Genetic and epigenetic features in radiation sensitivity. Part II: implications for clinical practice and radiation protection.

Recent progress especially in the field of gene identification and expression has attracted greater attention to the genetic and epigenetic susceptibility to cancer, possibly enhanced by ionising radiation. This issue is especially important for radiation therapists since hypersensitive patients may suffer from adverse effects in normal tissues following standard radiation therapy, while normally sensitive patients could receive higher doses of radiation, offering a better likelihood of cure for malignant tumours. Although only a small percentage of individuals are "hypersensitive" to radiation effects, all medical specialists using ionising radiation should be aware of the aforementioned progress in medical knowledge. The present paper, the second of two parts, reviews human disorders known or strongly suspected to be associated with hypersensitivity to ionising radiation. The main tests capable of detecting such pathologies in advance are analysed, and ethical issues regarding genetic testing are considered. The implications for radiation protection of possible hypersensitivity to radiation in a part of the population are discussed, and some guidelines for nuclear medicine professionals are proposed.

Genetic and epigenetic features in radiation sensitivity Part I: cell signalling in radiation response.

Recent progress especially in the field of gene identification and expression has attracted greater attention to genetic and epigenetic susceptibility to cancer, possibly enhanced by ionising radiation. It has been proposed that the occurrence and severity of the adverse reactions to radiation therapy are also influenced by such genetic susceptibility. This issue is especially important for radiation therapists since hypersensitive patients may suffer from adverse effects in normal tissues following standard radiation therapy, while normally sensitive patients could receive higher doses of radiation offering a better likelihood of cure for malignant tumours. This paper, the first of two parts, reviews the main mechanisms involved in cell response to ionising radiation. DNA repair machinery and cell signalling pathways are considered and their role in radiosensitivity is analysed. The implication of non-targeted and delayed effects in radiosensitivity is also discussed.

The role of nitric oxide in the radiation-induced effects in the developing brain.

The immature and adult brain display clear differences in the way they respond to insults. The effects of prenatal irradiation on the developing brain are well known. Both epidemiological and experimental data indicate that ionizing radiation may disrupt developmental processes leading to deleterious effects on post-natal brain functions. A central role of reactive oxygen and nitrogen species (ROS/RNS) as important mediators in both neurotoxicity and neuroprotection has been demonstrated. However, data concerning the role of ROS/RNS in radiation-induced damage in the developing brain are scarce. The goal of this review was to summarize the current studies concerning the role of nitric oxide and its reactive intermediates in activation of signal transduction pathways involved in cellular radiation response, with particular focus on radiation-induced effects in the developing brain.

Increased activity and involvement of caspase-3 in radiation-induced apoptosis in neural cells precursors from developing rat brain.

Using primary cultures of neural precursor cells of cortex from developing rat brain, we demonstrated the involvement of caspase-3 in the apoptotic process induced by gamma irradiation. The precursor nature of cells was confirmed by nestin and GFAP immunoreactivity and by the capacity of differentiation in neuronal and glial cells after 5 days in culture. Neural precursors were irradiated with single doses ranging from 0.1 to 4Gy. Cellular death, determined 24 h post-irradiation (pi) was dose-dependent and the induction of apoptosis was confirmed by nuclear condensation, DNA fragmentation and hypodiploid DNA peak represented by the "sub G1" region. For the higher doses, apoptosis was evident after 4-6 h pi and increased during 24 h. Caspase-3 activity increased with doses and was maximal at 4-6 h pi with 3Gy and remained similar with 4Gy. The protection from radiation-induced apoptosis by caspase-3 inhibitor, zDEVD-fmk, confirmed that this enzyme is involved in the apoptotic mechanism in this system. The possibility of using this tissue culture system for studying the effects of ionizing radiation on morphological and molecular differentiation was considered.

[Evolutionary and bone marrow recovery indicators in bone marrow transplantation after total body irradiation]. / Indicadores evolutivos y de recuperación medular en trasplante de médula ósea después de irradiación corporal total.

Oxidative stress and reticulocyte maturity index (RMI) were studied in 27 patients who underwent bone marrow transplantation (BMT). Plasmatic lipoperoxide levels of those patients with unfavorable evolution were significantly increased on days 12-14 post-transplant (median 1.83 microM, range 0.78-5.82) compared with preconditioning levels (median 1.05 microM, range 0.36-1.84) (p < 0.05). Patients with favorable evolution revealed significantly higher lipoperoxide levels during conditioning regime (median 1.42 microM, range 0.31-4.50) (p < 0.05). Starting from the 3rd post-transplant week a significant and continuous decrease was observed, with a median of 0.77 microM (range 0.21-1.48 p < 0.05) for the 3rd, and a median of 0.60 microM (range 0.11-1.48 for the 4th week (p < 0.01). A significant increase in total antioxidant activity was observed in the three patients who died up to the 35 days post-transplant. Recovery of bone marrow function was detected by RMI after a median time of 17 days (range 11-24) post-allogeneic transplantation. The threshold established for absolute neutrophil count was achieved after a median of 21 days (range 14-28) (p < 0.001). An increase of plasma lipoperoxides on days 12-14 post-transplant may be a predictive value of unfavourable evolution. RMI was the earlier indicator of engraftment in allogeneic BMT.

[Telomeres and genomic damage repair. Their implication in human pathology]. / Telómeros y reparación de daño genómico. Su implicancia en patología humana.

Telomeres, functional complexes that protect eukaryotic chromosome ends, participate in the regulation of cell proliferation and could play a role in the stabilization of genomic regions in response to genotoxic stress. Their significance in human pathology becomes evident in several diseases sharing genomic instability as a common trait, in which alterations of the telomere metabolism have been demonstrated. Many of them are also associated with hypersensitivity to ionizing radiation and cancer susceptibility. Besides the specific proteins belonging to the telomeric complex, other proteins involved in the DNA repair machinery, such as ATM, BRCA1, BRCA2, PARP/tankyrase system, DNA-PK and RAD50-MRE11-NBS1 complexes, are closely related with the telomere. This suggests that the telomere sequesters DNA repair proteins for its own structure maintenance, which could also be released toward damaged sites in the genomic DNA. This communication describes essential aspects of telomere structure and function and their links with homologous recombination, non-homologous end-joining (NHEJ), V(D)J system and mismatch-repair (MMR). Several pathological conditions exhibiting alterations in some of these mechanisms are also considered. The cell response to ionizing radiation and its relationship with the telomeric metabolism is particularly taken into account as a model for studying genotoxicity.

Telómeros y reparación de daño genómico. Su implicancia en patologia humana / Telomeres and genomic damage repair. Their implication in human pathology

Los telómeros, complejos funcionales que protegen los extremos de los cromosomas eucariotes, participan en la regulación de la proliferación celular y pueden jugar un rol en la estabilización de cier-tas regiones del genoma en respuesta a estrés genotóxico. Su relevancia en patología humana se ha puesto de manifiesto en numerosas enfermedades que comparten como rasgo común la inestabilidad genómica, en las que se comprobaron alteraciones del metabolismo telomérico. Muchas de ellas se encuentran asociadas a hipersensi-bilidad a radiaciones ionizantes y susceptibilidad al cáncer. Además de las proteínas específicas que forman partedel complejo telomérico otras proteínas implicadas en la maquinaria de reparación del ADN tales como ATM,BRCA1, BRCA2 , sistema PARP/ tankirasa, complejo DNA-PK, y complejo RAD50- MRE11-NBS1, se encuentran en estrecha asociación con el mismo. Esto sugiere que el telómero secuestra proteínas de reparación para el mantenimiento de su propia estructura, las que podrían asimismo ser liberadas hacia sitios de daño en el ADN genómico. Esta comunicación describe los aspectos más relevantes de la estructura y función de los telómeros y su vinculación con los procesos de recombinación homóloga, recombinación no homóloga (NHEJ), sistema V(D)J y sistemas de reparación de apareamientos erróneos (MMR), considerando ciertas condiciones patológicas que exhiben alteraciones en algunos estos mecanismos. Se aborda en forma particular la respuesta celular a las ra-diaciones ionizantes y su relación con el metabolismo telomérico como un modelo de estudio de genotoxicidad

Eritodermia ictiosiforme congénita / Congenital ichtysiform erythroderma: a nosologic review related with one case

Las patologías ictiosiformes son un grupo de genodermatosis caracterizadas por un patrón hiperqueratósico de distribución variable y con mayor o menor gradode compromiso general.La eritrodernia ictiosiforme congénita o feto eb aelequín constituye la forma más severa de la ictiosis presentado una evolución rápidamente fatal.La aplicación de las medidas de aepsia externa,así como el uso de retenoides ha permitido modificar el curso de la enfermedad y losgras sobrevidas prolongadas.A propósito de una observación se discuten aspectos relacionados con la enferemdad y otros que hacen a la ubicación de esta patología en el registro de las ictiosis,así como aspectos terapeúticos y evolutivos