Germline variants in IL4, MGMT and AKT1 are associated with prostate cancer-specific mortality: An analysis of 12,082 prostate cancer cases.

BACKGROUND: Prostate cancer (PCa) is a leading cause of mortality and genetic factors can influence tumour aggressiveness. Several germline variants have been associated with PCa-specific mortality (PCSM), but further replication evidence is needed. METHODS: Twenty-two previously identified PCSM-associated genetic variants were genotyped in seven PCa cohorts (12,082 patients; 1544 PCa deaths). For each cohort, Cox proportional hazards models were used to calculate hazard ratios and 95% confidence intervals for risk of PCSM associated with each variant. Data were then combined using a meta-analysis approach. RESULTS: Fifteen SNPs were associated with PCSM in at least one of the seven cohorts. In the meta-analysis, after adjustment for clinicopathological factors, variants in the MGMT (rs2308327; HR 0.90; p-value = 3.5 × 10-2) and IL4 (rs2070874; HR 1.22; p-value = 1.1 × 10-3) genes were confirmed to be associated with risk of PCSM. In analyses limited to men diagnosed with local or regional stage disease, a variant in AKT1, rs2494750, was also confirmed to be associated with PCSM risk (HR 0.81; p-value = 3.6 × 10-2). CONCLUSIONS: This meta-analysis confirms the association of three genetic variants with risk of PCSM, providing further evidence that genetic background plays a role in PCa-specific survival. While these variants alone are not sufficient as prognostic biomarkers, these results may provide insights into the biological pathways modulating tumour aggressiveness.

Association of FGFR4 genetic polymorphisms with prostate cancer risk and prognosis.

The fibroblast growth factor receptor 4 (FGFR4) is thought to be involved in many critical cellular processes and has been associated with prostate cancer risk. Four single nucleotide polymorphisms (SNPs) within or near FGFR4 were analyzed in a population-based study of 1458 prostate cancer patients and 1352 age-matched controls. We found no evidence to suggest that any of the FGFR4 SNP genotypes were associated with prostate cancer risk or with disease aggressiveness, Gleason score or stage. A weak association was seen between rs351855 and prostate cancer-specific mortality. Subset analysis of cases that had undergone radical prostatectomy revealed an association between rs351855 and prostate cancer risk. Although our results confirm an association between FGFR4 and prostate cancer risk in radical prostatectomy cases, they suggest that the role of FGFR4 in disease risk and outcomes at a population-based level appears to be minor.

Weekly vitamin A and iron supplementation during pregnancy increases vitamin A concentration of breast milk but not iron status in Indonesian lactating women.

Studies on the effect of vitamin A and iron supplementation during pregnancy on maternal iron and vitamin A status postpartum are scarce. We investigated whether retinol and iron variables in breast milk and in serum postpartum were enhanced more with weekly vitamin A and iron supplementation during pregnancy than with weekly iron supplementation. During pregnancy, subjects were randomly allocated to two groups and received either (n = 88) a weekly supplement of iron (120 mg Fe as FeSO(4)) and folic acid (500 microg) or (n = 82) the same amount of iron and folic acid plus vitamin A [4800 retinol equivalents (RE)]. Transitional milk (4-7 d postpartum) had higher (P < 0.001) concentrations of retinol and iron than mature milk (3 mo postpartum). Compared with the weekly iron group, the weekly vitamin A and iron group had a greater (P < 0.05) concentration of retinol in transitional milk (as micromol/L) and in mature milk (as micromol/g fat). Although serum retinol concentrations approximately 4 mo postpartum did not differ significantly, the weekly vitamin A and iron group had significantly fewer (P < 0.01) subjects with serum retinol concentrations < or = 0.70 micromol/L than the weekly iron group. Iron status and concentrations of iron in transitional and mature milk did not differ between groups. We have shown that weekly vitamin A and iron supplementation during pregnancy enhanced concentrations of retinol in breast milk although not in serum by approximately 4 mo postpartum. However, no positive effects were observed on iron status and iron concentration in breast milk.

Weekly micronutrient supplementation to build iron stores in female Indonesian adolescents.

Different supplementation schemes to build iron stores in female Indonesian adolescents were investigated. Subjects were 273 high-school girls allocated randomly to four treatment groups. During a 3-mo period one group received 60 mg Fe, 750 micrograms retinol, 250 micrograms folic acid, and 60 mg vitamin C per day; a second group received 60 mg Fe, 6000 micrograms retinol, 500 mg folic acid, and 60 mg vitamin C once a week; a third group received 120 mg Fe and the same amount of the other three micronutrients as the second group once a week; and a fourth group received only placebos. All subjects were dewormed and supplement allocation was double blind. Blood samples were collected at baseline, after 2 and 3 mo of supplementation, and 6 mo after the last supplement. After 2 mo of supplementation, groups supplemented weekly and daily showed similar significant improvements (P < 0.001) in hemoglobin and retinol concentrations, and supplementation for 3 instead of 2 mo did not significantly increase these two indicators. After 3 mo, the increase in ferritin was approximately equal to 27 micrograms/L in the daily and 14-15 micrograms/L in the weekly groups (P < 0.001), the latter having a final concentration of 42-45 micrograms/L. At 6 mo postsupplementation there were no significant differences among daily and weekly groups, but the ferritin concentration was still approximately equal to 10-12-micrograms/L higher (P < 0.001) than in the placebo group. The group supplemented weekly with 60 mg Fe complained less about side effects than the other supplemented groups (P < 0.05). Weekly supplementation with 60 mg Fe and 6000 micrograms retinol for 3 mo was optimal for improving the iron status of the adolescents for approximately equal to 9 mo.

Refinement of the modified-relative-dose-response test as a method for assessing vitamin A status in a field setting: experience with Indonesian children.

The modified-relative-dose-response (MRDR) test, which has been used extensively throughout the world for assessing vitamin A status, has been simplified. The major methodologic change resulting from the current studies in Indonesia is the use of graded standard doses of 3,4-didehydroretinyl acetate (DRA) based on the age range of the population of interest. Instead of a dose of 0.35 mumol/kg body wt, standard doses of 5.3 mumol for children younger than 6 y, 7.0 mumol for children between 6 and 12 y of age, and 8.8 mumol for adults and children > 12 y of age are suggested for field use. The acceptable time between administering the oral dose and obtaining a blood sample was validated as being 4-7 h in a group of children (n = 84) by taking two blood samples per child between 3 and 7 h after dosing with DRA. Furthermore, DRA in vitamin E-containing corn oil, with or without the addition of 4.6 mmol all-rac-alpha-tocopheryl acetate/L, was found to be stable for > or = 18 mo at 2 degrees C and at -20 degrees C, but not at 22 degrees C or at 37 degrees C. When DRA was stored in amber glass vials, stability was affected more by temperature than by exposure to room light. In keeping with earlier studies in adults, the ratio of 3,4-didehydro-retinol to retino tends to be independent of body weight. Indeed, slower growing children (ie, those with lower weight-for-age) may have a somewhat better vitamin A status than their heavier counterparts.

Vitamin A status of Indonesian children infected with Ascaris lumbricoides after dosing with vitamin A supplements and albendazole.

In developing countries, both marginal vitamin A status and intestinal helminths are common among children. Indonesian children (n = 309, 0.6-6.6 y), known to be infected with Ascaris lumbricoides, were randomized into six different treatment groups (A-F). The treatments included 210 mumol vitamin A supplement and a dose of 400 mg albendazole (5-propylthio-1H-benzimidazol-2-yl carbamic acid methyl ester) administered orally either at the same health visit (Groups B and F) or at different contact times during a 1-mo period (groups A, C, D and E). Vitamin A status was assessed both before and 3-4 wk after the treatments by the modified relative dose response (MRDR) test. Vitamin A supplementation was most important in improving the vitamin A status (P < 0.0001) of these children, whereas treatment for ascariasis alone (P = 0.370) and the statistical interaction between treatment for ascariasis and vitamin A (P = 0.752) were not. Serum retinol concentrations marginally improved (P = 0.051) in two of the groups that received vitamin A and albendazole but not in the third group that received vitamin A only. The MRDR test proved a better discriminator of the effects of these treatments on vitamin A status than changes in serum retinol concentrations.

Daily supplements of vitamin A (8.4 mumol, 8000 IU) improve the vitamin A status of lactating Indonesian women.

The vitamin A statuses of lactating Indonesian women (n = 23) starting at 1-3 mo after delivery were determined at three monthly intervals (times 1, 2, and 3) during lactation and then again (time 4) after they had ingested vitamin A capsules (8.4 mumol, 8000 IU) daily for 35 d. Vitamin A status was determined by using the modified-relative-dose-response (MRDR) test and serum retinol concentrations. The mean MRDR ratio in these women rose from 0.084 +/- 0.047 (time 1) to 0.099 +/- 0.045 (time 2) and then to 0.100 +/- 0.054 (time 3). After supplementation the mean MRDR ratio fell to 0.040 +/- 0.021 (time 4) (P < 0.0001). Mean serum retinol concentrations at the first three times were 0.94 +/- 0.23, 0.87 +/- 0.20, and 0.80 +/- 0.20 mumol/L, but then rose to 1.10 +/- 0.31 mumol/L at time 4 (P < 0.04). After supplementation mean MRDR values and mean serum retinol concentrations were 60% lower and 38% higher, respectively, than those just before supplementation, MRDR values better distinguished the vitamin A statuses of the women than did serum retinol concentrations. Mean hemoglobin values increased during the study from 118 +/- 9 g/L at time 1 to 122 +/- 6 g/L at time 4 (P = 0.0187). The mean hematocrit also rose from 0.35 +/- 0.03 at time 1 to 0.361 +/- 0.17 at time 4 (P = 0.0478). Thus, iron status may also have improved marginally from time 1 to time 4, but most of the increase appeared before the vitamin A intervention.

Mother's health card: A simple technology for use in primary health care.

The incidence of low birth weight in Indonesia as well as other developing countries is high. This can be reduced, if at risk pregnant women can be identified and their risks lowered. A 2-year cohort prospective study of 1,281 pregnant women found that maternal nutrition, including height and weight during pregnancy affected the birth weight of infants. On the basis of these findings, a Mother's Health Card was developed to monitor maternal weight during pregnancy and to observe factors affecting low birth weight. The validation study of the use of this card in four different ethnic and geographic areas found that the prediction values for identifying women who were at risk of delivering low birth weight infants was adequately high. The card proved simple, usable by village cadres, action oriented, and facilitated health nutrition education as well as persuading women to use available health care services. It also promoted better maternal and foetal nutrition by increasing the level of awareness of the women, the cadres, and the health personnel.

Micronutrients and urban life style: selected studies in Jakarta.

Urbanisation runs in parallel with economic growth. Urban areas are characterised by income inequality between population groups. Because of inequality in socioeconomic situation, Indonesian urban areas are confronted with problems of undernutrition and overnutrition. Selected studies conducted by the SEAMEO-TROPMED Regional Centre for Community Nutrition have demonstrated that food intake of the lower socioeconomic class households is deficient. Furthermore, intrahousehold food distribution among the lower economic class households is contributory to the determination of food intake. The prevalence of anaemia in urban Jakarta ranges from as low as 4.5% in female school children to as high as 63.2% in pregnant women. Zinc deficiency might also be prevalent among lactating mothers. Strategies for improvement of urban micronutrient status are required and may include food-based, nutrient supplementation of fortification methods.

Application of the modified relative dose response test to pregnant Indonesian women for assessing vitamin A status.

OBJECTIVE: To determine the prevalence of subclinical vitamin A deficiency (vitamin A inadequacy) in Indonesian pregnant women as assessed by the modified relative dose response test. DESIGN: Cross-sectional study of the vitamin A statuses of pregnant (second trimester) women randomly selected from ten different villages. SETTING: West Java, Indonesia. SUBJECTS: A group of 144 pregnant women recruited from the local health posts. INTERVENTIONS: Modified relative dose response (MRDR) test, serum retinol determination and gynecological examinations. RESULTS: The mean (s.d.) MRDR ratio was 0.039 +/- 0.031. Of the women tested, the vitamin A status of 17% was provisionally classified as being marginal (subclinically deficient) (MRDR ratio > or = 0.060), of 35% as being uncertain (MRDR ratio between 0.030 and 0.060) and of 48% as being satisfactory (MRDR ratio < or = 0.030). CONCLUSION: If the vitamin A statuses of the 'uncertain' group are also deemed to be unsatisfactory, approximately half of the pregnant Indonesian women tested could benefit from an increased intake of vitamin A.

Lack of improvement in vitamin A status with increased consumption of dark-green leafy vegetables.

There is little evidence to support the general assumption that dietary carotenoids can improve vitamin A status. We investigated in Bogor District, West Java, Indonesia, the effect of an additional daily portion of dark-green leafy vegetables on vitamin A and iron status in women with low haemoglobin concentrations (< 130 g/L) who were breastfeeding a child of 3-17 months. Every day for 12 weeks one group (n = 57) received stir-fried vegetables, a second (n = 62) received a wafer enriched with beta-carotene, iron, vitamin C, and folic acid, and a third (n = 56) received a non-enriched wafer to control for additional energy intake. The vegetable supplement and the enriched wafer contained 3.5 mg beta-carotene, 5.2 mg and 4.8 mg iron, and 7.8 g and 4.4 g fat, respectively. Assignment to vegetable or wafer groups was by village. Wafers were distributed double-masked. In the enriched-wafer group there were increases in serum retinol (mean increase 0.32 [95% CI 0.23-0.40] mumol/L), breastmilk retinol (0.59 [0.35-0.84] mumol/L), and serum beta-carotene (0.73 [0.59-0.88] mumol/L). These changes differed significantly from those in the other two groups, in which the only significant changes were small increases in breastmilk retinol in the control-wafer group (0.16 [0.02-0.30] mumol/L) and in serum beta-carotene in the vegetable group (0.03 [0-0.06] mumol/L). Changes in iron status were similar in all three groups. An additional daily portion of dark-green leafy vegetables did not improve vitamin A status, whereas a similar amount of beta-carotene from a simpler matrix produced a strong improvement. These results suggest that the approach to combating vitamin A deficiency by increases in the consumption of provitamin A carotenoids from vegetables should be re-examined.

Effect of daily vs twice weekly iron supplementation in Indonesian preschool children with low iron status.

The effect of daily vs twice weekly iron supplementation on iron status was studied in preschool children with low iron status in a randomized double-masked field trial. Subjects (n = 87) were selected on the basis of their hemoglobin concentration being < 111 g/L in finger-prick blood, and were divided into two groups. For 8 wk one group received a daily supplement of 30 mg Fe, while the other group received 30 mg Fe twice per week. A complete data set was obtained from 32 children in the group supplemented daily and from 33 children in the group supplemented twice weekly. Hemoglobin, serum ferritin, and protoporphyrin increased significantly in both groups (P < 0.001). Changes in hemoglobin and protoporphyrin were correlated with initial hemoglobin concentration (P < 0.001). The difference in treatment effect between groups was not significant after correction for the initial hemoglobin concentration. It is concluded that in preschool children with low iron status, twice weekly iron supplementation has an effect on iron status similar to that of daily supplementation.

Changing prevalence of xerophthalmia in Indonesia, 1977-1992.

OBJECTIVE: The primary objective of this analysis was to determine if the prevalence of xerophthalmia in Indonesia has changed over the period 1977-78 to 1992. DESIGN: The design was two cross-sectional prevalence surveys conducted in the same rural sample locations 14 years apart. SETTING: The studies were conducted in 15 provinces of Indonesia using a stratified random selection of villages. SUBJECTS: All persons in selected villages < 6 years of age were eligible for participation. Children were recruited during a door-to-door census of villages and invited to present for an eye examination at a central point in the village. A total of 19,032 subjects were included in the 1977-78 and 18,508 children in the 1992 survey. RESULTS: Overall, the prevalence of active xerophthalmia among preschool children declined by 75% (1.33% in 1977-78 to 0.34% in 1992). Active corneal disease declined by 95% (1/1000 in 1977-78 to 0.05/1000 in 1992). While the overall declines were dramatic and highly significant (P < 0.0001), selected provinces continued to show rates higher than the WHO criteria for a problem of public health significance. CONCLUSIONS: The prevalence of xerophthalmia has declined significantly over the past 14 years in Indonesia. The specific reasons for this decline cannot be ascribed to any particular intervention due to the multitude of health and social changes that have occurred during this period.

Assessment of the vitamin A status in lactating and nonlactating, nonpregnant Indonesian women by use of the modified-relative-dose-response (MRDR) test.

The vitamin A statuses of two groups of Indonesian women were compared by using the modified-relative-dose-response (MRDR) test: 1) lactating, nonpregnant women of lower socioeconomic status (n = 64) and 2) better-educated, premenopausal, nonpregnant, nonlactating women (n = 14). At times from 3 to 6 h after dosing, the mean ratio of dehydroretinol to retinol (DR/R) in the serum was approximately threefold higher in the lactating women than in the control group, eg, 0.109 +/- 0.073 and 0.034 +/- 0.015, respectively, at 5 h. At a provisional DR/R cutoff of 0.06, the vitamin A statuses of 70% of the lactating women and of 7% of the control women were judged to be inadequate. Only 7% of the variability in abnormal MRDR ratios could be attributed to body weight. Both abnormal and normal responses were highly reproducible when performed 0.5-3.25 mo after the first test.

PIP: The vitamin A statuses of two groups of Indonesian women recruited from the suburban areas surrounding Bogor in West Java, Indonesia, were compared by using the modified-relative-dose-response (MRDR) test: 1) 64 lactating nonpregnant women of lower socioeconomic status aged 17-37 years with 1-10 children; and 2) better-educated, pre-menopausal, nonpregnant, nonlactating women, 29-41 years old, with 0-4 children (n = 14) recruited from the staff at the Nutrition Research and Development Center in Bogor. The two groups differed significantly in weight (P 0.001) and age (P 0.001). At times from 3 to 6 hours after dosing, the mean ratio of dehydroretinol to retinol (DR/R) in the serum was approximately threefold higher in the lactating women than in the control group, e.g., 0.109 + or - 0.073 and 0.034 + or - 0.015, respectively, at 5 hours. The slopes of the response means between the groups showed a highly significant difference (P 0.001). The mean DR/Rs obtained by combining 5-hours and 5-hours-predicted values for lactating and control groups were 0.109 + or - 0.073 and 0.034 + or - 0.015, respectively. These two values also showed a highly significant difference (p 0.001). At a provisional DR/R cutoff of 0.06, the vitamin A statuses of 70% of the lactating women and of 7% of the control women were judged to be inadequate. The MRDR values of the control group also show a significant negative correlation with body weight (P 0.01). The slopes [(change in DR/R)/kg body wt] were -0.0055/kg (-0.0036/kg for n - 1) and -0.0015/kg for the lactating and control groups, respectively. Only 7% of the variability in abnormal MRDR ratios could be attributed to body weight. Both abnormal and normal responses were highly reproducible when performed 0.5 -3.25 months after the first test. Thus, safe, low-dose oral supplements of vitamin A ( 8000 IU) should be made available to lactating and pregnant mothers in at-risk populations. Nontoxic provitamin A carotenoids might be preferable as supplements.

Comparison of vitamin A status assessment techniques in children from two Indonesian villages.

The vitamin A statuses of preschool-aged children without clinical eye signs of vitamin A deficiency in two villages near Bogor, West Java, Indonesia, were studied by the modified-relative-dose-response (MRDR) test and the conjunctival impression cytology (CIC) method. In the second village the relative-dose-response (RDR) test was also applied. Of the children examined, 71% in the first village (group 1, n = 75) and 36% in the second village (group 2, n = 83) fell below the third percentile of the WHO reference standard of weight-for-age. The following provisional cutoff values for inadequate vitamin A status in Indonesia were used: MRDR (> or = 0.06), RDR (> or = 20%), CIC (an abnormal impression in one eye). The percent abnormal values were as follows: group 1--MRDR 48%, CIC 51%; group 2--MRDR 12%, RDR 11%, CIC 5%. Thus, the indicators gave concordant results for the two populations but did not necessarily identify the same individuals at risk. The consistency of the RDR test was much improved by increasing the oral dose of 3.5 mumol and by retesting only after a 3-wk interval.

Supplementation with vitamin A and iron for nutritional anaemia in pregnant women in West Java, Indonesia.

Nutritional anaemia, thought to be caused by iron deficiency, affects 50-70% of pregnant women in the developing world. The influence of vitamin A and iron supplementation was studied in anaemic pregnant women in West Java, in a randomised, double-masked, placebo-controlled field trial. 251 women aged 17-35 years, parity 0-4, gestation 16-24 weeks, and haemoglobin between 80 and 109 g/L were randomly allocated to four groups: vitamin A (2.4 mg retinol) and placebo iron tablets; iron (60 mg elemental iron) and placebo vitamin A; vitamin A and iron; or both placebos, all daily for 8 weeks. Maximum haemoglobin was achieved with both vitamin A and iron supplementation (12.78 g/L, 95% Cl 10.86 to 14.70), with one-third of the response attributable to vitamin A (3.68 g/L, 2.03 to 5.33) and two-thirds to iron (7.71 g/L, 5.97 to 9.45). After supplementation, the proportion of women who became non-anaemic was 35% in the vitamin-A-supplemented group, 68% in the iron-supplemented group, 97% in the group supplemented with both, and 16% in the placebo group. Improvement in vitamin A status may contribute to the control of anaemic pregnant women.