Publications

BACKGROUND AND METHODS

In vivo neuroimaging studies have provided evidence of decreases in the gray matter volume of the cingulate gyrus in subjects with schizophrenia as compared to healthy controls. To investigate whether these changes might be related to heritable influences, we used high-resolution magnetic resonance imaging and labeled cortical mantle distance mapping to measure gray matter volume, as well as thickness and the area of the gray/white interface, in the anterior and posterior segments of the cingulate gyrus in 28 subjects with schizophrenia and their non-psychotic siblings, and in 38 healthy control subjects and their siblings.

RESULTS

There was a significant effect of group status on posterior cingulate cortex (PCC) gray matter volume (p=0.02). Subjects with schizophrenia and their non-psychotic siblings showed similar reductions of gray matter volume (approximately 10%) in the PCC compared to healthy control subjects and their siblings. In turn, trend level effects of group status were found for thickness (p=0.08) and surface area (p=0.11) of the PCC. In the combined group of schizophrenia subjects and their siblings, a direct correlation was observed between PCC gray matter volume and negative symptoms. However, the reduction in PCC gray matter volume in schizophrenia subjects and their siblings was proportionate to an overall reduction in whole cerebral volume, i.e., the effect of group on the volume of the PCC became non-significant when cerebral volume was included as a covariate (p=0.4). There was no significant effect of group on anterior cingulate cortex volume, thickness, or area.

CONCLUSIONS

Our findings suggest that decreases in the gray matter volume of the PCC occur in schizophrenia subjects and their siblings. The presence of such decreases in the non-psychotic siblings of schizophrenia subjects suggests that heritable factors may be involved in the development of cortical abnormalities in schizophrenia.

BACKGROUND

Nearly 1.8 million smokers in California receive their health insurance benefits through their employer. The extent to which these workers have coverage for tobacco-dependence treatments (TDTs) through their employer-sponsored health care is unknown.

METHODS

This research used the 2000 and 2005 data from the California Employer Health Benefits Surveys to determine coverage for TDTs by private firms. The overall response rates of firms to the survey were 41% and 36%, respectively. The samples used in this analysis are limited to private firms in California that offered employee health benefits in 2000 (n=729) or in 2005 (n=745).

RESULTS

This research found that among private firms offering health insurance coverage, there was a significant increase from 2000 to 2005 in the percentage of workers covered for any TDTs (44% to 57%). Rates of coverage for all three forms of TDTs (nicotine replacement therapy, Zyban, counseling) doubled from 11% to 22% over the 5-year time period.

CONCLUSIONS

Although coverage levels have improved, they still fall short of the recommendations made in the U.S. Public Health Service guidelines as well as in the Healthy People 2010 objectives. Given the effectiveness, cost effectiveness, public demand for coverage, and relatively low cost of covering TDTs--estimated to be $3-$6 per member per year--it is difficult to understand why such coverage is not more widely available in California.

BACKGROUND

Use of different methods for assessing the efficacy of artemisinin-based combination antimalarial treatments (ACTs) will result in different estimates being reported, with implications for changes in treatment policy.

METHODS

Data from different in vivo studies of ACT treatment of uncomplicated falciparum malaria were combined in a single database. Efficacy at day 28 corrected by PCR genotyping was estimated using four methods. In the first two methods, failure rates were calculated as proportions with either (1a) reinfections excluded from the analysis (standard WHO per-protocol analysis) or (1b) reinfections considered as treatment successes. In the second two methods, failure rates were estimated using the Kaplan-Meier product limit formula using either (2a) WHO (2001) definitions of failure, or (2b) failure defined using parasitological criteria only.

RESULTS

Data analysed represented 2926 patients from 17 studies in nine African countries. Three ACTs were studied: artesunate-amodiaquine (AS+AQ, N = 1702), artesunate-sulphadoxine-pyrimethamine (AS+SP, N = 706) and artemether-lumefantrine (AL, N = 518).Using method (1a), the day 28 failure rates ranged from 0% to 39.3% for AS+AQ treatment, from 1.0% to 33.3% for AS+SP treatment and from 0% to 3.3% for AL treatment. The median [range] difference in point estimates between method 1a (reference) and the others were: (i) method 1b = 1.3% [0 to 24.8], (ii) method 2a = 1.1% [0 to 21.5], and (iii) method 2b = 0% [-38 to 19.3].The standard per-protocol method (1a) tended to overestimate the risk of failure when compared to alternative methods using the same endpoint definitions (methods 1b and 2a). It either overestimated or underestimated the risk when endpoints based on parasitological rather than clinical criteria were applied. The standard method was also associated with a 34% reduction in the number of patients evaluated compared to the number of patients enrolled. Only 2% of the sample size was lost when failures were classified on the first day of parasite recurrence and survival analytical methods were used.

CONCLUSION

The primary purpose of an in vivo study should be to provide a precise estimate of the risk of antimalarial treatment failure due to drug resistance. Use of survival analysis is the most appropriate way to estimate failure rates with parasitological recurrence classified as treatment failure on the day it occurs.

MicroRNAs (miRNAs) are crucial for normal embryonic stem (ES) cell self-renewal and cellular differentiation, but how miRNA gene expression is controlled by the key transcriptional regulators of ES cells has not been established. We describe here the transcriptional regulatory circuitry of ES cells that incorporates protein-coding and miRNA genes based on high-resolution ChIP-seq data, systematic identification of miRNA promoters, and quantitative sequencing of short transcripts in multiple cell types. We find that the key ES cell transcription factors are associated with promoters for miRNAs that are preferentially expressed in ES cells and with promoters for a set of silent miRNA genes. This silent set of miRNA genes is co-occupied by Polycomb group proteins in ES cells and shows tissue-specific expression in differentiated cells. These data reveal how key ES cell transcription factors promote the ES cell miRNA expression program and integrate miRNAs into the regulatory circuitry controlling ES cell identity.

The prevention of autoimmunity requires the elimination of self-reactive T cells during their development and maturation. The expression of diverse self-antigens by stromal cells in the thymus is essential to this process and depends, in part, on the activity of the autoimmune regulator (Aire) gene. Here we report the identification of extrathymic Aire-expressing cells (eTACs) resident within the secondary lymphoid organs. These stromally derived eTACs express a diverse array of distinct self-antigens and are capable of interacting with and deleting naïve autoreactive T cells. Using two-photon microscopy, we observed stable antigen-specific interactions between eTACs and autoreactive T cells. We propose that such a secondary network of self-antigen-expressing stromal cells may help reinforce immune tolerance by preventing the maturation of autoreactive T cells that escape thymic negative selection.