[Proper lighting for color vision testing: The TRUE COLOR LED lamp - an innovation in this field]. / Bien éclairer les tests de vision des couleurs, la lampe TRUE COLOR LED : une innovation dans ce domaine.

Given the latest trend in light sources, and in particular, the widespread use of LED lamps, we began to rethink the old lighting standards for colour vision testing. We (J. Leid) therefore conceived a new, easy to use, calibrated lamp with a specific ergonomic design, emitting light with a spectrum close to that of the standard D65, and perfectly adapted to pigmentary colour vision tests. A prototype conforming to a strict set of specifications in terms of quality and quantity of light, as well as ergonomics, was tested against a Macbeth lamp and fluorescent lighting, on controls and patients with congenital and acquired dyschromatopsia. Tests performed using our new lighting reveal, at a minimum, the same types of dyschromatopsia as the ones found with the old devices, and, in some cases, led to a more precise diagnosis, which we confirmed using an anomaloscope. These results demonstrate that an appropriate LED lamp permits perfect colour vision testing and appears superior to prior technology. The objective of the True Color LED Lamp is to offer practitioners a modern, energy-efficient, maintenance-free, compact, effective technological tool with specific ergonomics and a colour spectrum that provides optimal lighting for pigmentary colour vision testing, coupled with a double level illumination, which constitutes a favourable replacement for older devices which are no longer available or insufficiently calibrated.

Mycobacterium tuberculosis exposure of livestock in a German dairy farm: implications for intra vitam diagnosis of bovine tuberculosis in an officially tuberculosis-free country.

Germany has been an officially bovine tuberculosis (bTB)-free (OTF) country since 1996. Gradually rising numbers of bTB herd incidents due to Mycobacterium bovis and M. caprae in North-Western and Southern Germany during the last few years prompted the competent authorities to conduct a nationwide bTB survey in 2013/2014. This led to the detection of a dairy herd in which as many as 55 cattle reacted positively to consecutive intra vitam testing. Test-positive animals lacked visible lesions indicative of bTB at necropsy. Extensive mycobacterial culturing as well as molecular testing of samples from 11 tissues for members of the M. tuberculosis complex (MTC) yielded negative results throughout. However, caseous lymphadenitis of Ln. mandibularis accessorius was observed during meat inspection of a fattening pig from the same farm at regular slaughter at that time. Respective tissue samples tested MTC positive by polymerase chain reaction, and M. tuberculosis T1 family were identified by spoligotyping. Four human reactors within the farmer's family were also found to be immunoreactive. As exposure of livestock to M. tuberculosis is not generally considered, its impact may result in regulatory and practical difficulties when using protocols designed to detect classical bTB, particularly in OTF countries.

Nutritional regulation of the anabolic fate of amino acids within the liver in mammals: concepts arising from in vivo studies.

At the crossroad between nutrient supply and requirements, the liver plays a central role in partitioning nitrogenous nutrients among tissues. The present review examines the utilisation of amino acids (AA) within the liver in various physiopathological states in mammals and how the fates of AA are regulated. AA uptake by the liver is generally driven by the net portal appearance of AA. This coordination is lost when demands by peripheral tissues is important (rapid growth or lactation), or when certain metabolic pathways within the liver become a priority (synthesis of acute-phase proteins). Data obtained in various species have shown that oxidation of AA and export protein synthesis usually responds to nutrient supply. Gluconeogenesis from AA is less dependent on hepatic delivery and the nature of nutrients supplied, and hormones like insulin are involved in the regulatory processes. Gluconeogenesis is regulated by nutritional factors very differently between mammals (glucose absorbed from the diet is important in single-stomached animals, while in carnivores, glucose from endogenous origin is key). The underlying mechanisms explaining how the liver adapts its AA utilisation to the body requirements are complex. The highly adaptable hepatic metabolism must be capable to deal with the various nutritional/physiological challenges that mammals have to face to maintain homeostasis. Whereas the liver responds generally to nutritional parameters in various physiological states occurring throughout life, other complex signalling pathways at systemic and tissue level (hormones, cytokines, nutrients, etc.) are involved additionally in specific physiological/nutritional states to prioritise certain metabolic pathways (pathological states or when nutritional requirements are uncovered).

Experimental study of nuclear fragmentation of 200 and 400 MeV/u (12)C ions in water for applications in particle therapy.

Carbon ion beams in the energy range of about 100-450 MeV/u offer excellent conditions for tumour therapy, in particular for the treatment of deep-seated radio-resistant tumours. Their depth-dose distribution is characterized by a low dose in the entrance channel, small lateral beam spread and an elevated biological effectiveness in the Bragg peak region. In comparison to protons the radiation field of heavier ions stopping in tissue is however more complex due to nuclear fragmentation reactions occurring along their stopping path. This results in an attenuation of the primary beam flux and a build-up of lower-Z fragments with longer ranges causing the characteristic dose tail beyond the Bragg peak. In the present work the characteristics of secondary charged particles at various depths of water were investigated experimentally using (12)C ion beams of 200 and 400 MeV/u delivered by the heavy-ion synchrotron SIS-18 at GSI Darmstadt. The nuclear charge Zf of secondary fragments was identified by combining energy loss and time-of-flight (TOF) measurements. Energy spectra and yields were recorded at lab angles of 0° - 10° and at seven different water depths corresponding to the entrance channel, the Bragg peak region and the tail of the Bragg curve.

A prospective, randomized, controlled trial of autologous haematopoietic stem cell transplantation for aggressive multiple sclerosis: a position paper.

BACKGROUND: Haematopoietic stem cell transplantation (HSCT) has been tried in the last 15 years as a therapeutic option in patients with poor-prognosis autoimmune disease who do not respond to conventional treatments. Worldwide, more than 600 patients with multiple sclerosis (MS) have been treated with HSCT, most of them having been recruited in small, single-centre, phase 1-2 uncontrolled trials. Clinical and magnetic resonance imaging outcomes from case series reports or Registry-based analyses suggest that a major response is achieved in most patients; quality and duration of response are better in patients transplanted during the relapsing-remitting phase than in those in the secondary progressive stage. OBJECTIVES: An interdisciplinary group of neurologists and haematologists has been formed, following two international meetings supported by the European and American Blood and Marrow Transplantation Societies, for the purpose of discussing a controlled clinical trial, to be designed within the new scenarios of evolving MS treatments. CONCLUSIONS: Objectives of the trial, patient selection, transplant technology and outcome assessment were extensively discussed. The outcome of this process is summarized in the present paper, with the goal of establishing the background and advancing the development of a prospective, randomized, controlled multicentre trial to assess the clinical efficacy of HSCT for the treatment of highly active MS.

Autologous hematopoietic cell transplantation following high-dose immunosuppressive therapy for advanced multiple sclerosis: long-term results.

The purpose of the study was to determine the long-term safety and effectiveness of high-dose immunosuppressive therapy (HDIT) followed by autologous hematopoietic cell transplantation (AHCT) in advanced multiple sclerosis (MS). TBI, CY and antithymocyte globulin were followed by transplantation of autologous, CD34-selected PBSCs. Neurological examinations, brain magnetic resonance imaging and cerebrospinal fluid (CSF) for oligoclonal bands (OCB) were serially evaluated. Patients (n=26, mean Expanded Disability Status Scale (EDSS)=7.0, 17 secondary progressive, 8 primary progressive, 1 relapsing/remitting) were followed for a median of 48 months after HDIT followed by AHCT. The 72-month probability of worsening ≥1.0 EDSS point was 0.52 (95% confidence interval, 0.30-0.75). Five patients had an EDSS at baseline of ≤6.0; four of them had not failed treatment at last study visit. OCB in CSF persisted with minor changes in the banding pattern. Four new or enhancing lesions were seen on MRI, all within 13 months of treatment. In this population with high baseline EDSS, a significant proportion of patients with advanced MS remained stable for as long as 7 years after transplant. Non-inflammatory events may have contributed to neurological worsening after treatment. HDIT/AHCT may be more effective in patients with less advanced relapsing/remitting MS.

Radioprotection (un)awareness in cardiologists, and how to improve it.

In 2010 the International Atomic Energy Agency launched the "3 A's campaign": Audit, Appropriateness and Awareness for radiological justification, which is an effective tool for cancer prevention. Cardiologists prescribe the majority of radiological testing, but their awareness of doses and risks of ionizing cardiac imaging test is low. To assess radioprotection awareness of prescribing and practicing physicians (mainly cardiologists) before and after a radioprotection course. We held a 1-day 6-h primer of radioprotection for a limited number (20-35) of physicians. The course offered 8 continuing education credits from the Italian Health Ministry and was held 9 times over 3 years. We had 425 attendees, but full data sets (with complete questionnaires) were available for 403 physicians (55% women, age 45 ± 6 years), including 55% cardiologists, 40% general practitioners, 5% others (mainly cardiology fellows). For each attendee, a radiological awareness score was obtained before and after the course, with a survey containing 10 multiple-choice questions (5 answers) on radioprotection basics (doses of common examinations in multiples of chest x-rays; associated cancer risk, etc.). Each answer was scored from 0 ("don't know"), 1 ("strongly disagree") to 4 ("strongly agree"). The radiological awareness score of the 403 attendees improved from 31 ± 3 (before) to 37 ± 2 (after training, P < 0.001 vs. pre-training). As an example, before training, 25% of attendees believed that radiation-induced cancer risk disappears after 6 months (10% of respondents), 12 months (8%) or 5 years (7%), whereas 75% (becoming 98% after training) correctly estimated that radiological damage is cumulative over one's lifetime. Awareness of radiological doses and risks, albeit essential for risk-benefit assessment of radiological testing, is suboptimal among cardiologists, but can dramatically improve with a limited teaching effort through targeted training.

Calculation and experimental verification of the RBE-weighted dose for scanned ion beams in the presence of target motion.

We present an algorithm suitable for the calculation of the RBE-weighted dose for moving targets with a scanned particle beam. For verification of the algorithm, we conducted a series of cell survival measurements that were compared to the calculations. Calculation of the relative biological effectiveness (RBE) with respect to tumor motion was included in the treatment planning procedure, in order to fully assess its impact on treatment delivery with a scanned ion beam. We implemented an algorithm into our treatment planning software TRiP4D which allows determination of the RBE including its dependence on target tissue, absorbed dose, energy and particle spectra in the presence of organ motion. The calculations are based on time resolved computed tomography (4D-CT) and the corresponding deformation maps. The principal of the algorithm is illustrated in in silico simulations that provide a detailed view of the different compositions of the energy and particle spectra at different target positions and their consequence on the resulting RBE. The calculations were experimentally verified with several cell survival measurements using a dynamic phantom and a scanned carbon ion beam. The basic functionality of the new dose calculation algorithm has been successfully tested in in silico simulations. The algorithm has been verified by comparing its predictions to cell survival measurements. Four experiments showed in total a mean difference (standard deviation) of -1.7% (6.3%) relative to the target dose of 9 Gy (RBE). The treatment planning software TRiP is now capable to calculate the patient relevant RBE-weighted dose in the presence of target motion and was verified against cell survival measurements.

Physiologic action of glucagon on liver glucose metabolism.

Glucagon is a primary regulator of hepatic glucose production (HGP) in vivo during fasting, exercise and hypoglycaemia. Glucagon also plays a role in limiting hepatic glucose uptake and producing the hyperglycaemic phenotype associated with insulin deficiency and insulin resistance. In response to a physiological rise in glucagon, HGP is rapidly stimulated. This increase in HGP is entirely attributable to an enhancement of glycogenolysis, with little to no acute effect on gluconeogenesis. This dramatic rise in glycogenolysis in response to hyperglucagonemia wanes with time. A component of this waning effect is known to be independent of hyperglycemia, though the molecular basis for this tachyphylaxis is not fully understood. In the overnight fasted state, the presence of basal glucagon secretion is essential in countering the suppressive effects of basal insulin, resulting in the maintenance of appropriate levels of glycogenolysis, fasting HGP and blood glucose. The enhancement of glycogenolysis in response to elevated glucagon is critical in the life-preserving counterregulatory response to hypoglycaemia, as well as a key factor in providing adequate circulating glucose for working muscle during exercise. Finally, glucagon has a key role in promoting the catabolic consequences associated with states of deficient insulin action, which supports the therapeutic potential in developing glucagon receptor antagonists or inhibitors of glucagon secretion.

Adaptations of hepatic amino acid uptake and net utilisation contributes to nitrogen economy or waste in lambs fed nitrogen- or energy-deficient diets.

We investigated the effect of relative changes in dietary nitrogen (N) and energy supply and the subsequent variations in net portal appearance (NPA) of nitrogenous and energy nutrients on the net amino acid (AA) uptake by the liver and net N supply to the peripheral tissues. Six lambs were catheterised across the splanchnic tissues and received, in a replicated Latin square, one of three dietary treatments. The diets were formulated to either match the requirements of N and energy (C), or supply only 0.8 of the N requirement (LN) or 0.8 of the energy requirement (LE). Net fluxes of AA and urea-N were measured across the portal-drained viscera, and estimation of arterial hepatic flow allowed the estimation of hepatic fluxes. Catheters were implanted into the portal and hepatic veins as well as in the abdominal aorta for the measurement of AA fluxes. Animals fed the LN diet showed more efficient N retention (0.59 of digested N) than did the C and LE diet (0.50 and 0.33, respectively; P < 0.001). The NPA of total AA-N for the LN diet was only 0.60 of the value measured for the control (C) diet (P < 0.01). Despite this, the total estimated AA-N net splanchnic fluxes were not significantly different across the three diets (3.3, 1.9 and 2.6 g total AA-N/day for C, LN and LE, respectively, P = 0.52). Thus, different metabolic regulations must have taken place across the liver between the three experimental diets. A combination of decreased net uptake of total AA-N by the liver of animals in the LN diet (0.61 of the C diet; P = 0.002) and reduced urinary urea-N production (0.52 of the C diet; P = 0.001) spared AA from catabolism in the LN diet relative to the other two diets. For the LE diet, the urinary urea-N output was 1.3 times the value of the C diet (P = 0.01). This may relate to an increased catabolism of AA by the muscle and/or, to a lesser extent, to an increased utilisation of AA for gluconeogenesis in the liver. These effects may explain the reduced whole body protein retention observed with the LE diet.

Dietary nitrogen-to-energy ratio alters amino acid partition in the whole body and among the splanchnic tissues of growing rams.

The aim of this study was to determine whether subtle changes in the energy-to-N ratio of medium-concentrate diets alters hepatic export protein synthesis and the partition of protein metabolism in the whole body of growing rams. Rams (n = 6; 41.5 +/- 2.6 kg of BW) were fitted with catheters for measurement of Leu and Phe tracer kinetics across the portal drained-viscera (PDV) and liver. Rams were assigned to receive 3 dietary treatments according to a duplicated Latin square design. Animals received forage-concentrate-based diets that were balanced for ME and available N (CON), 20% imbalanced (reduced) in available N (LN), or 20% imbalanced in ME (LE). After 15 d on each experimental diet, [ring-(2)H(5)]Phe (4.3 micromolxkg(-1)xh(-1)) and [1-(13)C]Leu (8.6 micromolxkg(-1)xh(-1)) were continuously infused into the vena cava for 10 h and, over the last 7 h of infusion, matched sets of blood samples were taken. Daily BW gain was less (P < 0.05) for the LE (0.191 kgxd(-1)) diet compared with CON (0.265 kg/d) and LN (258 kgxd(-1)) diets. Compared with CON, whole body irreversible loss rate (ILR) of Leu and Phe was less (10 to 16%, P < 0.02) for LN and LE diets, which for Leu reflected its decreased (20 to 24%, P < 0.05) net PDV absorption. The decreased whole body ILR is due to a decreased PDV ILR in both diets with a relative contribution of the PDV to the whole body ILR decreased (P < 0.05) in the LN (27%) diet compared with the CON (36%) and LE (33%) diets. This decreased PDV ILR was associated with a decreased net Leu PDV uptake in LN and LE diets (-25 and -20%, respectively; P < 0.05). Conversely, the decreased whole body Phe ILR is explained by a decreased hepatic ILR (and contribution to the whole body ILR) and was associated with a decreased net hepatic uptake of Phe in LN (-25%) and LE (-20%) diets compared with CON (P = 0.03). The fractional and absolute synthesis rates of total proteins and albumin were decreased by 10% in LE animals (P < 0.05), whereas they were not affected by the LN diet. These results suggest a specific decreased utilization of Leu at the PDV due to a specific sparing mechanism in the LN diet. Conversely, a decreased Phe utilization occurred in the liver in both diets (due to a decreased export protein synthesis and a probable decreased oxidation in LE diet, whereas only oxidation is reduced in LN diet).

Nitrogen- and energy-imbalanced diets affect hepatic protein synthesis and gluconeogenesis differently in growing lambs.

The aim of this study was to assess the metabolic fate of AA (endogenous or export protein synthesis, gluconeogenesis, or oxidation) after an imbalanced supply of energy and N in the diet of growing lambs. Eighteen INRA 401 lambs (3 mo old, 29.7 +/- 0.45 kg of BW) were fed 3 experimental diets, one providing a N and energy supply according to recommended allowances (control), one with 23% less N supply relative to energy (LN), and one with 19% less ME supply relative to N (LE). Animals were assigned to 6 blocks of 3, with each animal receiving 1 of the 3 diets, and the animals from each block were slaughtered on the same day. Liver slices from these lambs were incubated in a minimum salt medium (Krebs-Henseleit) containing physiological concentrations of propionate and AA as energy and N sources, similarly across all 3 treatments. Protein synthesis (endogenous and export) using [U-(14)C]valine and [(35)S]methionine, gluconeogenesis from [1-(14)C]propionate and [U-(14)C]alanine, and oxidation were measured. A relative sparing of AA at the liver level was observed with the LN diet because of reduced urinary N (-42%, LN vs. control, P < 0.001). The AA were also directed toward anabolic purposes in the LN diet via an increased endogenous and total export protein synthesis (+51%, LN vs. control, P = 0.01; also observed for fibrinogen synthesis, but not for albumin or transferrin) associated with a tendency for increased gluconeogenesis from alanine (+58%, LN vs. LE, P = 0.08). On the other hand, the LE diet resulted in a marked loss of N in urine (+24%, LE vs. control, P < 0.05), but no notable effect of the LE diet was demonstrated for protein synthesis or gluconeogenesis ex vivo. These data demonstrate a more efficient utilization of AA for anabolic purposes in the lambs fed LN, probably via an activation of some AA transport systems, to address the shortage of nitrogenous nutrients in the LN diet. By contrast, no such adaptation occurred in the LE lambs, probably because the regulatory mechanisms that prevailed in this case were the nutrient supply or hormones, which were not altered in our ex vivo experimental model.

Prevalence of sleep problems in individuals with multiple sclerosis.

BACKGROUND: Sleep disturbance in multiple sclerosis has received little research attention despite the potential influence it may have on disease impact. OBJECTIVE: To estimate the prevalence of sleep disorders in a large community sample of individuals with multiple sclerosis. METHODS: A cross-sectional self-report survey of 1063 persons with multiple sclerosis. Sleep was assessed using the Women's Health Initiative Insomnia Rating Scale and Medical Outcomes Study Sleep measure. RESULTS: The prevalence of sleep problems in multiple sclerosis is significantly higher than in the general population or other chronic diseases and may affect women with multiple sclerosis more than men. CONCLUSION: Sleep disturbance should routinely be evaluated in patients with multiple sclerosis and new interventions developed.

Setting the agenda for multiple sclerosis rehabilitation research.

BACKGROUND: Recognizing the need for more evidence-based multiple sclerosis (MS) rehabilitation, in the mid-2000s several initiatives were undertaken to explore why there had been a paucity of such research and to determine strategies to reverse this pattern. EXPERT-OPINION-PAPER: In 2004 the National Multiple Sclerosis Society (NMSS) convened an expert opinion panel, reviewed evidence-based MS rehabilitation research, and published the paper on the web. It was concluded that much of the MS rehabilitation carried out was based on experience, with little research backing it up. INCREASING THE QUALITY AND QUANTITY OF MS REHABILITATION RESEARCH: Largely as a result of the conclusions of the Expert-Opinion-Paper, the NMSS convened a conference of a large number of MS and rehabilitation experts in New York in May, 2005. This conference made many recommendations of ways to increase the quantity and quality of MS research. STATE OF THE SCIENCE CONFERENCE: In September, 2006, a follow-up conference was held in Washington, D.C... This conference, primarily sponsored by the University of Washington Multiple Sclerosis Rehabilitation Research and Training Center (MS RRTC), focused on some of the under-studied "hidden" disabilities present in persons with MS. This paper discusses the details and recommendations of these latter two conferences.

Agricultural pollutant penetration and steady state in thick aquifers.

The leakage of pollutants from agricultural lands to aquifers has increased greatly, driven by increasing fertilizer and pesticide use. Because this increase is recent, ground water pollutant concentrations, loads, and exports may also be increasing as pollutants penetrate more deeply into aquifers. We established in an aquifer profile a ground water recharge and pollutant leakage chronology in an agricultural landscape where 30 m of till blankets a 57-m thick sandstone aquifer. Pollutant concentrations increased from older ground water (1963) at the aquifer base to younger ground water (1985) at its top, a signal of increasing pollutant leakage. Nitrate-N increased from 0.9 to 13.2 mg/L, implying that leakage increased from 1.9 to 16.5 kg/ha/year. Nitrate load and export could increase from 130% to 230% before reaching a steady state in 20 to 40 years. Chloride increases were similar. Pesticide residues alachlor ethane sulfonic acid (ESA), metolachlor ESA, and atrazine residues partially penetrated the aquifer profile. Their concentration-age-date patterns exhibited an initial increase and then a leveling corresponding to the timing of product adoption and leveling of demand. Unlike NO(3), projecting pesticide residue steady states is complicated by the phasing in and out of pesticide products over time; for example, neither alachlor nor atrazine is currently used in the area, and newer products, which have not had time to transit to the aquifer, have been adopted. The circumstances that resulted in the lack of a pollutant steady state are not rare; thus, the lack of steady states in agricultural region aquifers may not be uncommon.

Antidepressant use in multiple sclerosis: epidemiologic study of a large community sample.

Depressive symptoms and disorders among individuals with multiple sclerosis (MS) are more common when compared to other chronic illnesses and the general population, but relatively little is known about the use of antidepressant medication in this population. In this cross-sectional study of 542 community-dwelling adults with MS, we examined the prevalence of antidepressant use and employed multivariate logistic regression modeling to identify factors significantly associated with antidepressant use. Thirty-five percent of the sample reported currently using at least one antidepressant medication. Gender, marital status, insurance status, fatigue, and use of disease modifying therapies were all significantly associated with antidepressant use. Just over half of the sample endorsed a clinically significant level of depressive symptoms, and the majority of this group was not currently taking an antidepressant. Conversely, 41% of those with depressive symptoms reported taking at least one antidepressant medication. More research is needed to better understand why people with MS and depressive symptoms use or do not use antidepressant medications and to further explore the possibility of an under-treatment of depressive disorder in this population. Rigorous studies testing the feasibility, acceptability, and efficacy of currently available therapies for depression in the MS population should also be conducted.

Experimental and theoretical study of the neutron dose produced by carbon ion therapy beams.

High-energy (12)C ions offer favourable conditions for the treatment of deep-seated local tumours. Several facilities for the heavy ion therapy are planned or under construction, for example the new clinical ion-therapy unit HIT at the Radiological University Clinics in Heidelberg. In order to improve existing treatment planning models, it is essential to evaluate the secondary fragment production and to include these contributions to the therapy dose with higher accuracy. Secondary neutrons are most abundantly produced in the reactions between (12)C beams and tissues. The dose contribution to tissues by a neutron is fairly small compared with the projectile and the other charged fragments due to no ionisation and the small reaction cross-sections; however, it distributes in a considerably wider region beyond the bragg-peak because of the strong penetrability. Systematic data on energy spectra and doses of secondary neutrons produced by (12)C beams using water targets of different thicknesses for various detection angles have therefore been measured in this study at GSI Darmstadt.

The scope and nature of pain in persons with multiple sclerosis.

Much remains unknown about the scope, nature, and impact of pain on the lives of persons with multiple sclerosis (MS). In the present study, 180 community dwelling adults with MS completed a postal survey that included demographic measures, MS disease measures, and several standardized measures of pain, including pain intensity, variability, location, and pain-related interference. Some 66% of the sample reported pain, 25% of whom reported severe pain. Persons with pain reported an average of 6.6 distinct pain sites. Using the Brief Pain Inventory Interference Scale, the average level of overall pain interference was 3.33 (0-10 scale) in the group reporting pain. The highest levels of pain interference were reported for sleep, recreational activities, and work in and outside the home. Persons with pain were more likely to report greater MS disease severity, poorer psychological functioning, and poorer health than persons with MS but not pain. Persons with pain were also less likely to be employed. These findings are consistent with previous research that shows that pain is common in MS, that it is severe in a substantial subset of these individuals and has the potential to negatively impact physical and psychosocial functioning over and above the effects of MS itself.

The physical and radiobiological basis of the local effect model: a response to the commentary by R. Katz.

The physical and biological basis of our model to calculate the biological effects of charged particles, termed the local effect model (LEM), has recently been questioned in a commentary by R. Katz. Major objections were related to the definition of the target size and the use of the term cross section. Here we show that the objections raised against our approach are unjustified and are largely based on serious misunderstandings of the conceptual basis of the local effect model. Furthermore, we show that the approach developed by Katz and coworkers itself suffers from exactly those deficiencies for which Katz criticizes our model. The essential conceptual differences between the two models are discussed by means of some illustrative examples, based on a comparison with experimental data. For these examples, the predictions of the local effect model are fully consistent with the experimental data. In contrast, e.g. for very heavy ions, there are significant discrepancies observed for the Katz approach. These discrepancies can be attributed to the inadequate definition of the target size in this model. Experimental data are thus clearly in favor of the definition of the target as used in the local effect model. Agreement with experimental data is achieved for protons within the Katz approach but at the cost of questionable approximations in combination with the violation of the fundamental physical principle of energy conservation.