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Androgen deprivation therapy (ADT) remains the cornerstone of advanced prostate cancer treatment. However, the progression towards castration-resistant prostate cancer is inevitable, as the cancer cells reactivate androgen receptor signaling and adapt to the castrate state through autoregulation of the androgen receptor. Additionally, the upfront use of novel hormonal agents such as enzalutamide and abiraterone acetate may result in long-term toxicities and may trigger the selection of AR-independent cells through “Darwinian” treatment-induced pressure. Therefore, it is crucial to develop new strategies to overcome these challenges. Bipolar androgen therapy (BAT) is one such approach that has been devised based on studies demonstrating the paradoxical inhibitory effects of supraphysiologic testosterone on prostate cancer growth, achieved through a variety of mechanisms acting in concert. BAT involves rapidly alternating testosterone levels between supraphysiological and near-castrate levels over a period of a month, achieved through monthly intramuscular injections of testosterone plus concurrent ADT. BAT is effective and well-tolerated, improving quality of life and potentially re-sensitizing patients to previous hormonal therapies after progression. By exploring the mechanisms and clinical evidence for BAT, this review seeks to shed light on its potential as a promising new approach to prostate cancer treatment.

Objective: to describe the experiences of pregnant women at advanced maternal age assisted in a private hospital. Methods: a qualitative study, carried out with 17 women, by means of semi-structured interviews via telephone. The data was submitted to Thematic Content Analysis. Results: the participants were between 35 and 40 years old. Two categories emerged: Experiencing pregnancy as a couple and family: the preparation of the couple for pregnancy and childbirth (Pregnancy after 35 years old as an element of potentiality; Change in the family routine for the baby’s arrival) and Experiencing pregnancy and its changes: perceiving pregnancy as a healthy and calm experience (Change in emotional patterns related to the pregnancy process). Conclusion: experiencing pregnancy late in life was not a concern for women. Maturity and favorable socioeconomic conditions may have a protective influence on the course of healthy pregnancies in women attending the private health service.

This study exposed analysis fractal by the dimension D in the rock art. The Fractals is a new tool in the software application and digital photography for the recognition of raw materials, the study of its form, degradation, specific parts of paint, and providing new data the virtual reconstruction. The analyzes focus on various pictorial sets of the region Mezquital Valley, Hidalgo, Mexico; region where are concentrated more than 100 caves, comparing 74 images to analyze the various pictorial traditions. The structure fractal describes the dimension of the represented objects, not only according to its space where the figure is placed, but the possibility of being a fraction in which all the surfaces can be observed (rock, paint).

Abstract Background Hadruroides lunatus is the most abundant scorpion species in the Peruvian central coast, where most of the accidents involving humans are registered. In spite of its prevalence, there are only very few studies on H. lunatus envenomation. The aim of the present study was to analyze the cardiorespiratory alterations caused by H. lunatus envenomation in rodents. Methods Wistar rats injected with H. lunatus scorpion venom were submitted to electrocardiography. After euthanasia, rat lungs were collected and histopathologically analyzed. Mouse cardiomyocytes were used to perform immunofluorescence and calcium transient assays. Data were analyzed by ANOVA or Student’s t-test. The significance level was set at p< 0.05. Results It was observed that H. lunatus venom increased heart rate and caused arrhythmia, thereby impairing the heart functioning. Lungs of envenomed animals showed significant alterations, such as diffuse hemorrhage. In addition, immunofluorescence showed that H. lunatus venom was capable of binding to cardiomyocytes. Furthermore, mouse ventricular cardiomyocytes incubated with H. lunatus venom showed a significant decrease in calcium transient, confirming that H. lunatus venom exerts a toxic effect on heart. Conclusion Our results showed that H. lunatus venom is capable of inducing cardiorespiratory alterations, a typical systemic effect of scorpionism, stressing the importance of medical monitoring in envenomation cases.

Cholinergic control of the heart is exerted by two distinct branches; the autonomic component represented by the parasympathetic nervous system, and the recently described non-neuronal cardiomyocyte cholinergic machinery. Previous evidence has shown that reduced cholinergic function leads to deleterious effects on the myocardium. Yet, whether conditions of increased cholinergic signaling can offset the pathological remodeling induced by sympathetic hyperactivity, and its consequences for these two cholinergic axes are unknown. Here, we investigated two models of sympathetic hyperactivity: i) the chronic beta-adrenergic receptor stimulation evoked by isoproterenol (ISO), and ii) the α2A/α2C-adrenergic receptor knockout (KO) mice that lack pre-synaptic adrenergic receptors. In both models, cholinergic signaling was increased by administration of the cholinesterase inhibitor, pyridostigmine. First, we observed that isoproterenol produces an autonomic imbalance characterized by increased sympathetic and reduced parasympathetic tone. Under this condition transcripts for cholinergic proteins were upregulated in ventricular myocytes, indicating that non-neuronal cholinergic machinery is activated during adrenergic overdrive. Pyridostigmine treatment prevented the effects of ISO on autonomic function and on the ventricular cholinergic machinery, and inhibited cardiac remodeling. α2A/α2C-KO mice presented reduced ventricular contraction when compared to wild-type mice, and this dysfunction was also reversed by cholinesterase inhibition. Thus, the cardiac parasympathetic system and non-neuronal cardiomyocyte cholinergic machinery are modulated in opposite directions under conditions of increased sympathetic drive or ACh availability. Moreover, our data support the idea that pyridostigmine by restoring ACh availability is beneficial in heart disease.

Autonomic dysfunction is observed in many cardiovascular diseases and contributes to cardiac remodeling and heart disease. We previously reported that a decrease in the expression levels of the vesicular acetylcholine transporter (VAChT) in genetically-modified homozygous mice (VAChT KD(HOM)) leads to decreased cholinergic tone, autonomic imbalance and a phenotype resembling cardiac dysfunction. In order to further understand the molecular changes resulting from chronic long-term decrease in parasympathetic tone, we undertook a transcriptome-based, microarray-driven approach to analyze gene expression changes in ventricular tissue from VAChT KD(HOM) mice. We demonstrate that a decrease in cholinergic tone is associated with alterations in gene expression in mutant hearts, which might contribute to increased ROS levels observed in these cardiomyocytes. In contrast, in another model of cardiac remodeling and autonomic imbalance, induced through chronic isoproterenol treatment to increase sympathetic drive, these genes did not appear to be altered in a pattern similar to that observed in VAChT KD(HOM) hearts. These data suggest the importance of maintaining a fine balance between the two branches of the autonomic nervous system and the significance of absolute levels of cholinergic tone in proper cardiac function.

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We have identified a novel putative transcriptional regulator called strawberry notch homolog 2 (Sbno2) as a prominent IL-6-stimulated gene in astrocytes. The aim of this study was to: (i) examine the regulation of Sbno2 in astrocytes in vitro and in vivo , and (ii) establish lentiviral transduction of cells with a Sbno2 transgene for the functional characterization of Sbno2. In murine cultured astrocytes Sbno2 gene expression was significantly up-regulated in a dose- and time-dependent fashion following treatment with hyper-IL-6 (IL-6 + soluble IL-6 receptor). These changes were reflected by corresponding alterations in the level of the SBNO2 protein. The level of Sbno2 mRNA was up-regulated significantly in murine astrocytes by other glycoprotein130 cytokine-family members and the pro-inflammatory cytokines IL-1 β and TNF- α . Cycloheximide treatment resulted in markedly higher Sbno2 mRNA and did not abolish the up-regulation of Sbno2 mRNA mediated by hyper-IL-6. Following intra-peritoneal LPS injection in mice, Sbno2 mRNA levels in the brain increased significantly and was localized predominantly to astrocytes and the choroid plexus, and to a lesser extent to microglia, endothelial cells, and neurons. Characterisation of transduced NIH-3T3 fibroblasts revealed transgenic SBNO2 localised exclusively to the nucleus but not the nucleoli. Our findings indicate that the Sbno2 gene is broadly regulated in astrocytes and likely encodes a nuclear factor involved in the innate host response. A mouse model for the conditional deletion of the Sbno2 gene in astrocytes developed by us will provide an invaluable tool for evaluating function of Sbno2 in mammalian cells. Funding: NHMRC APP1047265; FWF J3081-B09. [ABSTRACT FROM AUTHOR]