Estrategia para bloquear la entrada del virus de la Hepatitis C (HCV) en hepatocitos primarios

En esta memoria se presenta una propuesta para desarrollar un proyecto de investigación que permita establecer la eficacia de una estrategia original para evitar la entrada del virus de la hepatitis C (HCV) en las células hepáticas. Se propone la utilización combinada de dos anticuerpos contra dos factores esenciales para la entrada HCV en las células hepáticas, como son las moléculas CD81 y SR-BI. La eficacia para reducir la capacidad infectiva del HCV de bloquear individualmente cada una de estas moléculas ha sido previamente demostrada, así que en este proyecto proponemos que un uso combinado de moléculas que bloqueen ambos receptores permitiría avanzar en la búsqueda de vacunas que eviten eficazmente la infección del HCV.

Pharmacogenetics of MicroRNAs and MicroRNAs Biogenesis Machinery in Pediatric Acute Lymphoblastic Leukemia

Despite the clinical success of acute lymphoblastic leukemia (ALL) therapy, toxicity is frequent. Therefore, it would be useful to identify predictors of adverse effects. In the last years, several studies have investigated the relationship between genetic variation and treatment-related toxicity. However, most of these studies are focused in coding regions. Nowadays, it is known that regions that do not codify proteins, such as microRNAs (miRNAs), may have an important regulatory function. MiRNAs can regulate the expression of genes affecting drug response. In fact, the expression of some of those miRNAs has been associated with drug response. Genetic variations affecting miRNAs can modify their function, which may lead to drug sensitivity. The aim of this study was to detect new toxicity markers in pediatric B-ALL, studying miRNA-related polymorphisms, which can affect miRNA levels and function. We analyzed 118 SNPs in pre-miRNAs and miRNA processing genes in association with toxicity in 152 pediatric B-ALL patients all treated with the same protocol (LAL/SHOP). Among the results found, we detected for the first time an association between rs639174 in DROSHA and vomits that remained statistically significant after FDR correction. DROSHA had been associated with alterations in miRNAs expression, which could affect genes involved in drug transport. This suggests that miRNA-related SNPs could be a useful tool for toxicity prediction in pediatric B-ALL.

Standard and routine metabolic rates of juvenile sandbar sharks (Carcharhinus plumbeus), including the effects of body mass and acute temperature change*

Standard and routine metabolic rates (SMRs and RMRs, respectively) of juvenile sandbar sharks (Carcharhinus plumbeus) were measured over a range of body sizes (n=34) and temperatures normally associated with western Atlantic coastal nursery areas. The mean SMR Q10 (increase in metabolic rate with temperature) was 2.9 ±0.2. Heart rate decreased with increasing body mass but increased with temperature at a Q10 of 1.8−2.2. Self-paired measures of SMR and RMR were obtained for 15 individuals. Routine metabolic rate averaged 1.8 ±0.1 times the SMR and was not correlated with body mass. Assuming the maximum metabolic rate of sandbar sharks is 1.8−2.75 times the SMR (as is observed in other elasmobranch species), sandbar sharks are using between 34% and 100% of their metabolic scope just to sustain their routine continuous activity. This limitation may help to explain their slow individual and population growth rates, as well as the slow recoveries from overfishing of many shark stocks worl

Liver genomic responses to ciguatoxin: evidence for activation of Phase I and Phase II detoxification pathways following an acute hypothermic response in mice

Ciguatoxins (CTX) are polyether neurotoxins that target voltage-gated sodium channels and are responsible for ciguatera, the most common fish-borne food poisoning in humans. This study characterizes the global transcriptional response of mouse liver to a symptomatic dose (0.26 ng/g) of the highly potent Pacific ciguatoxin-1 (P-CTX-1). At 1 h post-exposure 2.4% of features on a 44K whole genome array were differentially expressed (p ≤ 0.0001), increasing to 5.2% at 4 h and decreasing to 1.4% by 24 h post-CTX exposure. Data were filtered (|fold change| ≥ 1.5 and p ≤ 0.0001 in at least one time point) and a trend set of 1550 genes were used for further analysis. Early gene expression was likely influenced prominently by an acute 4°C decline in core body temperature by 1 h, which resolved by 8 h following exposure. An initial downregulation of 32 different solute carriers, many involved in sodium transport, was observed. Differential gene expression in pathways involving eicosanoid biosynthesis and cholesterol homeostasis was also noted. Cytochrome P450s (Cyps) were of particular interest due to their role in xenobiotic metabolism. Twenty-seven genes, mostly members of Cyp2 and Cyp4 families, showed significant changes in expression. Many Cyps underwent an initial downregulation at 1 h but were quickly and strongly upregulated at 4 and 24 h post-exposure. In addition to Cyps, increases in several glutathione S-transferases were observed, an indication that both phase I and phase II metabolic reactions are involved in the hepatic response to CTX in mice.

Acute effect of sumithion on certain blood parameters and mortality rate of fish, Heteropneustes fossilis (Bloch)

The acute toxic effect of the toxicant sumithion (50% E.C.) on mortality rate (after 24, 48, 72, and 96 h), total RBC count and haemoglobin content (after 48 and 72 h) on Heteropneustes fossilis was investigated at four concentrations (9.7, 10.7 and 11.1 ppm). The sumithion treated fishes showed lower RBC and Hb levels than the untreated ones. A gradual decrease in the total RBC counts and Hb contents was recorded with increasing concentration of toxicant after 72 h but the blood showed fluctuating values after 48 h of treatment.

Toxic effects of dimecron to fingerlings of Labeo rohita (Ham.) during acute and chronic exposures

The toxic effects of dimecron on growth, body composition and oxygen consumption of fingerlings of Labeo rohita were studied. Dimecron concentrations of 4 and 8 mg/l were used. Both acute (3-h) and chronic (15- 42 d) exposure schedules were followed. Compared with the control fish, both 4 and 8 mg/l dimecron treatment significantly suppressed weight gained in fish by 9.71% and 30% respectively during a 42 day exposure period. However, the length of fish was suppressed by 11.46% significantly only in fish group exposed to 8 mg/l dimecron. Similarly, the protein content was also significantly reduced in the above group of fish. The oxygen consumption of fish was elevated considerably, but not significantly in both group of treated fish (8.5% and 26.07%) during acute exposure. However, after 15 days of exposure the rate decreased by 18.98% significantly only in fish exposed to 8 mg/l dimecron. The threshold level of DO at low oxygen environment found to be slightly higher in fish at 8 mg/l dimecron. The survival time at the above oxygen condition was reduced during acute exposure (3-h) and that was extended during chronic (15-d) exposure.

Acute toxicity of chlorpyrifos, cadusafos and diazinon to three Indian major carps (Catla catla, Labeo rohita and Cirrhinus mrigala) fingerlings

Fingerlings of three Indian major carps, viz. Catla catla (Hamilton-Buchanon), Labeo rohita (Hamilton-Buchanon) and Cirrhinus mrigala (Hamilton-Buchanon), were exposed to different concentrations of chlorpyrifos (lorsban 10 G), cadusafos (rugby 10 G) and diazinon (basudin 10 G) for a period of 96h with a view to determine the median lethal concentrations (LC sub50) values for each of chemicals. Of the tested concentrations, chlorpyrifos at a dose of 6.65 ppm, cadusafos at 2.0 ppm and diazinon at a dose of 8.40 ppm or above induced 100% mortalities within 96h of exposure. The 96h LC sub50 values of chlorpyrefos, cadusafos and diazinon were 1.66, 0.72 and 2.10 ppm for C. catla, 2.35, 0.72 and 2.97 for L. rohita and 2.35, 0.72 and 2.10 ppm for C. mrigala, respectively. Pesticide induced behavioral abnormalities observed in the present study included erratic movements, rapid operculum activities, jumping of fish out of the test media, violent spasm and convulsion.

Effect of some environmental factors on the acute toxicity of deltamethrin to common carp: a laboratory study under aerobic condition

The toxicity of xenobiotic in aquatic ecosystems is influenced by many factors such as ambient temperature, water hardness, pond soil type, etc. In the present study, it was observed that air temperature, water hardness and soil sediment have profound influence on the toxicity of deltamethrin to common carp fry (ay. length 3.5 ± 0.5 cm, ay. weight 0.58 ± 0.25 g); 96h LC(sub)50 values for common carp at 38.07 ± 2.20°C maximum and 27.86 ± 1.22°C minimum air temperature in soft and very hard water were 0.102 and 0.495 µg lˉ¹, respectively. This value had increased significantly to 2.37 and 3.02 µg at 30.55 ± 1.21°C maximum and 26.04 ± 0.61°C minimum air temperature, respectively. When sediment was included, 96h LC(sub)50 at 38.07°C maximum temperature in very hard water was 1.808 µg 1ˉ¹ and this had increased to 8.073 µg 1ˉ¹ when tested at 30.55°C maximum temperature. Due to the 7.5°C increase in maximum and 1.7°C in minimum temperature, toxicity increased significantly. Lower toxicity in very hard water in comparison to soft water may be due to the lower solubility of deltarnethrin and high level of calcium. Adsorption reaction of deltamethrin with clay, humus, FeOOH, MnOOH and particulate organic carbon, and complexation reaction with dissolved organic carbon were responsible for the lowered toxicity in the experiment with sediment. Exposure time had no significant effect on acute toxicity of deltamethrin.

Influence of some abiotic factors on the acute toxicity of cadmium to Cyprinus carpio

Hardness of water had significant effect on the acute toxicity of cadmium to common carp, Cyprinus carpio. The 96h LC sub(50) and safe application rate increased from 43.17 and 22.77 mg 1 super(-1) in soft water (0.9 mM Ca super(2+) l super(-1)) to 310.48 and 177.66 mg l super(-1), respectively, in very hard water (6.0 mM Ca super(2+) l super(-1)). In medium hard and hard water, 96h LC sub(50) values were 48.39 and 116.45 mg l super(-1). When sediments were included in the medium hard, hard and very hard water treatments, the 96h LC sub(50) were 111.20, 133.71 and 334.47 mg l super(-1), respectively. Among these values, the one for medium hard water with sediment treatment was significantly higher than medium hard water treatment; values for the other two treatments were non-significant when compared with respective water treatments. Sediment was able to reduce the acute toxicity of cadmium mainly due to the complexation of cadmium with dissolved organic carbon (DOC). At the lower hardness level, cadmium complexed with DOC and the acute toxicity was reduced significantly. At higher hardness, most of the DOC sites were occupied by calcium and the acute toxicity of cadmium was not significantly reduced in hard water with sediment and very hard water with sediment experiments in comparison to respective water treatments.

Acute toxicity of copper, zinc and mercury on intertidal gastropods of Mumbai coast

The acute toxicity test conducted by static bioassay techniques have revealed that among selected heavy metals, copper is more toxic than zinc and mercury to Planaxis sulcatus and Trochus radiatus. The natural availability of heavy metals in the surrounding environment of these organisms is found to be deciding factor for their toxicity. Natural habitat of the animal also contributes to the sensitivity of a particular animal to the heavy metals tested. In addition the tendency of the animal to overcome the adverse conditions in their surrounding also plays a significant role in toxicity of pollutants.

Toxic effects of dimecron to Labeo rohita Ham. fingerlings during acute and chronic exposures: histopathological changes

The exposure to the highest dimecron cone. (8 mg/1) resulted in severe histopathological changes in different tissues of Labeo rohita fingerling. Cell necrosis, cytoplasmic vacuolation and pycnotic nuclei were major abnormalities observed in liver tissue. The degeneration of glomeruli and proximal tubules, cytoplasmic vacuolation and focal haemorrhagic area were noted in case of kidney tissues. Major changes observed in intestinal tissues were degeneration of villi, disintegrity of mucosal layers, necrosis of epithelial cells etc. However, hypertrophy of cells and granulation of cytoplasm were major histopathological changes observed in fish at lower dimecron cones. (4 mg/1).

Acute toxicity of four heavy metals to Sphaeroma walkeri and Ciroiana bovina (Crustacea:Isopoda)

The median lethal concentrations (LC50) of two Isopoda species exposed to each tested metal (Cu. Co, Cd and Zn) in static tests for different exposure periods are quite variable depending on the tested metal The LC50 values for Sphaeroma walkeri after 24 hours exposure to Cu and Co were estimated graphically to be 11.20 and 7.00 mg/1 respectively. The correspoding values for Cirolana bovina exposed to Cu, Co, Cd and Zn were 3.60, 11.0, 3.80 and 4.80 mg/1 respectively. For 2 days the LC50 of S. walkeri exposed to Cd was 5.60 mg/l, but it was 10.10 mg/l for 3 days exposure to Zn. After prolonged exposure the LC50 values decreased proportionally with the exposure duration of the test the percentages of surviving animals demonstrated a progressive decrease with increasing concentratins as a main factor from the analysis of variance (ANOV A). The sensitivity of adult S. walkeri exposed to the four heavy metals for different exposure times ranked: Cd>Co>Zn>Cu. Cirolana bovina appeared to be more sensitive to Cu. Cd and Zn than to Co. Species in order of increasing sensitivity is C. bovina more than S. walker.