Immune mechanisms underlying the premunition against Plasmodium falciparum malaria

The most unique characteristic of a parasite when it is in its normal host is the ability to make itself tolerated, which clearly indicates that it has sophisticated means to ensure the neutrality of its host. This is true also in the case of Plasmodium falciparum, since after numerous malaria attacks an equilibrium is reached with a chronic stage of infection, characterized by a relatively low parasitemia, and low or no disease (Sergent & Parrot 1935). We shall briefly review the main characteristics of this state of "premunition", and present data suggesting that the underlying mechanisms of defense rely on the cooperation between cell and antibodies, leading to an antibody dependent cellular inhibition of the intra-erythrocytic growth of the parasite.

Estimation of the radiation risks in diagnostic procedures to populations and patients

Since 1895, when X-rays were discovered, ionizing radiation became part of our life. Its use in medicine has brought significant health benefits to the population globally. The benefit of any diagnostic procedure is to reduce the uncertainty about the patient's health. However, there are potential detrimental effects of radiation exposure. Therefore, radiation protection authorities have become strict regarding the control of radiation risks.¦There are various situations where the radiation risk needs to be evaluated. International authority bodies point to the increasing number of radiologic procedures and recommend population surveys. These surveys provide valuable data to public health authorities which helps them to prioritize and focus on patient groups in the population that are most highly exposed. On the other hand, physicians need to be aware of radiation risks from diagnostic procedures in order to justify and optimize the procedure and inform the patient.¦The aim of this work was to examine the different aspects of radiation protection and investigate a new method to estimate patient radiation risks.¦The first part of this work concerned radiation risk assessment from the regulatory authority point of view. To do so, a population dose survey was performed to evaluate the annual population exposure. This survey determined the contribution of different imaging modalities to the total collective dose as well as the annual effective dose per caput. It was revealed that although interventional procedures are not so frequent, they significantly contribute to the collective dose. Among the main results of this work, it was shown that interventional cardiological procedures are dose-intensive and therefore more attention should be paid to optimize the exposure.¦The second part of the project was related to the patient and physician oriented risk assessment. In this part, interventional cardiology procedures were studied by means of Monte Carlo simulations. The organ radiation doses as well as effective doses were estimated. Cancer incidence risks for different organs were calculated for different sex and age-at-exposure using the lifetime attributable risks provided by the Biological Effects of Ionizing Radiations Report VII. Advantages and disadvantages of the latter results were examined as an alternative method to estimate radiation risks. The results show that this method is the most accurate, currently available, to estimate radiation risks. The conclusions of this work may guide future studies in the field of radiation protection in medicine.¦-¦Depuis la découverte des rayons X en 1895, ce type de rayonnement a joué un rôle important dans de nombreux domaines. Son utilisation en médecine a bénéficié à la population mondiale puisque l'avantage d'un examen diagnostique est de réduire les incertitudes sur l'état de santé du patient. Cependant, leur utilisation peut conduire à l'apparition de cancers radio-induits. Par conséquent, les autorités sanitaires sont strictes quant au contrôle du risque radiologique.¦Le risque lié aux radiations doit être estimé dans différentes situations pratiques, dont l'utilisation médicale des rayons X. Les autorités internationales de radioprotection indiquent que le nombre d'examens et de procédures radiologiques augmente et elles recommandent des enquêtes visant à déterminer les doses de radiation délivrées à la population. Ces enquêtes assurent que les groupes de patients les plus à risque soient prioritaires. D'un autre côté, les médecins ont également besoin de connaître le risque lié aux radiations afin de justifier et optimiser les procédures et informer les patients.¦Le présent travail a pour objectif d'examiner les différents aspects de la radioprotection et de proposer une manière efficace pour estimer le risque radiologique au patient.¦Premièrement, le risque a été évalué du point de vue des autorités sanitaires. Une enquête nationale a été réalisée pour déterminer la contribution des différentes modalités radiologiques et des divers types d'examens à la dose efficace collective due à l'application médicale des rayons X. Bien que les procédures interventionnelles soient rares, elles contribuent de façon significative à la dose délivrée à la population. Parmi les principaux résultats de ce travail, il a été montré que les procédures de cardiologie interventionnelle délivrent des doses élevées et devraient donc être optimisées en priorité.¦La seconde approche concerne l'évaluation du risque du point de vue du patient et du médecin. Dans cette partie, des procédures interventionnelles cardiaques ont été étudiées au moyen de simulations Monte Carlo. La dose délivrée aux organes ainsi que la dose efficace ont été estimées. Les risques de développer des cancers dans plusieurs organes ont été calculés en fonction du sexe et de l'âge en utilisant la méthode établie dans Biological Effects of Ionizing Radiations Report VII. Les avantages et inconvénients de cette nouvelle technique ont été examinés et comparés à ceux de la dose efficace. Les résultats ont montré que cette méthode est la plus précise actuellement disponible pour estimer le risque lié aux radiations. Les conclusions de ce travail pourront guider de futures études dans le domaine de la radioprotection en médicine.

Beyond splitting: observer-rated defense mechanisms in borderline personality disorder

Defense mechanism is a key concept in the psychoanalytic psychopathology of borderline personality disorder (BPD). Theoretical and empirical elaborations on this question are briefly reviewed and discussed with respect to process assessment of defense mechanisms; we put forward observer-rater methodology as an accurate means of assessing unconscious in-session processes. A sample of 25 patients presenting with BPD were interviewed, as were subjects from a matched control group without psychiatric symptoms (n = 25), using a psychodynamic interview paradigm. These interviews were transcribed and rated using the Defense Mechanisms Rating Scales. The results indicate that, compared to controls, patients with BPD used higher percentages of a action, borderline, disavowal, narcissistic, and hysteric defenses, along with lower levels of mature and obsessional defenses. Overall defensive functioning was significantly lower in the patients with BPD, compared to controls. Narcissistic defenses were related with symptom level. These results are discussed in light of previous studies on defensive functioning of BPD and the literature on psychoanalytic psychopathology. These results have several important clinical implications.

Novel mechanisms of immune evasion by Schistosoma mansoni

The interaction of Schistosoma mansoni with its host's immune system is largely affected by multiple specific and non-specific evasion mechanisms employed by the parasite to reduce the host's immune reactivity. Only little is known about these mechanisms on the molecular level. The four molecules described below are intrinsic parasitic proteins recently identified and studied in our laboratory. 1. m28-A 28kDa membrane serine protease. m28 cleaves iC3b and can thus restrict attack by effector cells utilizing complement receptors (especially CR3). Treatment with protease inhibitors potentiates killing of schistosomula by complement plus neutrophils. 2. Smpi56-A 56kDa serine protease inhibitor. Smpi56 binds covalently to m28 and to neutrophil's elastase and blocks their proteolytic activity. 3. P70-A 70kDa C3b binding protein. The postulated activity of P70 includes binding to C3b and blocking of complement activation of the C3 step. 4. SCIP-1-A 94kDa schistosome complement inhibitor. SCIP-1 shows antigenic and functional similarities to the human 18kDa complement inhibitor CD59. Like CD59, SCIP-1 binds to C8 and C9 and blocks formation of the complement membrane attack complex. Antibodies directed to human CD59 bind to schistosomula and potentiate their killing by complement. The structure and function of these four proteins as well as their capacity to induce protection from infection with S. mansoni are under investigation.

Mechanisms of skin adherence and invasion by dermatophytes.

Dermatophytes are keratinophilic fungi that can be pathogenic for humans and animals by infecting the stratum corneum, nails, claws or hair. The first infection step consists of adherence of arthroconidia to the stratum corneum. The mechanisms and the kinetics of adherence have been investigated using different in vitro and ex vivo experimental models, most notably showing the role of a secreted serine protease from Microsporum canis in fungal adherence to feline corneocytes. After germination of the arthroconidia, dermatophytes invade keratinised structures that have to be digested into short peptides and amino acids to be assimilated. Although many proteases, including keratinolytic ones, have been characterised, the understanding of dermatophyte invasion mechanisms remains speculative. To date, research on mechanisms of dermatophyte infection focused mainly on both secreted endoproteases and exoproteases, but their precise role in both fungal adherence and skin invasion should be further explored.

Feasibility and efficacy of subcutaneous amifostine therapy in patients with head and neck cancer treated with curative accelerated concomitant-boost radiation therapy.

OBJECTIVE: To assess the feasibility and efficacy of subcutaneous amifostine therapy in patients with head and neck cancer treated with curative accelerated radiotherapy (RT). DESIGN: Retrospective study. SETTING: University of Lausanne, Lausanne, Switzerland. PATIENTS: Thirty-three consecutive patients (male-female ratio, 4.5; median age, 54 years [age range, 39-76 years]). INTERVENTIONS: Between November 2000 and January 2003, the 33 patients were treated with curative definitive (n = 19) or postoperative (n = 14) RT with (n = 26) or without (n = 7) chemotherapy. All patients received conformal RT. Fractionation schedule consisted of concomitant-boost (Friday afternoon session) accelerated RT using 70 Gy (2 Gy per fraction) in 6 weeks in patients treated with definitive RT and 66 Gy (2 Gy per fraction) in 5 weeks and 3 days in the postoperative setting. Parotid glands received at least 50 Gy in all patients. Amifostine was administered to a total dose of 500 mg subcutaneously, 15 to 30 minutes before morning RT sessions. RESULTS: All patients received their planned treatment (including chemotherapy). Ten patients received the full schedule of amifostine (at least 25 injections), 9 received 20 to 24 doses, 4 received 10 to 19 doses, 5 received 5 to 9 doses, and 5 received fewer than 5 doses. Fifteen patients (45%) did not show any intolerance related to amifostine use. Amifostine therapy was discontinued because of nausea in 11 patients (33%) and hypotension in 6 patients (18%), and 1 patient refused treatment. No grade 3, amifostine-related, cutaneous toxic effects were observed. Radiotherapy-induced grade 3 acute toxic effects included mucositis in 14 patients (42%), erythema in 14 patients (42%), and dysphagia in 13 patients (39%). Late toxic effects included grade 2 or more xerostomia in 17 patients (51%) and fibrosis in 3 patients (9%). Grade 2 or more xerostomia was observed in 8 (42%) of 19 patients receiving 20 injections or more vs 9 (64%) of 14 patients receiving fewer than 20 injections (P = .15). CONCLUSIONS: Subcutaneous amifostine administration in combination with accelerated concomitant-boost RT with or without chemotherapy is feasible. The major adverse effect of subcutaneous administration was nausea despite prophylactic antiemetic medication, and hypotension was observed in only 6 patients (18%).

Mechanisms of postprandial hyperglycemia in liver transplant recipients: comparison of liver transplant patients with kidney transplant patients and healthy controls.

Impaired glucose tolerance or diabetes mellitus are frequent complications after organ transplantation, and are usually attributed to glucocorticoid and immunosuppressive treatments. Liver transplantation results in total hepatic denervation which may also affect glucoregulation. We therefore evaluated postprandial glucose metabolism in a group of patients with liver cirrhosis before and after orthotopic liver transplantation. Seven patients with liver cirrhosis of various etiologies, 6 patients having received a kidney transplant, and 6 healthy subjects were studied. Their glucose metabolism was evaluated in the basal state and over 4 hours after ingestion of a glucose load with 6.6 (2) H glucose dilution analysis. The patients with liver cirrhosis were studied before, and again 4 weeks (range 2-6) and 38 weeks (range 20-76, n=6) after orthotopic liver transplantation. Basal glucose metabolism was similar in liver and kidney transplant recipients. Impaired glucose tolerance was present in both groups, but postprandial hyperglycemia was exaggerated and lasted longer in liver transplant patients. Postprandial insulinemia was lower in liver transplant recipients, while C-peptide concentrations were comparable to those of kidney transplant recipients, indicating increased insulin clearance. Glucose turnover was not altered in both groups of patients during the initial 3 hours after glucose ingestion, but was higher in liver transplant early after transplantation during the fourth hour. Postprandial hyperglycemia remained unchanged in liver transplant recipients 38 weeks after liver transplantation, despite substantial reduction of immunosuppressive and glucocorticoid doses. We conclude that liver transplant recipients have severe postprandial hyperglycemia which can be attributed to insulinopenia (secondary, at least in part, to increased insulin clearance) and a late increased glucose turnover. These changes may be secondary to hepatic denervation.

Mechanisms of agglomeration: Evidence from the location of new manufacturing firms in Spain

El objetivo de esta investigación es aportar evidencia sobre las fuentes de las economías de aglomeración para el caso español. De todas las maneras posibles que se han tomado en la literatura para medir las economías de aglomeración, nosotros lo analizamos a partir de las decisiones de localización de las empresas manufactureras. La literatura reciente ha puesto de relieve que el análisis basado en la disyuntiva localización / urbanización (relaciones dentro de un mismo sector) no es suficiente para entender las economías de aglomeración. Sin embargo, las relaciones entre los diferentes sectores sí resultan significativas al examinar por qué las empresas que pertenecen a diferentes sectores se localizan unas al lado de las otras. Con esto en mente, intentamos explicar que relaciones entre diferentes sectores pueden explicar coaglomeración. Para ello, nos centramos en aquellas relaciones entre sectores definidos a partir de los mecanismos de aglomeración de Marshall, es decir, labor market, input sharing y knowledge spillovers. Trabajamos con el labor market pooling en la medida en que los dos sectores utilizan los mismos trabajadores (clasificación de ocupaciones). Con el segundo mecanismo de Marshall, input sharing, introducimos cómo dos sectores tienen una relación de comprador / vendedor. Por último, nos referimos a dos sectores que utilizan las mismas tecnologías en cuanto a los knowledge spillovers. Con el fin de capturar todos los efectos de los mecanismos de aglomeracion en España, en esta investigación trabajamos con dos ámbitos geográficos, los municipios y los mercados de trabajo locales. La literatura existente nunca se ha puesto de acuerdo en cual es el ámbito geográfico en el que mejor trabajan los mecanismos Marshall, por lo que hemos cubierto todas las unidades geográficas potenciales.

Fecundity Changes Induced by Low-Doses of Gamma Radiation on Biomphalaria straminea (Dunker, 1848)

A population of 420 snails Biomphalaria straminea, an intermediate host of Schistosoma mansoni, received gamma-rays obtained from a 60Co source in low-doses (0/2,5/5/7,5/10/15/20 and 25 Gy); half population was kept in colonies (allowing cross fertilization) and the other half was mantained in sexual isolation (allowing self fertilization). Results showed that 15 Gy stimulates the fertility of both groups but the colonies were more sensitive and at this dose its fertility overpasses the control group dose. The possible hormonal role played in the observed phenomena is under investigation

Regulation of microtubule dynamics by the neuronal growth-associated protein SCG10.

Dynamic assembly and disassembly of microtubules is essential for cell division, cell movements, and intracellular transport. In the developing nervous system, microtubule dynamics play a fundamental role during neurite outgrowth, elongation, and branching, but the molecular mechanisms involved are unknown. SCG10 is a neuron-specific protein that is membrane-associated and highly enriched in growth cones. Here we show that SCG10 binds to microtubules, inhibits their assembly, and can induce microtubule disassembly. We also show that SCG10 overexpression enhances neurite outgrowth in a stably transfected neuronal cell line. These data identify SCG10 as a key regulator of neurite extension through regulation of microtubule instability.

Smooth multibidding mechanisms

We propose a smooth multibidding mechanism for environments where a group of agents have to choose one out of several projects (possibly with the help of a social planner). Our proposal is related to the multibidding mechanism (Pérez-Castrillo and Wettstein, 2002) but it is "smoother" in the sense that small variations in an agent's bids do not lead to dramatic changes in the probability of selecting a project. This mechanism is shown to possess several interesting properties. Unlike in the study by Pérez Castrillo and Wettstein (2002), the equilibrium outcome is unique. Second, it ensures an equal sharing of the surplus that it induces. Finally, it enables reaching an outcome as close to effciency as is desired.

Mechanisms of formation and function of eosinophil lipid bodies: inducible intracellular sites involved in arachidonic acid metabolism

Lipid bodies, inducible lipid-rich cytoplasmic inclusions, are characteristically abundant in cells associated with inflammation, including eosinophils. Here we reviewed the formation and function of lipid bodies in human eosinophils. We now have evidence that the formation of lipid bodies is not attributable to adverse mechanisms, but is centrally mediated by specific signal transduction pathways. Arachidonic acid and other cis fatty acids by an NSAID-inhibitable process, diglycerides, and PAF by a 5-lipoxygenase dependent pathway are potent stimulators of lipid body induction. Lipid body formation develops rapidly by processes that involve PKC, PLC, and de novo mRNA and protein synthesis. These structures clearly serve as repositoires of arachidonyl-phospholipids and are more than inert depots. Specific enzymes, including cytosolic phospholipase A2, MAP kinases, lipoxygenases and cyclooxygenases, associate with lipid bodies. Lipid bodies appear to be dynamic, organelle-like structures involved in intracellular pathways of lipid mobilization and metabolism. Indeed, increases in lipid body numbers correlated with enhanced production of both lipoxygenase- and cyclooxygenase-derived eicosanoids. We hypothesize that lipid bodies are distinct inducible sites for generating eicosanoids as paracrine mediators with varied activities in inflammation. The capacity of lipid body formation to be specifically and rapidly induced in leukocytes enhances eicosanoid mediator formation, and conversely pharmacologic inhibition of lipid body induction represents a potential novel and specific target for anti-inflammatory therapy.

Mechanisms of cell accumulation induced by Mycobacterium bovis BCG

Mycobacteria, specially Mycobacterium tuberculosis are among the micro-organisms that are increasing dramatically the number of infections with death, all over the world. A great number of animal experimental models have been proposed to investigate the mechanisms involved in the host response against these intracellular parasites. Studies of airway infection in guinea-pigs and rabbits, as well as, in mice intravenously infected with BCG have made an important contribution to our understanding of the virulence, pathogenesis and the immunology of mycobacterial infections. Although, there are few models to study the mechanisms of the initial inflammatory process induced by the first contact with the Mycobacteria, and the relevance of the acute generation of inflammatory mediators, cytokines and leukocyte infiltration to the development of the mycobacterial infection. In this work we reviewed our results obtained with a model of M. bovis BCG-induced pleurisy in mice, describing the mechanisms involved in the leukocyte influx induced by BCG at 24 hr. Different mechanisms appear to be related with the influx of neutrophils, eosinophils and mononuclear cells and distinct inflammatory mediators, cytokines and adhesion molecules are involved in the BCG-induced cell accumulation.