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Garcia-Perez J.,Carlos III Institute of Health | Garcia-Perez J.,CIBER ISCIII | Morales-Piga A.,Rare Disease Research Institute IIER | Morales-Piga A.,Consortium for Biomedical Research in Rare Diseases CIBERER | And 12 more authors.
Environmental Research | Year: 2016

Background: Few risk factors for childhood renal tumors are well established. While a small fraction of cases might be attributable to susceptibility genes and congenital anomalies, the role of environmental factors needs to be assessed. Objectives: To explore the possible association between residential proximity to environmental pollution sources (industrial and urban areas, and agricultural crops) and childhood renal cancer, taking into account industrial groups and toxic substances released. Methods: We conducted a population-based case-control study of childhood renal cancer in Spain, including 213 incident cases gathered from the Spanish Registry of Childhood Tumors (period 1996-2011), and 1278 controls individually matched by year of birth, sex, and region of residence. Distances were computed from the respective subject's residences to the 1271 industries, the 30 urban areas with ≥75,000 inhabitants, and the agricultural crops located in the study area. Using logistic regression, odds ratios (ORs) and 95% confidence intervals (95%CIs) for categories of distance to pollution sources were calculated, with adjustment for matching variables and socioeconomic confounders. Results: Excess risk (OR; 95%CI) of childhood renal tumors was observed for children living near (≤2.5 km) industrial installations as a whole (1.97; 1.13-3.42) - particularly glass and mineral fibers (2.69; 1.19-6.08), galvanization (2.66; 1.14-6.22), hazardous waste (2.59; 1.25-5.37), ceramic (2.35; 1.06-5.21), surface treatment of metals (2.25; 1.24-4.08), organic chemical industry (2.22; 1.15-4.26), food and beverage sector (2.19; 1.18-4.07), urban and waste-water treatment plants (2.14; 1.07-4.30), and production and processing of metals (1.98; 1.03-3.82) -, and in the proximity of agricultural crops (3.16; 1.54-8.89 for children with percentage of crop surface ≥24.35% in a 1-km buffer around their residences). Conclusions: Our study provides some epidemiological evidence that living near certain industrial areas and agricultural crops may be a risk factor for childhood renal cancer. © 2016 Elsevier Inc.


Garcia-Perez J.,Carlos III Institute of Health | Garcia-Perez J.,CIBER ISCIII | Morales-Piga A.,Rare Disease Research Institute IIER | Morales-Piga A.,Consortium for Biomedical Research in Rare Diseases CIBERER | And 9 more authors.
Environmental Research | Year: 2016

Background Few epidemiologic studies have explored risk factors for rare tumors in children, and the role of environmental factors needs to be assessed. Objectives To ascertain the effect of residential proximity to both industrial and urban areas on childhood cancer risk, taking industrial groups into account. Methods We conducted a population-based case-control study of five childhood cancers in Spain (retinoblastoma, hepatic tumors, soft tissue sarcomas, germ cell tumors, and other epithelial neoplasms/melanomas), including 557 incident cases from the Spanish Registry of Childhood Tumors (period 1996–2011), and 3342 controls individually matched by year of birth, sex, and region of residence. Distances were computed from the residences to the 1271 industries and the 30 urban areas with ≥75,000 inhabitants located in the study area. Using logistic regression, odds ratios (ORs) and 95% confidence intervals (95%CIs) for categories of distance to industrial and urban pollution sources were calculated, with adjustment for matching variables and socioeconomic confounders. Results Children living near industrial and urban areas as a whole showed no excess risk for any of the tumors analyzed. However, isolated statistical associations (OR; 95%CI) were found between retinoblastoma and proximity to industries involved in glass and mineral fibers (2.49; 1.01–6.12 at 3 km) and organic chemical industries (2.54; 1.10–5.90 at 2 km). Moreover, soft tissue sarcomas registered the lower risks in the environs of industries as a whole (0.59; 0.38–0.93 at 4 km). Conclusions We have found isolated statistical associations between retinoblastoma and proximity to industries involved in glass and mineral fibers and organic chemical industries. © 2016 Elsevier Inc.


Lopez-Nieva P.,Autonomous University of Madrid | Lopez-Nieva P.,Institute of Health Research | Malave M.,Autonomous University of Madrid | Malave M.,Institute of Health Research | And 13 more authors.
BMC Genomics | Year: 2016

Background: Radio-Adaptive Response (RAR) is a biological defense mechanism whereby exposure to low dose ionizing radiation (IR) mitigates the detrimental effects of high dose irradiation. RAR has been widely observed in vivo using as endpoint less induction of apoptosis. However, sex differences associated with RAR and variations between males and females on global gene expression influenced by RAR have not been still investigated. In addition, the response to radiation-induced apoptosis is associated with phosphorylation of TRP53 at both the serine 15 (ser-18 in the mouse) and serine 392 (ser-389 in mice) residues, but the role of these two phosphorylated forms in male and female RAR remains to be elucidated. Results: We analyzed the effect of administering priming low dose radiation (0.075 Gy of X-rays) prior to high dose radiation (1.75 Gy of γ-rays) on the level of caspase-3-mediated apoptosis and on global transcriptional expression in thymocytes of male and female mice. Here, we provide the first evidence of a differential sex effect of RAR on the reduction of thymocyte apoptosis with males showing lesser levels of caspase-3-mediated apoptosis than females. Analysis of transcriptomic profiles of 1944 genes involved in apoptosis signaling in radio-adapted thymocytes identified 17 transcripts exhibiting differential expression between both sexes. Among them, Dlc1 and Fis1 are closely related to the apoptosis mediated by the TRP53 protein. Our data demonstrate that overexpression of Dlc1 and Fis1 occur concomitantly with a highest accumulation of phosphoserine-18-TRP53 and caspase-3 in radio-adapted thymocytes of female mice. In an opposite way, both down-modulation of Fis1 and phosphoserine-389-TRP53 accumulation appear to be associated with protection from thymocyte apoptosis mediated by caspase-3 in males. Conclusions: Transcriptomic analysis performed in this work reveals for the first time sex-specific differences in gene expression influenced by RAR. Our results also suggest a sex-dependent dual role for phosphoserine-18-TRP53 and phosphoserine-389-TRP53 in the regulation of the radio-adaptive response in mouse thymocytes. © 2016 The Author(s).


Garcia-Perez J.,Carlos III Institute of Health | Garcia-Perez J.,CIBER ISCIII | Lopez-Abente G.,Carlos III Institute of Health | Lopez-Abente G.,CIBER ISCIII | And 10 more authors.
Environmental Research | Year: 2015

Background: Few risk factors for the childhood leukemia are well established. While a small fraction of cases of childhood leukemia might be partially attributable to some diseases or ionizing radiation exposure, the role of industrial and urban pollution also needs to be assessed. Objectives: To ascertain the possible effect of residential proximity to both industrial and urban areas on childhood leukemia, taking into account industrial groups and toxic substances released. Methods: We conducted a population-based case-control study of childhood leukemia in Spain, covering 638 incident cases gathered from the Spanish Registry of Childhood Tumors and for those Autonomous Regions with 100% coverage (period 1990-2011), and 13,188 controls, individually matched by year of birth, sex, and autonomous region of residence. Distances were computed from the respective subject's residences to the 1068 industries and the 157 urban areas with ≥10,000 inhabitants, located in the study area. Using logistic regression, odds ratios (ORs) and 95% confidence intervals (95%CIs) for categories of distance to industrial and urban pollution sources were calculated, with adjustment for matching variables. Results: Excess risk of childhood leukemia was observed for children living near (≤2.5. km) industries (OR=1.31; 95%CI=1.03-1.67) - particularly glass and mineral fibers (OR=2.42; 95%CI=1.49-3.92), surface treatment using organic solvents (OR=1.87; 95%CI=1.24-2.83), galvanization (OR=1.86; 95%CI=1.07-3.21), production and processing of metals (OR=1.69; 95%CI=1.22-2.34), and surface treatment of metals (OR=1.62; 95%CI=1.22-2.15) - , and urban areas (OR=1.36; 95%CI=1.02-1.80). Conclusions: Our study furnishes some evidence that living in the proximity of industrial and urban sites may be a risk factor for childhood leukemia. © 2015 Elsevier Inc.


Garcia-Perez J.,Carlos III Institute of Health | Garcia-Perez J.,CIBER ISCIII | Morales-Piga A.,Rare Disease Research Institute IIER | Morales-Piga A.,Consortium for Biomedical Research in Rare Diseases CIBERER | And 11 more authors.
Environment International | Year: 2016

Background: Neuroblastoma is the most common extracranial solid tumor in children but its etiology is not clearly understood. While a small fraction of cases might be attributable to genetic factors, the role of environmental pollution factors needs to be assessed. Objectives: To ascertain the effect of residential proximity to both industrial and urban areas on neuroblastoma risk, taking into account industrial groups and toxic substances released. Methods: We conducted a population-based case-control study of neuroblastoma in Spain, including 398 incident cases gathered from the Spanish Registry of Childhood Tumors (period 1996-2011), and 2388 controls individually matched by year of birth, sex, and region of residence. Distances were computed from the respective subject's residences to the 1271 industries and the 30 urban areas with ≥. 75,000 inhabitants located in the study area. Using logistic regression, odds ratios (ORs) and 95% confidence intervals (95%CIs) for categories of distance (from 1 km to 5 km) to industrial and urban pollution sources were calculated, with adjustment for matching variables and socioeconomic confounders. Results: Excess risk (OR; 95%CI) of neuroblastoma was detected for the intersection between industrial and urban areas: (2.52; 1.20-5.30) for industrial distance of 1 km, and (1.99; 1.17-3.37) for industrial distance of 2 km. By industrial groups, excess risks were observed near 'Production of metals' (OR = 2.05; 95%CI = 1.16-3.64 at 1.5 km), 'Surface treatment of metals' (OR = 1.89; 95%CI = 1.10-3.28 at 1 km), 'Mines' (OR = 5.82; 95%CI = 1.04-32.43 at 1.5 km), 'Explosives/pyrotechnics' (OR = 4.04; 95%CI = 1.31-12.42 at 4 km), and 'Urban waste-water treatment plants' (OR = 2.14; 95%CI = 1.08-4.27 at 1.5 km). Conclusions: These findings support the need for more detailed exposure assessment of certain substances released by these industries. © 2016 Elsevier Ltd.


Gomez-Barroso D.,CIBER ISCIII | Gomez-Barroso D.,Carlos III Institute of Health | Garcia-Perez J.,CIBER ISCIII | Garcia-Perez J.,Carlos III Institute of Health | And 9 more authors.
International Journal of Health Geographics | Year: 2016

Background: Childhood cancer is the main cause of disease-related death in children in Spain. Although little is known about the etiology, environmental factors are potential explanations for a fraction of the cases. Previous studies have shown pesticides to be associated with childhood cancer. The difficulty of collecting personal environmental exposure data is an important limitation; this lack of information about pesticides motivates the development of new methods to subrogate this exposure. We developed a crop exposure index based on geographic information to study the relationship between exposure to different types of crops and risk of childhood tumors. Methods: We conducted a population-based case-control study of childhood cancer covering 3350 cases and 20,365 controls in two Spanish regions. We used CORINE Land Cover to obtain data about agricultural land use. We created a 1 km buffer around every child and calculated the percentage of crop surface within the buffer (Global Crop Index) for total crops and for individual types of crops. We fitted mixed multiple unconditional logistic regression models by diagnostic group. Results: We found excess of risk among children living in the proximity of crops. For total crops our results showed excesses of risk for almost all diagnostic groups and increasing risk with increasing crop index value. Analyses by region and individual type of crop also showed excess of risk. Conclusion: The results suggest that living in the proximity of cultivated land could be a risk factor for several types of cancer in children. © 2016 The Author(s).


Morales-Piga A.,Rare Disease Research Institute Instituto Of Investigacion Of Enfermedades Raras Iier | Bachiller-Corral J.,Ramon y Cajal Hospital | Trujillo-Tiebas M.J.,Fundacion Jimenez Diaz | Trujillo-Tiebas M.J.,Consortium for Biomedical Research in Rare Diseases CIBERER | And 10 more authors.
Bone | Year: 2012

We aimed to investigate the epidemiological determinants, clinical features, and genetic pattern of FOP in our country by evaluating the entire population of patients identified according to a combination of methods. To achieve this, 24 individuals were confirmed as FOP cases, 17 of whom were alive at the end of 2011 (point prevalence=0.36×10-6). The gender distribution (male/female ratio=13/11) and the concurrent range of ages (from 4 to 53years; mean±SD: 30.2±13.8) are in agreement with similar reports. Twenty-one (87.5%) had characteristic congenital malformations of the big toe, and short thumbs were found in 65.2% of cases. In addition, other skeletal malformations such us fusion of the posterior elements of the cervical spine (89.0%), knee osteochondromas (71%), scoliosis (54.5%), and short and broad femoral neck (52.6%) were observed. All had developed mature ossicles of heterotopic bone in typical anatomic and temporal patterns, ranging in number from 1 to 17 (9.5±3.9). Age at appearance of first ossifying lesion varied from 3months to 15years. Mean age at diagnosis was 7.3±5.1years and the average delay in reaching the correct diagnosis after the onset of heterotopic ossification was 2.7years (range=0-12years). Biopsy of the pre-osseous lesions was performed in 11 of 20 (55.0%), providing no useful information for the diagnosis of FOP. Seven of 18 (38.9%) reported some hearing loss, and 5 (27.8%) experienced diffuse thinning of the hair or were bald. No patient had relatives with a typical FOP clinical picture. Fourteen of the 16 cases which were genetically investigated displayed the single heterozygous mutation c.617G>A in exon 4 of the ACVR1 gene. One of the two patients who did not present with the canonical ACVR1 mutation showed a heterozygous mutation c.774G>C in exon 5 leading to the substitution of Arginine 258 with a serine. The other patient had a heterozygous c.774G>T substitution in exon 5 leading to the same amino acid change (p.Arg258Ser). These two patients had only nonspecific abnormalities of the great toe, lacked the typical anatomic and developmental pattern of heterotopic ossification, and shared a trend toward uncommon clinical features. These results provide new insight on the epidemiological and clinical traits of FOP, reinforcing the notion of its worldwide homogeneity. The molecular characterization of ACVR1 sequence variation will contribute to the understanding of the genetic profile of this devastating disease in different geographical areas. © 2012 Elsevier Inc.


Taruscio D.,Instituto Superiore Of Sanita | Gainotti S.,Instituto Superiore Of Sanita | Mollo E.,Instituto Superiore Of Sanita | Vittozzi L.,Instituto Superiore Of Sanita | And 5 more authors.
Public Health Genomics | Year: 2013

Background: Registries are considered key instruments for developing rare disease (RD) clinical research, enhancing patient care and health planning, and improving social, economic and quality-of-life outcomes. Indeed, it is usually the case that no single institution, and in many cases no single country, has sufficient data to provide results that can be applied broadly to clinical and translational research. However, the fragmentation and heterogeneity of the registries, which are often the result of spontaneous initiatives, limit the general applicability of their observations. Methods: An inquiry has been carried out by the EPIRARE, a European Union (EU)-funded project ('Building Consensus and Synergies for the EU Registration of Rare Disease Patients') aiming at paving the way to the creation of a European Platform for RD Registries, by means of an on-line questionnaire among European RD registries on their main activities and needs, the way they deal with methodological, technical and regulatory issues and the way they find resources to carry on their activities. Results: In spite of the heterogeneity of the European registries, some elements of relevance for an action to improve the situation of patient registries in the EU are apparent. The needs more frequently indicated by registry holders were financial support, motivation of data providers, data quality assessment, improvement of communication and visibility, and extension of collaborations. Moreover, the registry holders were in favor of a common EU platform providing services for RD registries. Conclusion: It appears that the current situation of the European registries provides the transition towards a more uniform, higher quality and better coordinated approach. © 2013 S. Karger AG, Basel.

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