Pharmacological and local toxicity studies of a liposomal formulation for the novel local anaesthetic ropivacaine

This study reports an investigation of the pharmacological activity, cytotoxicity, and local effects of a liposomal formulation of the novel local anaesthetic ropivacaine (RVC) compared with its plain solution. RVC was encapsulated into large unilamellar vesicles (LUVs) composed of egg phosphatidylcholine, cholesterol and a-tocopherol (4:3:0.07, mole %). Particle size, partition coefficient determination and in-vitro release studies were used to characterize the encapsulation process. Cytotoxicity was evaluated by the tetrazolium reduction test using sciatic nerve Schwann cells in culture. Local anaesthetic activity was assessed by mouse sciatic and rat infraorbital nerve blockades. Histological analysis was performed to verify the myotoxic effects evoked by RVC formulations. Plain (RVCPLAIN) and liposomal RVC (RVCLUV) samples were tested at 0.125%, 0.25% and 0.5% concentrations. Vesicle size distribution showed liposomal populations of 370 and 130 nm (85 and 15%, respectively), without changes after RVC encapsulation. The partition coefficient value was 132 26 and in-vitro release assays revealed a decrease in RVC release rate (1.5 fold, P < 0.001) from liposomes. RVCLUV presented reduced cytotoxicity (P < 0.001) when compared with RVCPLAIN Treatment with RVCLUV increased the duration (P < 0.001) and intensity of the analgesic effects either on sciatic nerve blockade (1.4-1.6 fold) and infraorbital nerve blockade tests (1.5 fold), in relation to RVCPLAIN. Regarding histological analysis, no morphological tissue changes were detected in the area of injection and sparse inflammatory cells were observed in only one of the animals treated with RVCPLAIN or RVCLUV at 0.5%. Despite the differences between these preclinical studies and clinical conditions, we suggest RVCLUV as a potential new formulation, since RVC is a new and safe local anaesthetic agent.

An Isoflavone From Dipteryx Alata Vogel Is Active Against The In Vitro Neuromuscular Paralysis Of Bothrops Jararacussu Snake Venom And Bothropstoxin I, And Prevents Venom-induced Myonecrosis.

Snakebite is a neglected disease and serious health problem in Brazil, with most bites being caused by snakes of the genus Bothrops. Although serum therapy is the primary treatment for systemic envenomation, it is generally ineffective in neutralizing the local effects of these venoms. In this work, we examined the ability of 7,8,3'-trihydroxy-4'-methoxyisoflavone (TM), an isoflavone from Dipteryx alata, to neutralize the neurotoxicity (in mouse phrenic nerve-diaphragm preparations) and myotoxicity (assessed by light microscopy) of Bothrops jararacussu snake venom in vitro. The toxicity of TM was assessed using the Salmonella microsome assay (Ames test). Incubation with TM alone (200 μg/mL) did not alter the muscle twitch tension whereas incubation with venom (40 μg/mL) caused irreversible paralysis. Preincubation of TM (200 μg/mL) with venom attenuated the venom-induced neuromuscular blockade by 84% ± 5% (mean ± SEM; n = 4). The neuromuscular blockade caused by bothropstoxin-I (BthTX-I), the major myotoxic PLA2 of this venom, was also attenuated by TM. Histological analysis of diaphragm muscle incubated with TM showed that most fibers were preserved (only 9.2% ± 1.7% were damaged; n = 4) compared to venom alone (50.3% ± 5.4% of fibers damaged; n = 3), and preincubation of TM with venom significantly attenuated the venom-induced damage (only 17% ± 3.4% of fibers damaged; n = 3; p < 0.05 compared to venom alone). TM showed no mutagenicity in the Ames test using Salmonella strains TA98 and TA97a with (+S9) and without (-S9) metabolic activation. These findings indicate that TM is a potentially useful compound for antagonizing the neuromuscular effects (neurotoxicity and myotoxicity) of B. jararacussu venom.

Nanoparticles for the remediation of agrogenic contaminated soil and groundwater – a review

The wide spread use and strong reliance on both fertilizers and pesticides made of agrigenic pollution one of the major contemporary threats to environment and human health. Impacts on the environment vary from local effects, such as eutrophycation1, 2, loss of biodiversity and diminished ecosystem health3, to global effects, such as the aggravation of global warming2, 4 and ozone layer depletion5. The novelty of nanoremediation and its early successes, reported for various contexts, present the prospect for the development of relevant applications for agrigenic contaminants.

Estudo da exposição profissional a formaldeído em laboratórios hospitalares de anatomia patológica

RESUMO - A exposição a formaldeído é reconhecidamente um dos mais importantes factores de risco presente nos laboratórios hospitalares de anatomia patológica. Neste contexto ocupacional, o formaldeído é utilizado em solução, designada comummente por formol. Trata-se de uma solução comercial de formaldeído, normalmente diluída a 10%, sendo pouco onerosa e, por esse motivo, a eleita para os trabalhos de rotina em anatomia patológica. A solução é utilizada como fixador e conservante do material biológico, pelo que as peças anatómicas a serem processadas são previamente impregnadas. No que concerne aos efeitos para a saúde do formaldeído, os efeitos locais parecem apresentar um papel mais importante comparativamente com os efeitos sistémicos, devido à sua reactividade e rápido metabolismo nas células da pele, tracto gastrointestinal e pulmões. Da mesma forma, a localização das lesões correspondem principalmente às zonas expostas às doses mais elevadas deste agente químico, ou seja, o desenvolvimento dos efeitos tóxicos dependerá mais da intensidade da dose externa do que da duração da exposição. O efeito do formaldeído no organismo humano mais facilmente detectável é a acção irritante, transitória e reversível sobre as mucosas dos olhos e aparelho respiratório superior (naso e orofaringe), o que acontece em geral para exposições frequentes e superiores a 1 ppm. Doses elevadas são citotóxicas e podem conduzir a degenerescência e necrose das mucosas e epitélios. No que concerne aos efeitos cancerígenos, a primeira avaliação efectuada pela International Agency for Research on Cancer data de 1981, actualizada em 1982, 1987, 1995 e 2004, considerando-o como um agente cancerígeno do grupo 2A (provavelmente carcinogénico). No entanto, a mais recente avaliação, em 2006, considera o formaldeído no Grupo 1 (agente carcinogénico) com base na evidência de que a exposição a este agente é susceptível de causar cancro nasofaríngeo em humanos. Constituiu objectivo principal deste estudo caracterizar a exposição profissional a formaldeído nos laboratórios hospitalares de anatomia patológica Portugueses. Pretendeu-se, ainda, descrever os fenómenos ambientais da contaminação ambiental por formaldeído e explorar eventuais associações entre variáveis. Considerou-se uma amostra de 10 laboratórios hospitalares de anatomia patológica, avaliada a exposição dos três grupos profissionais por comparação com os dois referenciais de exposição e, ainda, conhecidos os valores de concentração máxima em 83 actividades. Foram aplicados simultaneamente dois métodos distintos de avaliação ambiental: um dos métodos (Método 1) fez uso de um equipamento de leitura directa com o princípio de medição por Photo Ionization Detection, com uma lâmpada de 11,7 eV e, simultaneamente, realizou-se o registo da actividade. Este método disponibilizou dados para o referencial de exposição da concentração máxima; o outro método (Método 2) traduziu-se na aplicação do método NIOSH 2541, implicando o uso de bombas de amostragem eléctricas de baixo caudal e posterior processamento analítico das amostras por cromatografia gasosa. Este método, por sua vez, facultou dados para o referencial de exposição da concentração média ponderada. As estratégias de medição de cada um dos métodos e a definição dos grupos de exposição existentes neste contexto ocupacional, designadamente os Técnicos de Anatomia Patológica, os Médicos Anatomo-Patologistas e os Auxiliares, foram possíveis através da informação disponibilizada pelas técnicas de observação da actividade da análise (ergonómica) do trabalho. Estudaram-se diversas variáveis independentes, nomeadamente a temperatura ambiente e a humidade relativa, a solução de formaldeído utilizada, as condições de ventilação existentes e o número médio de peças processadas por dia em cada laboratório. Para a recolha de informação sobre estas variáveis foi preenchida, durante a permanência nos laboratórios estudados, uma Grelha de Observação e Registo. Como variáveis dependentes seleccionaram-se três indicadores de contaminação ambiental, designadamente o valor médio das concentrações superiores a 0,3 ppm em cada laboratório, a Concentração Média Ponderada obtida para cada grupo de exposição e o Índice do Tempo de Regeneração de cada laboratório. Os indicadores foram calculados e definidos através dos dados obtidos pelos dois métodos de avaliação ambiental aplicados. Baseada no delineado pela Universidade de Queensland, foi ainda aplicada uma metodologia de avaliação do risco de cancro nasofaríngeo nas 83 actividades estudadas de modo a definir níveis semi-quantitativos de estimação do risco. Para o nível de Gravidade considerou-se a informação disponível em literatura científica que define eventos biológicos adversos, relacionados com o modo de acção do agente químico e os associa com concentrações ambientais de formaldeído. Para o nível da Probabilidade utilizou-se a informação disponibilizada pela análise (ergonómica) de trabalho que permitiu conhecer a frequência de realização de cada uma das actividades estudadas. A aplicação simultânea dos dois métodos de avaliação ambiental resultou na obtenção de resultados distintos, mas não contraditórios, no que concerne à avaliação da exposição profissional a formaldeído. Para as actividades estudadas (n=83) verificou-se que cerca de 93% dos valores são superiores ao valor limite de exposição definido para a concentração máxima (VLE-CM=0,3 ppm). O “exame macroscópico” foi a actividade mais estudada e onde se verificou a maior prevalência de resultados superiores ao valor limite (92,8%). O valor médio mais elevado da concentração máxima (2,04 ppm) verificou-se no grupo de exposição dos Técnicos de Anatomia Patológica. No entanto, a maior amplitude de resultados observou-se no grupo dos Médicos Anatomo-Patologistas (0,21 ppm a 5,02 ppm). No que respeita ao referencial da Concentração Média Ponderada, todos os valores obtidos nos 10 laboratórios estudados para os três grupos de exposição foram inferiores ao valor limite de exposição definido pela Occupational Safety and Health Administration (TLV-TWA=0,75 ppm). Verificou-se associação estatisticamente significativa entre o número médio de peças processadas por laboratório e dois dos três indicadores de contaminação ambiental utilizados, designadamente o valor médio das concentrações superiores a 0,3 ppm (p=0,009) e o Índice do Tempo de Regeneração (p=0,001). Relativamente à temperatura ambiente não se observou associação estatisticamente significativa com nenhum dos indicadores de contaminação ambiental utilizados. A humidade relativa apresentou uma associação estatisticamente significativa apenas com o indicador de contaminação ambiental da Concentração Média Ponderada de dois grupos de exposição, nomeadamente com os Médicos Anatomo-Patologistas (p=0,02) e os Técnicos de Anatomia Patológica (p=0,04). A aplicação da metodologia de avaliação do risco nas 83 actividades estudadas permitiu verificar que, em cerca de dois terços (35%), o risco foi classificado como (pelo menos) elevado e, ainda, constatar que 70% dos laboratórios apresentou pelo menos 1 actividade com a classificação de risco elevado. Da aplicação dos dois métodos de avaliação ambiental e das informações obtidas para os dois referenciais de exposição pode concluir-se que o referencial mais adequado é a Concentração Máxima por estar associado ao modo de actuação do agente químico. Acresce, ainda, que um método de avaliação ambiental, como o Método 1, que permite o estudo das concentrações de formaldeído e simultaneamente a realização do registo da actividade, disponibiliza informações pertinentes para a intervenção preventiva da exposição por permitir identificar as actividades com a exposição mais elevada, bem como as variáveis que a condicionam. As peças anatómicas apresentaram-se como a principal fonte de contaminação ambiental por formaldeído neste contexto ocupacional. Aspecto de particular interesse, na medida que a actividade desenvolvida neste contexto ocupacional e, em particular na sala de entradas, é centrada no processamento das peças anatómicas. Dado não se perspectivar a curto prazo a eliminação do formaldeído, devido ao grande número de actividades que envolvem ainda a utilização da sua solução comercial (formol), pode concluir-se que a exposição a este agente neste contexto ocupacional específico é preocupante, carecendo de uma intervenção rápida com o objectivo de minimizar a exposição e prevenir os potenciais efeitos para a saúde dos trabalhadores expostos. ---------------- ABSTRACT - Exposure to formaldehyde is recognized as one of the most important risk factors present in anatomy and pathology laboratories from hospital settings. In this occupational setting, formaldehyde is used in solution, typically diluted to 10%, and is an inexpensive product. Because of that, is used in routine work in anatomy and pathology laboratories. The solution is applied as a fixative and preservative of biological material. Regarding formaldehyde health effects, local effects appear to have a more important role compared with systemic effects, due to his reactivity and rapid metabolism in skin, gastrointestinal tract and lungs cells. Likewise, lesions location correspond mainly to areas exposed to higher doses and toxic effects development depend more on external dose intensity than exposure duration. Human body formaldehyde effect more easily detectable is the irritating action, transient and reversible on eyes and upper respiratory tract (nasal and throat) membranes, which happen in general for frequent exposure to concentrations higher than 1 ppm. High doses are cytotoxic and can lead to degeneration, and also to mucous membranes and epithelia necrosis. With regard to carcinogenic effects, first assessment performed by International Agency for Research on Cancer in 1981, updated in 1982, 1987, 1995 and 2004, classified formaldehyde in Group 2A (probably carcinogenic). However, most recent evaluation in 2006, classifies formaldehyde carcinogenic (Group 1), based on evidence that exposure to this agent is likely to cause nasopharyngeal cancer in humans. This study principal objective was to characterize occupational exposure to formaldehyde in anatomy and pathology hospital laboratories, as well to describe formaldehyde environmental contamination phenomena and explore possible associations between variables. It was considered a sample of 10 hospital pathology laboratories, assessed exposure of three professional groups for comparison with two exposure metrics, and also knows ceiling concentrations in 83 activities. Were applied, simultaneously, two different environmental assessment methods: one method (Method 1) using direct reading equipment that perform measure by Photo Ionization Detection, with 11,7 eV lamps and, simultaneously, make activity description and film. This method provided data for ceiling concentrations for each activity study (TLV-C). In the other applied method (Method 2), air sampling and formaldehyde analysis were performed according to NIOSH method (2541). This method provided data average exposure concentration (TLV-TWA). Measuring and sampling strategies of each methods and exposure groups definition (Technicians, Pathologists and Assistants) was possible by information provided by activities (ergonomic) analysis. Several independent variables were studied, including temperature and relative humidity, formaldehyde solution used, ventilation conditions, and also anatomic pieces mean value processed per day in each laboratory. To register information about these variables was completed an Observation and Registration Grid. Three environmental contamination indicators were selected has dependent variables namely: mean value from concentrations exceeding 0,3 ppm in each laboratory, weighted average concentration obtained for each exposure group, as well each laboratory Time Regeneration Index. These indicators were calculated and determined through data obtained by the two environmental assessment methods. Based on Queensland University proposal, was also applied a methodology for assessing nasopharyngeal cancer risk in 83 activities studied in order to obtain risk levels (semi-quantitative estimation). For Severity level was considered available information in scientific literature that defines biological adverse events related to the chemical agent action mode, and associated with environment formaldehyde concentrations. For Probability level was used information provided by (ergonomic) work analysis that helped identifies activity frequency. Environmental assessment methods provide different results, but not contradictory, regarding formaldehyde occupational exposure evaluation. In the studied activities (n=83), about 93% of the values were above exposure limit value set for ceiling concentration in Portugal (VLE-CM = 0,3 ppm). "Macroscopic exam" was the most studied activity, and obtained the higher prevalence of results superior than 0,3 ppm (92,8%). The highest ceiling concentration mean value (2,04 ppm) was obtain in Technicians exposure group, but a result wider range was observed in Pathologists group (0,21 ppm to 5,02 ppm). Concerning Method 2, results from the three exposure groups, were all lower than limit value set by Occupational Safety and Health Administration (TLV-TWA=0,75ppm). There was a statistically significant association between anatomic pieces mean value processed by each laboratory per day, and two of the three environmental contamination indicators used, namely average concentrations exceeding 0,3 ppm (p=0,009) and Time Regeneration Index (p=0,001). Temperature was not statistically associated with any environmental contamination used indicators. Relative humidity had a statistically significant association only with one environmental contamination indicator, namely weighted average concentration, particularly with Pathologists group (p=0,02) and Technicians group (p=0,04). Risk assessment performed in the 83 studied activities showed that around two thirds (35%) were classified as (at least) high, and also noted that 70% of laboratories had at least 1 activity with high risk rating. The two environmental assessment methods application, as well information obtained from two exposure metrics, allowed to conclude that most appropriate exposure metric is ceiling concentration, because is associated with formaldehyde action mode. Moreover, an environmental method, like Method 1, which allows study formaldehyde concentrations and relates them with activity, provides relevant information for preventive information, since identifies the activity with higher exposure, as well variables that promote exposure. Anatomic pieces represent formaldehyde contamination main source in this occupational setting, and this is of particular interest because all activities are focused on anatomic pieces processing. Since there is no prospect, in short term, for formaldehyde use elimination due to large number of activities that still involve solution use, it can be concluded that exposure to this agent, in this particular occupational setting, is preoccupant, requiring an rapid intervention in order to minimize exposure and prevent potential health effects in exposed workers.

Skin lesions in envenoming by cnidarians (Portuguese man-of-war and jellyfish): etiology and severity of accidents on the Brazilian coast

This work attempts to establish dermatological identification patterns for Brazilian cnidarian species and a probable correlation with envenoming severity. In an observational prospective study, one hundred and twenty-eight patients from the North Coast region of São Paulo State, Brazil were seen between 2002 and 2008. About 80% of these showed only local effects (erythema, edema, and pain) with small, less than 20 cm, oval or round skin marks and impressions from small tentacles. Approximately 20% of the victims had long, more than 20 cm, linear and crossed marks with frequent systemic phenomena, such as malaise, vomiting, dyspnea, and tachycardia. The former is compatible with the common hydromedusa from Southeast and Southern Brazil (Olindias sambaquiensis). The long linear marks with intense pain and systemic phenomena are compatible with envenoming by the box jellyfish Tamoya haplonema and Chiropsalmus quadrumanus and the hydrozoan Portuguese man-of-war (Physalis physalis). There was an association between skin marks and probable accident etiology. This simple observation rule can be indicative of severity, as the Cubozoa Class (box jellyfish) and Portuguese man-of-war cause the most severe accidents. In such cases, medical attention, including intensive care, is important, as the systemic manifestations can be associated with death.

Aliskiren penetrates adipose and skeletal muscle tissue, and reduces Renin-Angiotensin System activity in obese hypertensive patients

Introduction: Tissue Renin-Angiotensin System activity is increased in obesity and may contribute to obesity-related hypertension and metabolic abnormalities. This open-label pilot study investigated the local effects of Aliskiren in adipose tissue and skeletal muscle.Methods: After a 1-2 week washout, 10 patients with hypertension and abdominal obesity received placebo for 2 weeks, then Aliskiren 300 mg once daily for 4 weeks, followed by a 4-week washout period and then another 4 weeks treatment period with Amlodipine 5 mg once daily. Drug concentrations and Renin-Angiotensin Systembiomarkers were measured in interstitial fluid employing the microdialysis zero-flow method, and in biopsies from abdominal subcutaneous adipose and skeletal muscle.Results: After 4 weeks treatment, microdialysate concentrations (mean±SD) of Aliskiren were 2.4±2.1 ng/ml in adipose tissue, and 7.1±4.2 ng/ml in skeletal muscle. These concentrations were similar to the mean plasma concentration of 8.4±4.4 ng/ml. Tissue concentrations (ng/g) of Aliskiren were 29.0±16.7 ng/g in adipose tissue, and 107.3±68.6 ng/g in skeletal muscle after 4 weeks treatment. Angiotensin II concentrations in microdialysates were below the lower limit of quantification in most patients, but pooled data from two patients suggested that Angiotensin II was reduced by Aliskiren and unchanged by Amlodipine. Aliskiren 300 mg significantly reduced mean plasma Renin activity by 68% and Angiotensin II by 61% (p<0.05 vs. baseline). Amlodipine 5 mg increased plasma Renin activity by 48% (p<0.05 vs. baseline), and non-significantly increased Angiotensin II by 60%. Both treatments increased plasma Renin concentration.Conclusion: Aliskiren 300 mg once daily penetrates adipose and skeletal muscle tissue at concentrations sufficient to reduce tissue Renin-Angiotensin System activity in obese patients with hypertension.

A chemical Hamiltonian approach study of the basis set superposition error changes on electron densities and one- and two-center energy components

A comparision of the local effects of the basis set superposition error (BSSE) on the electron densities and energy components of three representative H-bonded complexes was carried out. The electron densities were obtained with Hartee-Fock and density functional theory versions of the chemical Hamiltonian approach (CHA) methodology. It was shown that the effects of the BSSE were common for all complexes studied. The electron density difference maps and the chemical energy component analysis (CECA) analysis confirmed that the local effects of the BSSE were different when diffuse functions were present in the calculations

Postoperative subconjunctival mitomycin-C injection after non-penetrating glaucoma surgery.

PURPOSE: To evaluate subconjunctival mitomycin C (MMC) injection efficacy and safety in patients with failing glaucoma non-penetrating filtering blebs. METHODS: Twenty-eight eyes were consecutively recruited for this study. Only one eye for each patient was randomly selected. All the recruited patients had glaucoma and uncontrolled intraocular pressure after a non-penetrating filtering glaucoma surgery and/or a pathological aspect of the filtering bleb (i.e., vascularized and/or encysted). One or more MMC injections were performed under the conjunctiva closed to the bleb to improve filtration. Local effects and complications of subconjunctival MMC injections were analyzed. RESULTS: Out of the 28 patients, 21 (75%) had MMC also applied intraoperatively. The mean postoperative IOP before MMC injections was 17 +/- 6.6 mmHg. The final IOP after MMC injections was 13.9 +/- 2.9 mmHg after a mean follow-up of 6 months. A total of 67 subconjunctival MMC injections were performed with a mean of 2.9 (ranging from 1 to 5) injections per patient. The only complication found to be possibly related to MMC injections was two cases of corneal Dellen. CONCLUSION: From these preliminary results, subconjunctival MMC injections in selected cases appear to be not only safe but also effective in promoting further the postoperative IOP drop.

Circum-Alpine marine circulation and paleoenvironmental conditions during the Miocene

Trace element and isotopic compositions of marine fossils and sediment were analyzed from several Miocene deposits in the circum-Alpine region in order to reconstruct the paleoceanographic and paleoclimatic changes related to sea level changes, basin evolution and Alpine orogeny. To the north and the east the Alps were border by an epicontinental sea, the Paratethys, while to the south the Mediterranean surrounded the uplifting mountains during the Miocene. The thesis mainly focused on sediments and fossils sampled from Miocene beds of these two oceanic provinces. The north Alpine Molasse, the Vienna and Pannonian Basins were located in the Western and Central Paratethys. O-isotope compositions of well-preserved phosphatic fossils in these sediments support deposition under sub-tropical to warm-temperate climate with water temperatures between 14 to 28 °C for the Miocene. δ18O values of fossil shark teeth from different horizons vary similarly to those of the global trend until the end of the Badenian, however the δ18O values show wider range, which indicates local effects iii the sub-basins. The trend of 87Sr/86Sr in the samples roughly agrees with an open ocean environment for the Miocene. Yet a number of samples deviate from typical open ocean compositions with higher ratios suggesting modification of seawater by local and old terrestrial sources. In contrast, two exceptional teeth from the locality of La Moliere have extremely low δ18O values and low 87Sr/86Sr. However, the REE patterns of their enameloid are similar to those of teeth having O and Sr isotopic compositions typical of a marine setting at this site. Collectively, this suggests that the two teeth formed while the sharks frequented a freshwater environment with very low 18O-content and 87Sr/86Sr controlled by Mesozoic calcareous rocks. This is consistent with a paleogeography of high-elevation (~2300m) Miocene Alps adjacent to a marginal sea. The local effects are also reflected in the εNd values of the Paratethyan fossils, which is compatible with input from ancient crystalline rocks and Mesozoic sediments, while other samples with elevated εNd values indicate an influence of Neogene volcanism on the water budget. Excluding samples whose isotopic compositions reflect a local influence on the water column, an average εNd value of -7.9 ± 0.5 may be inferred for the Paratethys seawater. This value is indistinguishable from the Miocene value of the Indian Ocean, supporting a dominant role of ludo-Pacific water masses in the Paratethys. Regarding the Mediterranean, stable C-and O-isotope compositions of benthic and planktonic foraminifera from the Umbria-Marche region (UMC) have an offset typical for their habitats and the changes in composition mimic global changes, suggesting that the regional conditions of climate and the carbon cycle were controlled by global changes. The radiogenic isotope compositions of the fossil assemblages allow for distinction of periods. From 25 to 19 Ma, high εNd values and low 87Sr/86Sr of sediments and fossils support intense tectonism and volcanism, related to the opening of the western Mediterranean. Between 19 and 13 Ma the Mediterranean has εNd values that are largely controlled by incursion of Indian Ocean water. Brief periods of local hinterland control on seawater compositions are indicated by spikes in the εNd record, coinciding with volcanic events and a short sea-level decrease at about 15.2 Ma. Lower 87Sr/86Sr compared to the open ocean is compatible with rapid uplift of the hinterland and intense influx of Sr from Mesozoic carbonates of the western Apennines, while higher 87Sr/86Sr for other sites indicates erosion of old crustal silicate rocks. Finally, from 13 to 7 Ma the fossils have 87Sr/86Sr similar to those of Miocene seawater and their εNd values indicates fluctuating influence of Atlantic, and Indian Ocean or Paratethys sources of seawater entering the Mediterranean, driven by global sealevel changes and local tectonism. RÉSUMÉ DE LA THÈSE Les compositions en éléments traces et isotopiques de fossiles marins et de sédiments on été analysées à partir de nombreux dépôts marins dans la région circum Alpine dans le but de reconstruire les changements paléocéanographiques et paléoclimatiques liés aux changements du niveau marin, à l'évolution en bassins et à l'orogénie alpine. Au nord et à l'est des Alpes, une mer épicontinentale appelée Paratéthys s'est ouverte, alors que plus au sud la mer Méditerranée bordait au Miocène les Alpes naissantes. Le but de cette recherche est de se concentrer sur les sédiments et les fossiles provenant des couches du Miocènes de ces deux provinces marines. Les bassins de la Molasse Alpine du nord, de Vienne et Pannonien étaient situés au niveau de la Paratéthys Occidentale et Centrale. Les compositions isotopiques de l'oxygène de fossiles phosphatés bien préservés dans ces sédiments étayent la théorie d'un dépôt sous un climat subtropical à tempéré chaud avec des températures entre 14 et 28°C pendant le Miocène. Les valeurs δ18O des fossiles sont similaires à la tendance globale jusqu'à la fin du Badénien. Cependant les larges fluctuations en δ18O indiquent des effets locaux au niveau des sous bassins. En outre, deux dents de requin exceptionnelles présentent des valeurs extrêmement basses de δ18O. Ces données suggèrent que ces deux dents se sont formées alors que les requins fréquentaient un environnement d'eau douce avec de faibles valeurs de 18O. Le calcul de la composition isotopique de l'oxygène de cette eau douce permet d'obtenir une estimation de la paléoélévatian moyenne des Alpes du Miocène (~2300m). La tendance 87Sr/86Sr pour ces échantillons concorde approximativement avec un environnement d'océan ouvert au cours du Miocène. Toutefois un nombre d'échantillons dévie des compositions d'océan ouvert typiques, avec des rapports élevés suggérant des modifications de l'eau de mer par des sources locales et terrestres. Les effets locaux sont aussi reflétés au niveau des valeurs en εNd des fossiles paratéthysiens. Ceci est cohérent avec un apport d'anciennes roches cristallines et de sédiments mésozoïques, tandis que d'autres échantillons avec des valeurs hautes de εNd indiquent une influence d'un volcanisme néogène dans le budget marin. En excluant les échantillons dont les compositions isotopiques confirment une influence locale, une valeur moyenne de εNd de 7.9 t 0.5 peut être déduite pour l'eau de la Parathétys. Cette valeur est semblable à la valeur correspondant à l'Océan Indien durant le Miocène, confirmant un rôle dominant de cet océan dans la Paratéthys. Au niveau de la Méditerranée, les compositions en isotopes stables du Carbone et de l'Oxygène de foraminifères planctoniques et benthique de la région Umbria-Marche présentent un offset typique à leurs habitats. De plus les changements dans leurs compositions suivent les changements globaux, suggérant ainsi que les conditions climatiques régionales et le cycle du carbone étaient contrôlés par des phénomènes globaux. La composition en isotopes radiogéniques d'assemblages fossiles permet une reconnaissance sur trois périodes distinctes. De 25 à 19 millions d'années (Ma), des valeurs élevées de εNd et un faible rapport 87Sr/86Sr dans les sédiments soutiennent l'idée d'une activité tectonique et volcanique intense, liée à l'ouverture de la Méditerranée occidentale. Entre 19 et 13 Ma, la Méditerranée montre des valeurs de εNd qui sont largement contrôlées par une incursion d'eau provenant de l'Océan Indien. En effet, aux alentours de 15,2 Ma, des pics dans l'enregistrement des valeurs de εNd, coïncidant avec des événements volcaniques et de brèves diminutions du niveau marin. Enfin, de 13 à 7 Ma, les fossiles ont des rapports ß7Sr/8fiSr similaires à ceux de l'eau de mer au Miocène. Leurs valeurs de εNd indiquent une influence changeante de l'océan Atlantique, et de l'océan Indien ou des sources d'eau de merde la Parathétys qui entrent dans les bassins méditerranéens. Ce changement est guidé par des modifications globales du niveau marin et par la tectonique locale. RÉSUMÉ DE LA THÈSE (POUR LE GRAND PUBLIC) Les analyses des compositions en éléments traces et isotopiques des fossiles marins sont un outil très utile pour reconstruire les conditions océaniques et climatiques anciennes. Ce travail de thèse se concentre sur les sédiments déposés dans un environnement marin proches des Alpes au cours du Miocène, entre 23 et 7 millions d'années (Ma). Cette période est caractérisée par une tectonique alpine active, ainsi que par des changements climatiques et océanographiques globaux importants. Dans le but de tracer ces changements, les compositions isotopiques du Strontium, du Néodyme, de l'Oxygène et du Carbone ont été analysées dans des fossiles bien préservés ainsi que les sédiments contemporains. Les échantillons proviennent de deux provinces océaniques distinctes, la première est la Mer Méditerranée, et l'autre est une mer épicontinentale appelée Parathétys, qui existait au nord et à l'est des Alpes durant le Miocène. Au niveau de la Parathétys Occidentale et Orientale, les compositions isotopiques d'oxygène de dents de requins confirment un dépôt sous un climat subtropical à tempéré chaud avec des températures d'eau entre 14 et 28°C au Miocène. En outre, deux dents de requins exceptionnelles ont enregistré des compositions isotopiques d'oxygène extrêmement basses. Cela suggère que ces deux dents se sont formées alors que les requins entraient dans un système d'eau douce. Le calcul de la composition isotopique de l'oxygène de cette eau douce permet d'obtenir une estimation de la paléoélévation des Alpes au Miocène qui est aussi élevée que celle d'aujourd'hui. La tendance isotopique du Strontium pour ces échantillons concorde approximativement avec un environnement d'océan ouvert. Cependant un certain nombre d'échantillons indique des modifications de l'eau de mer par des sources terrestres locales. Les effets locaux sont aussi visibles au niveau des compositions isotopiques du Néodyme, qui sont en accord avec un apport provenant de roches cristallines anciennes et de sédiments du Mésozoïque, alors que d'autres échantillons indiquent une influence volcanique néogène dans le budget marin. A l'exclusion des échantillons dont les compositions correspondent à une influence locale, les compositions isotopiques du Néodyme de la Parathétys sont très similaires aux valeurs de l'Océan Indien, montrant ainsi un rôle important des masses d'eau IndoPacifiques dans cette région. Au niveau de la Méditerranée, les compositions en isotopes stables du Carbone et de l'Oxygène de foraminifères planctoniques et benthique de la région Umbria-Marche présentent un offset typique à leurs habitats. De plus, les changements dans leurs compositions suivent les changements globaux, suggérant ainsi que les conditions climatiques régionales et le cycle du carbone étaient contrôlés par des phénomènes globaux. La composition en isotopes radiogéniques d'assemblages fossiles permet une reconnaissance sur trois périodes distinctes. De 25 à 19 Ma, des rapport isotopiques élevés pour le Néodyme et faibles pour le Strontium dans les sédiments et les fossiles soutiennent l'idée d'une activité tectonique et volcanique intense, liée à l'ouverture de la Méditerranée occidentale. Entre 19 et 13 Ma, la Méditerranée présente des rapports isotopiques du Néodyme qui sont largement contrôlés par une incursion d'eau provenant de l'Océan Indien. En effet, aux alentours de 15,2 Ma, des pics dans l'enregistrement des valeurs des isotopes du Néodyme coïncident avec des événements volcaniques et de brèves diminutions du niveau marin. Finalement, de 13 à 7 Ma, les fossiles ont des rapports isotope Strontium similaires à ceux de l'eau de mer au Miocène. Les rapports isotopiques du Néodyme indiquent une influence changeante de l'océan Atlantique, et de l'océan Indien ou des sources d'eau de mer de la Parathétys qui entrent dans les bassins méditerranéens. Ce changement est guidé par des modifications globales du niveau marin et par la tectonique locale.

Modelling of a Hydrogen Catalytic Recombiner for Nuclear Power Plant Containment Studies; Case: Siemens FR90/1-150 Recombiner in TONUS OD Code

Ydinvoimalaitokset on suunniteltu ja rakennettu niin, että niillä on kyky selviytyä erilaisista käyttöhäiriöistä ja onnettomuuksista ilman laitoksen vahingoittumista sekä väestön ja ympäristön vaarantumista. On erittäin epätodennäköistä, että ydinvoimalaitosonnettomuus etenee reaktorisydämen vaurioitumiseen asti, minkä seurauksena sydänmateriaalien hapettuminen voi tuottaa vetyä. Jäädytyspiirin rikkoutumisen myötä vety saattaa kulkeutua ydinvoimalaitoksen suojarakennukseen, jossa se voi muodostaa palavan seoksen ilman hapen kanssa ja palaa tai jopa räjähtää. Vetypalosta aiheutuvat lämpötila- ja painekuormitukset vaarantavat suojarakennuksen eheyden ja suojarakennuksen sisällä olevien turvajärjestelmien toimivuuden, joten tehokas ja luotettava vedynhallintajärjestelmä on tarpeellinen. Passiivisia autokatalyyttisiä vetyrekombinaattoreita käytetäänyhä useammissa Euroopan ydinvoimaitoksissa vedynhallintaan. Nämä rekombinaattorit poistavat vetyä katalyyttisellä reaktiolla vedyn reagoidessa katalyytin pinnalla hapen kanssa muodostaen vesihöyryä. Rekombinaattorit ovat täysin passiivisiaeivätkä tarvitse ulkoista energiaa tai operaattoritoimintaa käynnistyäkseen taitoimiakseen. Rekombinaattoreiden käyttäytymisen tutkimisellatähdätään niiden toimivuuden selvittämiseen kaikissa mahdollisissa onnettomuustilanteissa, niiden suunnittelun optimoimiseen sekä niiden optimaalisen lukumäärän ja sijainnin määrittämiseen suojarakennuksessa. Suojarakennuksen mallintamiseen käytetään joko keskiarvoistavia ohjelmia (Lumped parameter (LP) code), moniulotteisia virtausmalliohjelmia (Computational Fluid Dynamics, CFD) tai näiden yhdistelmiä. Rekombinaattoreiden mallintaminen on toteutettu näissä ohjelmissa joko kokeellisella, teoreettisella tai yleisellä (eng. Global Approach) mallilla. Tämä diplomityö sisältää tulokset TONUS OD-ohjelman sisältämän Siemens FR90/1-150 rekombinaattorin mallin vedynkulutuksen tarkistuslaskuista ja TONUS OD-ohjelmalla suoritettujen laskujen tulokset Siemens rekombinaattoreiden vuorovaikutuksista. TONUS on CEA:n (Commissariat à 1'En¬ergie Atomique) kehittämä LP (OD) ja CFD -vetyanalyysiohjelma, jota käytetään vedyn jakautumisen, palamisenja detonaation mallintamiseen. TONUS:sta käytetään myös vedynpoiston mallintamiseen passiivisilla autokatalyyttisillä rekombinaattoreilla. Vedynkulutukseen vaikuttavat tekijät eroteltiin ja tutkittiin yksi kerrallaan. Rekombinaattoreiden vuorovaikutuksia tutkittaessa samaan tilavuuteen sijoitettiin eri kokoisia ja eri lukumäärä rekombinaattoreita. Siemens rekombinaattorimalli TONUS OD-ohjelmassa laskee vedynkulutuksen kuten oletettiin ja tulokset vahvistavat TONUS OD-ohjelman fysikaalisen laskennan luotettavuuden. Mahdollisia paikallisia jakautumia tutkitussa tilavuudessa ei voitu havaita LP-ohjelmalla, koska se käyttäälaskennassa suureiden tilavuuskeskiarvoja. Paikallisten jakautumien tutkintaan tarvitaan CFD -laskentaohjelma.

Chemoreceptors and cardiovascular control in acute and chronic systemic hypoxia

This review describes the ways in which the primary bradycardia and peripheral vasoconstriction evoked by selective stimulation of peripheral chemoreceptors can be modified by the secondary effects of a chemoreceptor-induced increase in ventilation. The evidence that strong stimulation of peripheral chemoreceptors can evoke the behavioural and cardiovascular components of the alerting or defence response which is characteristically evoked by novel or noxious stimuli is considered. The functional significance of all these influences in systemic hypoxia is then discussed with emphasis on the fact that these reflex changes can be overcome by the local effects of hypoxia: central neural hypoxia depresses ventilation, hypoxia acting on the heart causes bradycardia and local hypoxia of skeletal muscle and brain induces vasodilatation. Further, it is proposed that these local influences can become interdependent, so generating a positive feedback loop that may explain sudden infant death syndrome (SIDS). It is also argued that a major contributor to these local influences is adenosine. The role of adenosine in determining the distribution of O2 in skeletal muscle microcirculation in hypoxia is discussed, together with its possible cellular mechanisms of action. Finally, evidence is presented that in chronic systemic hypoxia, the reflex vasoconstrictor influences of the sympathetic nervous system are reduced and/or the local dilator influences of hypoxia are enhanced. In vitro and in vivo findings suggest this is partly explained by upregulation of nitric oxide (NO) synthesis by the vascular endothelium which facilitates vasodilatation induced by adenosine and other NO-dependent dilators and attenuates noradrenaline-evoked vasoconstriction.

Inhibition of gastric emptying and intestinal transit in anesthetized rats by a Tityus serrulatus scorpion toxin

The effects of a fraction (T1) of Tityus serrulatus scorpion venom prepared by gel filtration on gastric emptying and small intestinal transit were investigated in male Wistar rats. Fasted animals were anesthetized with urethane, submitted to tracheal intubation and right jugular vein cannulation. Scorpion toxin (250 µg/kg) or saline was injected iv and 1 h later a bolus of saline (1.0 ml/100 g) labeled with 99m technetium-phytate (10 MBq) was administered by gavage. After 15 min, animals were sacrificed and the radioactivity remaining in the stomach was determined. Intestinal transit was evaluated by instillation of a technetium-labeled saline bolus (1.0 ml) through a cannula previously implanted in the duodenum. After 60 min, the progression of the marker throughout 7 consecutive gut segments was estimated by the geometric center method. Gastric retention of the liquid test meal in rats injected with scorpion toxin (median: 88%; range: 52-95%) was significantly higher (P<0.02) than in controls (54%; 21-76%), an effect which was not modified by gastric secretion blockade with ranitidine. The progression of the isotope marker throughout the small intestine was significantly slower (P<0.05) in rats treated with toxin (1.2; 1.0-2.5) than in control animals (2.3; 1.0-3.2). Inhibition of both gastric emptying and intestinal transit in rats injected with scorpion toxin suggests an increased resistance to aboral flow, which might be caused by abnormal neurotransmitter release or by the local effects of venom on smooth muscle cells.

Hypercalcemia and acute kidney injury caused by abuse of a parenteral veterinary compound containing vitamins A, D, and E

A previously healthy 19 year-old male presented to the hospital with anorexia, nausea, and vomiting. Laboratory studies were significant for hypercalcemia (peak calcium value of 14.8 mg/dL) and acute kidney injury (peak serum creatinine of 2.88 mg/dL). He admitted to using a parenteral formulation of vitamins A, D and E restricted for veterinary use containing 20,000,000 IU of vitamin A; 5,000,000 IU of vitamin D3; and 6,800 IU of vitamin E per 100 mL vial. The patient stated to have used close to 300 mL of the product over the preceding year. Interestingly, the young man was not interested in the massive amounts of vitamins that the product contained; he was only after the local effects of the oily vehicle. The swelling produced by the injection resulted in a silicone-like effect, which gave the impression of bigger muscles. Nevertheless, the product was absorbed and caused hypervitaminosis. The serum level of 25(OH) vitamin D was clearly elevated at 150 ng/mL (reference range from 30 to 60 ng/mL), but in most published cases of vitamin D toxicity, serum levels have been well above 200 ng/mL. His PTH level was undetectable and other potential causes of hypercalcemia were excluded. Therefore, we posit that the severity of the hypercalcemia observed in this case was the result of a synergistic effect of vitamins A and D. The patient was treated with normal saline, furosemide and zolendronic acid, with rapid normalization of calcium levels and renal function.

Écologie et implications trophiques de la cyanobactérie Lyngbya wollei dans le fleuve Saint-Laurent

Les proliférations nuisibles de la cyanobactérie filamenteuse benthique Lyngbya wollei qui forme des tapis déposés sur les sédiments ont augmenté en fréquence au cours des 30 dernières années dans les rivières, lacs et sources de l'Amérique du Nord. Lyngbya wollei produit des neurotoxines et des composés organiques volatils (géosmin, 2-méthylisobornéol) qui ont des répercussions sur la santé publique de même que des impacts d'ordre socioéconomiques. Cette cyanobactérie est considérée comme un habitat et une source de nourriture de piètre qualité pour les invertébrés en raison de sa gaine robuste et de sa production de toxines. Les proliférations de L. wollei ont été observées pour la première fois en 2005 dans le fleuve Saint-Laurent (SLR; Québec, Canada). Nous avons jugé important de déterminer sa distribution sur un tronçon de 250 km afin d'élaborer des modèles prédictifs de sa présence et biomasse en se basant sur les caractéristiques chimiques et physiques de l'eau. Lyngbya wollei était généralement observé en aval de la confluence de petits tributaires qui irriguent des terres agricoles. L’écoulement d’eaux enrichies à travers la végétation submergée se traduisait par une diminution de la concentration d’azote inorganique dissous (DIN), alors que les concentrations de carbone organique dissous (DOC) et de phosphore total dissous (TDP) demeuraient élevées, produisant un faible rapport DIN :TDP. Selon nos modèles, DOC (effet positif), TP (effet négatif) et DIN :TDP (effet négatif) sont les variables les plus importantes pour expliquer la répartition de cette cyanobactérie. La probabilité que L. wollei soit présent dans le SLR a été prédite avec exactitude dans 72 % à 92 % des cas pour un ensemble de données indépendantes. Nous avons ensuite examiné si les conditions hydrodynamiques, c'est-à-dire le courant généré par les vagues et l'écoulement du fleuve, contrôlent les variations spatiales et temporelles de biomasse de L. wollei dans un grand système fluvial. Nous avons mesuré la biomasse de L. wollei ainsi que les variables chimiques, physiques et météorologiques durant trois ans à 10 sites le long d'un gradient d'exposition au courant et au vent dans un grand (148 km2) lac fluvial du SLR. L'exposition aux vagues et la vitesse du courant contrôlaient les variations de biomasses spatiales et temporelles. La biomasse augmentait de mai à novembre et persistait durant l'hiver. Les variations interannuelles étaient contrôlées par l'écoulement de la rivière (niveau d'eau) avec la crue printanière qui délogeait les tapis de l'année précédente. Les baisses du niveau d'eau et l'augmentation de l'intensité des tempêtes anticipées par les scénarios de changements climatiques pourraient accroître la superficie colonisée par L. wollei de même que son accumulation sur les berges. Par la suite, nous avons évalué l'importance relative de L. wollei par rapport aux macrophytes et aux épiphytes. Nous avons examiné l'influence structurante de l'échelle spatiale sur les variables environnementales et la biomasse de ces producteurs primaires (PP) benthiques. Nous avons testé si leur biomasse reflétait la nature des agrégats d'habitat basées sur l'écogéomorphologie ou plutôt le continuum fluvial. Pour répondre à ces deux questions, nous avons utilisé un design à 3 échelles spatiales dans le SLR: 1) le long d'un tronçon de 250 km, 2) entre les lacs fluviaux localisés dans ce tronçon, 3) à l'intérieur de chaque lac fluvial. Les facteurs environnementaux (conductivité et TP) et la structure spatiale expliquent 59% de la variation de biomasse des trois PP benthiques. Spécifiquement, les variations de biomasses étaient le mieux expliquées par la conductivité (+) pour les macrophytes, par le ratio DIN:TDP (+) et le coefficient d'extinction lumineuse (+) pour les épiphytes et par le DOC (+) et le NH4+ (-) pour L. wollei. La structure spatiale à l'intérieur des lacs fluviaux était la plus importante composante spatiale pour tous les PP benthiques, suggérant que les effets locaux tels que l'enrichissement par les tributaire plutôt que les gradients amont-aval déterminent la biomasse de PP benthiques. Donc, la dynamique des agrégats d'habitat représente un cadre général adéquat pour expliquer les variations spatiales et la grande variété de conditions environnementales supportant des organismes aquatiques dans les grands fleuves. Enfin, nous avons étudié le rôle écologique des tapis de L. wollei dans les écosystèmes aquatiques, en particulier comme source de nourriture et refuge pour l'amphipode Gammarus fasciatus. Nous avons offert aux amphipodes un choix entre des tapis de L. wollei et soit des chlorophytes filamenteuses ou un tapis artificiel de laine acrylique lors d'expériences en laboratoire. Nous avons aussi reconstitué la diète in situ des amphipodes à l'aide du mixing model (d13C et δ15N). Gammarus fasciatus choisissait le substrat offrant le meilleur refuge face à la lumière (Acrylique>Lyngbya=Rhizoclonium>Spirogyra). La présence de saxitoxines, la composition élémentaire des tissus et l'abondance des épiphytes n'ont eu aucun effet sur le choix de substrat. Lyngbya wollei et ses épiphytes constituaient 36 et 24 % de l'alimentation in situ de G. fasciatus alors que les chlorophytes, les macrophytes et les épiphytes associées représentaient une fraction moins importante de son alimentation. Les tapis de cyanobactéries benthiques devraient être considérés comme un bon refuge et une source de nourriture pour les petits invertébrés omnivores tels que les amphipodes.

A chemical Hamiltonian approach study of the basis set superposition error changes on electron densities and one- and two-center energy components

A comparision of the local effects of the basis set superposition error (BSSE) on the electron densities and energy components of three representative H-bonded complexes was carried out. The electron densities were obtained with Hartee-Fock and density functional theory versions of the chemical Hamiltonian approach (CHA) methodology. It was shown that the effects of the BSSE were common for all complexes studied. The electron density difference maps and the chemical energy component analysis (CECA) analysis confirmed that the local effects of the BSSE were different when diffuse functions were present in the calculations