Moving Towards Common Data Elements and Core Outcome Measures in Frailty Research.

With aging populations around the world, frailty is becoming more prevalent increasing the need for health systems and social systems to deliver optimal evidence based care. However, in spite of the growing number of frailty publications, high-quality evidence for decision making is often lacking. Inadequate descriptions of the populations enrolled including frailty severity and frailty conceptualization, lack of use of validated frailty assessment tools, utilization of different frailty instruments between studies, and variation in reported outcomes impairs the ability to interpret, generalize and implement the research findings. The utilization of common data elements (CDEs) and core outcome measures (COMs) in clinical trials is increasingly being adopted to address such concerns. To catalyze the development and use of CDEs and COMs for future frailty studies, the Canadian Frailty Network (www.cfn-nce.ca; CFN), a not-for-profit pan-Canadian nationally-funded research network, convened an international group of experts to examine the issue and plan the path forward. The meeting was structured to allow for an examination of current frailty evidence, ability to learn from other COMs and CDEs initiatives, discussions about specific considerations for frailty COMs and CDEs and finally the identification of the necessary steps for a COMs and CDEs consensus initiative going forward. It was agreed at the onset of the meeting that a statement based on the meeting would be published and herein we report the statement.

Biomonitoring of several toxic metal(loid)s in different biological matrices from environmentally and occupationally exposed populations from Panasqueira mine area, Portugal.

In the Panasqueira mine area of central Portugal, some environmental media show higher metal(loid) concentrations when compared with the local geochemical background and the values proposed in the literature for these environmental media. In order to evaluate the effect of the external contamination on selected indexes of internal dose, As, Cd, Cu, Cr, Fe, Hg, Mg, Mn, Mo, Ni, Pb, S, Se, Si, and Zn were quantified by inductively coupled plasma mass spectrometry and inductively coupled plasma optical emission spectrometry in blood, urine, hair and nail samples from individuals environmentally (N = 41) and occupationally exposed (N = 41). A matched control group (N = 40) was also studied, and data from the three groups were compared. Results obtained agreed with those reported by environmental studies performed in this area, pointing to populations living nearby and working in the mine being exposed to metal(loid)s originated from mining activities. Arsenic was the element with the highest increase in exposed populations. The concentration of other elements such as Cr, Mg, Mn, Mo, Ni, Pb, S, Se, and Zn was also increased, although at a lesser extent, specifically in the individuals environmentally exposed and in females. These findings confirm the need for competent authorities to act as soon as possible in this area and implement strategies aimed to protect exposed populations and the entire ecosystem.

Genotoxic effects in a population of nurses handling antineoplastic drugs, and relationship with genetic polymorphisms in DNA repair enzymes.

BACKGROUND: Concern about the genotoxic risk associated with chronic handling of antineoplastic drugs has increased, and usual safety practices may not avoid exposure. METHODS: Comet assay and MN test were performed on 30 oncology nurses and 22 controls. Genetic polymorphisms of XRCC1, XRCC3, and APE1 genes were determined by PCR-RFLP. RESULTS: Data obtained showed increased cytogenetic and DNA damage in the exposed group, although statistical significance was only reached in the comet assay. Significant differences in TL were observed for carriers of the variant alleles of every gene analyzed. However, no significant effect was detected in the MN test. CONCLUSIONS: Evidence that the present handling practices of antineoplastic drugs in some Portuguese hospitals are not enough to prevent exposure are provided. Present data suggest that genetic polymorphisms in the studied DNA repair enzymes may influence the individual susceptibility to DNA damage related to chronic handling of antineoplastic drugs.

Papel de los polimorfismos genéticos para enzimas de reparación en el daño en el ADN inducido por el estireno y estireno-7, 8-óxido / Role of genetic polymorphisms of DNA repair enzymes in DNA damage induced by styrene and styrene- 7, 8-oxide

La respuesta individual al daño en el ADN inducido por agentes xenobióticos está condicionada por la eficacia de los sistemas de reparación. Algunos de los polimorfismos genéticos descritos en las enzimas de reparación del ADN pueden afectar a su función, determinando una variación en la susceptibilidad ante la exposición a agentes ambientales. El objetivo de este estudio ha consistido en investigar si las variantes alélicas más frecuentes de las enzimas de reparación XRCC1 ( Arg194Trp y Arg399Gln ), XRCC3 ( Thr241Met ) o APE1 ( Asp148Glu ) pueden condicionar el daño en el ADN inducido por el estireno y su principal metabolito, el estireno-7,8-óxido (EO). Leucocitos periféricos de 30 voluntarios sanos se trataron con estireno o EO, y el daño en el ADN inducido se evaluó mediante el ensayo del cometa. Tras el tratamiento con estireno, los individuos portadores de los alelos XRCC1 399Gln y XRCC3 241Met mostraron mayor nivel de roturas en el ADN, sugiriendo menor eficacia de los sistemas de reparación. Por el contrario, los portadores del alelo APE1 148Glu mostraron daño en el ADN significativamente menor que los individuos 148 Asp/Asp . Sin embargo, no se obtuvo ningún efecto significativo en las células expuestas a EO, debido probablemente a que el daño inducido es inicialmente mayor, y no permite que se pongan de manifiesto pequeñas diferencias en la eficacia de reparación de los genotipos analizados (AU)

Individual response to DNA damage induced by xenobiotic agents is conditioned by the efficiency of DNA repair systems. Some of the genetic polymorphisms described in DNA repair enzymes may affect the function of these proteins, and thus determine a modified susceptibility to the exposure to environmental agents. The purpose of the present study was to investigate if the most frequent allelic variants of the DNA repair genes XRCC1 ( Arg194Trp and Arg399Gln ), XRCC3 ( Thr241Met ) or APE1 ( Asp148Glu ) might alter the DNA damage induced by styrene and its principal metabolite, styrene-7,8- oxide (SO), in human leukocytes in vitro . Peripheral leukocytes from 30 healthy volunteers were treated with styrene or SO, and induced DNA damage was evaluated by the comet assay. After styrene treatment, carriers of XRCC1 399Gln and XRCC3 241Met alleles displayed higher level of DNA breakage, suggesting lesser efficiency of the DNA repair systems. In contrast, APE1 148Glu carriers showed significantly lower styreneinduced DNA damage than the 148 Asp/Asp individuals. Nevertheless, no significant effect was obtained in cells exposed to SO, probably due to the fact that the initially induced DNA damage is greater and because small differences in the repair efficiency of the selected genotypes are not manifested (AU)

Simultaneous high-performance liquid chromatographic determination of urinary mandelic and phenylglyoxylic acids as indirect evaluation of styrene exposure.

Styrene is rapidly metabolised to mandelic acid (MA) and phenylglyoxylic acid (PGA), which are excreted in urine. In this work, we have developed a simple, sensitive and specific high-performance liquid chromatographic method with minor sample preparation procedures for the simultaneous determination of MA and PGA in urine of workers exposed to styrene. Moreover, urine samples from workers of two plastic factories were analysed, styrene exposure levels of the workers were estimated and data obtained from the two factories were compared.

Genotoxic effects of styrene-7,8-oxide in human white blood cells: comet assay in relation to the induction of sister-chromatid exchanges and micronuclei.

Styrene is used in the production of plastics, resins and rubber. The highest human exposures to styrene take place by inhalation during the production of fiberglass reinforced plastics. Styrene is metabolized mainly in the liver to styrene-7,8-oxide (SO), its principal in vivo mutagenic metabolite. In this study, human peripheral white blood cells were exposed to several SO concentrations (10-200 microM) in order to evaluate its genotoxic properties by means of comet assay, sister-chromatid exchanges (SCE) and cytokinesis-blocked micronucleus (MN) test, in addition to determine its clastogenic or aneugenic properties by combining MN with fluorescence in situ hybridization (FISH) procedures. Our results show that SO induces DNA damage, SCE and MN in human leukocytes in vitro at concentrations above 50 microM, and that there is a strong relationship between DNA damage, as measured by the comet assay, and cytogenetic damage induced by SO at the doses employed. SO shows preferentially a clastogenic activity and produces a cytostatic effect at high doses, reflected by the significant decrease of the calculated proliferation indices. A good dose-effect relationship is obtained in the three tests performed at the concentration range assayed.

Effects of styrene-7,8-oxide over p53, p21, bcl-2 and bax expression in human lymphocyte cultures.

Styrene is one of the most important organic chemicals in use today. The highest human exposures to styrene take place by inhalation during the production of fibreglass-reinforced plastics. Styrene is oxidized by hepatic cytochrome P450 to styrene-7,8-oxide (SO), an epoxide that has been shown to induce chromosome aberrations, sister chromatid exchanges and micronuclei in many cell systems. In this work, the effect of SO on the expression of some genes involved in the cell cycle and apoptosis regulation in human white blood cells was studied. Lymphocyte cultures from four donors were exposed to 50 and 200 microM SO, 1% DMSO being the control. Aliquots of the cultures were taken at six different time points (30, 36, 42, 48, 60 and 72 h), total mRNA was extracted in each one of them and RT-PCR was carried out to analyze the expression of the genes p53, p21, bcl-2 and bax. Moreover, a cytokinesis block assay was performed to estimate cell proliferation kinetics by calculating the cytokinesis block proliferation index (CBPI), and to evaluate the number of cells undergoing apoptosis. Furthermore, apoptotic events were detected by the DNA fragmentation assay. In our results, a high interindividual variation in the expression of the studied genes was observed. Expression curves obtained for the four genes, together with the data from the CBPI and apoptotic cells scored, suggest that exposure to high levels of SO may induce a delay in the cell cycle, probably directed to allowing repair systems to act on the genotoxic damage produced, more than driving cells towards programmed cell death.