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Background: The value of KI67 in breast cancer prognostication has been questioned due to concerns on the analytical validity of visual KI67 assessment and methodological limitations of published studies. Here, we investigate the prognostic value of automated KI67 scoring in a large, multicentre study, and compare this with pathologists' visual scores available in a subset of patients., Methods: We utilised 143 tissue microarrays containing 15,313 tumour tissue cores from 8088 breast cancer patients in 10 collaborating studies. A total of 1401 deaths occurred during a median follow-up of 7.5 years. Centralised KI67 assessment was performed using an automated scoring protocol. The relationship of KI67 levels with 10-year breast cancer specific survival (BCSS) was investigated using Kaplan-Meier survival curves and Cox proportional hazard regression models adjusted for known prognostic factors., Results: Patients in the highest quartile of KI67 (>12 % positive KI67 cells) had a worse 10-year BCSS than patients in the lower three quartiles. This association was statistically significant for ER-positive patients (hazard ratio (HR) (95 % CI) at baseline = 1.96 (1.31-2.93); P = 0.001) but not for ER-negative patients (1.23 (0.86-1.77); P = 0.248) (P-heterogeneity = 0.064). In spite of differences in characteristics of the study populations, the estimates of HR were consistent across all studies (P-heterogeneity = 0.941 for ER-positive and P-heterogeneity = 0.866 for ER-negative). Among ER-positive cancers, KI67 was associated with worse prognosis in both node-negative (2.47 (1.16-5.27)) and node-positive (1.74 (1.05-2.86)) tumours (P-heterogeneity = 0.671). Further classification according to ER, PR and HER2 showed statistically significant associations with prognosis among hormone receptor-positive patients regardless of HER2 status (P-heterogeneity = 0.270) and among triple-negative patients (1.70 (1.02-2.84)). Model fit parameters were similar for visual and automated measures of KI67 in a subset of 2440 patients with information from both sources., Conclusions: Findings from this large-scale multicentre analysis with centrally generated automated KI67 scores show strong evidence in support of a prognostic value for automated KI67 scoring in breast cancer. Given the advantages of automated scoring in terms of its potential for standardisation, reproducibility and throughput, automated methods appear to be promising alternatives to visual scoring for KI67 assessment.

Purpose: Type 2 diabetes (T2D) has been reported to be associated with an elevated risk of breast cancer. It is unclear, however, whether this association is due to shared genetic factors., Methods: We constructed a genetic risk score (GRS) using risk variants from 33 known independent T2D susceptibility loci and evaluated its relation to breast cancer risk using the data from two consortia, including 62,328 breast cancer patients and 83,817 controls of European ancestry. Unconditional logistic regression models were used to derive adjusted odds ratios (ORs) and 95 % confidence intervals (CIs) to measure the association of breast cancer risk with T2D GRS or T2D-associated genetic risk variants. Meta-analyses were conducted to obtain summary ORs across all studies., Results: The T2D GRS was not found to be associated with breast cancer risk, overall, by menopausal status, or for estrogen receptor positive or negative breast cancer. Three T2D associated risk variants were individually associated with breast cancer risk after adjustment for multiple comparisons using the Bonferroni method (at p < 0.001), rs9939609 (FTO) (OR 0.94, 95 % CI = 0.92-0.95, p = 4.13E-13), rs7903146 (TCF7L2) (OR 1.04, 95 % CI = 1.02-1.06, p = 1.26E-05), and rs8042680 (PRC1) (OR 0.97, 95 % CI = 0.95-0.99, p = 8.05E-04)., Conclusions: We have shown that several genetic risk variants were associated with the risk of both T2D and breast cancer. However, overall genetic susceptibility to T2D may not be related to breast cancer risk., Competing Interests: Compliance with Ethical Standards Conflict of Interest: The authors declare that they have no conflict of interest.

Automated methods are needed to facilitate high-throughput and reproducible scoring of Ki67 and other markers in breast cancer tissue microarrays (TMAs) in large-scale studies. To address this need, we developed an automated protocol for Ki67 scoring and evaluated its performance in studies from the Breast Cancer Association Consortium. We utilized 166 TMAs containing 16,953 tumour cores representing 9,059 breast cancer cases, from 13 studies, with information on other clinical and pathological characteristics. TMAs were stained for Ki67 using standard immunohistochemical procedures, and scanned and digitized using the Ariol system. An automated algorithm was developed for the scoring of Ki67, and scores were compared to computer assisted visual (CAV) scores in a subset of 15 TMAs in a training set. We also assessed the correlation between automated Ki67 scores and other clinical and pathological characteristics. Overall, we observed good discriminatory accuracy (AUC = 85%) and good agreement (kappa = 0.64) between the automated and CAV scoring methods in the training set. The performance of the automated method varied by TMA (kappa range= 0.37-0.87) and study (kappa range = 0.39-0.69). The automated method performed better in satisfactory cores (kappa = 0.68) than suboptimal (kappa = 0.51) cores (p-value for comparison = 0.005); and among cores with higher total nuclei counted by the machine (4,000-4,500 cells: kappa = 0.78) than those with lower counts (50-500 cells: kappa = 0.41; p-value = 0.010). Among the 9,059 cases in this study, the correlations between automated Ki67 and clinical and pathological characteristics were found to be in the expected directions. Our findings indicate that automated scoring of Ki67 can be an efficient method to obtain good quality data across large numbers of TMAs from multicentre studies. However, robust algorithm development and rigorous pre- and post-analytical quality control procedures are necessary in order to ensure satisfactory performance.

Background: The ongoing progress of continuous glucose monitoring (CGM) systems results in an increasing interest in comparing their performance, in particular in terms of accuracy, that is, matching CGM readings with reference values measured at the same time. Most often accuracy is evaluated by the mean absolute relative difference (MARD). It is frequently overseen that MARD does not only reflect accuracy, but also the study protocol and evaluation procedure, making a cross-study comparison problematic., Methods: We evaluate the effect of several factors on the MARD statistical properties: number of paired reference and CGM values, distribution of the paired values, accuracy of the reference measurement device itself and the time delay between data pairs. All analysis is done using clinical data from 12 patients wearing 6 sensors each., Results: We have found that a few paired points can have a potentially high impact on MARD. Leaving out those points for evaluation thus reduces the MARD. Similarly, accuracy of the reference measurements greatly affects the MARD as numerical and graphical data show. Results also show that a log-normal distribution of the paired references provides a significantly different MARD than, for example, a uniform distribution., Conclusions: MARD is a reasonable parameter to characterize the performance of CGM systems when keeping its limitations in mind. To support clinicians and patients in selecting which CGM system to use in a clinical setting, care should be taken to make MARD more comparable by employing a standardized evaluation procedure., (© 2015 Diabetes Technology Society.)

Background: Continuous glucose monitoring (CGM) is a powerful tool to support the optimization of glucose control of patients with diabetes. However, CGM systems measure glucose in interstitial fluid but not in blood. Rapid changes in one compartment are not accompanied by similar changes in the other, but follow with some delay. Such time delays hamper detection of, for example, hypoglycemic events. Our aim is to discuss the causes and extent of time delays and approaches to compensate for these., Methods: CGM data were obtained in a clinical study with 37 patients with a prototype glucose sensor. The study was divided into 5 phases over 2 years. In all, 8 patients participated in 2 phases separated by 8 months. A total number of 108 CGM data sets including raw signals were used for data analysis and were processed by statistical methods to obtain estimates of the time delay., Results: Overall mean (SD) time delay of the raw signals with respect to blood glucose was 9.5 (3.7) min, median was 9 min (interquartile range 4 min). Analysis of time delays observed in the same patients separated by 8 months suggests a patient dependent delay. No significant correlation was observed between delay and anamnestic or anthropometric data. The use of a prediction algorithm reduced the delay by 4 minutes on average., Conclusions: Prediction algorithms should be used to provide real-time CGM readings more consistent with simultaneous measurements by SMBG. Patient specificity may play an important role in improving prediction quality., (© 2015 Diabetes Technology Society.)

Introduction: The accuracy of continuous glucose monitoring (CGM) systems is often assessed with respect to blood glucose (BG) readings. CGM readings are affected by a physiological and a technical time delay when compared to BG readings. In this analysis, the dependence of CGM performance parameters on the BG rate of change was investigated for 2 CGM systems., Methods: Data from a previously published study were retrospectively analyzed. An established CGM system (Dexcom G4, Dexcom, San Diego, CA; system A) and a prototype system (Roche Diagnostics GmbH, Mannheim, Germany; system B) with 2 sensors each were worn by 10 subjects in parallel. Glucose swings were induced to achieve rapidly changing BG concentrations. Mean absolute relative differences (MARD) were calculated in different BG rate-of-change categories. In addition, sensor-to-sensor precision was assessed., Results: At BG rates of change of -1 mg/dl/min to 0 mg/dl/min and 0 mg/dl/min to +1 mg/dl/min, MARD results were 12.6% and 11.3% for system A and 8.2% and 10.0% for system B. At rapidly changing BG concentrations (<-3 mg/dl/min and ≥+3 mg/dl/min), higher MARD results were found for both systems, but system B was less affected (system A: 24.9% and 29.6%, system B: 10.6% and 16.3%). The impact of rate of change on sensor-to-sensor precision was less pronounced., Conclusions: Both systems were affected by rapidly changing BG concentrations to some degree, although system B was mostly unaffected by decreasing BG concentrations. It would seem that technological advancements in CGM systems might allow for a more precise tracking of BG concentrations even at rapidly changing BG concentrations., (© 2015 Diabetes Technology Society.)

A large genotyping project within the Breast Cancer Association Consortium (BCAC) recently identified 41 associations between single nucleotide polymorphisms (SNPs) and overall breast cancer (BC) risk. We investigated whether the effects of these 41 SNPs, as well as six SNPs associated with estrogen receptor (ER) negative BC risk are modified by 13 environmental risk factors for BC. Data from 22 studies participating in BCAC were pooled, comprising up to 26,633 cases and 30,119 controls. Interactions between SNPs and environmental factors were evaluated using an empirical Bayes-type shrinkage estimator. Six SNPs showed interactions with associated p-values (pint ) <1.1 × 10(-3) . None of the observed interactions was significant after accounting for multiple testing. The Bayesian False Discovery Probability was used to rank the findings, which indicated three interactions as being noteworthy at 1% prior probability of interaction. SNP rs6828523 was associated with increased ER-negative BC risk in women ≥170 cm (OR = 1.22, p = 0.017), but inversely associated with ER-negative BC risk in women <160 cm (OR = 0.83, p = 0.039, pint = 1.9 × 10(-4) ). The inverse association between rs4808801 and overall BC risk was stronger for women who had had four or more pregnancies (OR = 0.85, p = 2.0 × 10(-4) ), and absent in women who had had just one (OR = 0.96, p = 0.19, pint = 6.1 × 10(-4) ). SNP rs11242675 was inversely associated with overall BC risk in never/former smokers (OR = 0.93, p = 2.8 × 10(-5) ), but no association was observed in current smokers (OR = 1.07, p = 0.14, pint = 3.4 × 10(-4) ). In conclusion, recently identified BC susceptibility loci are not strongly modified by established risk factors and the observed potential interactions require confirmation in independent studies., (© 2014 UICC.)

Candidate variant association studies have been largely unsuccessful in identifying common breast cancer susceptibility variants, although most studies have been underpowered to detect associations of a realistic magnitude. We assessed 41 common non-synonymous single-nucleotide polymorphisms (nsSNPs) for which evidence of association with breast cancer risk had been previously reported. Case-control data were combined from 38 studies of white European women (46 450 cases and 42 600 controls) and analyzed using unconditional logistic regression. Strong evidence of association was observed for three nsSNPs: ATXN7-K264R at 3p21 [rs1053338, per allele OR = 1.07, 95% confidence interval (CI) = 1.04-1.10, P = 2.9 × 10(-6)], AKAP9-M463I at 7q21 (rs6964587, OR = 1.05, 95% CI = 1.03-1.07, P = 1.7 × 10(-6)) and NEK10-L513S at 3p24 (rs10510592, OR = 1.10, 95% CI = 1.07-1.12, P = 5.1 × 10(-17)). The first two associations reached genome-wide statistical significance in a combined analysis of available data, including independent data from nine genome-wide association studies (GWASs): for ATXN7-K264R, OR = 1.07 (95% CI = 1.05-1.10, P = 1.0 × 10(-8)); for AKAP9-M463I, OR = 1.05 (95% CI = 1.04-1.07, P = 2.0 × 10(-10)). Further analysis of other common variants in these two regions suggested that intronic SNPs nearby are more strongly associated with disease risk. We have thus identified a novel susceptibility locus at 3p21, and confirmed previous suggestive evidence that rs6964587 at 7q21 is associated with risk. The third locus, rs10510592, is located in an established breast cancer susceptibility region; the association was substantially attenuated after adjustment for the known GWAS hit. Thus, each of the associated nsSNPs is likely to be a marker for another, non-coding, variant causally related to breast cancer risk. Further fine-mapping and functional studies are required to identify the underlying risk-modifying variants and the genes through which they act., (© The Author 2014. Published by Oxford University Press.)

Invasive lobular breast cancer (ILC) accounts for 10-15% of all invasive breast carcinomas. It is generally ER positive (ER+) and often associated with lobular carcinoma in situ (LCIS). Genome-wide association studies have identified more than 70 common polymorphisms that predispose to breast cancer, but these studies included predominantly ductal (IDC) carcinomas. To identify novel common polymorphisms that predispose to ILC and LCIS, we pooled data from 6,023 cases (5,622 ILC, 401 pure LCIS) and 34,271 controls from 36 studies genotyped using the iCOGS chip. Six novel SNPs most strongly associated with ILC/LCIS in the pooled analysis were genotyped in a further 516 lobular cases (482 ILC, 36 LCIS) and 1,467 controls. These analyses identified a lobular-specific SNP at 7q34 (rs11977670, OR (95%CI) for ILC = 1.13 (1.09-1.18), P = 6.0 × 10(-10); P-het for ILC vs IDC ER+ tumors = 1.8 × 10(-4)). Of the 75 known breast cancer polymorphisms that were genotyped, 56 were associated with ILC and 15 with LCIS at P<0.05. Two SNPs showed significantly stronger associations for ILC than LCIS (rs2981579/10q26/FGFR2, P-het = 0.04 and rs889312/5q11/MAP3K1, P-het = 0.03); and two showed stronger associations for LCIS than ILC (rs6678914/1q32/LGR6, P-het = 0.001 and rs1752911/6q14, P-het = 0.04). In addition, seven of the 75 known loci showed significant differences between ER+ tumors with IDC and ILC histology, three of these showing stronger associations for ILC (rs11249433/1p11, rs2981579/10q26/FGFR2 and rs10995190/10q21/ZNF365) and four associated only with IDC (5p12/rs10941679; rs2588809/14q24/RAD51L1, rs6472903/8q21 and rs1550623/2q31/CDCA7). In conclusion, we have identified one novel lobular breast cancer specific predisposition polymorphism at 7q34, and shown for the first time that common breast cancer polymorphisms predispose to LCIS. We have shown that many of the ER+ breast cancer predisposition loci also predispose to ILC, although there is some heterogeneity between ER+ lobular and ER+ IDC tumors. These data provide evidence for overlapping, but distinct etiological pathways within ER+ breast cancer between morphological subtypes.

Part of the substantial unexplained familial aggregation of breast cancer may be due to interactions between common variants, but few studies have had adequate statistical power to detect interactions of realistic magnitude. We aimed to assess all two-way interactions in breast cancer susceptibility between 70,917 single nucleotide polymorphisms (SNPs) selected primarily based on prior evidence of a marginal effect. Thirty-eight international studies contributed data for 46,450 breast cancer cases and 42,461 controls of European origin as part of a multi-consortium project (COGS). First, SNPs were preselected based on evidence (P < 0.01) of a per-allele main effect, and all two-way combinations of those were evaluated by a per-allele (1 d.f.) test for interaction using logistic regression. Second, all 2.5 billion possible two-SNP combinations were evaluated using Boolean operation-based screening and testing, and SNP pairs with the strongest evidence of interaction (P < 10(-4)) were selected for more careful assessment by logistic regression. Under the first approach, 3277 SNPs were preselected, but an evaluation of all possible two-SNP combinations (1 d.f.) identified no interactions at P < 10(-8). Results from the second analytic approach were consistent with those from the first (P > 10(-10)). In summary, we observed little evidence of two-way SNP interactions in breast cancer susceptibility, despite the large number of SNPs with potential marginal effects considered and the very large sample size. This finding may have important implications for risk prediction, simplifying the modelling required. Further comprehensive, large-scale genome-wide interaction studies may identify novel interacting loci if the inherent logistic and computational challenges can be overcome.

Purpose: (1) To explore participation in leisure time physical activities (LTPAs) in children with developmental coordination disorder (DCD) compared with children developing typically. (2) To examine the association between participation in LTPA and aerobic fitness., Methods: Thirty-eight children with DCD (aged 7-12 years) were age and gender matched with 38 children developing typically. Participation in LTPA was self-administered by using an activity questionnaire, and aerobic fitness was estimated using a Shuttle Run Test., Results: Children with DCD spent significantly less time in overall, nonorganized, and vigorous LTPA compared with children developing typically. Aerobic fitness was significantly lower for children with DCD. The best model, including age, group, and overall LTPA, explained 46.2% of the variance in aerobic fitness., Conclusions: Suitable physical activities should be fostered in children with DCD, who have a low participation rate and aerobic fitness level.

Women using menopausal hormone therapy (MHT) are at increased risk of developing breast cancer (BC). To detect genetic modifiers of the association between current use of MHT and BC risk, we conducted a meta-analysis of four genome-wide case-only studies followed by replication in 11 case-control studies. We used a case-only design to assess interactions between single-nucleotide polymorphisms (SNPs) and current MHT use on risk of overall and lobular BC. The discovery stage included 2920 cases (541 lobular) from four genome-wide association studies. The top 1391 SNPs showing P values for interaction (Pint) <3.0 × 10(-3) were selected for replication using pooled case-control data from 11 studies of the Breast Cancer Association Consortium, including 7689 cases (676 lobular) and 9266 controls. Fixed-effects meta-analysis was used to derive combined Pint. No SNP reached genome-wide significance in either the discovery or combined stage. We observed effect modification of current MHT use on overall BC risk by two SNPs on chr13 near POMP (combined Pint≤8.9 × 10(-6)), two SNPs in SLC25A21 (combined Pint≤4.8 × 10(-5)), and three SNPs in PLCG2 (combined Pint≤4.5 × 10(-5)). The association between lobular BC risk was potentially modified by one SNP in TMEFF2 (combined Pint≤2.7 × 10(-5)), one SNP in CD80 (combined Pint≤8.2 × 10(-6)), three SNPs on chr17 near TMEM132E (combined Pint≤2.2×10(-6)), and two SNPs on chr18 near SLC25A52 (combined Pint≤4.6 × 10(-5)). In conclusion, polymorphisms in genes related to solute transportation in mitochondria, transmembrane signaling, and immune cell activation are potentially modifying BC risk associated with current use of MHT. These findings warrant replication in independent studies.

Background: Even though a Clinical and Laboratory Standards Institute proposal exists on the design of studies and performance criteria for continuous glucose monitoring (CGM) systems, it has not yet led to a consistent evaluation of different systems, as no consensus has been reached on the reference method to evaluate them or on acceptance levels. As a consequence, performance assessment of CGM systems tends to be inconclusive, and a comparison of the outcome of different studies is difficult., Materials and Methods: Published information and available data (as presented in this issue of Journal of Diabetes Science and Technology by Freckmann and coauthors) are used to assess the suitability of several frequently used methods [International Organization for Standardization, continuous glucose error grid analysis, mean absolute relative deviation (MARD), precision absolute relative deviation (PARD)] when assessing performance of CGM systems in terms of accuracy and precision., Results: The combined use of MARD and PARD seems to allow for better characterization of sensor performance. The use of different quantities for calibration and evaluation, e.g., capillary blood using a blood glucose (BG) meter versus venous blood using a laboratory measurement, introduces an additional error source. Using BG values measured in more or less large intervals as the only reference leads to a significant loss of information in comparison with the continuous sensor signal and possibly to an erroneous estimation of sensor performance during swings. Both can be improved using data from two identical CGM sensors worn by the same patient in parallel., Conclusions: Evaluation of CGM performance studies should follow an identical study design, including sufficient swings in glycemia. At least a part of the study participants should wear two identical CGM sensors in parallel. All data available should be used for evaluation, both by MARD and PARD, a good PARD value being a precondition to trust a good MARD value. Results should be analyzed and presented separately for clinically different categories, e.g., hypoglycemia, exercise, or night and day., (© 2013 Diabetes Technology Society.)

Background: The performance of a continuous glucose monitoring (CGM) system in the early stage of development was assessed in an inpatient setting that simulates daily life conditions of people with diabetes. Performance was evaluated at low glycemic, euglycemic, and high glycemic ranges as well as during phases with rapid glucose excursions., Methods: Each of the 30 participants with type 1 diabetes (15 female, age 47 ± 12 years, hemoglobin A1c 7.7% ± 1.3%) wore two sensors of the prototype system in parallel for 7 days. Capillary blood samples were measured at least 16 times per day (at least 15 times per daytime and at least once per night). On two subsequent study days, glucose excursions were induced. For performance evaluation, the mean absolute relative difference (MARD) between CGM readings and paired capillary blood glucose readings and precision absolute relative difference (PARD), i.e., differences between paired CGM readings were calculated., Results: Overall aggregated MARD was 9.2% and overall aggregated PARD was 7.5%. During induced glucose excursions, MARD was 10.9% and PARD was 7.8%. Lowest MARD (8.5%) and lowest PARD (6.4%) were observed in the high glycemic range (euglycemic range, MARD 9.1% and PARD 7.4%; low glycemic range, MARD 12.3% and PARD 12.4%)., Conclusions: The performance of this prototype CGM system was, particularly in the hypoglycemic range and during phases with rapid glucose fluctuations, better than performance data reported for other commercially available systems. In addition, performance of this prototype sensor was noticeably constant over the whole study period. This prototype system is not yet approved, and performance of this CGM system needs to be further assessed in clinical studies., (© 2013 Diabetes Technology Society.)

The core element of a continuous glucose monitoring (CGM) system is the glucose sensor, which should enable reliable CGM readings in the interstitial fluid in subcutaneous tissue for a period of several days. The aim of this article is to describe the layout and constituents of a novel glucose sensor and the rationale behind the measures that were used to optimize its performance. In order to achieve a stable glucose sensor signal, special attention was paid to the sensor materials and architecture, i.e., biocompatible coating of the sensor, limitation of glucose flux into the working electrode, low oxidation potential by use of manganese dioxide, and a tissue-averaging sensor design. A series of in vitro and in vivo evaluations showed that the sensor enables stable and accurate glucose sensing in the subcutaneous tissue for up to 7 days. Parallel measurements with four sensors in a single patient showed a close agreement between these sensors. In summary, this high-performance needle-type glucose sensor is well suited for CGM in patients with diabetes., (© 2013 Diabetes Technology Society.)

Context: Endogenous sex hormones are risk factors for postmenopausal breast cancer. A potential route for favorable hormonal modification is weight loss., Objective: The objective of the study was to measure change in plasma estradiol and testosterone levels in postmenopausal women in relation to change in body mass index (BMI) and plasma leptin., Setting: The setting was a cohort study of over 100,000 female volunteers from the general population, United Kingdom., Participants: The participants were a sample of 177 postmenopausal women aged over 45 years who provided blood samples during 2004-2005 and again during 2010-2011., Main Outcome Measure: Outcomes were percentage change in plasma estradiol and testosterone levels per 1 kg/m² change in BMI and per 1 ng/mL change in plasma leptin., Results: Among women with reduction in BMI, estradiol decreased 12.7% (95% confidence interval: [6.4%, 19.5%]; P < .0001) per kg/m² and among women with increased BMI estradiol increased 6.4% [0.2%, 12.9%] (P = .042). The corresponding figures for testosterone were 10.7% [3.0%, 19.0%] (P = .006) and 1.9% [-5.4%, 9.7%] (P = .61) per kg/m². For women with decreases and increases in leptin, estradiol decreased by 3.6% [1.3%, 6.0%] (P = .003) per ng/mL and increased by 1.7% [-0.3%, 3.6%] (P = .094), respectively. The corresponding figures for testosterone were 4.8% [2.0%, 7.8%] (P = .009) and 0.3% [-2.0%, 2.6%] (P = .82) per ng/mL., Conclusions: In postmenopausal women, changes in BMI and plasma leptin occurring over several years are associated with changes in estradiol and testosterone levels. The results suggest that fat loss by an individual can result in substantial decreases in postmenopausal estradiol and testosterone levels and provides support for weight management to lessen breast cancer risk.

Early menopause (EM) affects up to 10% of the female population, reducing reproductive lifespan considerably. Currently, it constitutes the leading cause of infertility in the western world, affecting mainly those women who postpone their first pregnancy beyond the age of 30 years. The genetic aetiology of EM is largely unknown in the majority of cases. We have undertaken a meta-analysis of genome-wide association studies (GWASs) in 3493 EM cases and 13 598 controls from 10 independent studies. No novel genetic variants were discovered, but the 17 variants previously associated with normal age at natural menopause as a quantitative trait (QT) were also associated with EM and primary ovarian insufficiency (POI). Thus, EM has a genetic aetiology which overlaps variation in normal age at menopause and is at least partly explained by the additive effects of the same polygenic variants. The combined effect of the common variants captured by the single nucleotide polymorphism arrays was estimated to account for ∼30% of the variance in EM. The association between the combined 17 variants and the risk of EM was greater than the best validated non-genetic risk factor, smoking.

Background: Our recent genome-wide association study identified a novel breast cancer susceptibility locus at 9q31.2 (rs865686)., Methods: To further investigate the rs865686-breast cancer association, we conducted a replication study within the Breast Cancer Association Consortium, which comprises 37 case-control studies (48,394 cases, 50,836 controls)., Results: This replication study provides additional strong evidence of an inverse association between rs865686 and breast cancer risk [study-adjusted per G-allele OR, 0.90; 95% confidence interval (CI), 0.88; 0.91, P = 2.01 × 10(-29)] among women of European ancestry. There were ethnic differences in the estimated minor (G)-allele frequency among controls [0.09, 0.30, and 0.38 among, respectively, Asians, Eastern Europeans, and other Europeans; P for heterogeneity (P(het)) = 1.3 × 10(-143)], but no evidence of ethnic differences in per allele OR (P(het) = 0.43). rs865686 was associated with estrogen receptor-positive (ER(+)) disease (per G-allele OR, 0.89; 95% CI, 0.86-0.91; P = 3.13 × 10(-22)) but less strongly, if at all, with ER-negative (ER(-)) disease (OR, 0.98; 95% CI, 0.94-1.02; P = 0.26; P(het) = 1.16 × 10(-6)), with no evidence of independent heterogeneity by progesterone receptor or HER2 status. The strength of the breast cancer association decreased with increasing age at diagnosis, with case-only analysis showing a trend in the number of copies of the G allele with increasing age at diagnosis (P for linear trend = 0.0095), but only among women with ER(+) tumors., Conclusions: This study is the first to show that rs865686 is a susceptibility marker for ER(+) breast cancer., Impact: The findings further support the view that genetic susceptibility varies according to tumor subtype., (2012 AACR)

Background: Epidemiological studies have provided strong evidence for a role of endogenous sex steroids in the etiology of breast cancer. Our aim was to identify common variants in genes involved in sex steroid synthesis or metabolism that are associated with hormone levels and the risk of breast cancer in premenopausal women., Methods: We measured urinary levels of estrone glucuronide (E1G) using a protocol specifically developed to account for cyclic variation in hormone levels during the menstrual cycle in 729 healthy premenopausal women. We genotyped 642 single-nucleotide polymorphisms (SNPs) in these women; a single SNP, rs10273424, was further tested for association with the risk of breast cancer using data from 10 551 breast cancer case patients and 17 535 control subjects. All statistical tests were two-sided., Results: rs10273424, which maps approximately 50 kb centromeric to the cytochrome P450 3A (CYP3A) gene cluster at chromosome 7q22.1, was associated with a 21.8% reduction in E1G levels (95% confidence interval [CI] = 27.8% to 15.3% reduction; P = 2.7 × 10(-9)) and a modest reduction in the risk of breast cancer in case patients who were diagnosed at or before age 50 years (odds ratio [OR] = 0.91, 95% CI = 0.83 to 0.99; P = .03) but not in those diagnosed after age 50 years (OR = 1.01, 95% CI = 0.93 to 1.10; P = .82)., Conclusions: Genetic variation in noncoding sequences flanking the CYP3A locus contributes to variance in premenopausal E1G levels and is associated with the risk of breast cancer in younger patients. This association may have wider implications given that the most predominantly expressed CYP3A gene, CYP3A4, is responsible for metabolism of endogenous and exogenous hormones and hormonal agents used in the treatment of breast cancer.

Breast cancer is the most common cancer among women. To date, 22 common breast cancer susceptibility loci have been identified accounting for ∼8% of the heritability of the disease. We attempted to replicate 72 promising associations from two independent genome-wide association studies (GWAS) in ∼70,000 cases and ∼68,000 controls from 41 case-control studies and 9 breast cancer GWAS. We identified three new breast cancer risk loci at 12p11 (rs10771399; P = 2.7 × 10(-35)), 12q24 (rs1292011; P = 4.3 × 10(-19)) and 21q21 (rs2823093; P = 1.1 × 10(-12)). rs10771399 was associated with similar relative risks for both estrogen receptor (ER)-negative and ER-positive breast cancer, whereas the other two loci were associated only with ER-positive disease. Two of the loci lie in regions that contain strong plausible candidate genes: PTHLH (12p11) has a crucial role in mammary gland development and the establishment of bone metastasis in breast cancer, and NRIP1 (21q21) encodes an ER cofactor and has a role in the regulation of breast cancer cell growth.

The 6q25.1 locus was first identified via a genome-wide association study (GWAS) in Chinese women and marked by single nucleotide polymorphism (SNP) rs2046210, approximately 180 Kb upstream of ESR1. There have been conflicting reports about the association of this locus with breast cancer in Europeans, and a GWAS in Europeans identified a different SNP, tagged here by rs12662670. We examined the associations of both SNPs in up to 61,689 cases and 58,822 controls from forty-four studies collaborating in the Breast Cancer Association Consortium, of which four studies were of Asian and 39 of European descent. Logistic regression was used to estimate odds ratios (OR) and 95% confidence intervals (CI). Case-only analyses were used to compare SNP effects in Estrogen Receptor positive (ER+) versus negative (ER-) tumours. Models including both SNPs were fitted to investigate whether the SNP effects were independent. Both SNPs are significantly associated with breast cancer risk in both ethnic groups. Per-allele ORs are higher in Asian than in European studies [rs2046210: OR (A/G) = 1.36 (95% CI 1.26-1.48), p = 7.6 × 10(-14) in Asians and 1.09 (95% CI 1.07-1.11), p = 6.8 × 10(-18) in Europeans. rs12662670: OR (G/T) = 1.29 (95% CI 1.19-1.41), p = 1.2 × 10(-9) in Asians and 1.12 (95% CI 1.08-1.17), p = 3.8 × 10(-9) in Europeans]. SNP rs2046210 is associated with a significantly greater risk of ER- than ER+ tumours in Europeans [OR (ER-) = 1.20 (95% CI 1.15-1.25), p = 1.8 × 10(-17) versus OR (ER+) = 1.07 (95% CI 1.04-1.1), p = 1.3 × 10(-7), p(heterogeneity) = 5.1 × 10(-6)]. In these Asian studies, by contrast, there is no clear evidence of a differential association by tumour receptor status. Each SNP is associated with risk after adjustment for the other SNP. These results suggest the presence of two variants at 6q25.1 each independently associated with breast cancer risk in Asians and in Europeans. Of these two, the one tagged by rs2046210 is associated with a greater risk of ER- tumours.

The parent-rated Developmental Coordination Disorder Questionnaire (DCDQ) has been revised to incorporate a wider age range, including adolescence. In this exploratory study, internal consistency and validity of the DCDQ-2007 was assessed using a community-based sample of 87 adolescents. Psychometric properties of the DCDQ-2007 were investigated and concurrent validity, sensitivity, and specificity were assessed with the MABC-2 as a criterion standard. The results demonstrated high internal consistency for the DCDQ-2007 and a relationship with the MABC-2 was found. The DCDQ-2007 met the recommended standard for sensitivity, although the confidence interval was large; however, it failed to meet the recommended standard for specificity. This has important implications concerning the suitability of the DCDQ-2007. Although promising psychometric properties were found within the current study, the applicability of the DCDQ-2007 as a screening measure for motor difficulties requires careful consideration.

Background: Genome-wide association studies have identified several common genetic variants associated with breast cancer risk. It is likely, however, that a substantial proportion of such loci have not yet been discovered., Methods: We compared 296,114 tagging single-nucleotide polymorphisms in 1694 breast cancer case subjects (92% with two primary cancers or at least two affected first-degree relatives) and 2365 control subjects, with validation in three independent series totaling 11,880 case subjects and 12,487 control subjects. Odds ratios (ORs) and associated 95% confidence intervals (CIs) in each stage and all stages combined were calculated using unconditional logistic regression. Heterogeneity was evaluated with Cochran Q and I(2) statistics. All statistical tests were two-sided., Results: We identified a novel risk locus for breast cancer at 9q31.2 (rs865686: OR = 0.89, 95% CI = 0.85 to 0.92, P = 1.75 × 10(-10)). This single-nucleotide polymorphism maps to a gene desert, the nearest genes being Kruppel-like factor 4 (KLF4, 636 kb centromeric), RAD23 homolog B (RAD23B, 794 kb centromeric), and actin-like 7A (ACTL7A, 736 kb telomeric). We also identified two variants (rs3734805 and rs9383938) mapping to 6q25.1 estrogen receptor 1 (ESR1), which were associated with breast cancer in subjects of northern European ancestry (rs3734805: OR = 1.19, 95% CI = 1.11 to 1.27, P = 1.35 × 10(-7); rs9383938: OR = 1.18, 95% CI = 1.11 to 1.26, P = 1.41 × 10(-7)). A variant mapping to 10q26.13, approximately 300 kb telomeric to the established risk locus within the second intron of FGFR2, was also associated with breast cancer risk, although not at genome-wide statistical significance (rs10510102: OR = 1.12, 95% CI = 1.07 to 1.17, P = 1.58 × 10(-6))., Conclusions: These findings provide further evidence on the role of genetic variation in the etiology of breast cancer. Fine mapping will be needed to identify causal variants and to determine their functional effects.

Purpose: The authors prospectively determined the natural course of pain in patients with conservatively treated acute osteoporotic vertebral compression fractures (VCF). In addition, the type of conservative therapy that these patients received was assessed., Materials and Methods: Patients older than 50 years, referred for spine radiography for acute back pain, were asked to complete a baseline clinical questionnaire. Patients with an acute VCF were followed up at 6 and 23 months with a questionnaire that included a Visual Analog Score (VAS) and type of pain medication and other conservative treatment. Significant pain relief was defined as a decrease in VAS of 50% or more., Results: Forty-nine patients (mean age, 78 years; range, 51-95) with acute VCF were followed up for almost 2 years. Significant pain relief was noted in 22 of 35 patients (63%) at 6 months and in 25 of 36 (69%) at 23 months. In patients with persisting pain at 23 months (mean VAS 6.4), some decrease in VAS was apparent at 6 months but not in the 6-23 months interval. No predictors for significant pain relief could be identified. Patients with significant pain relief used less pain medication and had less physical therapy., Conclusions: In most patients with an acute VCF, pain decreases significantly with conservative therapy, predominantly in the first 6 months. However, almost 2 years after an acute VCF, a third of patients still had severe pain necessitating pain medication and physical therapy in the majority. No predictors for transition from acute to chronic pain could be identified., (Copyright 2010 SIR. Published by Elsevier Inc. All rights reserved.)

The human telomerase reverse transcriptase (hTERT) gene is upregulated in a majority of malignant tumours. A variable tandem repeat, MNS16A, has been reported to be of functional significance for hTERT expression. Published data on the clinical relevance of MNS16A variants in brain tumours have been contradictory. The present population-based study in the Nordic countries and the United Kingdom evaluated brain-tumour risk and survival in relation to MNS16A minisatellite variants in 648 glioma cases, 473 meningioma cases and 1,359 age, sex and geographically matched controls. By PCR-based genotyping all study subjects with fragments of 240 or 271 bp were judged as having short (S) alleles and subjects with 299 or 331 bp fragments as having long (L) alleles. Relative risk of glioma or meningioma was estimated with logistic regression adjusting for age, sex and country. Overall survival was analysed using Kaplan-Meier estimates and equality of survival distributions using the log-rank test and Cox proportional hazard ratios. The MNS16A genotype was not associated with risk of occurrence of glioma, glioblastoma (GBM) or meningioma. For GBM there were median survivals of 15.3, 11.0 and 10.7 months for the LL, LS and SS genotypes, respectively; the hazard ratio for having the LS genotype compared with the LL was significantly increased HR 2.44 (1.56-3.82) and having the SS genotype versus the LL was nonsignificantly increased HR 1.46 (0.81-2.61). When comparing the LL versus having one of the potentially functional variants LS and SS, the HR was 2.10 (1.41-3.1). However, functionality was not supported as there was no trend towards increasing HR with number of S alleles. Collected data from our and previous studies regarding both risk and survival for the MNS16A genotypes are contradictory and warrant further investigations.

To identify risk variants for glioma, we conducted a meta-analysis of two genome-wide association studies by genotyping 550K tagging SNPs in a total of 1,878 cases and 3,670 controls, with validation in three additional independent series totaling 2,545 cases and 2,953 controls. We identified five risk loci for glioma at 5p15.33 (rs2736100, TERT; P = 1.50 x 10(-17)), 8q24.21 (rs4295627, CCDC26; P = 2.34 x 10(-18)), 9p21.3 (rs4977756, CDKN2A-CDKN2B; P = 7.24 x 10(-15)), 20q13.33 (rs6010620, RTEL1; P = 2.52 x 10(-12)) and 11q23.3 (rs498872, PHLDB1; P = 1.07 x 10(-8)). These data show that common low-penetrance susceptibility alleles contribute to the risk of developing glioma and provide insight into disease causation of this primary brain tumor.

Caspase 8 (CASP8) is a key regulator of apoptosis or programmed cell death, and hence a defence against cancer. The CASP8 polymorphism D302H has recently been shown to influence the risk of breast cancer. We tested the hypothesis that the CASP8 polymorphism D302H may influence risk of meningioma through analysis of five independent series of case patients and controls (n=631 and 637, respectively). Carrier status for 302H was not associated with a statistically significantly increased risk (OR=1.16; 95% CI: 0.87-1.53; P=0.31) making it unlikely that this variant contributes to the inherited risk of meningioma.

Folate metabolism plays an important role in carcinogenesis. To test the hypothesis that polymorphic variation in the folate metabolism genes 5,10-methylenetetrahydrofolate reductase (MTHFR), methionine synthase (MTRR), and methionine synthase reductase (MTR) influences the risk of primary brain tumors, we genotyped 1,005 glioma cases, 631 meningioma cases, and 1,101 controls for the MTHFR C677A and A1298C, MTRR A66G, and MTR A2756G variants. MTHFR C677T-A1298C diplotypes were associated with risk of meningioma (P = 0.002) and glioma (P = 0.02); risks were increased with genotypes associated with reduced MTHFR activity. The highest risk of meningioma was associated with heterozygosity for both MTHFR variants [odds ratio (OR), 2.11; 95% confidence interval (95% CI), 1.42-3.12]. The corresponding OR for glioma was 1.23 (95% CI, 0.91-1.66). A significant association between risk of meningioma and homozygosity for MTRR 66G was also observed (OR, 1.41; 95% CI, 1.02-1.94). Our findings provide support for the role of folate metabolism in the development of primary brain tumors. In particular, genotypes associated with increased 5,10-methylenetetrahydrofolate levels are associated with elevated risk.

Caspase 8 (CASP8) is a key regulator of apoptosis or programmed cell death, and, hence, a defense against cancer. We tested the hypothesis that the CASP8 polymorphism D302H influences risk of glioma through analysis of five series of glioma case patients and controls (n = 1,005 and 1,011, respectively). Carrier status for the rare allele of D302H was associated with a 1.37-fold increased risk (95% confidence interval, 1.10-1.70; P = 0.004). The association of CASP8 D302H with glioma risk indicates the importance of inherited variation in the apoptosis pathway in susceptibility to this form of primary brain tumor.

Much of the variation in inherited risk of glioma is likely to be explained by combinations of common low risk variants. The established relationship between glioma risk and exposure to ionizing radiation led us to examine whether variants in the DNA repair genes contribute to disease susceptibility. We evaluated 1127 haplotype-tagging single-nucleotide polymorphisms (SNPs) supplemented with 388 putative functional SNPs to capture most of the common variation in 136 DNA repair genes, in five unique case-control series from four different countries (1013 cases, 1016 controls). We identified 16 SNPs associated with glioma risk at the 1% significance level. The highest association observed across the five independent case-control datasets involved rs243356, which maps to intron 3 of CHAF1A (trend odds ratio, 1.32; 95% confidence interval 1.14-1.54; P = 0.0002; false-positive report probability = 0.055, based on a prior probability of 0.01). Our results provide additional support for the hypothesis that low penetrance variants contribute to the risk of developing glioma and suggest that a genetic variant located in or around the CHAF1A gene contributes to disease risk.

Background: Meningiomas account for up to 37% of all primary brain tumors. Genetic susceptibility to meningioma is well established, with the risk among relatives of meningioma patients being approximately threefold higher than that in the general population. A relationship between risk of meningioma and exposure to ionizing radiation is also well known and led us to examine whether variants in DNA repair genes contribute to disease susceptibility., Methods: We analyzed 1127 tagging single-nucleotide polymorphisms (SNPs) that were selected to capture most of the common variation in 136 DNA repair genes in five case-control series (631 case patients and 637 control subjects) from four countries in Europe. We also analyzed 388 putative functional SNPs in these genes for their association with meningioma. All statistical tests were two-sided., Results: The SNP rs4968451, which maps to intron 4 of the gene that encodes breast cancer susceptibility gene 1-interacting protein 1, was consistently associated with an increased risk of developing meningioma. Across the five studies, the association was highly statistically significant (trend odds ratio = 1.57, 95% confidence interval = 1.28 to 1.93; P(trend) = 8.95 x 10(-6); P = .009 after adjusting for multiple testing)., Conclusions: We have identified a novel association between rs4968451 and meningioma risk. Because approximately 28% of the European population are carriers of at-risk genotypes for rs4968451, the variant is likely to make a substantial contribution to the development of meningioma.

The very rapid worldwide increase in mobile phone use in the last decade has generated considerable interest in the possible health effects of exposure to radio frequency (RF) fields. A multinational case-control study, INTERPHONE, was set-up to investigate whether mobile phone use increases the risk of cancer and, more specifically, whether the RF fields emitted by mobile phones are carcinogenic. The study focused on tumours arising in the tissues most exposed to RF fields from mobile phones: glioma, meningioma, acoustic neurinoma and parotid gland tumours. In addition to a detailed history of mobile phone use, information was collected on a number of known and potential risk factors for these tumours. The study was conducted in 13 countries. Australia, Canada, Denmark, Finland, France, Germany, Israel, Italy, Japan, New Zealand, Norway, Sweden, and the UK using a common core protocol. This paper describes the study design and methods and the main characteristics of the study population. INTERPHONE is the largest case-control study to date investigating risks related to mobile phone use and to other potential risk factors for the tumours of interest and includes 2,765 glioma, 2,425 meningioma, 1,121 acoustic neurinoma, 109 malignant parotid gland tumour cases and 7,658 controls. Particular attention was paid to estimating the amount and direction of potential recall and participation biases and their impact on the study results.

The aim of this study was to prove the feasibility of continuous subcutaneous glucose monitoring in humans using the comparative microdialysis technique (CMT). The performance of the CMT was determined by comparing tissue glucose values with venous or capillary blood glucose values in healthy volunteers and type 1 diabetic subjects. The CMT is a microdialysis-based system for continuous online glucose monitoring in humans. This technique does not require calibration by the patient. Physiological saline with glucose (5.5 mM) is pumped in a stop-flow mode through a microdialysis probe inserted into the abdominal s.c. tissue. Tissue glucose concentration is calculated by comparing the dialysate and perfusate glucose concentrations. The time delay due to the measurement process is 9 min. We tested the CMT on six healthy volunteers and six type 1 diabetic patients for 24 h in our clinical setting. Comparisons were made to HemoCue analyzer (Angelholm, Sweden) capillary blood glucose measurements (healthy volunteers) and to venous blood glucose concentration determined with a Hitachi analyzer (diabetic patients). The mean absolute relative error of the CMT glucose values from the blood glucose values was 17.8+/-15.5% (n = 167) for the healthy volunteers and 11.0+/-10.8% (n = 425) for the diabetic patients. The mean difference was 0.42+/-1.06 mM (healthy volunteers) and -0.17+/-1.22 mM (diabetic patients). Error grid analysis for the values obtained in diabetic patients demonstrated that 99% of CMT glucose values were within clinically acceptable regions (regions A and B of the Clarke Error Grid). The study results show that the CMT is an accurate technique for continuous online glucose monitoring.

The aim of this review was to investigate the selection criteria used in the past in studies of children with developmental motor problems (excluding those suffering from neurological dysfunctions such as cerebral palsy, muscular dystrophy, etc.). We therefore conducted an extensive analysis of 176 publications. First, an overview of the main characteristics of these studies (terminology, population, type and purpose) and the selection criteria that are reported in these publications are presented. Following this, the DSM-IV selection criteria for developmental coordination disorder (DCD) are contrasted with the selection criteria reported in 41 publications that have used this terminology to classify the children. The results of this comparison show that the inclusion criteria are largely followed, albeit with little consistency concerning selection instruments and quantitative cut-offs, while adherence to the exclusion criteria is not common practice. Strengths and weaknesses of the DSM-IV criteria, complementary to the previous discussion by Henderson and Barnett in the HMS special issue on DCD in 1998 on this same topic, are discussed. The results of the review also show that many studies have used additional selection criteria related to the specific research questions of the study concerned. In the broader context of clinical practice as well as basic research, the latter result suggests the usefulness of a distinction between Clinical Diagnostic Criteria and Research Diagnostic Criteria. This distinction helps to develop a unifying view on the use of diagnostic criteria for research and clinical practice. We conclude with a number of recommendations concerning the selection criteria for children with DCD.

A 33-year-old woman suffered from an early postpartum bleeding (15 hours after delivery) and a 29-year-old patient from a late one (nine days postpartum). Both women were treated with conservative methods including curettage and surgical evacuation of the haematoma in one case. However, blood loss didn't stop. Instead of hysterectomy it was decided to embolize the appropriate cervicouterine branch of the A. uterina in these young women, which appeared to be effective. In case of non-effective treatment of postpartum bleeding, hysterectomy is not the only remaining therapy. Gynaecologists and radiologists together may consider embolization therapy. This has proved to be a minimally invasive and successful treatment. Unlike hysterectomy, the uterus will be preserved, making an additional pregnancy possible.

Objectives: This study investigated the influence of sociodemographic and occupational factors on the risk of 1st injury among Brazilian steelworkers., Methods: Workers 1st employed between 1 January 1977 and 31 December 1985 and still employed on 1 December 1983 were followed from the date of hire until 30 October 1992. Occupational injuries were ascertained from a database. Kaplan-Meier curves for time to 1st injury were calculated for the total cohort and for different subgroups. A multivariate analysis of risk factors for 1st injury was carried out using the Cox proportional hazards regression model., Results: Forty-one percent of the workers had > or = 1 occupational injuries, and 39% of 1st injuries occurred in the 1st year of employment. Lacerations, contusions, penetration by foreign bodies, bums, sprains, and fractures constituted the main diagnostic groups. Injuries to the hands, eyes, feet, arms, and legs dominated. Over 5% of the injured workers were on temporary disability leave (cumulative total 10,660 days). The probability for an occupational injury was 16% for the 1st year, rising to 25% in the 2nd year. The risk of nonfatal injury was highest for laborers [hazard ratio (HR) 1.76, 95% confidence interval (95% CI) 1.35-2.29] and employees in the steel mill (HR 1.40, 95% CI 1.21-1.63), and inversely related to worker age and educational level. The risk of injury decreased significantly with calendar period of employment., Conclusions: Substantial reductions in nonfatal injuries may reflect changes in work organization, increased automation, and improved safety standards. Knowledge of predictors of work-related injury may contribute to injury prevention strategies, especially among newly employed workers.

Neurophysiological functioning was studied prospectively in children treated for acute lymphoblastic leukaemia with a low dose vincristine regime (8 x 1.5 mg/m2/dose), to obtain more insight into vincristine neuropathy. A WHO neurotoxicity score was estimated and vibration sense and electrophysiological measurements were taken at standardized times during vincristine treatment. The WHO neurotoxicity score showed decreased or disappearance of Achilles tendon reflexes, and mild sensory disturbances, but a grade 3-4 neurotoxicity was not demonstrated by any of the children. Vibration perception thresholds increased progressively during treatment and amplitudes of action potentials of peroneal and sensory ulnar and median nerves decreased, whereas nerve conduction velocities stayed unchanged. Both vibration perception thresholds and the electrophysiological findings hardly exceeded the limits of normality. We conclude that children treated for acute lymphoblastic leukaemia with a low dose vincristine regimen have mild axonal neuropathy which may be responsible for the motor problems in these children.

Background: Daily life motor skills of children with acute lymphoblastic leukemia (ALL) were studied during treatment using the Movement Assessment Battery for Children (Movement ABC). In addition, the possible relation with vincristine treatment was investigated., Procedure: Seventeen children treated for ALL, aged 4-12 years, were compared to an age- and sex-matched control group., Results: The leukemia group performed more poorly than the control group on both fine and gross motor skills. In looking at the number of children with ALL who scored in the clinical range of the different subtests, problems in balance skills were found to be most pronounced at the end of induction therapy. Remarkably, half a year after reinduction therapy, problems with balance had decreased, whereas the number of children with fine motor problems had increased., Conclusions: A relation between the gross motor problems and vincristine neurotoxicity seems plausible based on a descriptive analysis of the data, but this was not supported statistically., (Copyright 1999 Wiley-Liss, Inc.)

The objective of this report is to present a summary of progress of the Marshall Islands Nationwide Thyroid Study. As well known, the US atomic weapons testing program in the Pacific was conducted primarily between 1946 and 1958 in the Marshall Islands. The nuclear tests resulted in radioactive contamination of a number of atolls and resulted in exposure of Marshallese to undefined levels before our study. Little information has been paid to health consequences among residents of the nearly twenty inhibited atolls except for some information about nodular thyroid disease which was reported on by an US group. In a cooperative agreement with the Government of the Marshall Islands, between 1993 and 1997 we studied the prevalence of both thyroid nodules and thyroid cancer among 4766 Marshallese potentially exposed to radioiodines from bomb test fallout. That group represents more than 65% of the population at risk. We diagnosed 45 thyroid cancers and 1398 benign thyroid nodules. In addition, 23 study participants had been operated on prior to our study for thyroid cancer. Presently, we are developing a database of information to estimate radiation doses and planning a statistical analysis to determine if a dose-response relationship exists. These data will be important for the health promotion of exposed people all over the world including Hiroshima, Nagasaki, Semipalatinsk, Chernobyl and other locations. A timely completion is important for purpose of assisting Marshallese as well as to add the global understanding of radiation induced thyroid cancer.

Motor skills were investigated in 18 children 2 years after treatment for acute lymphoblastic leukemia (ALL). Gross and fine motor functioning were examined with the Movement Assessment Battery for Children. Handwriting as a specific fine motor skill was studied with a computerized writing task. We conclude that 2 years after cessation of treatment motor problems in ALL survivors were still present. Dysfunctions were mainly pronounced in handwriting and fine motor skills.

In a prospective study during the period January-May 1992, 362 consecutive out-patients above 65 years of age, attending the pulmonary department for chronic obstructive airways disease (COPD), were ultrasonographically screened for an aneurysm of the abdominal aorta (AAA). Data from pulmonary function tests together with history of cardiac disease, diabetes mellitus, hypertension, hypercholesterolaemia, peripheral arterial obstructive disease, smoking and corticosteroid medication were collected. 30/282 men and 6/80 women with COPD had an AAA > or = 30 mm in diameter, which equals a prevalence of 9.9% (95% confidence limits: 6.8-13.0%). COPD patients with severe emphysema, having a decreased forced expiratory volume/vital capacity ratio (FEV/VC) of < 55%, have a significantly higher prevalence of aortic dilatation or AAA compared to COPD patients with mild or moderate decreased FEV/VC (chi-squared test: p < 0.05, alpha = 0.05). In the group of patients with AAA, significantly more smokers were seen compared to the group with normal and dilated aortas (chi-squared test: p < 0.05).

This study deals with comparative investigation of the protective effects of disodium cromoglycate (DSCG, Lomudal, Intal) and beclomethasone dipropionate aerosol (BDA, Aldecin, Becotide, Beclovent) on 103 immediate asthmatic responses (IARs) to allergen challenge recorded in 103 patients with an allergic bronchial asthma. Disodium cromoglycate demonstrated highly significant protective effects on the IAR in patients investigated (P less than .01). The protective effects of BDA on the IAR were found to be non-significant (P greater than .01). It is suggested that DSCG should be the first choice in controlling allergic bronchial asthma when the immediate asthmatic response to allergen plays the predominant role.