Some environmental contaminants interact with hormones and may exert adverse consequences as a result of their actions as endocrine disrupting chemicals (EDCs). Exposure in people is typically a ...result of contamination of the food chain, inhalation of contaminated house dust or occupational exposure. EDCs include pesticides and herbicides (such as dichlorodiphenyl trichloroethane or its metabolites), methoxychlor, biocides, heat stabilisers and chemical catalysts (such as tributyltin), plastic contaminants (e.g. bisphenol A), pharmaceuticals (i.e. diethylstilbestrol; 17α‐ethinylestradiol) or dietary components (such as phytoestrogens). The goal of this review is to address the sources, effects and actions of EDCs, with an emphasis on topics discussed at the International Congress on Steroids and the Nervous System. EDCs may alter reproductively‐relevant or nonreproductive, sexually‐dimorphic behaviours. In addition, EDCs may have significant effects on neurodevelopmental processes, influencing the morphology of sexually‐dimorphic cerebral circuits. Exposure to EDCs is more dangerous if it occurs during specific ‘critical periods’ of life, such as intrauterine, perinatal, juvenile or puberty periods, when organisms are more sensitive to hormonal disruption, compared to other periods. However, exposure to EDCs in adulthood can also alter physiology. Several EDCs are xenoestrogens, which can alter serum lipid concentrations or metabolism enzymes that are necessary for converting cholesterol to steroid hormones. This can ultimately alter the production of oestradiol and/or other steroids. Finally, many EDCs may have actions via (or independent of) classic actions at cognate steroid receptors. EDCs may have effects through numerous other substrates, such as the aryl hydrocarbon receptor, the peroxisome proliferator‐activated receptor and the retinoid X receptor, signal transduction pathways, calcium influx and/or neurotransmitter receptors. Thus, EDCs, from varied sources, may have organisational effects during development and/or activational effects in adulthood that influence sexually‐dimorphic, reproductively‐relevant processes or other functions, by mimicking, antagonising or altering steroidal actions.
Down syndrome (DS) is a genetic pathology characterized by intellectual disability and brain hypotrophy. Widespread neurogenesis impairment characterizes the fetal and neonatal DS brain, strongly ...suggesting that this defect may be a major determinant of mental retardation. Our goal was to establish, in a mouse model for DS, whether early pharmacotherapy improves neurogenesis and cognitive behavior. Neonate Ts65Dn mice were treated from postnatal day (P) 3 to P15 with fluoxetine, an antidepressant that inhibits serotonin (5-HT) reuptake and increases proliferation in the adult Ts65Dn mouse (Clark et al., 2006). On P15, they received a BrdU injection and were killed after either 2 h or 1 month. Results showed that P15 Ts65Dn mice had notably defective proliferation in the hippocampal dentate gyrus, subventricular zone, striatum, and neocortex and that proliferation was completely rescued by fluoxetine. In the hippocampus of untreated P15 Ts65Dn mice, we found normal 5-HT levels but a lower expression of 5-HT1A receptors and brain-derived neurotrophic factor (BDNF). In Ts65Dn mice, fluoxetine treatment restored the expression of 5-HT1A receptors and BDNF. One month after cessation of treatment, there were more surviving cells in the dentate gyrus of Ts65Dn mice, more cells with a neuronal phenotype, more proliferating precursors, and more granule cells. These animals were tested for contextual fear conditioning, a hippocampus-dependent memory task, and exhibited a complete recovery of memory performance. Results show that early pharmacotherapy with a drug usable by humans can correct neurogenesis and behavioral impairment in a model for DS.
Highly active antiretroviral therapy (HAART) has had a significant impact on the natural history of human immunodeficiency virus (HIV) infection, leading to a remarkable decrease in its morbidity and ...mortality, but is frequently associated with clinical and metabolic complications. Fat redistribution or lipodystrophy, hypertriglyceridaemia, hypercholesterolaemia, insulin resistance and diabetes mellitus have been extensively reported in subjects treated with protease inhibitor (PI)-based antiretroviral regimens. In particular, dyslipidaemia occurs in up to 70–80% of HIV-infected individuals receiving HAART and can be associated with all the available PIs, although hypertriglyceridaemia appears to be more frequent in patients treated with ritonavir, ritonavir–saquinavir, or ritonavir–lopinavir. The potential long-term consequences of HAART-associated hyperlipidaemia are not completely understood, but an increased risk of premature coronary artery disease has been reported in young HIV-positive persons receiving PIs. Dietary changes, regular aerobic exercise and switching to a PI-sparing regimen may act favourably on dyslipidaemia. Lipid-lowering therapy is often required with statins or fibrates. The choice of hypolipidaemic drugs should take into account potential pharmacological interactions with antiretroviral agents.
J. Neurochem. (2010) 115, 897-909. ABSTRACT: Polychlorinated dibenzo‐dioxins, furans and dioxin‐like polychlorinated biphenyls are ubiquitous in foodstuffs of animal origin and accumulate in the ...fatty tissues of animals and humans. The most toxic congener is 2,3,7,8‐tetrachlorodibenzo‐p‐dioxin (TCDD), a lipophilic endocrine‐disrupting molecule that accumulates in adipose tissue, placenta and milk. polychlorinated biphenyls and TCDD are known to interfere with thyroid hormone metabolism and signaling in the developing brain. As thyroid hormone is critical in the myelination process during development, we investigated the effect of a single dose of TCDD prenatal exposure (gestational day 18) on the myelination process. A semi‐quantitative analysis of oligodendrocyte markers at different stages of maturation was performed in the offspring's medulla oblongata, cerebellum, diencephalon and telenchephalon at different postnatal days (2/3, 14, 30 and 135). The most significant alterations observed were: (i) cerebellum and medulla oblongata: altered expression of oligodendroglial lineage and platelet‐derived growth factor alpha receptor, myelin basic protein (MBP) mRNAs (P2/3, P135) and MBP protein (P135); (ii) diencephalon: increase in platelet‐ derived growth factor alpha receptor mRNA level (P2/3); (iii) telenchephalon: decrease in MBP mRNA expression. The oligodendroglial generation capability of adult neural stem/precursor cells obtained ex vivo from TCDD and vehicle‐treated dams was then explored. TCDD impairs neurosphere proliferation and retards CNPase‐positive cell generation from adult neurospheres.
Remyelination failure is a key landmark in chronic progression of multiple sclerosis (MS), the most diffuse demyelinating disease in human, but the reasons for this are still unknown. It has been ...shown that thyroid hormone administration in the rodent models of acute and chronic demyelinating diseases improved their clinical course, pathology and remyelination. In the present study, we translated this therapeutic attempt to experimental allergic encephalomyelitis (EAE) in the non‐human primate Callithrix Jacchus (marmoset). We report that short protocols of triiodothyronine treatment shifts the demyelination/remyelination balance toward remyelination, as assessed by morphology, immunohistochemistry and molecular biology, and improves the clinical course of the disease. We also found that severely ill animals display hypothyroidism and severe alteration of deiodinase and thyroid hormone receptor mRNAs expression in the spinal cord, which was completely corrected by thyroid hormone treatment. We therefore suggest that thyroid hormone treatment improves myelin sheath morphology in marmoset EAE, by correcting the dysfunction of thyroid hormone cellular effectors.
Objectives
The aim of the study was to assess plasma concentrations of darunavir/ritonavir and raltegravir in older patients compared with younger patients with HIV‐1 infection.
Methods
In this ...observational, open‐label study, adult HIV‐infected out‐patients aged ≤ 40 years (younger patients) or ≥ 60 years (older patients) and treated with tenofovir/emtricitabine plus darunavir/ritonavir (800/100 mg daily) or raltegravir (400 mg twice daily) were asked to participate. The trough concentrations (Ctrough) of darunavir/ritonavir and raltegravir were assessed at steady state using a validated high‐performance liquid chromatography (HPLC)−tandem mass spectrometry method.
Results
A total of 88 HIV‐positive patients were enrolled in the study. Forty‐six patients were treated with darunavir/ritonavir, and 42 with raltegravir. The geometric mean plasma Ctrough (coefficient of variation) of raltegravir was comparable between the 19 older and 23 younger subjects: 106 ng/mL (151%) and 94 ng/mL (129%), respectively geometric mean ratio (GMR) 0.85; 95% confidence interval (CI) 0.71–1.57; P = 0.087. In contrast, the geometric mean plasma Ctrough of darunavir was significantly higher among the 21 older patients 2209 ng/mL (139%) than among the 25 younger patients 1876 ng/mL (162%); GMR 1.56; 95% CI: 1.22–1.88; P = 0.004. Similarly, the geometric mean Ctrough of ritonavir was significantly higher among older than among younger individuals.
Conclusions
The mean plasma Ctrough of darunavir and ritonavir was significantly higher in older patients than in younger patients with HIV‐1 infection, while the mean plasma level of raltegravir was comparable in the two groups. However, both regimens showed good tolerability in both younger and older subjects.
Nerve growth factor (NGF) is recognized as a pleiotropic molecule, exerting a variety of biological effects on different cell types and pathophysiological conditions, and its role in tissue wound ...healing has been recently highlighted. However, the preferential cellular target of NGF is still elusive in the complex cellular and molecular cross talk that accompanies wound healing. Thus, to explore possible NGF cellular targets in skin wound healing, we investigated the in vitro NGF responsiveness of keratinocytes (cell line HEKa), fibroblasts (cell line BJ), and endothelial cells (cell line HUVEC), also in the presence of adverse microenvironmental conditions, e.g., hyperglycemia. The main results are summarized as follows:
) NGF stimulates keratinocyte proliferation and HUVEC proliferation and angiogenesis in a dose-dependent manner although it has no effect on fibroblast proliferation;
) NGF stimulates keratinocyte but not fibroblast migration in the wound healing assay; and
) NGF completely reverts the proliferation impairment of keratinocytes and the angiogenesis impairment of HUVECs induced by high d-glucose concentration in the culture medium. These results contribute to better understanding possible targets for the therapeutic use of NGF in skin repair.
The possible use of cell therapies for neurological lesions and disorders is regarded as a very promising strategy. However, many issues related to cell type, tissue donor, expected biological action ...etc., are still open. In this study human mesenchymal stem cells derived from different fetal and adult tissues were examined in order to explore growth and neurotrophic factor synthesis and biological action, also considering the individual variability of the donors. Cells were derived from different human tissues and characterized according to the guidelines of the International Society for Cellular Therapy. Growth and neurotrophic factor synthesis was evaluated by real time PCR, biological assays and ELISA. It was found that human mesenchymal stem cells produce vascular endothelial-, nerve-growth factor (VEGF, NGF), brain-derived-, ciliary- and glial-derived neurotrophic factors (BDNF, CDGF, GDNF), which are neuroprotective molecules, but the source and the donor influence the synthesis rate. Accordingly, it is suggested that the source and the individual variability are key issues to be considered in the perspective of the clinical use of mesenchymal stem cells in neurological disorders.
Objectives
Recent clinical studies and one meta‐analysis have shown a modest but significant increase in the incidence of diabetes mellitus associated with statin exposure, so this correlation was ...investigated in a cohort of HIV‐positive subjects.
Methods
A retrospective cohort study including adult HIV‐1‐infected patients followed at our Clinic of Infectious Diseases between 2007 and 2014 was performed.
Results
We assessed 3170 HIV‐positive patients with a median follow‐up of 5.2 years. The incidence of diabetes mellitus was 1.2 per 100 person‐years and it was not significantly associated with the prescription of statins hazard ratio (HR) 1.09 per year of statin exposure; 95% confidence interval (CI) 0.7–1.49; P = 0.067, while it was associated with older age, chronic hepatitis C, antiretroviral‐naïve vs. antiretroviral experienced condition, high body mass index, and high serum concentration of triglycerides.
Conclusions
In our study, a higher risk of diabetes mellitus was not associated with statin treatment, but with some traditional risk factors.
Due to shared risk factors for transmission, coinfection with human immunodeficiency virus (HIV) and hepatitis C virus (HCV) is a very common event. The prevalence of HCV infection among HIV-positive ...patients averages about 35% in the United States and Europe, but in clinical populations where there is a great prevalence of intravenous drug use as a risk factor for acquiring HIV, this value may be as high as 80-90%. Several studies have confirmed that HIV coinfection accelerates the natural course of chronic hepatitis C and an increased risk of liver cirrhosis, hepatocellular carcinoma, and decompensated liver disease has been found in coinfected subjects. Other studies have shown an increased risk of progression to acquired immunodeficiency syndrome (AIDS) and AIDS-related death among HIV-HCV-positive persons, suggesting that HCV coinfection may accelerate the course of HIV disease. In addition, hepatitis C may affect the management of HIV infection, increasing the incidence of liver toxicity associated with the antiretroviral regimens. The optimal therapeutic approach to HCV infection in HIV coinfected patients is still uncertain, because of the complex pathogenesis of both infections, potential drugdrug interactions, and the poor literature and information available about safety and efficacy of an interferon (IFN) and ribavirin combination in this clinical population. Available data show that the sustained virological response rates in coinfected persons treated with standard IFN plus ribavirin range from 18-40%, and several studies with pegylated IFN plus ribavirin are ongoing.
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