PPARα mediates night neon light-induced weight gain: role of lipid homeostasis.

Rationale: Light pollution leads to high risk of obesity but the underlying mechanism is not known except for the influence of altered circadian rhythm. Peroxisome proliferator-activated receptor α (PPARα) regulates lipid metabolism, but its role in circadian-related obesity is not clear. Methods: Wild-type (WT) and Ppara-null (KO) mice on a high-fat diet (HFD) were treated with neon light at night for 6 weeks. Body weights were recorded and diet consumption measured. The hypothalamus, liver, adipose and serum were collected for mechanism experimentation. Results: WT mice on a HFD and exposed to night neon light gained about 19% body weight more than the WT control mice without light exposure and KO control mice on a HFD and exposed to night neon light. The increase in adipose tissue weight and adipocyte size led to the differences in body weights. Biochemical analysis suggested increased hepatic lipid accumulated and increased transport of lipid from the liver to peripheral tissues in the WT mice that gained weight under neon light exposure. Unlike KO mice, the expression of genes involved in lipid metabolism and the circadian factor circadian locomotor output cycles kaput (CLOCK) in both liver and adipose tissues were elevated in WT mice under neon light exposure. Conclusions: PPARα mediated weight gain of HFD-treated mice exposed to night neon light. More lipids were synthesized in the liver and transported to peripheral tissue leading to adaptive metabolism and lipid deposition in the adipose tissue. These data revealed an important mechanism of obesity induced by artificial light pollution where PPARα was implicated.

Spatial fractionation of the dose using neon and heavier ions: A Monte Carlo study.

PURPOSE: This work explores a new radiation therapy approach which might trigger a renewed use of neon and heavier ions to treat cancers. These ions were shown to be extremely efficient in radioresistant tumor killing. Unfortunately, the efficient region also extends into the normal tissue in front of the tumor. The strategy the authors propose is to profit from the well-established sparing effect of thin spatially fractionated beams, so that the impact on normal tissues might be minimized while a high tumor control is achieved. The main goal of this work is to provide a proof of concept of this new approach. With that aim, a dosimetric study was carried out as a first step to evaluate the interest of further explorations of this avenue. METHODS: The gate/geant4 v.6.1 Monte Carlo simulation platform was employed to simulate arrays of rectangular minibeams (700 µm × 2 cm) of four ions (Ne, Si, Ar, and Fe). The irradiations were performed with a 2 cm-long spread-out Bragg peak centered at 7 cm-depth. Dose distributions in a water phantom were scored considering two minibeams center-to-center distances: 1400 and 3500 µm. Peak and valley doses, peak-to-valley dose ratios (PVDRs), beam penumbras, and relative contribution of nuclear fragments and electromagnetic processes were assessed as figures of merit. In addition, the type and proportion of the secondary nuclear fragments were evaluated in both peak and valley regions. RESULTS: Extremely high PVDR values (>100) and low valley doses were obtained. The higher the atomic number (Z) of the primary ion is, the lower the valleys and the narrower the penumbras. Although the yield of secondary nuclear products increases with Z, the actual dose being deposited by the secondary nuclear fragments in the valleys starts to be the dominant contribution at deeper points, helping in the sparing of proximal normal tissues. Additionally, a wider center-to-center distance leads to a minimized contribution of heavier secondary fragments in valleys. CONCLUSIONS: The computed dose distributions suggest that a spatial fractionation of the dose combined to the use of submillimetric field sizes might allow profiting from the high efficiency of neon and heavier ions for the treatment of radioresistant tumors, while preserving normal tissues. The authors' results support the further exploration of this avenue. Next steps include the realization of biological experiment to confirm the shifting of normal tissue complication probability curves.

Adaptive response of low linear energy transfer X-rays for protection against high linear energy transfer accelerated heavy ion-induced teratogenesis.

BACKGROUND: Adaptive response (AR) of low linear energy transfer (LET) irradiations for protection against teratogenesis induced by high LET irradiations is not well documented. In this study, induction of AR by X-rays against teratogenesis induced by accelerated heavy ions was examined in fetal mice. METHODS: Irradiations of pregnant C57BL/6J mice were performed by delivering a priming low dose from X-rays at 0.05 or 0.30 Gy on gestation day 11 followed one day later by a challenge high dose from either X-rays or accelerated heavy ions. Monoenergetic beams of carbon, neon, silicon, and iron with the LET values of about 15, 30, 55, and 200 keV/µm, respectively, were examined. Significant suppression of teratogenic effects (fetal death, malformation of live fetuses, or low body weight) was used as the endpoint for judgment of a successful AR induction. RESULTS: Existence of AR induced by low-LET X-rays against teratogenic effect induced by high-LET accelerated heavy ions was demonstrated. The priming low dose of X-rays significantly reduced the occurrence of prenatal fetal death, malformation, and/or low body weight induced by the challenge high dose from either X-rays or accelerated heavy ions of carbon, neon or silicon but not iron particles. CONCLUSIONS: Successful AR induction appears to be a radiation quality event, depending on the LET value and/or the particle species of the challenge irradiations. These findings would provide a new insight into the study on radiation-induced AR in utero.

[Effect of accelerated heavy ions of carbon 12C, neon 20Ne and iron 56Fe on the chromosomal apparatus of human blood lymphocytes in vitro].

Cytogenetic assay of the chromosomal apparatus of human blood lymphocytes was carried out after in vitro irradiation by heavy charged particles with high LET values. Blood plasm samples enriched with lymphocytes were irradiated by accelerated ions of carbon 12C (290 MeV/nucleon and LET = 70 keV/microm), neon 20Ne (400 MeV/nucleon and LET = 70 keV/microm), and iron 56Fe (500 MeV/nucleon and LET = 200 keV/microm) in the dose range from 0.25 to 1 Gy. Rate of chromosome aberrations showed a linear dependence on doses from the densely ionizing radiations with high LET values. Frequency of dicentrics and centric rings in human lymphocytes irradiated by 12C with the energy of 290 MeV/nucleon was maximal at 1 Gy (p < 0.05) relative to the other heavy particles. It was found that relative biological effectiveness of heavy nuclei is several times higher than of 60Co gamma-radiation throughout the range of doses in this investigation.

[Diving: barometric pressure and neurochemical mechanisms]. / La plongée: pression barométrique et mécanismes neurochimiques.

The studies of Paul Bert, presented in his book "La Pression Barométrique" in 1878, were at the origin of the modern hyperbaric physiology. Indeed his research demonstrated the effects of oxygen at high pressure, that compression effects must be dissociated from decompression effects, and that neurological troubles and death of divers during or after decompression were due to the fast rate of decompression. However, it is only in 1935 that the work of Behnke et al. attributed the complaints reported at 3 bars and above in compressed air or nitrogen-oxygen mixture to the increase in partial pressure of nitrogen which induces nitrogen narcosis. Little is known about the origins and mechanisms of this narcosis. The traditional view was that anaesthesia or narcosis occurred when the volume of a hydrophobic membrane site was caused to expand beyond a critical amount by the absorption of molecules of a narcotic gas. The observation of the pressure reversal effect during general anaesthesia has long supported this lipid theory. However, recently, protein theories have met with increasing recognition since results with gaseous anaesthetics have been interpreted as evidence for a direct gas-protein interaction. The question is to know whether inert gases, that disrupt dopamine and GABA neurotransmissions and probably glutamatergic neurotransmission, act by binding to neurotransmitter protein receptors.

The response of tissue-equivalent proportional counters to heavy ions.

The paper presents a theoretical model for the response of a tissue-equivalent proportional counter (TEPC) irradiated with charged particles. Heavy ions and iron ions in particular constitute a significant part of radiation in space. TEPCs are used for all space shuttle and International Space Station (ISS) missions to estimate the dose and radiation quality (in terms of lineal energy) inside spacecraft. The response of the tissue-equivalent proportional counters shows distortions at the wall/cavity interface. In this paper, we present microdosimetric investigation using Monte Carlo track structure calculations to simulate the response of a TEPC to charged particles of various LET (1 MeV protons, 2.4 MeV alpha particles, 46 MeV/nucleon 20Ne, 55 MeV/nucleon 20Ne, 45 MeV/nucleon 40Ar, and 1.05 GeV/nucleon 56Fe). Data are presented for energy lost and energy absorbed in the counter cavity and wall. The model calculations are in good agreement with the results of Rademacher et al. (Radiat. Res. 149, 387-389, 1998), including the study of the interface between the wall and the sensitive region of the counter. It is shown that the anomalous response observed at large event sizes in the experiment is due to an enhanced entry of secondary electrons from the wall into the gas cavity.

Minimum alveolar concentrations of noble gases, nitrogen, and sulfur hexafluoride in rats: helium and neon as nonimmobilizers (nonanesthetics)

UNLABELLED: We assessed the anesthetic properties of helium and neon at hyperbaric pressures by testing their capacity to decrease anesthetic requirement for desflurane using electrical stimulation of the tail as the anesthetic endpoint (i.e., the minimum alveolar anesthetic concentration [MAC]) in rats. Partial pressures of helium or neon near those predicted to produce anesthesia by the Meyer-Overton hypothesis (approximately 80-90 atm), tended to increase desflurane MAC, and these partial pressures of helium and neon produced convulsions when administered alone. In contrast, the noble gases argon, krypton, and xenon were anesthetic with mean MAC values of (+/- SD) of 27.0 +/- 2.6, 7.31 +/- 0.54, and 1.61 +/- 0.17 atm, respectively. Because the lethal partial pressures of nitrogen and sulfur hexafluoride overlapped their anesthetic partial pressures, MAC values were determined for these gases by additivity studies with desflurane. Nitrogen and sulfur hexafluoride MAC values were estimated to be 110 and 14.6 atm, respectively. Of the gases with anesthetic properties, nitrogen deviated the most from the Meyer-Overton hypothesis. IMPLICATIONS: It has been thought that the high pressures of helium and neon that might be needed to produce anesthesia antagonize their anesthetic properties (pressure reversal of anesthesia). We propose an alternative explanation: like other compounds with a low affinity to water, helium and neon are intrinsically without anesthetic effect.

[High density respiratory syndrome: III. The functional role of oscillation of respiratory flow during respiration in dense gas media]. / Dykhatel'nyi sindrom vysokoi plotnosti: III. Funktsional'noe znachenie ostsilliatsii respiratornykh potokov pri dykhanii v plotnykh gazovykh sredakh.

It is found out that when reaching critical density of gas medium (20.4-24.0 kg/m3), the relative power of oscillations on the "flow-volume" curves and pneumotachograms sharply increases. At the same time the maximal rate of exhale, rates of expiratory flows in large bronchi decrease significantly and the rates of expiratory flows in bronchi of middle and small calibers reduce to zero. Within the range of densities of different gas medium (from 1.3 to 32.7 kg/m3) the changes in the relative power of oscillations of respiratory flows correlate well with the changes in permeability of upper respiratory tracts (r = -0.932 +/- 0.054). A regression equation describing this dependence is obtained. A detailed description is given to symptoms of high-density breathing syndrome: a decrease in rates of gas flows in tracheobronchial tree, early development of dynamic compression of airway, tremor of breathing muscles and appearance of respiratory flow oscillations, pronounced dyspnea and hypoventilation of alveoli. A hypothetic scheme of its development is presented. The functional significance of respiratory flow oscillations as a mechanism improving gas exchange in gas media with extremely high density is under discussion.

Patterns of interaction of effects of light metabolically inert gases with those of hydrostatic pressure as such--a review.

This review of available literature attempts to interpret net effects of metabolically inert light gases (He, H2, and Ne) as the resultant of hydrostatic pressure and intrinsic pharmacological effects associated with exposure to these gases, and to assess the relative importance of each component with respect to a number of biological responses. A common pattern is recognizable for pressure reversal of anesthesia, high pressure convulsions, high pressure bradycardia, and certain characteristics of liposome model systems. Using the method of analysis proposed, these lightest gases can be shown to conform to the pattern of relation of potency to physical properties characteristic of more potent gaseous anesthetics, including N2, N2O, and Xe. The relations between effect produced and partial pressure of the acting gas are approximately linear to total pressures of 100 ATA for anesthesia or pressure reversal of anesthesia and (or to a much smaller extent) for the liposome model systems, but not for high pressure convulsions. As a result of these general factors no single gas can be expected to neutralize the effects of hydrostatic pressure with regard to all of the biological responses tested over any significant pressure range. A series of experiments with single cells and tissue cultures have revealed interactions between high pressure and inert gas that do not conform to the pattern set by the responses mentioned so far. These responses cannot yet be shown to constitute a homogeneous group and may represent at least two subgroups. Responses falling into this second heterogeneous category include cell motility, development of cell abnormalities and lysis, and cell and perhaps virus replication or multiplication. The implication of these results for the formulation of biophysical hypotheses to explain interactions between inert gas and high pressure, for considerations of high pressure effects as a safety hazard, and for the problem of experimental approaches to the study of pressure acclimation are discussed briefly.

Effects of heavy ions on rabbit tissues: alopecia.

During extended investigations of the radiation responses of optic and proximate tissues of New Zealand white rabbits (Oryctolagus cuniculus), the skin surrounding the eyes was exposed to the Bragg plateau regions of 530 MeV/amu Ar ions and 365 MeV/amu Ne ions, and also to 60Co gamma rays. The linear energy transfers (LET infinity s) for the radiations were 90 +/- 5, 35 +/- 3, and 0.3 keV/micron, respectively. Alopecia was measured after irradiation with subjective indices of baldness (0-5) that were calibrated against hair loss in other rabbits irradiated with Ne and Ar ions at the central region of the ear. The patterns of post-irradiation alopecia, which conformed to the model proposed by Casarett (1963) for the long-term expression of radiation damage in proliferating animal tissues, were modified by radiation quality in the following ways: (1) For acute (early) losses, the magnitude of the recovery phase decreased as the LET infinity of the incident radiation increased; (2) In the intermediate or plateau phase of radiation response, the values of relative biological effectiveness (r.b.e) approached those reported for proliferating cells in culture, but differences were found that may be related to the changes in the magnitude of the recovery phase; (3) For a given level of intermediate damage, the onset of the late degenerative phase of radiation response, which was expressed years after irradiation, occurred earlier the higher the LET infinity of the incident radiation. Taken overall, the most important finding of these experiments was that the r.b.e.s for alopecia varied with post-irradiation time.

Morphologic and morphometric analysis of the early effects of x-ray and heavy-ion irradiation of hamster lung.

Morphometric methods were to used to compare the early effects of graded single doses of x-rays with accelerated heavy particle (helium or neon) irradiation of hamster lung. Increased values in the volume densities of both capillary lumina and inflammatory cells at 2 weeks postirradiation were observed. Neon-ion irradiation wes statisically different from x-irradiation at all dose levels, while helium-ion irradiation showed significant increases only at higher doses (1000 to 1500 rads). At 1 month post-irradiation, the volume densities of capillary lumina after heavy particle irradiation began to return to control values, while those in x=irradiated lungs continued to be elevated. The volume density of inflammatory cells remained increased for all types of irradiation, and the highest values were obtained in neon-ion irradiated lungs. Accelerated heavy particle irradiation would therefore appear to elicit a more intense early radiation than does x-irradiation but the chronic significance of these findings is not yet known.

A new gas lesion syndrome in man, induced by "isobaric gas counterdiffusion".

Normal men have been found to develop pruritus and gas bubble lesions in the skin, and disruption of vestibular function, when breathing nitrogen or neon with oxygen while surrounded by helium at increased ambient pressure. This phenomenon, which occurs at stable ambient pressures, at 1 or many ATA, has been designated the "isobaric gas counterdiffusion syndrome." In a series of analyses and experiments in vivo and in vitro the cause of the syndrome has been established as due to gas accumulation and development of gas bubbles in tissues as a result of differences in selective diffusivities, for various respired and ambient gases, in the tissue substances between capillary blood and the surrounding atmosphere. The phenomenon here described in man is an initial stage of a process shown later in animals to progress to continuous, massive, lethal, intravascular gas embolization.