A model of cellular dosimetry for macroscopic tumors in radiopharmaceutical therapy.

PURPOSE: In the radiopharmaceutical therapy approach to the fight against cancer, in particular when it comes to translating laboratory results to the clinical setting, modeling has served as an invaluable tool for guidance and for understanding the processes operating at the cellular level and how these relate to macroscopic observables. Tumor control probability (TCP) is the dosimetric end point quantity of choice which relates to experimental and clinical data: it requires knowledge of individual cellular absorbed doses since it depends on the assessment of the treatment's ability to kill each and every cell. Macroscopic tumors, seen in both clinical and experimental studies, contain too many cells to be modeled individually in Monte Carlo simulation; yet, in particular for low ratios of decays to cells, a cell-based model that does not smooth away statistical considerations associated with low activity is a necessity. The authors present here an adaptation of the simple sphere-based model from which cellular level dosimetry for macroscopic tumors and their end point quantities, such as TCP, may be extrapolated more reliably. METHODS: Ten homogenous spheres representing tumors of different sizes were constructed in GEANT4. The radionuclide 131I was randomly allowed to decay for each model size and for seven different ratios of number of decays to number of cells, N(r): 1000, 500, 200, 100, 50, 20, and 10 decays per cell. The deposited energy was collected in radial bins and divided by the bin mass to obtain the average bin absorbed dose. To simulate a cellular model, the number of cells present in each bin was calculated and an absorbed dose attributed to each cell equal to the bin average absorbed dose with a randomly determined adjustment based on a Gaussian probability distribution with a width equal to the statistical uncertainty consistent with the ratio of decays to cells, i.e., equal to Nr-1/2. From dose volume histograms the surviving fraction of cells, equivalent uniform dose (EUD), and TCP for the different scenarios were calculated. Comparably sized spherical models containing individual spherical cells (15 microm diameter) in hexagonal lattices were constructed, and Monte Carlo simulations were executed for all the same previous scenarios. The dosimetric quantities were calculated and compared to the adjusted simple sphere model results. The model was then applied to the Bortezomib-induced enzyme-targeted radiotherapy (BETR) strategy of targeting Epstein-Barr virus (EBV)-expressing cancers. RESULTS: The TCP values were comparable to within 2% between the adjusted simple sphere and full cellular models. Additionally, models were generated for a nonuniform distribution of activity, and results were compared between the adjusted spherical and cellular models with similar comparability. The TCP values from the experimental macroscopic tumor results were consistent with the experimental observations for BETR-treated 1 g EBV-expressing lymphoma tumors in mice. CONCLUSIONS: The adjusted spherical model presented here provides more accurate TCP values than simple spheres, on par with full cellular Monte Carlo simulations while maintaining the simplicity of the simple sphere model. This model provides a basis for complementing and understanding laboratory and clinical results pertaining to radiopharmaceutical therapy.

Biosafety assessment of probiotics used for human consumption: recommendations from the EU-PROSAFE project

On June 26-27, 2006, 60 academic and industry scientists gathered during the PROSAFE workshop to discuss recommendations on taxonomy, antibiotic resistance, in vitro assessment of virulence and in vivo assessment of safety of probiotics used for human consumption. For identification of lactic acid bacteria (LAB) intended for probiotic use, it was recommended that conventional biochemical methods should be complemented with molecular methods and that these should be performed by an expert lab. Using the newly developed LAB Susceptibility test Medium (LSM), tentative epidemiological cut-off values were proposed. It was recommended that potentially probiotic strains not belonging to the wildtype distributions of relevant antimicrobials should not be developed as future products for human or animal consumption. Furthermore, it was recommended that the use of strains harbouring known and confirmed virulence genes should be avoided. Finally, for in vivo assessment of safety by investigating strain pathogenicity in animal models, the rat endocarditis model appeared to be the most reliable model tested in the PROSAFE project. Moreover, consensus was reached for approving the necessity of a human colonisation study in a randomised placebo-controlled double-blind design; however, further discussions are needed on the details of such as study.

Early-onset Crohn's disease is a risk factor for smaller final height

OBJECTIVES: Growth retardation is a frequent complication of paediatric inflammatory bowel disease (IBD). Only a few studies report the final height of these patients, with controversial results. We compared adult height of patients with paediatric IBD with that of patients with adult-onset disease. METHODS: Height data of 675 women 19-44 years of age and 454 men 23-44 years of age obtained at inclusion in the Swiss IBD cohort study registry were grouped according to the age at diagnosis: (a) prepubertal (men≤13, women≤11 years), (b) pubertal (men 13-22, women 11-18 years) and (c) adult (men>22, women>18 years of age), and compared with each other and with healthy controls. RESULTS: Male patients with prepubertal onset of Crohn's disease (CD) had significantly lower final height (mean 172±6 cm, range 161-182) compared with men with pubertal (179±6 cm, 161-192) or adult (178±7 cm, 162-200) age at onset and the general population (178±7 cm, 142-204). Height z-scores standardized against heights of the normal population were significantly lower in all patients with a prepubertal diagnosis of CD (-0.8±0.9) compared with the other patient groups (-0.1±0.8, P<0.001). Prepubertal onset of CD emerged as a risk factor for reduced final height in patients with prepubertal CD. No difference for final height was found between patients with ulcerative or unclassified IBD diagnosed at prepubertal, pubertal or adult age. CONCLUSION: Prepubertal onset of CD is a risk for lower final height, independent of the initial disease location and the necessity for surgical interventions.

Traitement de l'asthme et de la rhinite durant la grossesse et l'allaitement [Treatment of asthma and rhinitis during pregnancy and breast feeding]

Inhaled therapies are preferred to systemic ones during pregnancy and breast feeding. A real paradox exists however between the necessity to ensure an optimal treatment for pregnant women with asthma, in order to prevent fetal hypoxia, and the precaution linked to any drug prescription during pregnancy. Thus, the use of topical corticosteroids remains the first choice for asthma as well as rhinitis. Inhaled beta2-agonists are also recommended. Systemic corticosteroids may however be prescribed without hesitation when their use is required for asthma treatment. It is also interesting to note that oral second-generation antihistamines are currently allowed during pregnancy and breast feeding. This type of antihistamines is indeed to be preferred to first-generation ones that generate more side-effects and generally are thus not to be prescribed during breast feeding.

A detailed urinary excretion time course study of captan and folpet biomarkers in workers for the estimation of dose, main route-of-entry and most appropriate sampling and analysis strategies

Captan and folpet are two fungicides largely used in agriculture, but biomonitoring data are mostly limited to measurements of captan metabolite concentrations in spot urine samples of workers, which complicate interpretation of results in terms of internal dose estimation, daily variations according to tasks performed, and most plausible routes of exposure. This study aimed at performing repeated biological measurements of exposure to captan and folpet in field workers (i) to better assess internal dose along with main routes-of-entry according to tasks and (ii) to establish most appropriate sampling and analysis strategies. The detailed urinary excretion time courses of specific and non-specific biomarkers of exposure to captan and folpet were established in tree farmers (n = 2) and grape growers (n = 3) over a typical workweek (seven consecutive days), including spraying and harvest activities. The impact of the expression of urinary measurements [excretion rate values adjusted or not for creatinine or cumulative amounts over given time periods (8, 12, and 24 h)] was evaluated. Absorbed doses and main routes-of-entry were then estimated from the 24-h cumulative urinary amounts through the use of a kinetic model. The time courses showed that exposure levels were higher during spraying than harvest activities. Model simulations also suggest a limited absorption in the studied workers and an exposure mostly through the dermal route. It further pointed out the advantage of expressing biomarker values in terms of body weight-adjusted amounts in repeated 24-h urine collections as compared to concentrations or excretion rates in spot samples, without the necessity for creatinine corrections.

L'expérience des grands brûlés de la face : épreuves sociales et travail de reconnaissance

L'épreuve « factuelle » et physique de la brûlure grave des grands brûlés de la face fait l'objet d'une analyse sociologique systématique : alors qu'un accident peut, en quelques secondes, provoquer une véritable rupture biographique, l'acceptation du nouveau statut et la « reconstruction » d'un rapport à soi et aux autres prend beaucoup de temps. Les modalités de cette reconstruction et les tentatives pour retrouver une impossible « apparence normale » dans la vie publique sont ici analysées. Tout en étant attentive aux modalités de l'interaction, la présente étude relève d'une démarche sociologique compréhensive menée à partir d'observations et d'entretiens conduits avec ces personnes, amenant dans le giron de la sociologie une expérience éprouvanteencore peu connue, celle des grands brûlés de la face. Le registre discursif adossé à cette dernière vient compléter certaines représentations véhiculées par les médias, les fictions et qui influent sur la perception et la visibilité de ceux-ci. A l'aune du concept d'épreuve issu de la « sociologie pragmatique », le parcours du grand brûlé peut être examiné en prêtant une attention particulière au moment initial du parcours post¬brûlure : l'accident. La mise en récit de cette première épreuve est révélatrice des tentatives pour le grand brûlé de maintenir un lien entre un avant et un après l'accident. S'ensuit un continuum d'épreuves intervenant dès le moment où les grands brûlés se présentent physiquement face à autrui dans l'espace public suscitant des réactions de gêne et de malaise. Dans le prolongement des travaux d'Erving Goffman, on peut les concevoir comme des motifs d'« inconfort interactionnel ». Cette mise en évidence de l'inconfort interactionnel montre la nécessité de ne pas se limiter à une sociologie de la brûlure grave qui s'attarderait seulement sur les ajustements des interactions. A partir des travaux d'Axel Honneth sur la reconnaissance, il est possible de lire cette gestion des situations d'interaction dans une autre optique, celle qui, pour le grand brûlé, consiste à se préserver du mépris. Ce travail met l'accent sur des habiletés interactionnelles, des compétences qui fonctionnent comme des ressorts et permettent au grand brûlé de gérer des situations susceptibles de conduire au mépris. En s'appuyant sur des situations d'interaction racontées, deux formes de lutte individuelle, de quête de reconnaissance, peuvent être dégagées : d'une part, la « lutte contre » la trop grande visibilité et contre la prégnance de certains préjugés et, d'autre part, la « lutte pour » faire connaître des aspects invisibles ou moins visibles de la brûlure grave. - This thesis analyzes the "factual" and physical ordeal of a severe burn as experienced by victims of severe facial burns. In a few seconds, an accident provokes a biographical rupture and persons involved need time to integrate their new status. This thesis concentrates on the "reconstruction" modes of the relationship with oneself and with others, and on attempts to find an impossible "normal appearance" in public life. While being attentive to the modalities of interaction, the study uses comprehensive sociology based on observations and interviews. This thesis brings into sociology litde known views of those suffering severe facial burns. These views supplement certain media representations that influence perceptions and visibility of the people involved. Applying the concept of test, a key concept of pragmatic sociology, the progression of a severely burned person can be described by focusing on the initial moment: the accident. The recounting of this first challenge reveals the severely burned person's efforts to link the "before" and "after" the accident. A continuum of challenges follows. These tests occur when the severely burned person physically faces others in a public space and when visible discomfort and embarrassment show, reactions which we consider, following Erving Goffman's works, as situations of "interactional discomfort." Emphasis on interactional discomfort shows the necessity of expanding the sociology of severe burns to more than just adjustments to interactions. Based on Axel Honneth's works, we can read the management of interactions from another point of view, in which the severely burned person tries to avoid contempt. This work emphasizes interactional aptitudes, skills that act like rebounding springs, and allow the severely burned person to manage situations that might lead to contempt. Starting with descriptions of interactions, we have determined two forms of individual struggle that appear to be a search for recognition: on one hand, the "struggle against" too much visibility and against the strength of certain prejudices, and, on the other hand, a "struggle for" making known rtain invisible or less visible aspects of a severe burn.

Mechanisms of successful amoxicillin prophylaxis of experimental endocarditis due to Streptococcus intermedius.

Prophylaxis with amoxicillin (40 mg/kg) was studied in rats with aortic valve vegetations. Bacteria on the valves were quantitated early (10 min to 6 hr) and late (three days) after intravenous challenge with tolerant Streptococcus intermedius. Amoxicillin reduced by 40% the number of bacteria per valve 10 min after intravenous challenge with 10(5) S. intermedius (P less than .05) and by 74% the incidence of endocarditis three days thereafter (P less than .0001). Bacterial multiplication started 2 hr after challenge in control rats, whereas bacteria disappeared in 6 hr in amoxicillin-treated rats. Intravenous penicillinase 30 min after challenge abolished successful amoxicillin prophylaxis, a result demonstrating the necessity of prolonged growth inhibition for protection. Growth inhibition for 18 hr (two subsequent amoxicillin doses) was necessary for protection after intravenous challenge with 10(5) S. intermedius. Thus, in the absence of bacterial killing, inhibition of valvular colonization by amoxicillin was not as important a mechanism of endocarditis prophylaxis as was prolonged inhibition of bacterial growth, which allowed adherent bacteria to be cleared from the valves.

Iowa Transportation Laws, HR-234, 1985

Research project HR-234 was sponsored by the Iowa Highway Research Board and the Iowa Department of Transportation. In the preparation of this compilation of highway and street laws of Iowa, an attempt has been made to include those sections of the Code to which reference is frequently required by the Department of Transportation, counties, cities and towns in their conduct of highway and street administration, construction and maintenance. Because of the broad scope of highway and street work and the many interrelated provisions of Iowa law, and in the interests of keeping this volume in a convenient and usable size, some Code provisions which have some bearing on the principal subject were of necessity omitted. The volume has been compiled in loose leaf form with the expectation that periodic updates will keep the reader informed regarding changes in the law and/or new laws. A general index is provided at the end of the text of this volume. Each major topic is divided into relevant subtopics and are accompanied by appropriate Code sections. This publication is offered with the hope and belief that it will prove to be of value and assistance to those concerned with the problems of establishing, maintaining and administering a highway and street system. The reader is cautioned to consult legal counsel on all matters beyond the scope of this text.

Dense Concrete Layer as Top Course of Bridge Deck Construction, HR-502, 1990

The use of deicing salts in this part of the country is a necessity to remove ice from our bridges. The use of these salts has always been a problem since the chloride-ions penetrate the concrete and reach the steel and cause corrosion which eventually cause deterioration of both the steel and concrete. One method used to try to prevent this from happening was to apply a waterproof membrane to the concrete after it was placed. This method did help, but was not cost effective as the longevity of the membrane system was of relatively short duration. For this reason, this research project was initiated. After the original deck was placed a second layer of concrete about 1 1/2" thick was placed on top. Biennial evaluation of the decks included testing for delaminations and steel corrosion. Cores were also obtained for a chloride analysis. Testing and observations showed the two-layer bridge deck to be effective in preventing corrosion. Since the time this project was initiated, epoxy steel has been introduced and is a cost effective way to protect the steel from corrosion.

Induction of human papillomavirus oncogene-specific CD8 T-cell effector responses in the genital mucosa of vaccinated mice.

Cervical cancer, the second leading cause of cancer mortality in women worldwide, results from infection with a subset of human papillomaviruses (HPV), HPV-16 being the most prevalent type. The available prophylactic vaccines are an effective strategy to prevent this cancer in the long term. However, they only target 70-80% of all cervical cancers and cannot control existing HPV infections and associated lesions. Therapeutic vaccines are thus necessary for women who cannot benefit from prophylactic vaccination. Induction of protective immune responses in the genital mucosa (GM) may be crucial for efficacy of HPV therapeutic vaccines. We report here that mice that received a single subcutaneous (s.c.) vaccination of an adjuvanted long synthetic HPV16 E7(1-98) polypeptide showed induction of 100% tumor protection against s.c. TC-1 tumors and that tumor regression was mainly provided by CD8 T cells. In vivo cytotoxic assay revealed high E7-specific cytolytic T lymphocytes activity in spleen and in genital draining lymph nodes (LN), and E7-specific CD8 T cells could be detected in GM by tetramer staining. More importantly, high-avidity E7-specific INF-gamma secreting CD8 T cells were induced not only in blood, spleen and LN but also in GM of vaccinated mice, thus providing evidence that a parenteral vaccination may be sufficient to provide regression of genital tumors. In addition, there was no correlation between the responses measured in blood with those measured in GM, highlighting the necessity and relevance to determine the immune responses in the mucosa where HPV-tumors reside.

Diagnostic et traitement des tumeurs intra-oculaires chez l'enfant [Diagnosis and treatment of intraocular tumors in the child]

PURPOSE: To remind of the absolute necessity for early diagnosis in the presence of ocular signs in children giving rise to possible intraocular tumours. METHOD: Based on our own experience of intraocular tumours in children, together with findings from the literature, diagnostic criteria and methods of treatment are presented. RESULTS: Retinoblastoma is the predominant cause of intraocular tumours in children, representing over 80% of cases under the age of 15 years. Other diseases may give rise to the same initial signs, usually leukocoria, sometimes strabismus, more rarely other atypical signs. Elements taken into account for diagnosis include age, sex, laterality, heredity, size of the globe, clinical aspect of the tumours, presence of calcifications and vitreous seeding. Full fundus examination under general anaesthetic is usually necessary. Biological examination, ultrasonography, computerized tomography and MRI enable an accurate diagnosis to be made in the majority of doubtful cases. The management of retinoblastoma is adapted for each individual case from the wide range of treatments available. Enucleation, radioactive applicators (...), brachytherapy (...), cryo- and photocoagulation represent classical measures. Primary chemotherapy, combined with other treatments such as thermotherapy, has become the treatment of choice in those cases where external beam radiotherapy has been used up to now, or in some instances before enucleation. Enucleation is usually carried out for medullo-epitheliomas, but brachytherapy may offer an alternative. CONCLUSION: Any unexplained ocular sign in children should be considered as a possible retinoblastoma, making an accurate and certain diagnosis imperative. Early treatment may save not only the life but also the vision of patients carrying this highly malignant lesion.

Effects of the relatedness of arbuscular mycorrhizal fungi on associated species ecology

More than 80 % of vascular plants in the world form symbioses with arbuscular mycorrhizal fungi (AMF). AMF supply plants with nutrients such as phosphate and nitrogen, and can also help the plants to take up water. Hence, the symbiosis can greatly influence the growth and the defence of plants. By modifying plant productivity and diversity, AMF are considered as keystone species in ecosystems, playing a role that ultimately affects many food webs. This is why mycorrhizal symbioses have been investigated for several decades by many research groups.¦However, a large part of the scientific research done on AMF symbiosis has focused on the interaction between one plant and one fungus. This situation is far from realistic, as in natural ecosystems, many different fungal strains and species are co-existing and interacting in a belowground network. The main goal of this PhD was to investigate first, the interaction occurring among different co-existing AMF depending on their genetic relatedness and second, the outcome of the interaction and their effects on associated species.¦We found that AMF genetic relatedness partly explains the interaction among AMF, and this was in agreement with theories made for completely different species. Briefly, we demonstrated that AMF isolates of the same species coexisted more easily when they were closely-related, whereas AMF from different species were more in competition in this case of high relatedness. We also demonstrated that coexistence and competition among AMF can mediate plant growth as well as herbivore behaviour, opening new insights in our understanding of AMF effects on ecosystem functioning.¦Overall, the results of the different experiments of this PhD highlight the necessity of using multiple AMF to understand their interactions. Even so, we demonstrated here that simple species richness is not enough to understand these interactions and genetic relatedness among the co-existing AMF is a parameter that must be taken into account.¦-¦Sur Terre, plus de 80 % des plantes vasculaires forment des symbioses avec des champignons endomycorhiziens à arbuscules (CEA). Ces CEA permettent aux plantes d'acquérir plus facilement des nutriments tels que des phosphates, des nitrates, ou simplement de l'eau. Ainsi, cette symbiose peut avoir un effet important à la fois sur la croissance mais aussi sur la défense des plantes. En modulant la productivité et la diversité des plantes, les CEA sont donc des espèces clefs dans l'écosystème. Leur présence peut avoir des répercussions sur l'ensemble des réseaux trophiques. C'est pourquoi de nombreuses équipes de recherches étudient ces symbioses mycorhizienes depuis plusieurs décennies.¦La plupart des études concernant ces symbioses se sont focalisées sur l'action d'une espèce de CEA sur une espèce de plante. Malheureusement, cette situation ne correspond pas à ce que l'on peut retrouver dans la nature, où de nombreuses souches et de nombreuses espèces de CEA coexistent et interagissent dans un réseau mycélien souterrain. Le principal but de cette thèse était d'étudier, premièrement les interactions entre les différent CEA en fonction de leur apparentement génétique, et deuxièmement, d'étudier l'effet de ces interactions fongiques sur l'écologie des espèces associées.¦Au cours des différentes expériences de cette thèse, nous avons démontré que l'apparentement génétique entre les CEA expliquait une part non négligeable de leurs interactions. En résumé, plus l'apparentement génétique entre des souches de CEA d'une même espèce sera grand, plus ces souches seront capables de coexister. En revanche, s'il s'agit d'espèces différentes de CEA, plus elles seront apparentées, plus la compétition sera grande entre elles. Nous avons également démontré que la coexistence et la compétition entre différents CEA peut modifier à la fois la croissance des plantes mais aussi le comportement de leur prédateurs, ce qui ouvre de nouvelles perspectives sur notre compréhension des effets des CEA dans le fonctionnement des écosystèmes.¦Globalement, les résultats de nos différentes expériences mettent en évidence la nécessité d'utiliser plusieurs souches ou espèces de CEA pour mieux comprendre leurs interactions. Quand bien même, nos expériences démontrent que le simple recensement du nombre d'espèces de CEA n'est pas suffisant pour comprendre les interactions et que l'apparentement génétique des CEA coexistants est un paramètre qui doit être pris en compte.

Madrid 2020, ahora o nunca

Aquest treball té la voluntat de ser un reportatge d’investigació sobre la cursa olímpica de Madrid, des de la candidatura de 2012 fins la de 2020. Els defensors dels Jocs Olímpics a la capital espanyola justifiquen el seu tercer intent consecutiu en el fet de tenir el 80% de les infraestructures necessàries construïdes. En canvi, l’oposició ha trobat en la crisi econòmica el millor motiu per posicionar-se en contra de la celebració dels JJOO.Hem realitzat una sèrie de 15 entrevistes amb tota mena d’experts i personalitats de l’àmbit, intentant albergar sempre tots els possible punts de vista que hagin sorgit al respecte. El resultat ha sigut un article de llarga extensió que fa un repàs a tota la història olímpica de Madrid fins a dia d’avui i intenta interpretar tots els esdeveniments ocorreguts fins ara.

Veure Àfrica a través de la mirada de Riszard Kapuściʼnski

El profund i humaníssim interès i la defensa que va exercir Ryszard Kapuściński de la identitat cultural africana constitueix un model a seguir sobre la construcció i el tractament dels “altres” en els textos periodístics. El present treball analitza la vida i la obra del corresponsal polonès per tal de plantejar qüestions com l’etnocentrisme del discurs dels mitjans de comunicació, la importància d’un tractament de subjecte de les fonts, la identitat cultural o la comunicació intercultural. A través dels objectius amb els quals Kapuściński definia el periodisme –“traductor de cultures” i “advocat d’Àfrica”- i la manera com exercia la professió de corresponsal es planteja quina és la visió i la mirada que Occident i el periodisme tenen de les altres cultures –establint com a context la civilització africana en el procés de descolonització del continent- i la necessitat d’una pràctica periodística respectuosa amb la diversitat cultural.

Traducción comentada del ámbito biomédico:«La integración de los genomas»

El presente trabajo consiste en la traducción comentada de un artículo científico. Nuestros objetivos son reflexionar sobre las características y problemas de la traducción especializada, analizar las estrategias y las soluciones propuestas, y producir un texto meta ‘adecuado’ teniendo en cuenta la tipología textual y el ámbito al que pertenece.