Tamoxifen induces cellular stress in the nervous system by inhibiting cholesterol synthesis

Background: Tamoxifen (TAM) is an important cancer therapeutic and an experimental tool for effecting genetic recombination using the inducible Cre-Lox technique. Despite its widespread use in the clinic and laboratory, we know little about its effects on the nervous system. This is of significant concern because TAM, via unknown mechanisms, induces cognitive impairment in humans. A hallmark of cellular stress is induction of Activating Transcription Factor 3 (Atf3), and so to determine whether TAM induces cellular stress in the adult nervous system, we generated a knock-in mouse in which Atf3 promoter activity drives transcription of TAM-dependent Cre recombinase (Cre-ERT2); when crossed with tdtomato reporter mice, Atf3 induction results in robust and permanent genetic labeling of cells in which it is up-regulated even transiently. Results: We found that granular neurons of the olfactory bulb and dentate gyrus, vascular cells and ependymal cells throughout the brain, and peripheral sensory neurons expressed tdtomato in response to TAM treatment. We also show that TAM induced Atf3 up-regulation through inhibition of cholesterol epoxide hydrolase (ChEH): reporter expression was mitigated by delivery in vitamin E-rich wheat germ oil (vitamin E depletes ChEH substrates), and was partially mimicked by a ChEH-specific inhibitor. Conclusions: This work demonstrates that TAM stresses cells of the adult central and peripheral nervous systems and highlights concerns about clinical and experimental use of TAM. We propose TAM administration in vitamin E-rich vehicles such as wheat germ oil as a simple remedy

Intensity Modulated Radiotherapy (IMRT) and Fractionated Stereotactic Radiotherapy (FSRT) for children with head-and-neck-rhabdomyosarcoma

<p>Abstract</p> <p>Background</p> <p>The present study evaluates the outcome of 19 children with rhabdomyosarcoma of the head-and-neck region treated with Intensity Modulated Radiotherapy (IMRT) or Fractionated Stereotactic Radiotherapy (FSRT) between August 1995 and November 2005.</p> <p>Methods</p> <p>We treated 19 children with head-and-neck rhabdomyosarcoma with FSRT (n = 14) or IMRT (n = 5) as a part of multimodal therapy. Median age at the time of radiation therapy was 5 years (range 2–15 years). All children received systemic chemotherapy according to the German Soft Tissue Sarcoma Study protocols.</p> <p>Median size of treatment volume for RT was 93,4 ml. We applied a median total dose of 45 Gy (range 32 Gy – 54 Gy) using a median fractionation of 5 × 1,8 Gy/week (range 1,6 Gy – 1,8 Gy).</p> <p>The median time interval between primary diagnosis and radiation therapy was 5 months (range 3–9 months).</p> <p>Results</p> <p>After RT, the 3- and 5-year survival rate was 94%. The 3- and 5-year actuarial local control rate after RT was 89%.</p> <p>The actuarial freedom of distant metastases rate at 3- and 5-years was 89% for all patients.</p> <p>Radiotherapy was well tolerated in all children and could be completed without interruptions > 4 days. No toxicities >CTC grade 2 were observed. The median follow-up time after RT was 17 months.</p> <p>Conclusion</p> <p>IMRT and FSRT lead to excellent outcome in children with head-and-neck RMS with a low incidence of treatment-related side effects.</p

Imaging findings in craniofacial childhood rhabdomyosarcoma

Rhabdomyosarcoma (RMS) is the commonest paediatric soft-tissue sarcoma constituting 3–5% of all malignancies in childhood. RMS has a predilection for the head and neck area and tumours in this location account for 40% of all childhood RMS cases. In this review we address the clinical and imaging presentations of craniofacial RMS, discuss the most appropriate imaging techniques, present characteristic imaging features and offer an overview of differential diagnostic considerations. Post-treatment changes will be briefly addressed

Metabolic Consequences and Vulnerability to Diet-Induced Obesity in Male Mice under Chronic Social Stress

Social and psychological factors interact with genetic predisposition and dietary habit in determining obesity. However, relatively few pre-clinical studies address the role of psychosocial factors in metabolic disorders. Previous studies from our laboratory demonstrated in male mice: 1) opposite status-dependent effect on body weight gain under chronic psychosocial stress; 2) a reduction in body weight in individually housed (Ind) male mice. In the present study these observations were extended to provide a comprehensive characterization of the metabolic consequences of chronic psychosocial stress and individual housing in adult CD-1 male mice. Results confirmed that in mice fed standard diet, dominant (Dom) and Ind had a negative energy balance while subordinate (Sub) had a positive energy balance. Locomotor activity was depressed in Sub and enhanced in Dom. Hyperphagia emerged for Dom and Sub and hypophagia for Ind. Dom also showed a consistent decrease of visceral fat pads weight as well as increased norepinephrine concentration and smaller adipocytes diameter in the perigonadal fat pad. On the contrary, under high fat diet Sub and, surprisingly, Ind showed higher while Dom showed lower vulnerability to obesity associated with hyperphagia. In conclusion, we demonstrated that social status under chronic stress and individual housing deeply affect mice metabolic functions in different, sometime opposite, directions. Food intake, the hedonic response to palatable food as well as the locomotor activity and the sympathetic activation within the adipose fat pads all represent causal factors explaining the different metabolic alterations observed. Overall this study demonstrates that pre-clinical animal models offer a suitable tool for the investigation of the metabolic consequences of chronic stress exposure and associated psychopathologies

Effects of the social environment during adolescence on the development of social behaviour, hormones and morphology in male zebra finches (Taeniopygia guttata)

Abstract Background Individual differences in behaviour are widespread in the animal kingdom and often influenced by the size or composition of the social group during early development. In many vertebrates the effects of social interactions early in life on adult behaviour are mediated by changes in maturation and physiology. Specifically, increases in androgens and glucocorticoids in response to social stimulation seem to play a prominent role in shaping behaviour during development. In addition to the prenatal and early postnatal phase, adolescence has more recently been identified as an important period during which adult behaviour and physiology are shaped by the social environment, which so far has been studied mostly in mammals. We raised zebra finches ( Taeniopygia guttata ) under three environmental conditions differing in social complexity during adolescence\ua0-\ua0juvenile pairs, juvenile groups, and mixed-age groups - and studied males\u2019 behavioural, endocrine, and morphological maturation, and later their adult behaviour. Results As expected, group-housed males exhibited higher frequencies of social interactions. Group housing also enhanced song during adolescence, plumage development, and the frequency and intensity of adult courtship and aggression. Some traits, however, were affected more in juvenile groups and others in mixed-age groups. Furthermore, a testosterone peak during late adolescence was suppressed in groups with adults. In contrast, corticosterone concentrations did not differ between rearing environments. Unexpectedly, adult courtship in a test situation was lowest in pair-reared males and aggression depended upon the treatment of the opponent with highest rates shown by group-reared males towards pair-reared males. This contrasts with previous findings, possibly due to differences in photoperiod and the acoustic environment. Conclusion Our results support the idea that effects of the adolescent social environment on adult behaviour in vertebrates are mediated by changes in social interactions affecting behavioural and morphological maturation. We found no evidence that long-lasting differences in behaviour reflect testosterone or corticosterone levels during adolescence, although differences between juvenile and mixed-age groups suggest that testosterone and song behaviour during late adolescence may be associated

Imaging findings in noncraniofacial childhood rhabdomyosarcoma

Rhabdomyosarcoma (RMS) is the most common soft-tissue sarcoma of childhood. This paper is focuses on imaging for diagnosis, staging, and follow-up of noncraniofacial RMS

The developmental impact of prenatal stress, prenatal dexamethasone and postnatal social stress on physiology, behaviour and neuroanatomy of primate offspring: studies in rhesus macaque and common marmoset

RATIONALE: Exposure of the immature mammalian brain to stress factors, including stress levels of glucocorticoids, either prenatally or postnatally, is regarded as a major regulatory factor in short- and long-term brain function and, in human, as a major aetiological factor in neuropsychiatric disorders. Experimental human studies are not feasible and animal studies are required to demonstrate causality and elucidate mechanisms. A number of studies have been conducted and reviewed in rodents but there are relatively few studies in primates. OBJECTIVES: Here we present an overview of our published studies and some original data on the effects of: (1) prenatal stress on hypothalamic-pituitary-adrenal (HPA) re/activity and hippocampus neuroanatomy in juvenile-adolescent rhesus macaques; (2) prenatal dexamethasone (DEX) on HPA activity, behaviour and prefrontal cortex neuroanatomy in infant-adolescent common marmosets; (3) postnatal daily parental separation stress on HPA re/activity, behaviour, sleep and hippocampus and prefrontal cortex neuroanatomy in infant-adolescent common marmoset. RESULTS: Prenatal stress increased basal cortisol levels and reduced neurogenesis in macaque. Prenatal DEX was without effect on HPA activity and reduced social play and skilled motor behaviour in marmoset. Postnatal social stress increased basal cortisol levels, reduced social play, increased awakening and reduced hippocampal glucocorticoid and mineralocorticoid receptor expression in marmoset. CONCLUSIONS: Perinatal stress-related environmental events exert short- and long-term effects on HPA function, behaviour and brain status in rhesus macaque and common marmoset. The mechanisms mediating the enduring effects remain to be elucidated, with candidates including increased basal HPA function and epigenetic programming

Surviving Sepsis Campaign: International guidelines for management of severe sepsis and septic shock: 2008

SCOPUS: ar.jinfo:eu-repo/semantics/publishe