Cerebroprotective activity of Wedelia calendulacea on global cerebral ischemia in rats

The present study was to investigate the effect of W. calendulacea on ischemia and reperfusion-induced cerebral injury. Cerebral ischemia was induced by occluding right and left common carotid arteries (global cerebral ischemia) for 30 min followed by reperfusion for 1 h and 4 h individually. Various biochemical alterations, produced subsequent to the application of bilateral carotid artery occlusion (BCAO) followed by reperfusion viz. increase in lipid peroxidation (LPO), hydrogen peroxide (H(2)O(2)), and decrease in reduced glutathione (GSH), catalase (CAT) and superoxide dismutase (SOD), level in the brain tissue, Western blot analysis (Cu-Zn-SOD and CAT) and assessment of cerebral infarct size were measured. All those enzymes are markedly reversed and restored to near normal level in the groups pre-treated with W. calendulacea (250 and 500 mg/kg given orally in single and double dose/day for 10 days) in dose-dependent way. The effect of W. calendulacea had increased significantly the protein expression of copper/zinc superoxide dismutase (Cu-Zn-SOD) and CAT in cerebral ischemia. W. claendulacea was markedly decrease cerebral infarct damages but results are not statistically significant. It can be concluded that W. calendulacea possesses a neuroprotective activity against cerebral ischemia in rat.

Simulation-driven design of helmets for head impact protection using an injury-based criterion

The current paper suggests a new procedure for designing helmets for head impact protection for users such as motorcycle riders. According to the approach followed here, a helmet is mounted on a featureless Hybrid 3 headform that is used in assessing vehicles for compliance to the FMVSS 201 regulation in the USA for upper interior head impact safety. The requirement adopted in the latter standard, i.e. not exceeding a threshold HIC(d) limit of 1000, is applied in the present study as a likely criterion for adjudging the efficacy of helmets. An impact velocity of 6 m/s (13.5 mph) for the helmet-headform system striking a rigid target can probably be acceptable for ascertaining a helmet's effectiveness as a countermeasure for minimizing the risk of severe head injury. The proposed procedure is demonstrated with the help of a validated LS-DYNA model of a featureless Hybrid 3 headform in conjunction with a helmet model comprising an outer polypropylene shell to the inner surface of which is bonded a protective polyurethane foam padding of a given thickness. Based on simulation results of impact on a rigid surface, it appears that a minimum foam padding thickness of 40 mm is necessary for obtaining an acceptable value of HIC(d).

Remarkable Effect of Chalcogen Substitution on an Enzyme Mimetic for Deiodination of Thyroid Hormones

Iodothyronine deiodinases are selenoenzymes which regulate the thyroid hormone homeostasis by catalyzing the regioselective deiodination of thyroxine (T4). Synthetic deiodinase mimetics are important not only to understand the mechanism of enzyme catalysis, but also to develop therapeutic agents as abnormal thyroid hormone levels have implications in different diseases, such as hypoxia, myocardial infarction, critical illness, neuronal ischemia, tissue injury, and cancer. Described herein is that the replacement of sulfur/selenium atoms in a series of deiodinase mimetics by tellurium remarkably alters the reactivity as well as regioselectivity toward T4. The tellurium compounds reported in this paper represent the first examples of deiodinase mimetics which mediate sequential deiodination of T4 to produce all the hormone derivatives including T0 under physiologically relevant conditions.

Soluble Angiopoietin Receptor Tie-2 In Patients With Acute Myocardial Infarction And Its Detection By Optical Protein-Chip

The Tie-2 receptor has been shown to play a role in angiogenesis in atherosclerosis. The conventional method assaying the level of soluble Tie-2 (sTie-2) was ELISA. However, this method has some disadvantages. The aims of this research are to establish a more simple detection method, the optical protein-chip based on imaging ellipsomtry (OPC-IE) applying to Tie-2 assay. The sTie-2 biosensor surface on silicon wafer was prepared first, and then serum levels of sTie-2 in 38 patients with AMI were measured on admission (day 1), day 2, day 3 and day 7 after onset of chest pain and 41 healthy controls by ELISA and OPC-IE in parallel. Median level of sTie-2 increased significantly in the AMI patients when compared with the controls. Statistics showed there was a significant correlation in sTie-2 results between the two methods (r=0.923, P0.01). The result of this study showed that the level of sTie-2 increased in AMI, and OPC-IE assay was a fast, reliable, and convenient technique to measure sTie-2 in serum.

Spinal cord injury therapy through active learning

Therapy employing epidural electrostimulation holds great potential for improving therapy for patients with spinal cord injury (SCI) (Harkema et al., 2011). Further promising results from combined therapies using electrostimulation have also been recently obtained (e.g., van den Brand et al., 2012). The devices being developed to deliver the stimulation are highly flexible, capable of delivering any individual stimulus among a combinatorially large set of stimuli (Gad et al., 2013). While this extreme flexibility is very useful for ensuring that the device can deliver an appropriate stimulus, the challenge of choosing good stimuli is quite substantial, even for expert human experimenters. To develop a fully implantable, autonomous device which can provide useful therapy, it is necessary to design an algorithmic method for choosing the stimulus parameters. Such a method can be used in a clinical setting, by caregivers who are not experts in the neurostimulator's use, and to allow the system to adapt autonomously between visits to the clinic. To create such an algorithm, this dissertation pursues the general class of active learning algorithms that includes Gaussian Process Upper Confidence Bound (GP-UCB, Srinivas et al., 2010), developing the Gaussian Process Batch Upper Confidence Bound (GP-BUCB, Desautels et al., 2012) and Gaussian Process Adaptive Upper Confidence Bound (GP-AUCB) algorithms. This dissertation develops new theoretical bounds for the performance of these and similar algorithms, empirically assesses these algorithms against a number of competitors in simulation, and applies a variant of the GP-BUCB algorithm in closed-loop to control SCI therapy via epidural electrostimulation in four live rats. The algorithm was tasked with maximizing the amplitude of evoked potentials in the rats' left tibialis anterior muscle. These experiments show that the algorithm is capable of directing these experiments sensibly, finding effective stimuli in all four animals. Further, in direct competition with an expert human experimenter, the algorithm produced superior performance in terms of average reward and comparable or superior performance in terms of maximum reward. These results indicate that variants of GP-BUCB may be suitable for autonomously directing SCI therapy.

Simulation of shock-induced bubble collapse with application to vascular injury in shockwave lithotripsy

Shockwave lithotripsy is a noninvasive medical procedure wherein shockwaves are repeatedly focused at the location of kidney stones in order to pulverize them. Stone comminution is thought to be the product of two mechanisms: the propagation of stress waves within the stone and cavitation erosion. However, the latter mechanism has also been implicated in vascular injury. In the present work, shock-induced bubble collapse is studied in order to understand the role that it might play in inducing vascular injury. A high-order accurate, shock- and interface-capturing numerical scheme is developed to simulate the three-dimensional collapse of the bubble in both the free-field and inside a vessel phantom. The primary contributions of the numerical study are the characterization of the shock-bubble and shock-bubble-vessel interactions across a large parameter space that includes clinical shockwave lithotripsy pressure amplitudes, problem geometry and tissue viscoelasticity, and the subsequent correlation of these interactions to vascular injury. Specifically, measurements of the vessel wall pressures and displacements, as well as the finite strains in the fluid surrounding the bubble, are utilized with available experiments in tissue to evaluate damage potential. Estimates are made of the smallest injurious bubbles in the microvasculature during both the collapse and jetting phases of the bubble's life cycle. The present results suggest that bubbles larger than 1 μm in diameter could rupture blood vessels under clinical SWL conditions.

Apaf-1 Inhibitors Protect from Unwanted Cell Death in In Vivo Models of Kidney Ischemia and Chemotherapy Induced Ototoxicity

Background: Excessive apoptosis induces unwanted cell death and promotes pathological conditions. Drug discovery efforts aimed at decreasing apoptotic damage initially targeted the inhibition of effector caspases. Although such inhibitors were effective, safety problems led to slow pharmacological development. Therefore, apoptosis inhibition is still considered an unmet medical need. Methodology and Principal Findings: The interaction between Apaf-1 and the inhibitors was confirmed by NMR. Target specificity was evaluated in cellular models by siRNa based approaches. Cell recovery was confirmed by MTT, clonogenicity and flow cytometry assays. The efficiency of the compounds as antiapoptotic agents was tested in cellular and in vivo models of protection upon cisplatin induced ototoxicity in a zebrafish model and from hypoxia and reperfusion kidney damage in a rat model of hot ischemia. Conclusions: Apaf-1 inhibitors decreased Cytc release and apoptosome-mediated activation of procaspase-9 preventing cell and tissue damage in ex vivo experiments and in vivo animal models of apoptotic damage. Our results provide evidence that Apaf-1 pharmacological inhibition has therapeutic potential for the treatment of apoptosis-related diseases.

Perinatal hipoxic ischemic injury in the auditory pathway and the effect of several neuroprotective agents

192 p.

Análise da função diastólica em mulheres medicadas com antraciclínicos no tratamento do câncer de mama

O Câncer de mama é um dos problemas de saúde pública mais importantes em nosso país. São estimados, para 2010, 49.400 novos casos de câncer de mama no Brasil, com um risco estimado de 51 casos a cada 100 mil mulheres. A estratégia de tratamento das pacientes com tumores de mama pode passar pelo uso de quimioterapia. A doxorrubicina é uma das drogas mais ativas para o câncer de mama, pertencendo ao grupo das antraciclinas. A família das antraciclinas apresenta como efeito colateral dano ao miocárdio que pode chegar a 36% dependendo da dose utilizada. O efeito sobre o miocárdio costuma ocorrer mais comumente durante ou logo após o último ciclo de quimioterapia podendo, entretanto ocorrer após vários anos do último ciclo de quimioterapia. O objetivo deste estudo foi analisar as alterações da função diastólica ventricular esquerda em mulheres usuárias de antraciclínicos no tratamento do câncer de mama. Realizamos um estudo prospectivo, em uma coorte de mulheres entre 18 e 69 anos, com câncer de mama e indicação de quimioterapia com doxorrubicina. Acompanhamos por período não inferior a 18 meses um grupo de 38 pacientes que cumpriram os critérios de elegibilidade. A dose de doxorrubicina utilizada variou de 50 a 60 mg/m/SC. Todos os pacientes são do sexo feminino, e portadores do tipo histológico carcinoma ductal infiltrante. Duas pacientes faleceram durante o estudo, de causa não cardíaca. Em nossa avaliação, ao final do estudo observamos que os parâmetros: dimensões do átrio esquerdo, dimensões do ventrículo esquerdo na diástole, dimensões do ventrículo esquerdo na sístole, velocidade da onda E, relação da fase de enchimento rápido pela sístole atrial, velocidade diastólica tardia do anel mitral, velocidade diastólica precoce do anel mitral, tempo de desaceleração e a relação da velocidade de enchimento rápido precoce de VE pela velocidade diastólica precoce do anel mitral demonstraram serem parâmetros de grande utilidade para seguimento da lesão cardíaca por antraciclínicos. Já o que não ocorreu com: a fração de encurtamento, fração de ejeção, volume do AE, volume do AE corrigido pela superfície corporal, velocidade diastólica tardia, tempo de relaxamento isovolumétrico, velocidade sistólica do anel mitral, que não apresentaram alterações significativas neste estudo. A análise da função diastólica utilizando o ecocardiograma mostrou ser um método eficaz, que em conjunto com a da função sistólica possibilita detectar precocemente o possível dano miocárdico, oriundo ao uso da quimioterapia com antraciclínicos, favorecendo uma intervenção terapêutica precoce e adequada.

Neuroprotective effects of resveratrol and docosahexaenoic acid antioxidants in perinatal hypoxic-ischemic brain injury in rats

295 p.

Injury Rates of Red King Crab, Paralithodes camtschaticus, Passing Under Bottom-trawl Footropes

The rate of injuries sustained by red king crab, Paralithodes camtschaticus, during passage under several types of bottom trawl footropes was examined using a modified bottom trawl in Bristol Bay, Alaska. Crabs were recaptured and examined for injuries after passing under each of three trawl footropes representing those commonly used in the bottom trawl fisheries of the eastern Bering Sea. Using the injury rate from tows with a floated footrope which minimized crab contact to account for handling injuries, injury rates of 5, 7, and 10% were estimated for crabs passing under the three commercial trawl footropes.

Avaliação dos testículos de ratos submetidos à torção testicular antes, durante e após a puberdade, e o efeito do tratamento com L-arginina

Torção testicular (TT) é uma síndrome urológica comumente encontrada em recém nascidos, crianças e adolescentes. Neste trabalho foi estudada as lesões morfológicas e a função reprodutiva em ratos adultos que sofreram TT, em diferentes idades de maturidade sexual e o efeito protetor da L-arginina, contra os danos causados pela isquemia/reperfusão na torção testicular. Dezoito ratos pré-púberes (4 semanas de vida) dezessete púberes (6 semanas de vida) e dezessete adultos (9 semanas de vida) foram submetidos à TT. Sob anestesia o testículo direito foi rotacionado em 720 e fixado, sendo então destorcido após 4 horas. Vinte e quatro ratos (ARG4, n=8, ARG6, n=8 e ARG9 n=8) foram submetidos ao tratamento com 650mg/kg de L-arginina, por via oral, durante 7 dias. Outros trinta ratos de mesma idade sofreram cirurgia simulada (SH4, n=10, SH6, n=10 e SH9, n=10). Com 12 semanas de idade, foram submetidos ao acasalamento controlado com 3 fêmeas e ao vigésimo dia de gestação o número de fetos, corpos lúteos, absorções e implatações foram contados. Na 14 semana, os ratos foram mortos e os espermatozóides coletados da cauda dos epidídimos, foi anotado o peso corporal, o peso e volume testicular. O soro foi usado para dosagem de testosterona. Foram avaliadas a concentração, motilidade e a viabilidade espermática. Os testículos coletados foram fixados em Bouin, pós-fixados em formalina e processados em parafina. Utilizando o programa de imagem Image J, lâminas coradas com HE, mensuramos a altura do epitélio, densidade volumétrica e diâmetro do túbulo seminífero. Para avaliar a integridade do epitélio seminífero foi utilizado a frequência dos estágios do ciclo do epitélio e o escorre de Johnsen. Também foi avaliado a proliferação do compartimento tubular e intertubular, através da imunomarcação com PCNA. Os dados foram tabulados e as médias dos grupos comparadas pelo teste de ANOVA com pós-teste de Bonferroni ou teste de Kruskal-Wallis com pós teste de Dunns (programa Graphpad Prism, com p < 0,05). Os resultados revelaram grandes danos produzidos pela injuria testicular, no testículo ipsilateral, com diminuição da capacidade reprodutiva, da concentração, viabilidade e mobilidade, do peso e volume testicular. Animais TT9 não apresentaram espermatozoides nas amostras coletas. Houve diminuição do diâmetro dos túbulos seminíferos e da altura do epitélio, aumento do compartimento intertubular, com ênfase dos vasos sanguíneos, aumento da proliferação celular estromal e diminuição da proliferação epitelial. Houve diminuição da concentração sérica de testosterona no grupo TT4, quando comparado como grupo TT9. Em geral, os animais submetidos à torção na fase adulta foram os mais acometidos. Não foram encontradas alterações dignas de nota, nos testículo contralaterais. Animais tratados com L-arginina obtiveram melhora dos índices reprodutivos, com aumento da potência em todas as idades. Houve aumento da concentração espermática no testículo contralateral de ARG4 e ARG6, mostrando que a L-arginina atuou como antioxidante. Não houve proteção para as lesões causadas pela torção na maioria dos grupos, mas os animais tratados ARG9 apresentaram concentração espermática mensuravel, quando comparados aos ratos TT9, que tinham azospermia.