Structure-based virtual screening of hypothetical inhibitors of the enzyme longiborneol synthase-a potential target to reduce Fusarium head blight disease.

Fusarium head blight (FHB) is one of the most destructive diseases of wheat and other cereals worldwide. During infection, the Fusarium fungi produce mycotoxins that represent a high risk to human and animal health. Developing small-molecule inhibitors to specifically reduce mycotoxin levels would be highly beneficial since current treatments unspecifically target the Fusarium pathogen. Culmorin possesses a well-known important synergistically virulence role among mycotoxins, and longiborneol synthase appears to be a key enzyme for its synthesis, thus making longiborneol synthase a particularly interesting target. This study aims to discover potent and less toxic agrochemicals against FHB. These compounds would hamper culmorin synthesis by inhibiting longiborneol synthase. In order to select starting molecules for further investigation, we have conducted a structure-based virtual screening investigation. A longiborneol synthase structural model is first built using homology modeling, followed by molecular dynamics simulations that provided the required input for a protein-ligand ensemble docking procedure. From this strategy, the three most interesting compounds (hits) were selected among the 25 top-ranked docked compounds from a library of 15,000 drug-like compounds. These putative inhibitors of longiborneol synthase provide a sound starting point for further studies involving molecular modeling coupled to biochemical experiments. This process could eventually lead to the development of novel approaches to reduce mycotoxin contamination in harvested grain.

[Necrotic leg ulcers induced by vitamin K antagonists: five cases]. / Ulcères de jambe nécrotiques induits par les anti-vitamines K : à propos de cinq cas.

BACKGROUND: Vitamin K antagonists (VKAs) are widely used in thromboembolic diseases. We report five cases of necrotic leg ulcers having a particularly severe course and in which withdrawal of VKA treatment alone enabled healing. CASE REPORTS: Five patients presented with necrotic leg ulcers clinically evocative of necrotic angiodermatitis or vasculitis. Histological features were variable, including inconstantly inflammatory lesions (leukocytoclastic vasculitis) and microthrombosis. None of the patients had laboratory signs of autoimmune disease. Healing occurred in all patients only after withdrawal of VKA therapy (fluindione or acenocoumarol). Associated vascular diseases included superficial venous, distal arterial insufficiency and postphlebitic disease. In three cases, thrombotic factors were observed: hyperhomocysteinaemia or heterozygous Factor V Leiden mutation. DISCUSSION: Although the causative role of VKAs is based solely on chronological criteria, this potential side effect deserves publication because of its practical therapeutic consequences. The physiopathological mechanisms accounting for the role of VKAs, including immunoallergic phenomena and, above all, microcirculatory thrombotic processes, are hypothetical and not universally accepted.

Risk assessment analysis of the future technical unit dedicated to the evaluation and treatment of motor disabilities.

OBJECTIVES: The National Hospital of Saint Maurice (HNSM) for Physical Medicine and Rehabilitation aims at strengthening its position as a pivot rehabilitation and physical therapy center. The opening in 2011 of a new unit for the evaluation and treatment of motor disabilities meets this objective. This project includes several parts: clinical, financial, architectural, organizational, applied clinical research as well as dealing with medical equipments and information system. This study focuses on the risk assessment of this future technical unit. METHODS: This study was conducted by a group of professionals working for the hospital. It started with the design of a functional model to better comprehend the system to be analyzed. Risk assessment consists in confronting this functional model to a list of dangers in order to determine the vulnerable areas of the system. Then the team designed some scenarios to identify the causes, securities barriers and consequences in order to rank the risks. RESULTS: The analysis targeted various dangers, e.g. political, strategic, financial, economical, marketing, clinical and operational. The team identified more than 70 risky scenarios. For 75% of them the criticality level was deemed initially tolerable and under control or unacceptable. The implementation of an action plan for reducing the level of risks before opening this technical unit brought the system down to an acceptable level at 66%. CONCLUSION: A year prior to opening this technical unit for the evaluation and treatment of motor disabilities, conducting this preliminary risk assessment, with its exhaustive and rigorous methodology, enabled the concerned professionals to work together around an action plan for reducing the risks.

[Polymorphic eruption of pregnancy and acquired hemophilia A]. / Éruption polymorphe de la grossesse associée à une hémophilie acquise A.

BACKGROUND: Acquired haemophilia A (AHA) is a rare and serious disease, and instances of association with skin diseases have been described. We report a case of postpartum AHA associated with atypical polymorphic eruption of pregnancy (PEP). PATIENTS AND METHODS: Following delivery of her second child, a 27-year-old woman developed a generalised pruritic erythematous papular and vesicular rash in plaques. The diagnosis of pemphigoid gestationis was ruled out on the basis of negative immunopathology results and a diagnosis of PEP was made. Lengthening of activated cephalin time was observed, without correction by addition of control plasma, and prothrombin time was normal. AHA was confirmed by the very low levels of factor VIII and the presence of antifactor VIII antibody. The patient was given intravenous activated recombinant factor VII for epistaxis and gingival bleeding, followed by an infusion of polyvalent immunoglobulins and systemic corticosteroids. Both diseases regressed within a few weeks. DISCUSSION: This case is original in terms of the atypical presentation of AHA associated with severe PEP. AHA was associated with the presence of antifactor VIII Ab. Although the disease generally occurs alone, it has already been reported during pregnancy and the postpartum period, and in association with various forms of dermatosis, including bullous pemphigoid, although to our knowledge, never in association with PEP or pemphigoid gestationis. However, neither the underlying mechanisms of this association of PEP and AHA, which was probably not a chance occurrence, nor the risks of relapse of these conditions during subsequent pregnancies have been elucidated.

[Tumoral calcinosis at an unusual site in a haemodialysis patient]. / Calcinose pseudotumorale de localisation inhabituelle chez un patient hémodialysé.

BACKGROUND: Tumour-like calcinosis is a rare cause of tissue calcification in patients on maintenance haemodialysis for chronic renal failure. Its estimated incidence is between 0.5 and 7% of haemodialysis patients. PATIENTS AND METHODS: A 29-year-old male patient was referred to our department with a large cervical mass lesion increasing in size for two months. The patient had been on maintenance haemodialysis for one year for chronic renal failure during which time he reported multiple episodes of cervical trauma. Cervical MRI demonstrated a 11 x 9 cm calcified tumoral mass extending to the cervical muscles and the lower cervical spine (C6, C7, T1), accompanied by C6 osteolysis. Laboratory studies revealed secondary hyperparathyroidism with elevated calcium-phosphorus product. The patient underwent parathyroidectomy and several weeks later, there was a dramatic regression of the tumoral calcinosis. Renal transplantation was performed secondarily with no recurrence of the tumoral calcification after six years of follow-up. DISCUSSION: Tumour-like calcinosis of the lower cervical spine with osteolysis of the cervical vertebrae is very rare. The principal contributing factors are hyperparathyroidism, elevation of calcium-phosphorus product and local trauma. Optimal treatment of these calcifications remains controversial. While surgical resection of the mass is commonly recommended, in our case report, despite the initial aggressiveness of the lesion, surgery was not performed and treatment of hyperparathyroidism alone was sufficient to ensure dramatic improvement with complete resolution of the calcinosis within few weeks.

Fenofibrate-loaded PLGA microparticles: effects on ischemic stroke.

Many drugs are not able to cross the Blood Brain Barrier (BBB) and, thus, cannot reach a target site within the Central Nervous System (CNS). Local controlled drug delivery can help to overcome this restriction. However, this is a highly challenging approach and only one product is yet available on the market: Gliadel, which is used to reduce the risk of local tumor recurrence upon resection of malignant glioma. The aim of this study was to evaluate the potential of local controlled drug delivery to the CNS to reduce the consequences of ischemic stroke. Fenofibrate as well as its active metabolite fenofibric acid were encapsulated within PLGA microparticles. Importantly, fenofibrate-loaded microparticles effectively reduced the consequences of ischemic stroke in Wistar rats: the total, cortical and striatal infarct volumes decreased from 257 to 197, 193 to 139, and 64 to 58 mm(3), respectively. Interestingly, fenofibric acid-loaded microparticles did not show significant in vivo efficacy, which might be attributable to a potentially limited distribution pattern within the brain and/or limited cell uptake. Thus, local controlled drug delivery to the CNS also has a significant potential for the treatment/prevention of other types of diseases than cancer. Furthermore, this approach can help to provide proof of concept in vivo in the early drug discovery phase, if the drug candidate cannot cross the BBB.

[Bullous amyloïdis revealing a light chains lambda myeloma]. / Amylose bulleuse révélant un myélome à chaînes légères lambda.

INTRODUCTION: Although rare, skin lesions are regularly reported in patients with systemic amyloidosis. The existence of bullous skin lesions however is very rare; only thirty cases have been previously reported. We report a new case of bullous amyloidosis revealing a light chains lambda myeloma, and underline the usual characteristics of this type of systemic amyloidosis. EXEGESIS: An 85-year-old man was hospitalised for a bullous eruption associated with a general asthenia. Bullous amyloidosis revealing a light chains lambda myeloma was diagnosed and confirmed by histopathological examination of a skin biopsy specimen. The patient died of a severe congestive heart failure, 15 days later, due to cardiac involvement of the amyloidosis. CONCLUSION: Bullous amyloidosis lesions can be an early manifestation of occult dysglobulinemia. Early diagnosis would allow rapid treatment, before onset of systemic amyloidosis, which is often lethal.

Design, synthesis and antimalarial activity of a glyoxylylhydrazone library.

Synthesis of a new family of quinolylhydrazone derivatives and evaluation of their activity against a chloroquine-resistant strain of Plasmodium falciparum are described. The best compound displayed an activity 6-fold higher than chloroquine. None of the active compounds were found to inhibit beta-hematin formation in vitro in the same range as chloroquine and five among them displayed lower calculated vacuolar accumulation ratios, suggesting the implication of a different mechanism of action.

Level of evidence as a future gold standard for the content quality of health resources on the internet.

OBJECTIVE: An assessment of the quality of health information on the Internet is an absolute necessity. In this study 'sensitive' information was defined as information found in documents published on the Internet, which could be used in a medical decision. For sensitive information, the main criterion chosen for the quality of the information was an indication of the level of evidence. A survey was conducted using the CISMeF health catalogue to assess how often a score of the level of evidence is mentioned in the information accessible on the Internet in French-language health resources. METHODS: Since 1999, members of the CISMeF team have systematically been searching for all documents containing 'sensitive' information and verifying whether the level of evidence was explicitly indicated as a score at least once in the document. RESULTS: As of June 2001, 10,190 resources were included in CISMeF; including 2964 textual 'sensitive' resources (29.1%). Out of all these resources, only 4.7% (95% confidence interval: 4.0 - 5.5%) indicated the level of evidence. A statistically significant difference in the prevalence of indicating the level of evidence according to resource types (e.g., 18.1% for guidelines compared to 0.0% for teaching material), year of publication (almost three times greater in 1997-2001 compared with 1990-1996) and publishers was observed. CONCLUSION: As the number of people accessing the growing amount of information on the Internet is increasing daily, publishers have an ethical obligation to inform their readers about the validity of 'sensitive' information their sites contain. However, the vast majority of the French language Internet resources that were surveyed do not mention a score of the level of evidence for their sensitive information.

[The effects of ionizing radiation on stem cells and hematopoietic progenitors: the place of apoptosis and the therapeutic potential of anti-apoptosis treatments]. / Effet des rayonnements ionisants sur les cellules souches et progeniteurs hematopoïétiques: place de l'apoptose et intérêt thérapeutique potentiel des traitements antiapoptotiques.

Abstract: Bone marrow aplasia observed following ionizing radiation exposure (Total Body Irradiation; gamma dose range: 2-10 Gy) is a result, in particular, of the radiation-induced (RI) apoptosis in hematopoietic stem and progenitor cells (HSPC). We have previously shown in a baboon model of mobilized peripheral blood CD34+ cell irradiation in vitro that RI apoptosis in HSPC was an early event, mostly occurring within the first 24 hours, which involves the CD95 Fas pathway. Apoptosis may be significantly reduced with a combination of 4 cytokines (4F): Stem Cell Factor (SCF), FLT-3 Ligand (FL), thrombopoietin (TPO), and interleukin-3 (IL-3), each at 50 ng x mL(-1) (15% survival versus <3% untreated cells, 24 h post-irradiation at 2.5 Gy). In this study we show that addition of TNF-alpha(800 IU/ml) induces an increase in 4F efficacy in terms of cell survival 24 h after incubation (26% survival after 24 h irradiation exposure at 2.5 Gy) and amplification (k) of CD34+ cells after 6 days in a serum free culture medium (SFM) (kCD34+ = 4.3 and 6.3 respectively for 4F and successive 4F + TNF-a/ 4F treatments). In addition, the 4F combination allows culture on pre-established allogenic irradiated stromal cells in vitro at 4 Gy (kCD34+ = 4.5). Overall this study suggests (i) the potential therapeutic interest for an early administration of anti-apoptotic cytokines with or without hematopoiesis inhibitors (emergency cytokine therapy) and (ii) the feasibility in the accidentally irradiated individual, of autologous cell therapy based on ex vivo expansion in order to perform autograft of residual HSPC collected after the accident.

Cost-benefit analysis of thrombolytic therapy.

Thrombolysis is a new treatment for myocardial infarct patients, 162 such patients were studied: 62 received thrombolytic treatment and 100 a classical therapy. For cost-benefit analysis, all patients were followed for at least 1 year and received an identical questionnaire to assess the costs induced by this disease. At 1 year, 10% had died in the two groups. Patients who received thrombolytic treatment had a hospital stay 2 days longer, on average, but were readmitted for shorter periods (10.3 days less). Thrombolysis was more expensive (10,550 pounds vs 8998 pounds). Therefore, it is necessary to invest 150 pounds to reduce rehospitalization time by 1 day. Benefits were almost 31% greater for thrombolysis patients and the cost-benefit ratio was about 0.7. Thus the monetary benefits, initially rather negative, became positive at the end of the first year.

[Short- and long-term outcome of 250 patients admitted in surgical intensive care units after multiple injuries]. / Devenir à court et à long terme de 250 patients admis en réanimation chirurgicale, au décours d'un polytraumatisme.

Two hundred and fifty polytrauma patients (mean age: 30 years) had been hospitalizated in the same trauma center, along a period of two years. Hospital mortality rate was 33% (11% in the first day). The mean I.S.S. of alive patients was 25, and 35 for dead patients. Long term survey was analysed by three questionnaires (before one year, between one and two years and after two years). Answer rate was about 80%. Sixty hundred p. cent of patients worked less than one year after multiple trauma, and 80% between one and two years; 75% noted that their family life was normal less than one year after injury; 80% presented sequelae two years after; they were subjective in 60% of cases. These sequelae did not interfere with family life or work. There was no parallelism between objective sequelae and duration of work stop in one side and gravity of lesions (I.S.S.) in other side.

[Activity in an emergency care unit: experience of a patient care team]. / Activité d'une salle de tri-déchocage: son vécu par les équipes soignantes.

An emergency and intensive care medical team (physicians, specialised nurses in anesthesia, paramedics) works in a mobile intensive care unit and in a Emergency room. The functions are to provide intensive care, to validate the pre-hospital diagnosis and also to prepare the optimal hospital admission. This organisation realize a "short route" to emergency hospitalisation. A questionnaire to this medical team enquired for their appreciation of the activity, for their implication and feeling, individual and collective, of death's experiences, of works organisation, and of requirements. Mainly, it appears that, with high level of education and various qualification, occupational stress and negative impact on patient care are not described. Further studies are needed to verify.

[On the management of aged patients in intensive and emergency care services]. / Réflexion sur la prise en charge des personnes âgées en réanimation et en médecine d'urgence.

The management of the elderly patients by the emergency medical service and in the intensive care unit refers to the human and professional experience of the medical team. The treatment of this kind of patients lays down a rule of conduct with the point of view of the economical and moral aspect.

[Socioeconomic implications of the practice of thrombolysis in the acute stage of myocardial infarction]. / Implications socio-économiques de la pratique de la thrombolyse à la phase aiguë de l'infarctus du myocarde.

The use of variegated and costly thrombolytic agents for the treatment of myocardial infarction in its acute phase may have medico-social advantages. In the present study, these advantages were evaluated after one year from two age and sex matched populations: 40 patients who underwent thrombolysis and 38 patients who did not. Compared with the first hospitalizations, the difference was + 4,000 francs, rising to + 11.000 francs with the drug Eminase. A questionnaire including medical, social and economic data was sent to the 78 patients and was filled by 63 of them, remaining unanswered by one patient who had thrombolysis and 10 patients who did not. Readmission to hospital showed a 44.000 francs difference to the benefit of patients who underwent thrombolysis. Ancillary care and return to work were similar in both groups. Cost expectancy was 119.500 francs for patients who had thrombolysis and 122.000 francs for those who did not. Thrombolysis therefore is a cost reduction factor, but its influence on costs is less pronounced when it is performed soon after the onset of myocardial infarction. Thrombolysis is more expensive when carried out at home than in hospital. In this study, the excess cost (+ 5.000 francs) was due to the relatively small number of patients and to the loss of professional activity which may be an uncertain factor. Mortality at one year was nil when thrombolysis was performed within the first two hours (12 patients) and rose to 16.6 percent between 2 and 3 hours (18 patients) and 30 percent after 3 hours (10 patients). Conducted on a necessarily limited number of patients, this multiple criteria study was also aimed at establishing a method to evaluate the health expenditures imposed by the introduction of new and costly treatment in the management of myocardial infarction.