Differential gene body methylation and reduced expression of cell adhesion and neurotransmitter receptor genes in adverse maternal environment.

Early life adversity, including adverse gestational and postpartum maternal environment, is a contributing factor in the development of autism, attention deficit hyperactivity disorder (ADHD), anxiety and depression but little is known about the underlying molecular mechanism. In a model of gestational maternal adversity that leads to innate anxiety, increased stress reactivity and impaired vocal communication in the offspring, we asked if a specific DNA methylation signature is associated with the emergence of the behavioral phenotype. Genome-wide DNA methylation analyses identified 2.3% of CpGs as differentially methylated (that is, differentially methylated sites, DMSs) by the adverse environment in ventral-hippocampal granule cells, neurons that can be linked to the anxiety phenotype. DMSs were typically clustered and these clusters were preferentially located at gene bodies. Although CpGs are typically either highly methylated or unmethylated, DMSs had an intermediate (20-80%) methylation level that may contribute to their sensitivity to environmental adversity. The adverse maternal environment resulted in either hyper or hypomethylation at DMSs. Clusters of DMSs were enriched in genes that encode cell adhesion molecules and neurotransmitter receptors; some of which were also downregulated, indicating multiple functional deficits at the synapse in adversity. Pharmacological and genetic evidence links many of these genes to anxiety.

The serotonin1A receptor gene as a genetic and prenatal maternal environmental factor in anxiety.

Low serotonin(1A) receptor (5-HT(1A)R) binding is a risk factor for anxiety and depression, and deletion of the 5-HT(1A)R results in anxiety-like behavior in mice. Here we show that anxiety-like behavior in mice also can be caused, independently of the offspring's own 5-HT(1A)R genotype, by a receptor deficit in the mother: a nongenetic transmission of a genetic defect. Some of the nongenetically transmitted anxiety manifestations were acquired prenatally and linked to a delay in dentate gyrus maturation in the ventral hippocampus of the offspring. Both the developmental delay and the anxiety-like phenotype were phenocopied by the genetic inactivation of p16(ink4a) encoding a cyclin-dependent kinase inhibitor implicated in neuronal precursor differentiation. No maternal 5-HT(1A)R genotype-dependent anxiety developed when the strain background was switched from Swiss Webster to C57BL/6, consistent with the increased resilience of this strain to early adverse environment. Instead, all anxiety manifestations were caused by the offspring's own receptor deficiency, indicating that the genetic and nongenetic effects converge to common anxiety manifestations. We propose that 5-HT(1A)R deficit represents a dual risk for anxiety and that vulnerability to anxiety associated with genetic 5-HT(1A)R deficiency can be transmitted by both genetic and nongenetic mechanisms in a population. Thus, the overall effect of risk alleles can be higher than estimated by traditional genetic assays and may contribute to the relatively high heritability of anxiety and psychiatric disorders in general.

Perception of forbidden colors in retinally stabilized equiluminant images: an indication of softwired cortical color opponency?

In color theory and perceptual practice, two color naming combinations are forbidden-reddish greens and bluish yellows-however, when multicolored images are stabilized on the retina, their borders fade and filling-in mechanisms can create forbidden colors. The sole report of such events found that only some observers saw forbidden colors, while others saw illusory multicolored patterns. We found that when colors were equiluminant, subjects saw reddish greens, bluish yellows, or a multistable spatial color exchange (an entirely novel perceptual phenomena); when the colors were nonequiluminant, subjects saw spurious pattern formation. To make sense of color opponency violations, we created a soft-wired model of cortical color opponency (based on winner-take-all competition) whose opponency can be disabled.

Interactions between short-term vertical phoria adaptation and nonconjugate adaptation of vertical pursuits.

We have demonstrated that short-term vertical position-specific phoria adaptation contributes to nonconjugate adaptation of vertical pursuits, but not to nonconjugate adaptation of vertical saccades. Binocular adaptation to multiple stationary vertical disparities resulted in both nonconjugate pursuits and phoria aftereffects but had little effect on the early step component of vertical saccades. Similarly, binocular nonconjugate adaptation of vertical pursuits produced both nonconjugate pursuits and fixation phoria aftereffects. Position-specific adaptation of nonconjugate pursuit was demonstrated by adapting to disparate motion in the upper field which resulted in nonconjugate pursuit aftereffects that were greater in the upper than the lower hemifield. These nonconjugate pursuits were accompanied by position-specific phoria aftereffects, indicating that common mechanisms underlie adaptation of vertical phoria and nonconjugate pursuits.

Directionally selective short-term nonconjugate adaptation of vertical pursuits.

We investigated the contribution of fixation phoria and dynamic processes to short term (1 hr) nonconjugate adaptation of vertical pursuits. Unequal aftereffects were observed in vertical phoria measured during stationary gaze and during pursuits (static fixation and pursuit phorias) demonstrating direction-specific aftereffects of pursuit phoria that were not evident in measures of fixation phoria. A linear model describes the combination of fixation phoria and three dynamic direction-specific components which include a gain component that determines nonconjugate velocity, a phase component that determines the relative position of binocular pursuits, and a small position specific pursuit phoria adjustment process. Larger position-specific variations of fixation phoria appear to compensate for inappropriate or incomplete adaptive changes produced by two of the dynamic mechanisms which are not position specific.

Spatial aspects of vertical phoria adaptation.

Vergence adaptation to vertical disparity spreads to unadapted directions of gaze. The spatial spread function for prism adaptation was estimated from aftereffects of a vertical disparity presented at a single position. Constraints limiting the spatial spread of adaptation were investigated with two stimuli of opposite disparity (hyper and hypo), presented at two different eye positions with a separation that varied from 6 to 18 deg in either the horizontal or vertical meridian. On average, phoria adaptation to the single point paradigm spread uniformly across the entire 18 deg test field. A resolution limit for adaptation to the two point paradigm was demonstrated by a reduction of phoria aftereffects with decreasing target separation (crowding). Vertical phoria aftereffects were reduced more by horizontal than by vertical crowding. A disparity gradient limit was demonstrated for a fixed target separation by a reduction of gain (phoria change/stimulus disparity) with increasing stimulus disparity.

How Nigeria built child survival themes into national television.

PIP: As part of the Government of Nigeria's goal of providing universal child immunization, a strategy was developed to strengthen the production capacity of the Nigerian Television Authority (NTA) and to award higher priority to health issues in NTA programming. At the national level, a child survival-oriented training, coordination, and production unit was established to produce "spot messages" on primary health care. In 1985-86, radio and television staff from all Nigerian states attended workshops at which Ministry of Health officials outlined Nigeria's maternal-child health problems and emphasized the potential of the broadcast media in health education. Each station was linked with an officer in the local Ministry of Health to ensure ongoing collaboration on technical problems and health programs in need of promotion. Another set of state-level workshops brought together media producers and radio and television writers to encourage them to integrate primary health care themes into their programs. In addition, a Nigerian nongovernmental organization has organized workshops for electronic media writers and producers aimed at incorporating family planning themes into several popular television programs. In 1986, both NTA and the Federal Radio Corporation of Nigeria signed agreements further committing their networks to the child survival campaign. The Nigerian experience exemplifies the potential for creating and institutionalizing long-term efforts to use the mass media to bring new information to the general population on health-related issues. Needed at this point is more knowledge about specific communication strategies that are most effective in promoting sustainable behavioral change on the family and community levels in a country with much social and cultural diversity.^ieng

A hospital energy audit project.

The project was carried out under the auspices of the Research Sub-Committee of the Victorian Branch of the Australian College of Health Service Administrators. It illustrates the way in which remedial action based on a thorough, systematic audit of energy losses can yield savings which are conservatively estimated to be worth tens of thousands of dollars per annum. While many of the energy saving functions proposed can be implemented at little or no cost, it is concluded that energy audits must be thoroughly and competently undertaken and the use of consultants is considered to have been well justified in this case.

Indomethacin enhancement of TPA tumor promotion in mice.

Skin tumor promotion in mice by 12-O-tetradecanoylphorbol-13-acetate (TPA) is characterized by hyperplasia and inflammation. Based on the inhibitory effect of the steroidal anti-inflammatory drugs, non-steroidal agents, such as indomethacin, were also expected to show some degree of inhibition; however, repeated tumor experiments demonstrate that indomethacin enhances TPA promotion in a dose-response manner. A time-of-application effect was evident such that indomethacin given 2 h prior to TPA resulted in the greatest enhancement. Flurbiprofen was also observed to enhance promotion slightly.

Studies on the mechanism of skin tumor promotion: evidence for several stages in promotion.

The effects of nonpromoting and weakly promoting diterpenes on skin tumor promotion by 12-O-tetradecanoylphorbol 13-acetate (TPA) were investigated. When phorbol and phorbol 12,13-diacetate (both nonpromoting) were given simultaneously with TPA after 7,12-dimethylbenz[a]-anthracene (DMBA) initiation in female mice, they had no effect on TPA promotion. However, the nonpromoter 4-O-methyl-TPA and the weak promoter mezerein were found to inhibit TPA promotion in a dose-dependent manner when given simultaneously with TPA. Because mezerein was found to be an effective inhibitor of TPA promotion when given simultaneously and because it induces many biological responses similar to those to TPA, the capacity of mezerein to act as an incomplete promoter in a two-stage promotion protocol was also investigated. Twice-weekly applications of 1,2, or 5 mug of TPA for 2 weeks after DMBA initiation produced 0, 0, and 0.5 papilloma per mouse, respectively, at 20 weeks. When the twice-weekly applications of TPA for 2 weeks were followed by twice-weekly treatments with 2 mug of mezerein for 18 weeks, the number of papillomas per mouse was 2.2, 3.5, and 9.0, respectively. Twice-weekly applications of 2 mug of TPA for 2 weeks followed by twice-weekly treatments with 1, 2, or 4 mug of mezerein for 18 weeks produced 2.1, 3.5, and 6.8 papillomas per mouse, respectively, in DMBA-treated mice. Twice-weekly doses as high as 40 mug of 4-O-methyl-TPA were not effective in producing tumors when given after a limited treatment with TPA; however, 4-O-methyl-TPA had weak activity as a first-stage promoter. The results suggest that although mezerein by itself is a weak promoter and mimics TPA in many biochemical and morphological effects it is a potent second-stage promoter in a two-stage promotion regimen.