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Toxoplasma gondii is a protozoan that infects up to a third of the world’s population. This parasite can cause serious problems, especially if a woman is infected during pregnancy, when toxoplasmosis can cause miscarriage, or serious complications to the baby, or in an immunocompromised person, when the infection can possibly affect the patient’s eyes or brain. To identify potential drug candidates that could counter toxoplasmosis, we selected 13 compounds which were pre-screened in silico based on the proteome of T. gondii to be evaluated in vitro against the parasite in a cell-based assay. Among the selected compounds, three demonstrated in vitro anti-T. gondii activity in the nanomolar range (almitrine, bortezomib, and fludarabine), and ten compounds demonstrated anti-T. gondii activity in the micromolar range (digitoxin, digoxin, doxorubicin, fusidic acid, levofloxacin, lomefloxacin, mycophenolic acid, ribavirin, trimethoprim, and valproic acid). Almitrine demonstrated a Selectivity Index (provided by the ratio between the Half Cytotoxic Concentration against human foreskin fibroblasts and the Half Effective Concentration against T. gondii tachyzoites) that was higher than 47, whilst being considered a lead compound against T. gondii. Almitrine showed interactions with the Na+/K+ ATPase transporter for Homo sapiens and Mus musculus, indicating a possible mechanism of action of this compound.

Abstract This paper proposes a review of the American literature, as well as the main rulings of Supreme Court of United States, aiming to map the pros and cons of inserting a mandatory pre-dispute arbitration clause in contracts between investors and brokerage/advisory firms that trade on the securities market. The study discusses some proposals to banish this sort of clause and some ideas to reach a middle ground solution.

Toxoplasma gondii is a protozoan that infects up to a third of the world's population. This parasite can cause serious problems, especially if a woman is infected during pregnancy, when toxoplasmosis can cause miscarriage, or serious complications to the baby, or in an immunocompromised person, when the infection can possibly affect the patient's eyes or brain. To identify potential drug candidates that could counter toxoplasmosis, we selected 13 compounds which were pre-screened in silico based on the proteome of T. gondii to be evaluated in vitro against the parasite in a cell-based assay. Among the selected compounds, three demonstrated in vitro anti-T. gondii activity in the nanomolar range (almitrine, bortezomib, and fludarabine), and ten compounds demonstrated anti-T. gondii activity in the micromolar range (digitoxin, digoxin, doxorubicin, fusidic acid, levofloxacin, lomefloxacin, mycophenolic acid, ribavirin, trimethoprim, and valproic acid). Almitrine demonstrated a Selectivity Index (provided by the ratio between the Half Cytotoxic Concentration against human foreskin fibroblasts and the Half Effective Concentration against T. gondii tachyzoites) that was higher than 47, whilst being considered a lead compound against T. gondii. Almitrine showed interactions with the Na+/K+ ATPase transporter for Homo sapiens and Mus musculus, indicating a possible mechanism of action of this compound. [ABSTRACT FROM AUTHOR]

Background and aims: The reactive oxygen species (ROS) shows intensification of tissue damage caused by type I diabetes mellitus, and N-acetylcysteine (NAC) can modulate this process by reducing its action. However, in diabetics, NAC seems to potentiate these damages because it stimulates a high infiltration of CD4 and CD8 T lymphocytes, which leads to an important therapeutic association with anti-CD4 / CD8 antibodies. Besides, physical exercise can complement this treatment by stimulating the body's natural antioxidant defense. The purpose of this study was to analyze the effects of a combined treatment with NAC, anti-CD4 / CD8, and physical exercise on the reduction of damage in the salivary tissues on NOD mice. Material and methods: Female mice were divided into 5 groups with 6 animals each, composed by: Balb/c; NOD; NOD + Ex; NOD + NAC + CDs NOD + NAC + CDs + Ex. The NAC was applied intraperitoneally for 21 days at a dosage of 50mg/kg. The anti-CD4/CD8 were applied intravenously at a dosage of 25 µg/ml on days 0, 7, 14, and 21. During the experimental period, the animals of the exercise groups were subjected daily to 30 minutes of swimming exercise. After 21 days, the tissues were assessed by light microscopy analysis, stereological and immunofluorescence techniques for verification of INS-R insulin receptors. Results: For animals in the NOD + Ex groups; NOD + NAC + CDs; NOD + NAC + CDs + Ex, it was noticed a decrease in lymphocytes and inflammatory processes, as well as a significant increase in the relative neutrophils numbers. There was also a statistically significant difference in the increase of nuclear, and cytoplasmic volume, and an intense INR-S marking when compared to the NOD group without treatment. Conclusion: The therapy used, when associated with NAC to anti-CD4/CD8 promoted the recovery of glandular architecture and INS-R, along with benefit in the reduction of inflammatory processes. It was also found that physical exercise potentiated the therapeutic action of the drug in the tissue restructuring of the salivary glands. [ABSTRACT FROM AUTHOR]

Background and aims: Diabetes affects the metabolism promoting damage in different tissues, including salivary glands. Current treatments, such as insulin, are ineffective to recovery of these tissues. In this aspect, the immunotherapy has been tested, but it can be inefficient as an agent for the control of damage caused by diabetes. The aim of this study to evaluate the association in anti-CD4 and anti-CD8 monoclonal antibody in the recovery of salivary glands of diabetic NOD mice. Material and methods: Fifteen spontaneously diabetic mice (NOD) were divided into three groups with 5 animals each: group I (Balb/C control mice), group II (untreated NOD mice), group III (NOD mice treated with CD4 and CD8 antibodies). The CD4 and CD8 antibodies (IMUNY, Rheabiotech Ltda, Brazil) were administered by intravenously injections (25 ug/days: 0, 7, 14, and 21). After treatment salivary glands samples were analyzed by immunofluorescence, microscopy, light microscopy and stereology. (ethical approval process: 304/11), Analysis of variance (ANOVA) and Kruskal-Wallis nonparametric test were used. Results: Elevated levels of glucose (mg/dl) were observed in untreated animals (group II) (605.25 ± 31.23, p≤0.05), whereas in treated animals (group III), were noted a decrease in these levels (464.77 ± 39.66, p≤0.05). Tissue restructure, characterized by cell volume recovery, also was observed in group III (nuclear volume of parotid glands: (109.91 ± 02.03, p≤0.05) and submandibular glands: (107.52 ± 02, p≤0.05) (cytoplasmic volume of parotid glands: (356.14 ± 26.34, p≤0.05) and submandibular glands: (331.22 ± 32.11, p≤0.05). Intense signaling (+++) of insulin receptors was observed in animals of group I. On the other hand, in group II was noted a reduction of these receptors (+). In treated animals (group III) were observed a recovery of the insulin receptors (+++). Conclusions: This treatment was effective in the recovery of salivary acinar cells, contributed also to homeostasis of body metabolism. Thus, this immunomodulation promoted a beneficial effect on the recovery of these tissues. [ABSTRACT FROM AUTHOR]

Chronic mucosal trauma is suggested as an additional etiologic risk factor for oral squamous cell carcinoma (OSCC), but there is a lack of experimental-molecular data. If chronic trauma of the oral mucosa is carcinogenic, it should be associated with early genetic alterations seen during typical progression of OSCC, like loss of heterozygosity (LOH). We investigated LOH in the key chromosomal arms 3p, 9p and 17p in inflammatory fibrous hyperplasia associated with removable dental prosthesis and also in normal oral mucosa, by using the polymorphic microsatellite markers D3S1300 at 3p14.2, D9S1748 at 9p21, D17S1289 at 17p12 and D17S974 at 17p13 and capillary electrophoresis. LOH was detected in 2/15 (13%) fibrous hyperplasia samples similarly to other reactive and inflammatory lesions. None of the normal mucosa samples presented LOH. Our experimental-molecular results do not support the hypothesis that trauma associated with dental prosthesis has an important role in oral carcinogenesis. [ABSTRACT FROM AUTHOR]