Cassia angustifolia L. (senna) is traditionally used as a laxative. Its major components are sennosides that are responsible for the laxative effect. Senna is recommended for the short-term treatment ...of acute constipation. Nevertheless people use its preparations as self-medication, often for long periods, to treat chronic constipation thus exposing themselves to adverse reactions. Most reactions were associated with hepatotoxicity.
The present study was aimed to evaluate the toxicity of a C. angustifolia leafextract (standardized at 60% of sennosides) on rat liver cells and the long-term effects on liver functions, in Wistar rats.
Cytotoxicity was assessed in a buffalo normal rat liver cell line (BRL-3A) by the trypan blue assay and the 3-4,5-dimethylthiazol-2-yl-2,5-diphenyltetrazolium bromide reduction test. In vivo effects were observed after oral administration of the extract for 4 or 8 weeks at doses of 12 and 58 mg/kg/day. At the end of treatment, animals were sacrificed, the postmortem examination was performed and serum was used for biochemical analysis. Liver samples were used for histomorphological and immunohistochemical examination along with the determination of oxidative stress parameters.
In BRL-3A cells, the extract was cytotoxic at concentrations that appear largely higher than those attainable in humans. In Wistar rats, the extract did not induce any significant change in all of the parameters tested. In summary, the present study indicates a lack of hepatotoxicity of senna at doses higher than those generally used in humans.
Abstract Background The available prognostic models for overall survival (OS) in patients with metastatic urothelial carcinoma (UC) have been derived from clinical trial populations of ...cisplatin-treated patients. Objective To develop a new model based on real-world patients. Design, setting, and participants Individual patient-level data from 29 centers were collected, including metastatic UC and first-line cisplatin- or carboplatin-based chemotherapy administered between January 2006 and January 2011. Intervention First-line, platinum-based, combination chemotherapy. Outcome measurements and statistical analysis The population was randomly split into a development and a validation cohort. Generalized boosted regression modelling was used to screen out irrelevant variables and address multivariable analyses. Two nomograms were built to estimate OS probability, the first based on baseline factors and platinum agent, the second incorporating objective response (OR). The performance of the above nomograms and that of other available models was assessed. We plotted decision curves to evaluate the clinical usefulness of the two nomograms. Results and limitations A total of 1020 patients were analyzed (development: 687, validation: 333). In a platinum-stratified Cox model, significant variables for OS were performance status ( p < 0.001), white blood cell count ( p = 0.013), body mass index ( p = 0.003), ethnicity ( p = 0.012), lung, liver, or bone metastases ( p < 0.001), and prior perioperative chemotherapy ( p = 0.012). The c-index was 0.660. The distribution of the nomogram scores was associated with OR ( p < 0.001), and incorporating OR into the model further improved the c-index in the validation cohort (0.670). Conclusions We developed and validated two nomograms for OS to be used before and after completion of first-line chemotherapy for metastatic UC. Patient summary We proposed two models for estimating overall survival of patients with metastatic urothelial carcinoma receiving first-line, platinum-based chemotherapy. These nomograms have been developed on real-world patients who were treated outside of clinical trials and may be used irrespective of the chemotherapeutic platinum agent used.
The activation of materials due to exposure to cosmic rays may become an important background source for experiments investigating rare event phenomena. DarkSide-20k, currently under construction at ...the Laboratori Nazionali del Gran Sasso, is a direct detection experiment for galactic dark matter particles, using a two-phase liquid-argon Time Projection Chamber (TPC) filled with 49.7 tonnes (active mass) of Underground Argon (UAr) depleted in 39Ar. Despite the outstanding capability of discriminating γ/β background in argon TPCs, this background must be considered because of induced dead time or accidental coincidences mimicking dark-matter signals and it is relevant for low-threshold electron-counting measurements. Here, the cosmogenic activity of relevant long-lived radioisotopes induced in the experiment has been estimated to set requirements and procedures during preparation of the experiment and to check that it is not dominant over primordial radioactivity; particular attention has been paid to the activation of the 120 t of UAr used in DarkSide-20k. Expected exposures above ground and production rates, either measured or calculated, have been considered in detail. From the simulated counting rates in the detector due to cosmogenic isotopes, it is concluded that activation in copper and stainless steel is not problematic. The activity of 39Ar induced during extraction, purification and transport on surface is evaluated to be 2.8% of the activity measured in UAr by DarkSide-50 experiment, which used the same underground source, and thus considered acceptable. Other isotopes in the UAr such as 37Ar and 3H are shown not to be relevant due to short half-life and assumed purification methods.
Microglial cells comprise a network of endogenous immunocompetent cells that pervade the brain and spinal cord. The primary function of this system is to provide continuous surveillance of the ...parenchyma and protect the central nervous system (CNS) during injury and disease. Here we discuss the involvement of microglia during brain aging and aging-related neurodegenerative disease, i.e. Alzheimers disease, and briefly summarize their possible roles in amyotrophic lateral sclerosis (ALS). In addition, we provide an overview of the neuroinflammation associated with primary brain tumors and how microglial tumor cytotoxicity could be targeted for immunotherapeutic approaches designed to treat these lesions.
The effect of increasing amounts of wheat bran (0, 5, 10, 20%) in AIN-76 semisynthetic diet on colonic luminal short chain fatty acids, epithelial cell histone acetylation, and cytokinetics, was ...studied for 2 weeks in groups of 10 male Sprague-Dawley rats. Luminal contents were removed from the colon at sacrifice, quick frozen, and analyzed for short chain fatty acids by gas-liquid chromatography. Histone acetylation was assessed in cells isolated from the same animals. Cell proliferation was measured after a short pulse in vivo with 3Hthymidine. Colonic luminal butyrate levels were lower in the 0 and 20% fiber groups, and higher in the 5 and 10% fiber groups. In contrast, cell proliferation, as determined by labeling index, was higher in the 0 and 20% fiber groups, and lower in the 5 and 10% fiber groups. This resulted in a significant inverse correlation between luminal butyrate levels and colonic cell proliferation. In addition, there was a positive linear correlation between luminal butyric acid levels and colon epithelial cell histone acetylation. From these data it was concluded that colonic butyrate levels can be modulated by the addition of wheat bran to the diet and that butyrate can modulate DNA synthesis (calculated as labeling index) in the proliferative compartments of colonic crypts. The localization of dividing cells was unchanged and no induction of terminal differentiation was detectable (contrary to what has been observed for transformed cells in culture).
In mares, endometrial fibrosis results from abnormal collagen deposition in the stroma and around the endometrial glands. The pathogenesis of endometrial fibrosis remains unknown, but the different ...types of collagens are a fundamental part of the process. The Picrosirius Red (PSR) staining is widely studied and necessary for collagen fiber and tissue remodeling. The present study aimed to determine the collagen deposition and the gene expression of collagen-2(COL-2) and collagen-3(COL-3) in the endometrium of mares with different degrees of fibrosis. Cyclic mares (n = 34) with a mean age of 14 ± 6.4 years old were used. A uterine biopsy from each mare was obtained at diestrus (D5–D10). Mares were grouped according to the degree of uterine fibrosis described by Kenney (1978): Grade I (n = 12), Grade II (n = 12), and Grade III (n = 10). Collagen in the equine endometrium was morphometrically quantified under PSR staining. The morphometric quantification of the images was performed from each sample after digital microphotographs were taken at 200x magnification, processed, and evaluated using the ImageJ 1.52a software. COL-2 and COL-3 expression was performed using qPCR. Grades were considered independent factors. Collagen-stained area and transcript expression were considered dependent factors. Data were analyzed with ANOVA andt-test. A Pearson correlation was performed between age and collagen deposition. The percentage of tissue collagen area stained with PSR revealed a significant increase between all groups in collagen deposition according to the degree of fibrosis: Grade I (11.7 ± 1.4%), Grade II (17.8 ± 1.3%), and Grade III (24.1 ± 1.9%). Age and the percentage of collagen deposited in the endometrial tissue correlated (r = 0.5) (P = 0.015). Grade II samples presented higher expression of COL-2 transcripts compared to Grade I (P = 0.026) and Grade III (P = 0.003). However, COL-3 did not show differences between groups. This study agrees with other studies that indicate that the worsening of degenerative changes coincides with advanced mare age. Sample evaluations emphasizing degenerative changes rely on an experienced evaluator, while the PSR, followed by computerized analysis, presents quantitative data. In conclusion, the increase in PSR analysis in Grade II and Grade III mares compared to Grade I demonstrates that this technique could play an important role in routine analyses for the detection, quantification, and dynamics of collagen in specific tissues. The study revealed that COL-2 might be involved in the progression and differentiation of healthy endometrium into an endometrium with severe fibrosis.
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