Epigenetic consequences of in utero exposure to rosuvastatin include altered histone methylation patterns in newborn rat brains

Rosuvastatin (RST) is primarily used in the treatment of high cholesterol levels. As it has potentially harmful but not well-documented effects on embryos, the use of statins is currently contraindicated during pregnancy. To demonstrate whether RST could induce molecular epigenetic events, measured as histone methylations, in the newborn brains, pregnant mothers were treated daily with oral RST doses from the 11th day of pregnancy for 10 days. On postnatal day 1, the brains of absolute control, vehicle-treated control, and RST-treated rats were removed for western blots and immunohistochemistry. We demonstrated that RST induced molecular epigenetic events in the brains of newborn rats when pregnant mothers were treated daily with oral RST. By analyzing cell-type-specific markers in the newborn brains we demonstrated that prenatal RST administration did not affect the light microscopic cytoarchitecture and cell type ratios of the nervous tissue as compared to the controls. However, we found that prenatal RST administration induced a general, nonsignificant increase in H2AK118me1, H2BK5me1, H3, H3K9me3, H3K27me3, H3K36me2, H4, H4K20me2, and H4K20me3 levels, as compared to the controls. Moreover, we found that significant changes were detected in the number of H3K4me1 and H3K4me3 sites (134.3% ± 19.2% and 127.8% ± 8.5% of the controls, respectively), which are generally recognized as transcriptional activators. Using fluorescent/confocal immunohistochemistry for cell-type-specific markers and histone methylation marks on tissue sections, we demonstrated that most of the increase at these sites belonged to neuronal cell nuclei. We concluded that prenatal RST treatment induced epigenetic changes that might affect neuronal differentiation and development, and such possibilities should be taken into account when human RST therapy is recommended

Raising the Standard for Expert Testimony: An Unwarranted Obstacle in Proving Claims of Child Sexual Abuse in Dependency Hearings

This comment will examine the Amber B. court\u27s decision to characterize evidence provided by the mental health professionals as scientific evidence and not as expert opinion. Secondly, this comment will explore the desirability of imposing the scientific evidence standard, usually applied in criminal cases, to dependency hearings. Finally, this comment will discuss the implications of the Amber B. decision in light of the already present evidentiary difficulties of proving child sexual abuse claims and the social policy of protecting the welfare of the abused child

Raising the Standard for Expert Testimony: An Unwarranted Obstacle in Proving Claims of Child Sexual Abuse in Dependency Hearings

This comment will examine the Amber B. court\u27s decision to characterize evidence provided by the mental health professionals as scientific evidence and not as expert opinion. Secondly, this comment will explore the desirability of imposing the scientific evidence standard, usually applied in criminal cases, to dependency hearings. Finally, this comment will discuss the implications of the Amber B. decision in light of the already present evidentiary difficulties of proving child sexual abuse claims and the social policy of protecting the welfare of the abused child

The Use of Senior Volunteers in the Care of Discharged Geriatric Patients

This article reports on a project that utilized senior volunteers in the role of health advocates for geriatric patients discharged from a hospital. The project was evaluated to determine if healthy and active seniors could make a contribution to the health and social welfare of such discharged elderly persons. The study was conducted in Montreal, Canada and funded by a federal grant from Health Canada. The research collaborators came from a 414-bed secondary care university-affiliated community hospital, a community social service agency with a mandate to respond to the needs of its frail elderly constituents, and a university-based research centr

Kynurenic Acid and Its Analog SZR104 Exhibit Strong Antiinflammatory Effects and Alter the Intracellular Distribution and Methylation Patterns of H3 Histones in Immunochallenged Microglia-Enriched Cultures of Newborn Rat Brains

Kynurenic acid (KYNA) is implicated in antiinflammatory processes in the brain through several cellular and molecular targets, among which microglia-related mechanisms are of paramount importance. In this study, we describe the effects of KYNA and one of its analogs, the brain-penetrable SZR104 (N-(2-(dimethylamino)ethyl)-3-(morpholinomethyl)-4-hydroxyquinoline-2-carboxamide), on the intracellular distribution and methylation patterns of histone H3 in immunochallenged microglia cultures. Microglia-enriched secondary cultures made from newborn rat forebrains were immunochallenged with lipopolysaccharide (LPS). The protein levels of selected inflammatory markers C-X-C motif chemokine ligand 10 (CXCL10) and C-C motif chemokine receptor 1 (CCR1), histone H3, and posttranslational modifications of histone H3 lys methylation sites (H3K9me3 and H3K36me2, marks typically associated with opposite effects on gene expression) were analyzed using quantitative fluorescent immunocytochemistry and western blots in control or LPS-treated cultures with or without KYNA or SZR104. KYNA and SZR104 reduced levels of the inflammatory marker proteins CXCL10 and CCR1 after LPS-treatment. Moreover, KYNA and SZR104 favorably affected histone methylation patterns as H3K9me3 and H3K36me2 immunoreactivities, and histone H3 protein levels returned toward control values after LPS treatment. The cytoplasmic translocation of H3K9me3 from the nucleus indicated inflammatory distress, a process that could be inhibited by KYNA and SZR104. Thus, KYNA signaling and metabolism, and especially brain-penetrable KYNA analogs such as SZR104, could be key targets in the pathway that connects chromatin structure and epigenetic mechanisms with functional consequences that affect neuroinflammation and perhaps neurodegeneration

The kynurenic acid analog SZR104 induces cytomorphological changes associated with the anti-inflammatory phenotype in cultured microglia

We previously showed the anti-inflammatory effects of kynurenic acid (KYNA) and its brain-penetrable analog N -(2-(dimethylamino)ethyl)-3-(morpholinomethyl)-4-hydroxyquinoline-2-carboxamide (SZR104) both in vivo and in vitro. Here, we identified the cytomorphological effects of KYNA and SZR104 in secondary microglial cultures established from newborn rat forebrains. We quantitatively analyzed selected morphological aspects of microglia in control (unchallenged), lipopolysaccharide (LPS)-treated (challenged), KYNA- or SZR104-treated, and LPS + KYNA or LPS + SZR104-treated cultures. Multicolor immunofluorescence labeling followed by morphometric analysis (area, perimeter, transformation index, lacunarity, density, span ratio, maximum span across the convex hull, hull circularity, hull area, hull perimeter, max/min radii, mean radius, diameter of bounding circle, fractal dimension, roughness, circularity) on binary (digital) silhouettes of the microglia revealed their morphological plasticity under experimental conditions. SZR104 and, to a lesser degree, KYNA inhibited proinflammatory phenotypic changes. For example, SZR104 treatment resulted in hypertrophied microglia characterized by a swollen cell body, enlarged perimeter, increased transformation index/decreased circularity, increased convex hull values (area, perimeter, mean radius, maximum span, diameter of the bounding circle and hull circularity), altered box-counting parameters (such as fractal dimension), and increased roughness/decreased density. Taken together, analysis of cytomorphological features could contribute to the characterization of the anti-inflammatory activity of SZR104 on cultured microglia

Metabolomics reveals distinct neurochemical profiles associated with stress resilience

Acute social defeat represents a naturalistic form of conditioned fear and is an excellent model in which to investigate the biological basis of stress resilience. While there is growing interest in identifying biomarkers of stress resilience, until recently, it has not been feasible to associate levels of large numbers of neurochemicals and metabolites to stress-related phenotypes. The objective of the present study was to use an untargeted metabolomics approach to identify known and unknown neurochemicals in select brain regions that distinguish susceptible and resistant individuals in two rodent models of acute social defeat. In the first experiment, male mice were first phenotyped as resistant or susceptible. Then, mice were subjected to acute social defeat, and tissues were immediately collected from the ventromedial prefrontal cortex (vmPFC), basolateral/central amygdala (BLA/CeA), nucleus accumbens (NAc), and dorsal hippocampus (dHPC). Ultra-high performance liquid chromatography coupled with high resolution mass spectrometry (UPLC-HRMS) was used for the detection of water-soluble neurochemicals. In the second experiment, male Syrian hamsters were paired in daily agonistic encounters for 2 weeks, during which they formed stable dominant-subordinate relationships. Then, 24 h after the last dominance encounter, animals were exposed to acute social defeat stress. Immediately after social defeat, tissue was collected from the vmPFC, BLA/CeA, NAc, and dHPC for analysis using UPLC-HRMS. Although no single biomarker characterized stress-related phenotypes in both species, commonalities were found. For instance, in both model systems, animals resistant to social defeat stress also show increased concentration of molecules to protect against oxidative stress in the NAc and vmPFC. Additionally, in both mice and hamsters, unidentified spectral features were preliminarily annotated as potential targets for future experiments. Overall, these findings suggest that a metabolomics approach can identify functional groups of neurochemicals that may serve as novel targets for the diagnosis, treatment, or prevention of stress-related mental illness

Olfactory sensitivity of the marine flatfish Solea senegalensis to conspecific body fluids

Chemical communication is better understood in freshwater fish than marine fish. The Senegalese sole (Solea senegalensis) is a marine flatfish wherein one of the problems in aquaculture is the poor reproductive performance of hatchery-bred males. Is chemical communication involved in the reproduction of this species? Urine, intestinal fluid and mucus samples were taken from adult fish (wild-caught and hatchery-bred) over the spawning season (March-May), and assessed for olfactory potency using the electro-olfactogram (EOG). The effect of stimulation of the olfactory system with adult female urine on circulating luteinizing hormone (LH) levels was also tested in males. Intestinal fluid and urine were potent olfactory stimuli for both juvenile and adult conspecifics, evoking large-amplitude, concentration-dependent EOG responses, with thresholds of detection at approximately 1:10(6). However, the amplitude of the response to urine depended on the sex and state of maturity of both the donor and the receiver. Most olfactory activity could be extracted by C18 solid-phase cartridges. Urine from mature females evoked a slight, but significant, increase in circulating LH levels in mature males 30 min after exposure. Furthermore, the olfactory potency of urine differed between wild-caught and hatchery-bred fish; however, contrary to expectations, urine from wild-caught females was less potent than that from hatchery-bred females. Taken together, these results strongly suggest that faeces-and urine-released odorants are involved in reproduction in the Senegalese sole, and establish a basis for further investigation into pheromonal communication in marine teleosts.Instituto Nacional de Investigacion y Tecnologia Agraria y Alimentaria; EU through FEDER [RTA2011-00050, RTA2014-00048]; Ministerio de Economia y Competitividad (MINECO) [AGL2013-41196-R, RTA2013-00023-C02-01]; FPI-INIA - MINECO, Spain; Fundacao para a Ciencia e a Tecnologia (Foundation for Science and Technology, Portugal) [UID/Multi/04326/2013]info:eu-repo/semantics/publishedVersio