The ENDORSE study: Research into environmental determinants of obesity related behaviors in Rotterdam schoolchildren

Background: Children and adolescents are important target groups for prevention of overweight and obesity as overweight is often developed early in life and tracks into adulthood. Research into behaviors related to overweight (energy balance-related behaviors) and the personal and environmental determinants of these behaviors is fundamental to inform prevention interventions. In the Netherlands and in other countries systematic research into environmental determinants of energy balance related behaviors in younger adolescents is largely lacking. This protocol paper describes the design, the components and the methods of the ENDORSE study (Environmental Determinants of Obesity in Rotterdam SchoolchildrEn), that aims to identify important individual and environmental determinants of behaviors related to overweight and obesity and the interactions between these determinants among adolescents. Methods: The ENDORSE study is a longitudinal study with a two-year follow-up of a cohort of adolescents aged 12–15 years. Data will be collected at baseline (2005/2006) and at two years follow-up (2007/2008). Outcome measures are body mass index (BMI), waist circumference, time spent in physical activity and sedentary behaviors, and soft drink, snack and breakfast consumption. The ENDORSE study consists of two phases, first employing qualitative research methods to inform the development of a theoretical framework to examine important energy balance related behaviors and their determinants, and to inform questionnaire development. Subsequently, the hypothetical relationships between behavioral determinants, energy balance related behaviors and BMI will be tested in a quantitative study combining school-based surveys and measurements of anthropometrical characteristics at baseline and two-year follow-up. Discussion: The ENDORSE project is a comprehensive longitudinal study that enables investigation of specific environmental and individual determinants of overweight and obesity among younger adolescents. The project will result in specific recommendations for obesity prevention interventions among younger adolescents

GATA3 haploinsufficiency causes a rapid deterioration of distortion product otoacoustic emissions (DPOAEs) in mice

Human HDR (hypoparathyroidism, deafness and renal dysplasia)-syndrome is caused by haploinsufficiency of zinc-finger transcription factor GATA3. The hearing loss due to GATA3 haploinsufficiency has been shown to be peripheral in origin, but it is unclear to what extent potential aberrations in the outer hair cells (OHCs) contribute to this disorder. To further elucidate the pathophysiological mechanism underlying the hearing defect in HDR-syndrome, we investigated the OHCs in heterozygous Gata3-knockout mice at both the functional and morphological level. While the signal-to-noise ratios of distortion product otoacoustic emissions (DPOAE) in wild type mice did not change significantly during the first half-year of live, those in the heterozygous Gata3 mice decreased dramatically. In addition, both light microscopic and transmission electron microscopic analyses showed that the number of OHCs containing vacuoles was increased in the mutants. Together, these findings indicate that outer hair cell malfunctioning plays a major role in the hearing loss in HDR-syndrome

Biologische zuivering van water verontreinigd met gewasbeschermingsmiddelen : onderzoeksresultaten 2008 t/m 2011

In dit rapport worden de resultaten beschreven van het onderzoek van WUR PPO, in samenwerking met WUR Alterra, naar de inzetbaarheid van biologische zuiveringstechnieken voor verwerking van afvalwater, dat verontreinigd is met gewasbeschermingsmiddelen. De onderzochte toepassingen zijn gericht op land- en tuinbouwbedrijven, inclusief loonbedrijven en exclusief glastuinbouwbedrijven. Voor de glastuinbouw worden de mogelijkheden van zuivering ook onderzocht, maar ligt de focus meer op andere technieken dan biologische zuivering. In de glastuinbouw gaat het met name om drain- en drainagewater. Omdat de basisprincipes van de werking van systemen voor biologische zuivering al onderzocht zijn door onder andere Vlaamse universiteiten en onderzoeksinstellingen, is er in Nederland vooral onderzoek gedaan naar het gebruik en de effectiviteit van deze installaties onder praktische omstandigheden

Prevalence of the most frequent BRCA1 mutations in Polish population

The purpose of our study was to establish the frequency and distribution of the four most common BRCA1 mutations in Polish general population and in a series of breast cancer patients. Analysis of the population frequency of 5382insC (c.5266dupC), 300T >G (p.181T >G), 185delAG (c.68_69delAG) and 3819del5 (c.3700_3704del5) mutations of the BRCA1 gene were performed on a group of respectively 16,849, 13,462, 12,485 and 3923 anonymous samples collected at birth in seven Polish provinces. The patient group consisted of 1845 consecutive female breast cancer cases. The most frequent BRCA1 mutation in the general population was 5382insC found in 29 out of 16,849 samples (0.17%). 300T >G and 3819del5 mutations were found in respectively 11 of 13,462 (0.08%) and four of 3923 (0.1%) samples. The population prevalence for combined Polish founder 5382insC and 300T >G mutations was 0.25% (1/400). The frequencies of 5382insC and 300T >G carriers among consecutive breast cancer cases were, respectively, 1.9% (35/1845) and 1.2% (18/1486). Comparing these data with the population frequency, we calculated the relative risk of breast cancer for 5382insC mutation at OR = 17 and for 300T >G mutation at OR = 26. Our results, based on large population studies, show high frequencies of founder 5382insC and 300T >G BRCA1 mutations in Polish general population. Carriage of one of these mutations is connected with a very high relative risk of breast cancer

BRCA2 gene mutations in families with aggregations of breast and stomach cancers

Stomach cancer ranks second to lung cancer in the global cancer burden. It is estimated that 25% of families meeting the criteria for hereditary diffuse gastric carcinoma (HDCG) will have germline mutations in the E-cadherin gene. Evidence suggests that stomach cancer might also be a malignant manifestation of other inherited predispositions to disease. Recently, it has been reported that the incidence of stomach cancer is significantly increased in BRCA2 gene mutation carriers. We analysed by direct sequencing the BRCA2 gene in 29 breast cancer patients derived from 29 families with an aggregation of at least one female breast cancer diagnosed before the age of 50 years and one male stomach cancer diagnosed before the age of 55 years. In all but one of these families at least one additional relative was also affected by a malignant tumour. We identified three frameshift mutations and three sequence variants – potentially missense mutations, in six unrelated patients representing 20.7% (six out of 29) of the families investigated. Our results confirm that BRCA2 gene mutations are also associated with familial aggregations of not only breast but also of stomach cancer. In comparison to the number of cancers expected in the study population compared to the general population there is an over-representation of several cancers with significant confidence intervals to suggest that the associations are real and not a selection artefact

Five recurrent BRCA1/2 mutations are responsible for cancer predisposition in the majority of Slovenian breast cancer families

<p>Abstract</p> <p>Background</p> <p>Both recurrent and population specific mutations have been found in different areas of the world and more specifically in ethnically defined or isolated populations. The population of Slovenia has over several centuries undergone limited mixing with surrounding populations.</p> <p>The current study was aimed at establishing the mutation spectrum of <it>BRCA1/2 </it>in the Slovenian breast/ovarian cancer families taking advantage of a complete cancer registration database. A second objective was to determine the cancer phenotype of these families.</p> <p>Methods</p> <p>The original population database was composed of cancer patients from the Institute of Oncology Ljubljana in Slovenia which also includes current follow-up status on these patients. The inclusion criteria for the <it>BRCA1/2 </it>screening were: (i) probands with at least two first degree relatives with breast and ovarian cancer; (ii) probands with only two first degree relatives of breast cancer where one must be diagnosed less than 50 years of age; and (iii) individual patients with breast and ovarian cancer, bilateral breast cancer, breast cancer diagnosed before the age of 40 and male breast cancer without any other cancer in the family.</p> <p>Results</p> <p>Probands from 150 different families met the inclusion criteria for mutation analysis of which 145 consented to testing. A <it>BRCA1/2 </it>mutation was found in 56 (39%). Two novel large deletions covering consecutive exons of <it>BRCA1 </it>were found. Five highly recurrent specific mutations were identified (1806C>T, 300T>G, 300T>A, 5382insC in the <it>BRCA1 </it>gene and IVS16-2A>G in the <it>BRCA2 </it>gene). The IVS16-2A>G in the <it>BRCA2 </it>gene appears to be a unique founder mutation in the Slovenian population. A practical implication is that only 4 PCR fragments can be used in a first screen and reveal the cancer predisposing mutation in 67% of the <it>BRCA1/2 </it>positive families. We also observed an exceptionally high frequency of 4 different pathogenic missense mutations, all affecting one of the cryptic cysteine residues of the <it>BRCA1 </it>Ring Finger domain.</p> <p>Conclusion</p> <p>A high mutation detection rate and the frequent occurrence of a limited array of recurring mutations facilitate <it>BRCA1/2 </it>mutation screening in Slovenian families.</p

Patients with an unexplained microsatellite instable tumour have a low risk of familial cancer

The cancer risk is unknown for those families in which a microsatellite instable tumour is neither explained by MLH1 promoter methylation nor by a germline mutation in a mismatch repair (MMR) gene. Such information is essential for genetic counselling. Families suspected of Lynch syndrome (n=614) were analysed for microsatellite instability, MLH1 promoter methylation and/or germline mutations in MLH1, MSH2, MSH6, and PMS2. Characteristics of the 76 families with a germline mutation (24 MLH1, 2 PMS2, 32 MSH2, and 18 MSH6) were compared with those of 18 families with an unexplained microsatellite instable tumour. The mean age at diagnosis of the index patients in both groups was comparable at 44 years. Immunohistochemistry confirmed the loss of an MMR protein. Together this suggests germline inactivation of a known gene. The Amsterdam II criteria were fulfilled in 50/75 families (66%) that carried a germline mutation in an MMR gene and in only 2/18 families (11%) with an unexplained microsatellite instable tumour (P<0.0001). Current diagnostic strategies can detect almost all highly penetrant MMR gene mutations. Patients with an as yet unexplained microsatellite instable tumour likely carry a different type of mutation that confers a lower risk of cancer for relatives

Characteristics of small breast and/or ovarian cancer families with germline mutations in BRCA1 and BRCA2

For families with a small number of cases of breast and/or ovarian cancer, limited data are available to predict the likelihood of genetic predisposition due to mutations in BRCA1 or BRCA2. In 104 families with three or more affected individuals (average 3.8) seeking counselling at family cancer clinics, mutation analysis was performed in the open reading frame of BRCA1 and BRCA2 by the protein truncation test and mutation-specific assays. In 31 of the 104 families tested, mutations were detected (30%). The majority of these mutations (25) occurred in BRCA1. Mutations were detected in 15 out of 25 families (60%) with both breast and ovarian cancer and in 16 out of 79 families (20%) with exclusively cases of breast cancer. Thus, an ovarian cancer case strongly predicted finding a mutation (P < 0.001). Within the group of small breast-cancer-only families, a bilateral breast cancer case or a unilateral breast cancer case diagnosed before age 40 independently predicted finding a BRCA1 or BRCA2 mutation (P = 0.005 and P = 0.02, respectively). Therefore, even small breast/ovarian cancer families with at least one case of ovarian cancer, bilateral breast cancer, or a case of breast cancer diagnosed before age 40, should be referred for mutation screening. © 1999 Cancer Research Campaig