Magnetization Transfer Imaging in Multiple Sclerosis

Magnetization transfer (MT) is a relatively new way of generating contrast in magnetic resonance (MR) images that is sensitive to the density of the macromolecules found throughout tissue structures such as membranes, myelin, and organelles. MT imaging (MTI) can provide a quantitative measure of macromolecular density, and therefore of tissue damage, and has been applied in the central nervous system in multiple sclerosis (MS) and other diseases. This article introduces the contrast mechanisms behind MTI and gives some practical guidance about implementing MTI and about quantitative analysis of the MT scans. An overview of MT measurements made in animal studies, in postmortem tissue samples, and in other demyelinating diseases attempts to rationalize the pathological basis of changes in MT contrast in MS. The application of MTI to MS is reviewed, with emphasis on the contribution that MTI has made to the current understanding of the MS disease process, both its natural history and the response to treatment. The pathological basis of abnormal MT contrast is still open to debate, with many conflicting reports; indeed, it is unlikely that a simple measure of MT effect will reveal the details of pathology that is a combination of inflammation, demyelination, remyelination, and axonal loss. There is no doubt, however, that MT measurements have contributed to the current understanding of both disease progression and the response to treatment and will prove to be a valuable tool in the future, particularly if more refined techniques can be applied practically in multicenter studies.     

Effects of endurance training on hyperammonaemia during a 45-min constant exercise intensity

Summary Eleven laboratory-pretrained subjects (initial =54 ml·kg⁻¹·min⁻¹) took part in a study to evaluate the effect of a short endurance training programme [8–12 sessions, 1 h per session, with an intensity varying from 60% to 90% maximal oxygen consumption ] on the responses of blood ammonia (b[NH ₄ ⁺ ]) and lactate (b[la]) concentrations during progressive and constant exercise intensities. After training, during which did not increase, significant decreases in b[NH ₄ ⁺ ], b[la] and muscle proton concentration were observed at the end of the 80% constant exercise intensity, although b[NH ₄ ⁺ ] and b[la] during progressive exercise were unchanged. On the other hand, no correlations were found between muscle fibre composition and b[NH ₄ ⁺ ] in any of the exercise procedures. This study demonstrated that a constant exercise intensity was necessary to reveal the effect of training on muscle metabolic changes inducing the decrease in b[NH ₄ ⁺ ] and b[la]. At a relative power of exercise of 80% , there was no effect of muscle fibre composition on b[NH ₄ ⁺ ] accumulation.     

A comparison of dose distributions of proton and photon beams in stereotactic conformal radiotherapy of brain lesions

Purpose: Micromultileaf collimators (mMLC) have recently been introduced to conform photon beams in stereotactic irradiation of brain lesions. Proton beams and stereotactic conformal radiotherapy (SCRT) can be used to tailor the dose to nonspherical targets, as most tumors of the brain are irregularly shaped. Comparative planning of brain lesions using either proton or stereotactically guided photon beams was done to assess the institution’s clinically available modality for three-dimensional conformal radiotherapy.

Methods and Materials: For the photon treatment, multiple stereotactically guided uniform intensity beams from a linear accelerator were used, each conformed to a projection of the planning target volume (PTV) by a mMLC. Proton beams were delivered from an isocentrically mounted gantry, using the spot-scanning technique and energy modulation. Seven patients were scanned in a stereotactic frame; target volumes and organs at risk (OAR) were delineated with the help of MR images. Four different lesions were selected: (1) concave, (2) ellipsoid isolated, (3) superficial and close to an organ at risk, and (4) irregular complex. Dose distributions in the PTV and critical structures were calculated using three-dimensional treatment-planning systems, followed by both a quantitative (by dose–volume histogram and conformity index) and qualitative (visual inspection) assessment of the plans.

Results: A high degree of conformation was achieved with a mMLC and stereotactic uniform intensity beams with comparable conformity indices to protons for 5 out of 7 plans, especially for superficial or spherical lesions. In the cases studied, the conformity index was better for protons than for photons for complex or concave lesions, or when the PTV was in the neighborhood of critical structures.

Conclusion: The results for the cases studied, show that for simple geometries or for superficial lesions, there is no advantage in using protons. However, for complex PTV shapes, or when the PTV is in the vicinity of critical structures, protons seem to be potentially better than the fixed-field photon technique.     

Positive visual phenomena in space: A scientific case and a safety issue in space travel

Most astronauts on Apollo, Skylab, and MIR reported 'flashes of light' occurring in different shapes and apparently moving across the visual field, in the absence of auditory, somatosensory, or olfactory abnormal percepts. A temporal correlation with heavy nuclei or protons has been documented in space and comparable phosphenes were observed by volunteers whose eyes were exposed to accelerated heavy ions at intensities below the threshold for Cerenkov visible radiation. An interaction between heavy ions and the retina was suggested. However, the biophysics of heavy ions or protons action remains undefined, the effects on photoreceptors and neuroretina have not been differentiated, and some direct action on the visual cortex never ruled out. Phosphenes are common in migraine and are known to occur also in response to the electrical stimulation of ganglion cells (in retinas without photoreceptors), optic pathways or visual cortex, with mechanisms that bypass the chemically gated channels. Intrinsic photosensitive ganglion cells exist in the retina of teleost fish and mammals. In the hypothesis of a peculiar sensitivity to subatomic particles of the visual system, phosphenes due to the activation of processes by-passing the photoreceptors would raise questions about human safety in space. The issue is particularly relevant with experiments of increasing duration being now operative in the International Space Station (ISS) and with plans of space travel outside the geomagnetic shield. Research is in progress both in the ISS and on animal models, in the framework of the NASA/ESA actions to improve the astronauts' health in space.     

Insurance coverage decisions for pediatric proton therapy

Proton beam therapy (PBT) holds promise for pediatric patients, but level 1 evidence is not available. In this context, we examined insurance coverage decisions at our facility from 2010 to 2015. PBT was initially denied for 11% of pediatric cases. However, nearly all denials were overturned on appeal—a process that often delayed care by more than a week. Despite unfavorable language in coverage policies, real‐world decisions were eventual approval in >99% of cases. Payers appear to have largely accepted the current level‐of‐evidence for pediatric PBT, but all parties spend significant time and resources on appeals. Streamlined approval processes could align incentives among stakeholders.     

Rubisco proton production can drive the elevation of CO2 within condensates and carboxysomes

Membraneless organelles containing the enzyme ribulose-1,5-bisphosphate carboxylase/oxygenase (Rubisco) are a common feature of organisms utilizing CO₂ concentrating mechanisms to enhance photosynthetic carbon acquisition. In cyanobacteria and proteobacteria, the Rubisco condensate is encapsulated in a proteinaceous shell, collectively termed a carboxysome, while some algae and hornworts have evolved Rubisco condensates known as pyrenoids. In both cases, CO₂ fixation is enhanced compared with the free enzyme. Previous mathematical models have attributed the improved function of carboxysomes to the generation of elevated CO₂ within the organelle via a colocalized carbonic anhydrase (CA) and inwardly diffusing HCO₃⁻, which have accumulated in the cytoplasm via dedicated transporters. Here, we present a concept in which we consider the net of two protons produced in every Rubisco carboxylase reaction. We evaluate this in a reaction–diffusion compartment model to investigate functional advantages these protons may provide Rubisco condensates and carboxysomes, prior to the evolution of HCO₃⁻ accumulation. Our model highlights that diffusional resistance to reaction species within a condensate allows Rubisco-derived protons to drive the conversion of HCO₃⁻ to CO₂ via colocalized CA, enhancing both condensate [CO₂] and Rubisco rate. Protonation of Rubisco substrate (RuBP) and product (phosphoglycerate) plays an important role in modulating internal pH and CO₂ generation. Application of the model to putative evolutionary ancestors, prior to contemporary cellular HCO₃⁻ accumulation, revealed photosynthetic enhancements along a logical sequence of advancements, via Rubisco condensation, to fully formed carboxysomes. Our model suggests that evolution of Rubisco condensation could be favored under low CO₂ and low light environments.

Carbon dioxide (CO₂) fixation into the biosphere has been primarily dependent upon action of the enzyme ribulose-1,5-bisphosphate carboxylase/oxygenase (Rubisco) over geological timescales. Rubisco is distinguished by the competitive inhibition of its carboxylation activity by the alternative substrate molecular oxygen (O₂), leading to loss of CO₂ and metabolic energy via a photorespiratory pathway in most phototrophs (1). Almost certainly the most abundant enzyme on the planet (2), Rubisco’s competing catalytic activities have required evolution of the enzyme, and/or its associated machinery, to maintain capture of sufficient carbon into organic molecules to drive life on Earth. In concert with geological weathering, the evolution of oxygenic photosynthesis ∼2.4 billion years ago has transformed the atmosphere from one rich in CO₂ and low in O₂ to one in which the relative abundances of these gases has overturned (3). Under these conditions, the Rubisco oxygenation reaction has increased, to the detriment of CO₂ capture. This catalytic paradox has led to different adaptive solutions to ensure effective rates of photosynthetic CO₂ fixation including the evolution of the kinetic properties of the enzyme (4), increases in Rubisco abundance in the leaves of many terrestrial C₃ plants (5), and the evolution of diverse and complex CO₂ concentrating mechanisms (CCMs) in many cyanobacteria, algae, and more recently hornworts, CAM, and C₄ plants (6, 7).A defining characteristic of contemporary cyanobacteria is the encapsulation of their Rubisco enzymes within specialized, protein-encased microcompartments called carboxysomes (8). These microbodies are central to the cyanobacterial CCM, in which cellular bicarbonate (HCO₃⁻) is elevated by a combination of membrane-associated HCO₃⁻ pumps and CO₂-to-HCO₃⁻ converting complexes (9–11), to drive CO₂ production within the carboxysome by an internal carbonic anhydrase (CA; 12, 13). This process results in enhanced CO₂ fixation, with a concomitant decrease in oxygenation, and is a proposed evolutionary adaptation to a low CO₂ atmosphere (14, 15).An analogous CCM operates in many algal and hornwort species, which contain chloroplastic Rubisco condensates called pyrenoids (16, 17). Pyrenoids are liquid–liquid phase separated Rubisco aggregates, which lack the protein shell of a carboxysome (18). These CCMs accumulate HCO₃⁻ and convert it to CO₂ within the pyrenoid to maximize CO₂ fixation. Common to cyanobacterial and algal systems is the presence of unique Rubisco-binding proteins, enabling condensation of Rubisco from the bulk cytoplasm (18–25). Condensation of proteins to form aggregates within the cell is increasingly recognized as a means by which cellular processes can be segregated and organized, across a broad range of biological systems (26–28). The commonality of pyrenoid and carboxysome function (29) despite their disparate evolutionary histories (6), suggests a convergence of function driven by Rubisco condensation. In addition, dependency of functional CCMs on their pyrenoids or carboxysomes (30, 31) has led to the speculation that the evolution of Rubisco organization into membraneless organelles likely preceded systems which enabled elevated cellular HCO₃⁻ (14), raising the possibility that Rubisco condensation and encapsulation may have been the first steps in modern aquatic CCM evolution.We consider here that, in a primordial model system without active HCO₃⁻ accumulation, co-condensation of Rubisco and CA enzymes is beneficial for the elevation of internal CO₂ because Rubisco carboxylation produces a net of two protons for every reaction turnover (SI Appendix, Fig. S1; 32, 33). These protons can be used within the condensate to convert HCO₃⁻ to CO₂, with pH lowered and CO₂ elevated as a result of restricted outward diffusion due to the high concentration of protein in the condensate and surrounding cell matrix acting as a barrier to diffusion. We propose that proton release within a primordial Rubisco condensate enabled the evolution of carboxysomes with enhanced carboxylation rates, prior to advancements which enabled cellular HCO₃⁻ accumulation.     

Development of a method for assessing non-targeted radiation damage in an artificial 3D human skin model

Purpose : Radon risks derive from exposure of bronchio-epithelial cells to high-linear energy transfer (LET) α -particles. α -particle exposure can result in bystander effects, where irradiated cells emit signals resulting in damage to nearby unirradiated bystander cells. This can result in non-linear dose-response relations, and inverse dose-rate effects. Domestic radon risk estimates are currently extrapolated from miner data, which are at both higher doses and higher dose-rates, so bystander effects on unhit cells could play a large role in the extrapolation of risks from mines to homes. Therefore, we extend an earlier quantitative mechanistic model of bystander effects to include protracted exposure, with the aim of quantifying the significance of the bystander effect for very prolonged exposures. Materials and methods : A model of high-LET bystander effects, originally developed to analyse oncogenic transformation in vitro, is extended to low dose-rates. The model considers radiation response as a superposition of bystander and linear direct e It attributes bystander effects to a small subpopulation of hypersensitive cells, with the bystander contribution dominating the direct contribution at very low acute doses but saturating as the dose increases. Inverse dose-rate effects are attributed to the replenishment of the hypersensitive subpopulation during prolonged irradiation. Results : The model was fitted to dose- and dose-rate-dependent radon-exposed miner data, suggesting that one directly hit target bronchio-epithelial cell can send bystander signals to about 50 neighbouring target cells. The model suggests that a naïve linear extrapolation of radon miner data to low doses, without accounting for dose-rate, would result in an underestimation of domestic radon risks by about a factor of 4, a value comparable with the empirical estimate applied in the recent BEIR-VI report on radon risk estimation. Conclusions : Bystander effects represent a plausible quantitative and mechanistic explanation of inverse dose-rate effects by high-LET radiation, resulting in non-linear dose-response relations and a complex interplay between the effects of dose and exposure time. The model presented provides a potential mechanistic underpinning for the empirical exposure-time correction factors applied in the recent BEIR-VI for domestic radon risk estimation.