Exposure to N-Ethyl-N-Nitrosourea in Adult Mice Alters Structural and Functional Integrity of Neurogenic Sites

BACKGROUND: Previous studies have shown that prenatal exposure to the mutagen N-ethyl-N-nitrosourea (ENU), a N-nitroso compound (NOC) found in the environment, disrupts developmental neurogenesis and alters memory formation. Previously, we showed that postnatal ENU treatment induced lasting deficits in proliferation of neural progenitors in the subventricular zone (SVZ), the main neurogenic region in the adult mouse brain. The present study is aimed to examine, in mice exposed to ENU, both the structural features of adult neurogenic sites, incorporating the dentate gyrus (DG), and the behavioral performance in tasks sensitive to manipulations of adult neurogenesis. METHODOLOGY/PRINCIPAL FINDINGS: 2-month old mice received 5 doses of ENU and were sacrificed 45 days after treatment. Then, an ultrastructural analysis of the SVZ and DG was performed to determine cellular composition in these regions, confirming a significant alteration. After bromodeoxyuridine injections, an S-phase exogenous marker, the immunohistochemical analysis revealed a deficit in proliferation and a decreased recruitment of newly generated cells in neurogenic areas of ENU-treated animals. Behavioral effects were also detected after ENU-exposure, observing impairment in odor discrimination task (habituation-dishabituation test) and a deficit in spatial memory (Barnes maze performance), two functions primarily related to the SVZ and the DG regions, respectively. CONCLUSIONS/SIGNIFICANCE: The results demonstrate that postnatal exposure to ENU produces severe disruption of adult neurogenesis in the SVZ and DG, as well as strong behavioral impairments. These findings highlight the potential risk of environmental NOC-exposure for the development of neural and behavioral deficits

Inadequate control of thyroid hormones sensitizes to hepatocarcinogenesis and unhealthy aging

An inverse correlation between thyroid hormone levels and longevity has been reported in several species and reduced thyroid hormone levels have been proposed as a biomarker for healthy aging and metabolic fitness. However, hypothyroidism is a medical condition associated with compromised health and reduced life expectancy. Herein, we show, using wild-type and the Pax8 ablated model of hypothyroidism in mice, that hyperthyroidism and severe hypothyroidism are associated with an overall unhealthy status and shorter lifespan. Mild hypothyroid Pax8 +/- mice were heavier and displayed insulin resistance, hepatic steatosis and increased prevalence of liver cancer yet had normal lifespan. These pathophysiological conditions were precipitated by hepatic mitochondrial dysfunction and oxidative damage accumulation. These findings indicate that individuals carrying mutations on PAX8 may be susceptible to develop liver cancer and/or diabetes and raise concerns regarding the development of interventions aiming to modulate thyroid hormones to promote healthy aging or lifespan in mammals

Ethical implications in the use of embryonic and adult neural stem cells

The advent and growth of technological advances have led to new routes of knowledge. Thereby, we currently face new challenges. We have just started to get a glimpse of the structural and functional role of neural stem cells in differentiation and migration processes, the origin of synaptic networks, and subsequent readjustments in specific circuits. A whole range of treatment possibilities originates from this knowledge that potentially can be used for different neurological diseases in humans. Although this is an encouraging scenario, it implies that the human brain is the object of such study, as well as its potential manipulation and transplantation. It is, therefore, pertinent that ethical principles should be followed in such research to have proper balance between what can be done and what should be done, according to every specific context. Hence, it is wise to consider ethical implications in every research project, along with potential clinical applications, under the principle of causing no harm, following risk and benefit rules in decision making and with respect of the human condition as a priority. Copyright � 2012 Rodrigo Ramos-Z��iga et al

The Smith-Robinson Approach to the Subaxial Cervical Spine: A Stepwise Microsurgical Technique Using Volumetric Models From Anatomic Dissections

BACKGROUND: The Smith-Robinson1 approach (SRA) is the most widely used route to access the anterior cervical spine. Although several authors have described this approach, there is a lack of the stepwise anatomic description of this operative technique. With the advent of new technologies in neuroanatomy education, such as volumetric models (VMs), the understanding of the spatial relation of the different neurovascular structures can be simplified. OBJECTIVE: To describe the anatomy of the SRA through the creation of VMs of anatomic dissections. METHODS: A total of 4 postmortem heads and a cervical replica were used to perform and record the SRA approach to the C4-C5 level. The most relevant steps and anatomy of the SRA were recorded using photogrammetry to construct VM. RESULTS: The SRA was divided into 6 major steps: positioning, incision of the skin, platysma, and muscle dissection with and without submandibular gland eversion and after microdiscectomy with cage positioning. Anatomic model of the cervical spine and anterior neck multilayer dissection was also integrated to improve the spatial relation of the different structures. CONCLUSION: In this study, we review the different steps of the classic SRA and its variations to different cervical levels. The VMs presented allow clear visualization of the 360-degree anatomy of this approach. This new way of representing surgical anatomy can be valuable resources for education and surgical planning

Impact of transient down-regulation of DREAM in human embryonic stem cell pluripotency: The role of DREAM in the maintenance of hESCs.

Journal Article;Little is known about the functions of downstream regulatory element antagonist modulator (DREAM) in embryonic stem cells (ESCs). However, DREAM interacts with cAMP response element-binding protein (CREB) in a Ca(2+)-dependent manner, preventing CREB binding protein (CBP) recruitment. Furthermore, CREB and CBP are involved in maintaining ESC self-renewal and pluripotency. However, a previous knockout study revealed the protective function of DREAM depletion in brain aging degeneration and that aging is accompanied by a progressive decline in stem cells (SCs) function. Interestingly, we found that DREAM is expressed in different cell types, including human ESCs (hESCs), human adipose-derived stromal cells (hASCs), human bone marrow-derived stromal cells (hBMSCs), and human newborn foreskin fibroblasts (hFFs), and that transitory inhibition of DREAM in hESCs reduces their pluripotency, increasing differentiation. We stipulate that these changes are partly mediated by increased CREB transcriptional activity. Overall, our data indicates that DREAM acts in the regulation of hESC pluripotency and could be a target to promote or prevent differentiation in embryonic cells.This work was supported by a nonprofit foundation ‘Fundación Progreso y Salud’ of the Andalusian Regional Ministry of Health; Consejería de Innovación Ciencia y Empresa, Junta de Andalucía and Fondo Europeo de Desarrollo Regional (FEDER) (CTS-6505; INP-2011-1615-900000 and P10-CVI-6095); Instituto de Salud Carlos III and Fondo Europeo de Desarrollo Regional (FEDER) (RD12/0019/0028; PI10/00964 and PI14/01015); the Ministry of Health and Consumer Affairs (Advanced Therapies Program Grant TRA-120)Ye