased sensitivity [relative sensitivity = 0.24 (95% CI: 0.06; 15)]. Wide CIs were found, probably being a consequence of the relative sparsity of interval cancer data. DISCUSSION: It is possible to estimate multiple parameters of disease progression and screening quality from case-control data. The reduction in sensitivity of the screening process associated with high-risk patterns presented here, could be of paramount interest for proposing new screening strategies, such as possible additional screening tools.

Breast Neoplasms↗

Prevalence and family history of colorectal cancer: implications for screening.

OBJECTIVES: To estimate the current prevalence of family history and associated risk of prevalent colorectal cancer among middle aged and older British adults. METHODS: Cross sectional analysis of colorectal cancer and self reported family history based on data from a large population based study in Norfolk, United Kingdom. RESULTS: Of the 30,353 participants, 2,069 (6.8%) participants had reported a family history of colorectal cancer in at least one first degree relative. The prevalence of colorectal cancer in those with a family history was 1% and 0.5% in those without. Of the 151 participants with prevalent colorectal cancer, 14.6% reported a family history of the disease. Also, a family history of colorectal cancer in first degree relatives was significantly associated with an increased risk of prevalent colorectal cancer (multivariate odds ratio (OR) 2.32 (95% confidence interval (95% CI) 1.43 to 3.76). For those with one affected relative below the age of 45, and for those with two affected relatives the multivariate ORs were 5.29 (1.63 to 17.17) and 4.93 (1.17 to 20.70), respectively. CONCLUSIONS: Although positive family history may identify a group with increased likelihood of colorectal cancer, screening strategies targeted solely at people with a family history will have limited impact on reducing mortality from colorectal cancer at the population level.

Aged↗

The effect of age, sex, and education on food consumption of a middle-aged English cohort-EPIC in East Anglia.

BACKGROUND: Different dietary patterns are associated with differing risks of chronic disease. Yet independent relationships between diet and demographic variables, such as age, sex, and education, are poorly described. METHODS: The first 1968 subjects enrolled to the European Prospective Investigation of Cancer (EPIC) cohort from general practices in East Anglia, UK, provided food frequency and demographic data. RESULTS: Men ate meat, eggs, milk, and sugary foods more frequently, but fruit and vegetables less frequently than women. Older subjects ate red meats and saturated bread spreads more frequently but consumed less poultry and drank less coffee than younger subjects. Better educated subjects ate less meat, more salads, and fewer cakes and sweet foods than those less educated. Five clusters representing different dietary patterns were readily identified. These were (a) younger well-educated, probably containing many vegetarians; (b) "low calorie," two-thirds female; (c) high alcohol, nuts, meat, largely male; (d) preferring fruits, vegetables, unsaturated fats, poultry, and fish, 71% female; (e) preferring meat, potatoes, sweet foods, saturated fats, less well-educated older men. CONCLUSIONS: The reported consumption of many foods varies by age, gender, and education. A pattern of eating that is generally considered less healthful was particularly seen in older men, placing them at increased risk of chronic disease.

Age Factors↗

Size, node status and grade of breast tumours: association with mammographic parenchymal patterns.

A case-control study was designed to assess the association of mammographic parenchymal patterns with the risk of in-situ and invasive breast cancer. In addition, the relationship between tumour characteristics and mammographic patterns were also investigated. A total of 875 patients with breast cancer were selected and matched with 2601 controls. Mammographic parenchymal patterns of breast tissue were assessed according to Wolfe's classification, and statistical analysis was by conditional logistic regression. Relative to the N1 pattern, the odds ratios of having an invasive breast cancer associated with the P2 and DY patterns were 1.8 and 1. 4, respectively. In addition, the odd ratios of having an invasive grade 3 breast cancer associated with the P2 and DY patterns were 2. 8 and 3.9, respectively. Relative to the combined N1/P1 pattern, the odd ratios of having a breast cancer smaller than 14 mm, 15-29 mm, or larger than 30 mm associated with the combined high-risk P2/DY pattern (P2 + DY) were 1.2, 1.6, and 2.0, respectively. Finally, women with the P2/DY pattern were twice as likely to have a breast cancer which had already spread to the axillary nodes, compared to women with women with the N1/P1 pattern (odds ratios of 2.1 and 1.4, respectively). Our results confirm previous findings suggesting that mammographic parenchymal patterns may serve as indicators of risk for breast cancer. Our results also suggest that mammographic parenchymal patterns are associated with the stage at which breast cancer is detected.

Breast Neoplasms↗

High risk mammographic parenchymal patterns and diet: a case-control study.

Mammographic parenchymal patterns are related to breast cancer risk and are also thought to be affected by diet. We designed a case-control study comprising 200 cases with high-risk (P2 and DY) mammographic parenchymal pattern and 200 controls with low-risk (N1 and P1) patterns in order to investigate the effect of food and nutrient intake on mammographic patterns. Mammograms were evaluated according to the Wolfe classification system. Dietary data were obtained from 7-day food diaries. Mean daily intake of nutrients was computed from standard UK food tables. The adjusted odds ratio (OR) of having a high-risk pattern in women in the highest tertile of total protein and carbohydrate intake was twice that of women in the lowest tertile (OR = 2.00; 95% confidence interval (CI) 1.06-3.77; P = 0.04 and OR = 1.93; 95% CI 1.03-3.59; P = 0.04 respectively). There was no excess risk for fat intake. In addition, there was no association between intake of vitamins and mammographic parenchymal patterns. Total meat intake was strongly and positively associated with high-risk patterns among post-menopausal women (OR = 2.50, 95% CI 1.09-5.69, P = 0.03). Our study suggests that certain macronutrients and foods such as protein, carbohydrate and meat intake influence the risk of breast cancer through their effects on breast tissue morphology, whereas fat and vitamins do not affect mammographic density. It seems that parenchymal pattern acts as an informative biomarker of the effect of some macronutrient and foodstuffs intake on breast cancer risk.

Adipose Tissue↗

High-risk mammographic parenchymal patterns, hormone replacement therapy and other risk factors: a case-control study.

BACKGROUND: Mammographic parenchymal patterns are of particular interest because the denser patterns reduce screening sensitivity as well as increasing breast cancer risk, and because they have been shown to be affected by exogenous oestrogens. METHODS: We designed a case-control study comprising 200 cases with high-risk (P2 and DY) pattern and 200 controls with low-risk (N1 and P1) pattern. Mammograms were evaluated according to the Wolfe classification. RESULTS: Parity, body mass index (BMI) and current smoking were inversely and independently associated, whereas late age of menarche and history of benign breast disease were positively associated with high-risk mammographic patterns. Current-users of hormone replacement therapy (HRT) were more than twice as likely to have a high-risk pattern than never-users (OR = 2.48, 95% CI : 1.32-4.61). Women who used HRT for more than 5 years were almost three times more likely to have a high-risk pattern than never-users (OR = 2.77, 95% CI : 1.11-6.91). Relative to never-users, women who started HRT before the menopause were more than twice as likely to have a high-risk pattern (OR = 2.53, 95% CI : 1.31-4.87). CONCLUSIONS: Careful clinical and mammographical follow-up might be appropriate in women undergoing HRT. The HRT-induced mammographic pattern might be regarded as a new baseline and changes with respect to this new pattern could then be monitored over time.

Aged↗

Smoking and high-risk mammographic parenchymal patterns: a case-control study.

STATEMENT OF FINDINGS: Current smoking was strongly and inversely associated with high-risk patterns, after adjustment for concomitant risk factors. Relative to never smokers, current smokers were significantly less likely to have a high-risk pattern. Similar results were obtained when the analysis was confined to postmenopausal women. Past smoking was not related to the mammographic parenchymal patterns. The overall effect in postmenopausal women lost its significance when adjusted for other risk factors for P2/DY patterns that were found to be significant in the present study, although the results are still strongly suggestive. The present data indicate that adjustment for current smoking status is important when evaluating the relationship between mammographic parenchymal pattern and breast cancer risk. They also indicate that smoking is a prominent potential confounder when analyzing effects of other risk factors such as obesity-related variables. It appears that parenchymal patterns may act as an informative biomarker of the effect of cigarette smoking on breast cancer risk.

Breast Neoplasms↗

High-risk mammographic parenchymal patterns and anthropometric measures: a case-control study.

Mammographic parenchymal patterns are related to breast cancer risk and are also affected by anthropometric measure. We carried out a case-control study comprising 200 cases with high-risk (P2 and DY) mammographic parenchymal pattern and 200 controls with low-risk (N1 and P1) patterns in order to investigate the effect of body size and shape and breast size on mammographic patterns. Women in the highest quartile of body mass index (BMI) distribution were significantly less likely to have a high-risk pattern (odds ratio (OR) = 0.21, 95% confidence interval (CI) 0.08-0.52, P-value for trend = 0.001) compared to those in the lowest quartile. Relative to women with a waist to hip ratio (WHR) of less than 0.75, the OR of having a high-risk pattern in women with a WHR greater than 0.80 was 0.30 (95% CI 0.14-0.63). Breast size as measured by cup size was significantly and negatively related to high-risk pattern. Our study indicates that both BMI and WHR are negatively associated with high-risk patterns. However, both phenomena are associated with increased risk of breast cancer in postmenopausal women. This negative confounding of two positive risk factors means that the effect of parenchymal patterns on risk will tend to be underestimated when not adjusted for BMI and WHR and vice versa. Thus we may have underestimated the importance of BMI and mammographic parenchymal patterns in the past. Further studies are needed to determine a measure of parenchymal density that is independent of anthropometric measures and breast size.

Aged↗

Dissociation of Janus kinase 2 and signal transducer and activator of transcription 5 activation after treatment of Nb2 cells with a molecular mimic of phosphorylated prolactin.

We have previously demonstrated that phosphorylated PRL acts as an antagonist to the Nb2 proliferative activities of unmodified PRL. A molecular mimic of phosphorylated PRL, which substitutes an aspartate residue for the normally phosphorylated serine (serine 179), has the same properties. Because it takes less than one fourth the amount of phosphorylated hormone, or the aspartate mutant, to block the proliferative activity of unmodified hormone, we have investigated whether the high potency of the aspartate mutant is achieved by the production of an alternate and interfering intracellular signal cascade. Nb2 cells were exposed to 5 or 500 ng/ml human NIDDK PRL, wild-type recombinant PRL (unmodified PRL), or aspartate mutant PRL (pseudophosphorylated PRL) for 1, 5, or 10 min at 37 C. At 5 ng/ml and 10 min, wild-type recombinant PRL showed greater activation of Janus kinase 2 (JAK 2) than the NIDDK preparation. This is consistent with a previous report of higher proliferative activity for the wild-type hormone and is primarily a reflection of the presence of some phosphorylated hormone in the NIDDK preparation. At 500 ng/ml and 10 min, saturation eliminated any differences between responses to the two preparations. JAK 2 activation was not seen in response to the aspartate mutant at either concentration. Signal transducer and activator of transcription 5 (STAT 5) activation was, however, just as robust for the aspartate-treated cells as for the other two groups. Time course experiments eliminated the possibility that STAT 5 phosphorylation in response to the aspartate mutant was the result of JAK 2 activation at earlier time points. Experiments in the present study also interestingly showed preassociation of JAK 2 and STAT 5 in the absence of PRL and the absence of detectable phosphorylation of either JAK 2 or STAT 5. Like JAK 2, receptor phosphorylation was absent with the aspartate mutant. A comparison between STAT 5a and STAT 5b activation showed a marked reduction in STAT 5b phosphorylation in response to the aspartate mutant, with concomitant reduction in STAT 5a-STAT 5b heterodimers. STAT 5a activation, however, was indistinguishable between the wild-type and aspartate mutant. We conclude that the nonproliferative aspartate mutant signals and activates STAT 5 without, or with minimal, use of JAK 2 or receptor phosphorylation. The wild-type proliferative PRL, on the other hand, uses receptor phosphorylation and JAK 2 activation.

Aspartic Acid↗

Electromagnetic field-induced stimulation of Bruton's tyrosine kinase.

Here we present evidence that exposure of DT40 lymphoma B-cells to low energy electromagnetic fields (EMF) results in activation of phospholipase C-gamma 2 (PLC-gamma2), leading to increased inositol phospholipid turnover. PLC-gamma2 activation in EMF-stimulated cells is mediated by stimulation of the Bruton's tyrosine kinase (BTK), a member of the Src-related TEC family of protein tyrosine kinases, which acts downstream of LYN kinase and upstream of PLC-gamma2. B-cells rendered BTK-deficient by targeted disruption of the btk gene did not show enhanced PLC-gamma2 activation in response to EMF exposure. Introduction of the wild-type (but not a kinase domain mutant) human btk gene into BTK-deficient B-cells restored their EMF responsiveness. Thus, BTK exerts a pivotal and mandatory function in initiation of EMF-induced signaling cascades in B-cells.

Agammaglobulinaemia Tyrosine Kinase↗