Genetic and environmental influences of white and gray matter signal contrast: a new phenotype for imaging genetics?

The estimation of cortical thickness is in part dependent on the degree of contrast in T1 signal intensity between white matter and gray matter along the cortical mantle. The ratio of white matter to gray matter signal (WM/GM contrast) has been found to vary as a function of age and Alzheimer's disease status, suggesting a biological component to what might otherwise be labeled as a nuisance variable. The aim of the present study was to determine if measures of WM/GM contrast are genetically influenced, as well as the degree to which this phenotype may be related to the genetic and environment determinants of cortical thickness. Participants were 514 male twins (130 monozygotic, 97 dizygotic pairs, and 60 unpaired individuals) from the Vietnam Era Twin Study of Aging. Ages ranged from 51 to 59 years. Measures of WM/GM contrast and cortical thickness were derived for 66 cortical regions of interest (ROI) using FreeSurfer-based methods. Univariate and bivariate twin analyses were used in order to estimate the heritability of WM/GM contrast, as well as the degree of shared genetic and environmental variance between WM/GM contrast and cortical thickness. WM/GM contrast was found to be significantly heritable in the majority of ROIs. The average heritability across individual ROIs was highest in the occipital lobe (.50), and lowest in the cingulate cortex (.24). Significant phenotypic correlations between WM/GM contrast and cortical thickness were observed for most of the ROIs. The majority of the phenotypic correlations were negative, ranging from ?.11 to ?.54. Of the 66 associations, only 17 significant genetic correlations were found, ranging from ?.16 to ?.34, indicating small amounts of shared genetic variance. The majority of the phenotypic correlations were accounted for by small unique environmental effects common between WM/GM contrast and cortical thickness. These findings demonstrate that like cortical thickness, WM/GM contrast is a genetically influenced brain structure phenotype. The lack of significant genetic correlations with cortical thickness suggests that this measure potentially represents a unique source of genetic variance, one that has yet to be explored by the field of imaging genetics.     

FLASH is an essential component of Cajal bodies

Cajal bodies are small nuclear organelles with a number of nuclear functions. Here we show that FLICE-associated huge protein (FLASH), originally described as a component of the apoptosis signaling pathway, is mainly localized in Cajal bodies and is essential for their structure. Reduction in FLASH expression by short hairpin RNA results in disruption of the normal architecture of the Cajal body and relocalization of its components. Because the function of FLASH in the apoptosis receptor signaling pathway has been strongly questioned, we have now identified a clear function for this protein.     

Prolonged stimulation of growth hormone (GH) and insulin-like growth factor I secretion by CJC-1295, a long-acting analog of GH-releasing hormone, in healthy adults

CONTEXT: Therapeutic use of GHRH to enhance GH secretion is limited by its short duration of action. OBJECTIVE: The objective of this study was to examine the pharmacokinetic profile, pharmacodynamic effects, and safety of CJC-1295, a long-acting GHRH analog. DESIGN: The study design was two randomized, placebo-controlled, double-blind, ascending dose trials with durations of 28 and 49 d. SETTING: The study was performed at two investigational sites. PARTICIPANTS: Healthy subjects, ages 21-61 yr, were studied. INTERVENTIONS: CJC-1295 or placebo was administered sc in one of four ascending single doses in the first study and in two or three weekly or biweekly doses in the second study. MAIN OUTCOME MEASURES: The main outcome measures were peak concentrations and area under the curve of GH and IGF-I; standard pharmacokinetic parameters were used for CJC-1295. RESULTS: After a single injection of CJC-1295, there were dose-dependent increases in mean plasma GH concentrations by 2- to 10-fold for 6 d or more and in mean plasma IGF-I concentrations by 1.5- to 3-fold for 9-11 d. The estimated half-life of CJC-1295 was 5.8-8.1 d. After multiple CJC-1295 doses, mean IGF-I levels remained above baseline for up to 28 d. No serious adverse reactions were reported. CONCLUSIONS: Subcutaneous administration of CJC-1295 resulted in sustained, dose-dependent increases in GH and IGF-I levels in healthy adults and was safe and relatively well tolerated, particularly at doses of 30 or 60 microg/kg. There was evidence of a cumulative effect after multiple doses. These data support the potential utility of CJC-1295 as a therapeutic agent.     

Estrogen deficiency and bone loss: an inflammatory tale

Estrogen plays a fundamental role in skeletal growth and bone homeostasis in both men and women. Although remarkable progress has been made in our understanding of how estrogen deficiency causes bone loss, the mechanisms involved have proven to be complex and multifaceted. Although estrogen is established to have direct effects on bone cells, recent animal studies have identified additional unexpected regulatory effects of estrogen centered at the level of the adaptive immune response. Furthermore, a potential role for reactive oxygen species has now been identified in both humans and animals. One major challenge is the integration of a multitude of redundant pathways and cytokines, each apparently capable of playing a relevant role, into a comprehensive model of postmenopausal osteoporosis. This Review presents our current understanding of the process of estrogen deficiency-mediated bone destruction and explores some recent findings and hypotheses to explain estrogen action in bone. Due to the inherent difficulties associated with human investigation, many of the lessons learned have been in animal models. Consequently, many of these principles await further validation in humans.     

The correlation of RANK, RANKL and TNFalpha expression with bone loss volume and polyethylene wear debris around hip implants

This study investigates receptor activator NF-kappaB (RANK), RANK ligand (RANKL) and tumour necrosis factor (TNFalpha), key factors regulating bone turnover, present in the tissues near peri-prosthetic osteolysis. Tissue was obtained from zones of peri-prosthetic osteolysis from 11 patients undergoing revision of total hip prostheses, analysed preoperatively by high-resolution spiral multislice CT using a metal artefact suppression protocol. Synovial tissue from 10 patients with osteoarthritis undergoing primary hip replacement was used as control tissue. Immunohistochemical analysis of formalin fixed tissue sections demonstrated that RANK, RANKL and TNFalpha were strongly expressed by large multinucleated cells containing polyethylene wear debris in revision tissues. Control tissue stained weakly for RANK, RANKL and TNFalpha. A strong statistical correlation (p<0.02) was found between the five parameters, volume of bone loss, polyethylene wear debris, RANK, RANKL and TNFalpha expression. Importantly, in vitro studies revealed that RANKL and TNFalpha synergise to increase the volume of bone resorbed, by more than seven fold, when compared to the effect of either cytokine treatment alone. This suggests that the interaction of TNFalpha and RANKL promotes osteoclast activity associated with polyethylene wear and therapies targeting TNF activity may be useful to treat peri-implant osteolysis.     

A population-based twin study of the relationship between neuroticism and internalizing disorders

OBJECTIVE: The anxiety and depressive disorders exhibit high levels of lifetime comorbidity with one another. The authors examined how genetic and environmental factors shared by the personality trait neuroticism and seven internalizing disorders may help explain this comorbidity. METHOD: Lifetime major depression, generalized anxiety disorder, panic disorder, agoraphobia, social phobia, animal phobia, situational phobia, and neuroticism were assessed in over 9,000 twins from male-male, female-female, and opposite-sex pairs through structured diagnostic interviews. Multivariate structural equation models were used to decompose the correlations between these phenotypes into genetic and environmental components, allowing for sex-specific factors. RESULTS: Genetic factors shared with neuroticism accounted for between one-third and one-half of the genetic risk across the internalizing disorders. When nonsignificant gender differences were removed from the models, the genetic correlations between neuroticism and each disorder were high, while individual-specific environmental correlations were substantially lower. In addition, the authors could identify a neuroticism-independent genetic factor that significantly increased risk for major depression, generalized anxiety disorder, and panic disorder. CONCLUSIONS: There is substantial, but not complete, overlap between the genetic factors that influence individual variation in neuroticism and those that increase liability across the internalizing disorders, helping to explain the high rates of comorbidity among the latter. This may have important implications for identifying the susceptibility genes for these conditions.