Changes in electrophysiological static and dynamic human brain functional architecture from childhood to late adulthood.

This magnetoencephalography study aimed at characterizing age-related changes in resting-state functional brain organization from mid-childhood to late adulthood. We investigated neuromagnetic brain activity at rest in 105 participants divided into three age groups: children (6-9 years), young adults (18-34 years) and healthy elders (53-78 years). The effects of age on static resting-state functional brain integration were assessed using band-limited power envelope correlation, whereas those on transient functional brain dynamics were disclosed using hidden Markov modeling of power envelope activity. Brain development from childhood to adulthood came with (1) a strengthening of functional integration within and between resting-state networks and (2) an increased temporal stability of transient (100-300 ms lifetime) and recurrent states of network activation or deactivation mainly encompassing lateral or medial associative neocortical areas. Healthy aging was characterized by decreased static resting-state functional integration and dynamic stability within the primary visual network. These results based on electrophysiological measurements free of neurovascular biases suggest that functional brain integration mainly evolves during brain development, with limited changes in healthy aging. These novel electrophysiological insights into human brain functional architecture across the lifespan pave the way for future clinical studies investigating how brain disorders affect brain development or healthy aging.

Radiation protection in mammography for breast cancer screening: not covered by the French press.

BACKGROUND: In the context of major exposure to medical-based ionizing radiation (IR), French health institutions agree that adopting a precautionary approach is essential. A number of scientific studies have highlighted the risk of developing breast cancer after exposure to IR, even from low doses. However, the information circulating on the subject is varied. OBJECTIVES: A study of the mainstream press was performed to better understand the elements constituting women's representations of IR in mammography for breast cancer screening. STUDY DESIGN: The data used came from a corpus created with the mainstream press database 'Europresse.' The keyword 'mammography' was chosen. The software package Iramuteq was used to perform a statistical analysis of textual data using the Reinert method. RESULTS: This study highlights a paradox between the social principle of prevention and the discourse elements on mammography screening present in the mainstream press. CONCLUSION: The general French press does not take into account radiation protection in cancer screening discourses. A greater effort to provide information on this subject is needed.

Individual response of humans to ionising radiation: governing factors and importance for radiological protection.

Tissue reactions and stochastic effects after exposure to ionising radiation are variable between individuals but the factors and mechanisms governing individual responses are not well understood. Individual responses can be measured at different levels of biological organization and using different endpoints following varying doses of radiation, including: cancers, non-cancer diseases and mortality in the whole organism; normal tissue reactions after exposures; and, cellular endpoints such as chromosomal damage and molecular alterations. There is no doubt that many factors influence the responses of people to radiation to different degrees. In addition to the obvious general factors of radiation quality, dose, dose rate and the tissue (sub)volume irradiated, recognized and potential determining factors include age, sex, life style (e.g., smoking, diet, possibly body mass index), environmental factors, genetics and epigenetics, stochastic distribution of cellular events, and systemic comorbidities such as diabetes or viral infections. Genetic factors are commonly thought to be a substantial contributor to individual response to radiation. Apart from a small number of rare monogenic diseases such as ataxia telangiectasia, the inheritance of an abnormally responsive phenotype among a population of healthy individuals does not follow a classical Mendelian inheritance pattern. Rather it is considered to be a multi-factorial, complex trait.

Neuromagnetic Cerebellar Activity Entrains to the Kinematics of Executed Finger Movements.

This magnetoencephalography (MEG) study aims at characterizing the coupling between cerebellar activity and the kinematics of repetitive self-paced finger movements. Neuromagnetic signals were recorded in 11 right-handed healthy adults while they performed repetitive flexion-extensions of right-hand fingers at three different movement rates: slow (~ 1 Hz), medium (~ 2 Hz), and fast (~ 3 Hz). Right index finger acceleration was monitored with an accelerometer. Coherence analysis was used to index the coupling between right index finger acceleration and neuromagnetic signals. Dynamic imaging of coherent sources was used to locate coherent sources. Coupling directionality between primary sensorimotor (SM1), cerebellar, and accelerometer signals was assessed with renormalized partial directed coherence. Permutation-based statistics coupled with maximum statistic over the entire brain volume or restricted to the cerebellum were used. At all movement rates, maximum coherence peaked at SM1 cortex contralateral to finger movements at movement frequency (F0) and its first harmonic (F1). Significant (statistics restricted to the cerebellum) coherence consistently peaked at the right posterior lobe of the cerebellum at F0 with no influence of movement rate. Coupling between Acc and cerebellar signals was significantly stronger in the afferent than in the efferent direction with no effective contribution of cortico-cerebellar or cerebello-cortical pathways. This study demonstrates the existence of significant coupling between finger movement kinematics and neuromagnetic activity at the posterior cerebellar lobe ipsilateral to finger movement at F0. This coupling is mainly driven by spinocerebellar, presumably proprioceptive, afferences.

[The enigma of the biological interpretation of the linear-quadratic model finally resolved? A summary for non-mathematicians]. / L'énigme de l'interprétation biologique du modèle linéaire-quadratique enfin résolue ? Une synthèse pour les non-mathématiciens.

The linear-quadratic (LQ) model is the only mathematical formula linking cellular survival and radiation dose that is sufficiently consensual to help radiation oncologists and radiobiologists in describing the radiation-induced events. However, this formula proposed in the 1970s and α and ß parameters on which it is based remained without relevant biological meaning. From a collection of cutaneous fibroblasts with different radiosensitivity, built over 12 years by more than 50 French radiation oncologists, we recently pointed out that the ATM protein, major actor of the radiation response, diffuses from the cytoplasm to the nucleus after irradiation. The evidence of this nuclear shuttling of ATM allowed us to provide a biological interpretation of the LQ model in its mathematical features, validated by a hundred of radiosensitive cases. A mechanistic explanation of the radiosensitivity of syndromes caused by the mutation of cytoplasmic proteins and of the hypersensitivity to low-dose phenomenon has been proposed, as well. In this review, we present our resolution of the LQ model in the most didactic way.

[Repeated radiation dose effect and DNA repair: Importance of the individual factor and the time interval between the doses]. / Effets de répétitions de doses d'irradiation et réparation de l'ADN : importance du facteur individuel et de l'intervalle de temps entre les doses.

The dose fractionation effect is a recurrent question of radiation biology research that remains unsolved since no model predicts the clinical effect only with the cumulated dose and the radiobiology of irradiated tissues. Such an important question is differentially answered in radioprotection, radiotherapy, radiology or epidemiology. A better understanding of the molecular response to radiation makes possible today a novel approach to identify the parameters that condition the fractionation effect. Particularly, the time between doses appears to be a key factor since it will permit, or not, the repair of certain radiation-induced DNA damages whose repair rates are of the order of seconds, minutes or hours: the fractionation effect will therefore vary according to the functionality of the different repair pathways, whatever for tumor or normal tissues.

Effect of movement rate on corticokinematic coherence.

AIMS OF THE STUDY: This study investigates the effect of movement rate on the coupling between cortical magnetoencephalographic (MEG) signals and the kinematics of repetitive active finger movements, i.e., the corticokinematic coherence (CKC). MATERIAL AND METHODS: CKC was evaluated in ten right-handed healthy adults performing repetitive flexion-extension of the right-hand fingers in three different movement rate conditions: slow (∼1 Hz, duration: 11 min), medium (∼2 Hz, duration: 5 min) and fast (∼3 Hz, duration: 3 min). Neuromagnetic signals were recorded with a whole-scalp-covering MEG (Elekta Oy) and index acceleration was monitored with a 3-axis accelerometer. Coherent sources were estimated on the time-course of the cross-correlogram using equivalent current dipole (ECD) modeling. RESULTS: Significant coherence was found at movement frequency or its first harmonics in all subjects and movement conditions. ECDs clustered at the primary sensorimotor cortex contralateral to hand movements. Movement rate had no effect on the coherence levels and the location of coherent sources. CONCLUSIONS: This study demonstrates that the movement rate does not affect coherence levels and CKC source location during active finger movements. This finding has direct implications for CKC functional mapping applications and studies investigating the pathophysiology of central nervous disorders affecting proprioceptive pathways.

[French radiotherapy database: results of a survey of French radiation oncology centers in 2007]. / Observatoire national de la radiothérapie: rapport de l'enquête conduite en 2008 sur l'année 2007.

For the second year, the French Radiotherapy Database presents information from French radiation oncology centers. Among 179 centers, 159 have participated (90 %). The number of accelerators increased from 371 to 384 between 2006 and 2007, 11 % of these machines are more than 15 years old. On average, centers are open 50 hours per week for treatment and 9.5 % more for maintenance. The lack of dedicated CT remains a difficulty: 158 from 159 centers have an access to a CT, but only 50 % have a dedicated scanner. There is no progress compared to 2006. The proportion of centers having a MU double calculation system has increased from 51 to 58 %. Two thirds of centers do not implement in vivo dosimetry. The activity is stable around 190 000 treatments per year. Three-dimension conformal radiotherapy is used for more than half of treatments in 77.2 % of private centers and 50 % of public hospitals. Intensity modulated radiotherapy remains rarely used. The number of radiation oncologists and technologists remains stable. The number of radiophysicists has increased from 7.6 %. Despite some progress, the difficulties of this speciality persist in France and are equally distributed across all regions, and between private and public centers. In 2009, the French Society for Radiation Oncology and the associated partners will continue this survey, which interest is recognized by both professionals and health administrations.

Pharmacological inhibition of DNA repair enzymes differentially modulates telomerase activity and apoptosis in two human leukaemia cell lines.

PURPOSE: To investigate the effect of wortmannin and 3-aminobenzamide (3-AB) on telomerase activity and apoptosis in two human leukaemia cells. MATERIALS AND METHODS: MOLT-4 (p53-wild type) and KG1a (p53-null) cells were irradiated with gamma-rays (3 Gy at 1.57 Gy min(-1)) and the effects of wortmannin and 3-AB were evaluated. Telomerase activity was measured by polymerase chain reaction and the expression of human telomerase reverse transcriptase, human telomerase RNA and telomerase-associated protein 1 was assessed by reverse transcriptase-polymerase chain reaction. Apoptosis was evaluated by fluorescence microscopy and flow cytometry. RESULTS: A radiation-induced up-regulation of telomerase activity was observed from 4 h post-irradiation in both cell lines. This up-regulation was abrogated by wortmannin and 3-AB. Telomerase activity was maximal 24 h post-irradiation, coinciding with an accumulation of human telomerase reverse transcriptase mRNA. Apoptosis and G2/M arrest were evident from 4 h post-irradiation in MOLT-4 cells. KG1a cells exhibited a G2/M block at 24 h post-irradiation and apoptosis increased between 24 and 48 h post-irradiation. 3-AB abolished G2/M blockage and enhanced radiation-induced apoptosis in both cell lines, while wortmannin increased apoptosis only in MOLT-4 cells. CONCLUSIONS: 3-AB inhibits the radiation-associated telomerase activity increase and enhances apoptosis in MOLT-4 and KG1a cells. Wortmannin, which also inhibits the radiation-associated telomerase activity increase in both cell lines, does not modify radiation-induced apoptosis in KG1a cells. DNA repair enzymes might be selective targets for enhancing radiosensitivity in certain tumour cells.

In vivo tracking of bone marrow fibroblasts with fluorescent carbocyanine dye.

Recent advances in the field of tissue engineering have culminated in new tissue substitutes that combine a biomaterial and precursor cells. The effectiveness of these materials is generally assessed in animals, but few studies explore the fate of the transplanted cells in vivo, despite its paramount importance for understanding the function of the engineered tissues. Current methods that use reporter genes or chimeric animals are not always well suited to solving tissue-engineering problems. We therefore developed a new method for irreversible labeling of cells to track their fate in vivo. We used a fluorescent lipophilic probe, CM-Dil, that avidly binds to the cell membrane. Human bone marrow stromal fibroblasts could be labeled with 20 microM CM-Dil in 30 min. The CM-Dil was not cytotoxic and did not affect cell proliferation in vitro. Cells could be monitored for up to 30 days when placed in a coral scaffold and implanted intramuscularly or in a bony site. However, the fluorescence intensity decreased roughly in parallel with the number of cell divisions. This fact needs to be taken into account during the design and interpretation of experiments. We believe that this technique is also of interest for other cell types.

Tissue-engineered bone regeneration.

Bone lesions above a critical size become scarred rather than regenerated, leading to nonunion. We have attempted to obtain a greater degree of regeneration by using a resorbable scaffold with regeneration-competent cells to recreate an embryonic environment in injured adult tissues, and thus improve clinical outcome. We have used a combination of a coral scaffold with in vitro-expanded marrow stromal cells (MSC) to increase osteogenesis more than that obtained with the scaffold alone or the scaffold plus fresh bone marrow. The efficiency of the various combinations was assessed in a large segmental defect model in sheep. The tissue-engineered artificial bone underwent morphogenesis leading to complete recorticalization and the formation of a medullary canal with mature lamellar cortical bone in the most favorable cases. Clinical union never occurred when the defects were left empty or filled with the scaffold alone. In contrast, clinical union was obtained in three out of seven operated limbs when the defects were filled with the tissue-engineered bone.

Health effects of therapeutic use of 131I in hyperthyroidism.

Since 1942, therapy with radioiodine (Na131I) has gained a major role in the treatment of benign thyroid disorders, notably hyperthyroidism caused by Graves' disease or toxic multinodular goiter. The very large series of patients treated so far offer the opportunity for an assessment of both benign and malignant side effects. Hyperthyroidism is sometimes observed after radioiodine therapy due to radiation induced thyroid hormone or by an immunological mechanism. Despite the numerous attempts to design dosage schedules aiming at euthyroidism, hypothyroidism occurs in the majority of patients throughout life. Transient hypothyroidism may be observed within the first year after therapy and is caused by an immunological mechanism. Radioiodine therapy in Graves' disease may induce or worsen ophthalmopathy, which can be prevented by steroids effectively. Hypoparathyroidism and hyperparathyroidism have been reported after radioiodine therapy but probably do not exceed the normal incidence. Sialitis is commonly observed but mostly in patients treated with radioiodine for thyroid cancer. There are no indications for induction of genetic abnormalities after radioiodine therapy although no definite conclusion can be reached. Much attention has been paid to malignant disease. In very large series, no effects of radioiodine therapy on survival have been observed. Some studies report an increased relative risk for certain types of cancer (notably thyroid cancer, stomach cancer, bladder and kidney cancer or hematological malignancies). However, these observations were not confirmed by other large studies, so that no definite conclusion with respect to risk for certain types of malignant disease can be drawn. However, radioiodine therapy for benign thyroid disorders has generally been considered safe and without major side effects, hypothyroidism being the most frequent one.

Genetic susceptibility to radiations. Which impact on medical practice?

Recent progress especially in the field of gene identification and expression have raised more attention on genetic susceptibility to cancer possibly enhanced by radiation. Radiation therapists are mostly concerned by this question since hypersensitive patients may suffer from adverse effects in normal tissues following a standard radiation therapy and normally sensitive patients could benefit from higher doses of radiation for better treatment of their malignant tumors. Although only a small percentage of individuals are "hypersensitive" to radiation effects, all medical specialists using ionising radiation should be aware of this new progress in medical knowledge. The present paper reviews the main pathologies (diseases, syndromes...) known or strongly suspected to be associated with a hypersensitivity to ionizing radiation. Then the main tests capable of detecting in advance such pathologies are analyzed and compared. Finally guidelines are provided, especially to the radiation therapists to limit the risk of severe complications (or even deaths) for this specific subset of patients suffering from a genetic disorder with a susceptibility to radiations.

Aspects of fetal thyroid dose following iodine-131 administration during early stages of pregnancy in patients suffering from benign thyroid disorders.

Detrimental effects on the thyroid of the developing fetus as a result of iodine-131 treatment for thyrotoxicosis of the mother in the first trimester of pregnancy are discussed. Dose estimations under typical clinical circumstances yield a fetal thyroid dose of 100- 450 Sv. This dose may increase considerably if the blood concentration of (131)I in the mother remains high. Under such circumstances there may be fetal thyroid dysfunction, which can lead to severe abnormalities.

FDG accumulation and tumor biology.

The tumoral uptake of fluorine-18-deoxyglucose (FDG) is based upon enhanced glycolysis. Following injection, FDG is phosphorylated and trapped intracellularly. An important mechanism to transport FDG into the transformed cell is based upon the action of glucose transporter proteins; furthermore, highly active hexokinase bound to tumor mitochondria helps to trap FDG into the cell. In addition, enhanced FDG uptake may be due to relative hypoxia in tumor masses, which activates the anaerobic glycolytic pathway. In spite of these processes, FDG uptake is relatively aspecific since all living cells need glucose. Clinical use is therefore recommended in carefully selected patients.

Diagnostic nuclear medicine and risk for the fetus.

The possible detrimental effects on the developing embryo subsequent to irradiation are discussed. The doses to the embryo or fetus encountered for the most common procedures in diagnostic nuclear medicine are evaluated with respect to the threshold doses and the risks per cGy. The threshold dose for fatal and non-fatal malformations or other defects is, at the lowest estimate, 5-10 cGy. The dose which the embryo or fetus receives from diagnostic nuclear medicine is below 1 cGy. For the induction of fatal cancer and for genetic defects no threshold dose is assumed. The risk for the induction of cancer is 0.03%-0.05% per cGy. The risk for the induction of genetic defects is even lower (0.024%-0.099% per cGy). It is concluded that for common diagnostic nuclear medicine procedures the risk of detrimental effects on the embryo or fetus due to radiation is negligible. On the basis of present knowledge there are no radiation safety indications for abortus provocatus as a consequence of a diagnostic nuclear medicine study.

Iodine-123 labelled radiopharmaceuticals and single-photon emission tomography: a natural liaison.

Most nuclear medicine departments possess one or more imaging apparatuses for single-photon emission tomography (SPET). Molecules of biological interest to assess metabolism and receptor function are often labelled with 123I, which allows proper SPET imaging. The various methods for radiolabelling are reviewed. As the biological integrity of these agents has been demonstrated for numerous radiopharmaceuticals, the purpose of this review is to summarize the efficacy in various fields of medicine, including the imaging of tumours, infection, myocardium and cerebrum.

Decrease in enkephalinase A number in kidney membranes from hypercholesterolemic and hypertensive rats.

The variation of enkephalinase A number on the hypertensive and hypercholesterolemia rats kidney membranes is studied using the [3H]-acetorphan, a potent inhibitor of enkephalinase A to label the protease in rat kidney. The binding of [3H]-acetorphan to kidney membrane determined in vitro with both equilibrium and kinetic methods is saturable and reversible involving a single class of sites with a dissociation constant of 4-5.3 nM. The [3H]-acetorphan binding capacity is identical, Bmax approximately 51 pmoles per mg of proteins, for kidney membranes from Sprague Dawley and Wistar Kyoto rats. In contrast, the enkephalinase A number is decreased in the pathological states studied: 20% for hypertensive rats and 50% for hypercholesterolemic rats. Such pharmacological results provide a great deal of information about the modification appeared in the metabolism of peptidic substrates of enkephalinase A in hypercholesterolemia and hypertension.