Mechanisms of GABAergic and cholinergic neurotransmission in auditory thalamus: Impact of aging.

Age-related hearing loss is a complex disorder affecting a majority of the elderly population. As people age, speech understanding becomes a challenge especially in complex acoustic settings and negatively impacts the ability to accurately analyze the auditory scene. This is in part due to an inability to focus auditory attention on a particular stimulus source while simultaneously filtering out other sound stimuli. The present review examines the impact of aging on two neurotransmitter systems involved in accurate temporal processing and auditory gating in auditory thalamus (medial geniculate body; MGB), a critical brain region involved in the coding and filtering of auditory information. The inhibitory neurotransmitter GABA and its synaptic receptors (GABAARs) are key to maintaining accurate temporal coding of complex sounds, such as speech, throughout the central auditory system. In the MGB, synaptic and extrasynaptic GABAARs mediate fast phasic and slow tonic inhibition respectively, which in turn regulate MGB neuron excitability, firing modes, and engage thalamocortical oscillations that shape coding and gating of acoustic content. Acoustic coding properties of MGB neurons are further modulated through activation of tegmental cholinergic afferents that project to MGB to potentially modulate attention and help to disambiguate difficult to understand or novel sounds. Acetylcholine is released onto MGB neurons and presynaptic terminals in MGB activating neuronal nicotinic and muscarinic acetylcholine receptors (nAChRs, mAChRs) at a subset of MGB afferents to optimize top-down and bottom-up information flow. Both GABAergic and cholinergic neurotransmission is significantly altered with aging and this review will detail how age-related changes in these circuits within the MGB may impact coding of acoustic stimuli.

Identification of a decidua-specific enhancer on the human prolactin gene with two critical activator protein 1 (AP-1) binding sites.

Deletion analysis of the human PRL promoter in endometrial stromal cells decidualized in vitro revealed a 536-bp enhancer located between nucleotide (nt) -2,040 to -1,505 in the 5'-flanking region. The 536-bp enhancer fragment ligated into a thymidine kinase (TK) promoter-luciferase reporter plasmid conferred enhancer activity in decidual-type cells but not nondecidual cells. DNase I footprint analysis of decidualized endometrial stromal cells revealed three protected regions, FP1-FP3. Transfection of overlapping 100-bp fragments of the 536-bp enhancer indicated that FP1 and FP3 each conferred enhancer activity. Gel shift assays indicated that both FP1 and FP3 bind activator protein 1 (AP-1), and JunD and Fra-2 are components of the AP-1 complex in decidual fibroblasts. Mutation of the AP-1 binding site in either FP1 or FP3 decreased enhancer activity by approximately 50%, while mutation of both sites almost completely abolished activity. Coexpression of the 536-bp enhancer and A-fos, a dominant negative to AP-1, decreased enhancer activity by approximately 70%. Conversely, coexpression of Fra-2 in combination with JunD or c-Jun and p300 increased enhancer activity 6- to 10-fold. Introduction of JunD and Fra-2 into nondecidual cells is sufficient to confer enhancer activity. JunD and Fra-2 protein expression was markedly increased in secretory phase endometrium and decidua of early pregnancy (high PRL content) compared with proliferative phase endometrium (no PRL). These investigations indicate that the 5'-flanking region of the human PRL gene contains a decidua-specific enhancer between nt -2,040/-1,505 and AP-1 binding sites within this enhancer region are critical for activity.

Microarray analysis of trophoblast differentiation: gene expression reprogramming in key gene function categories.

Placental development results from a highly dynamic differentiation program. We used DNA microarray analysis to characterize the process by which human cytotrophoblast cells differentiate into syncytiotrophoblast cells in a purified cell culture system. Of 6,918 genes analyzed, 141 genes were induced and 256 were downregulated by more than 2-fold. Dynamically regulated genes were divided by the K-means algorithm into 9 kinetic pattern groups, then by biologic classification into 6 overall functional categories: cell and tissue structural dynamics, cell cycle and apoptosis, intercellular communication, metabolism, regulation of gene expression, and expressed sequence tag (EST) and function unknown. Gene expression changes within key functional categories were tightly coupled to morphological changes. In several key gene function categories, such as cell and tissue structure, many gene members of the category were strongly activated while others were strongly repressed. These findings suggest that differentiation is augmented by "categorical reprogramming" in which the function of induced genes is enhanced by preventing the further synthesis of categorically related gene products.

Sweets, snacks, and dental caries: South African interracial patterns.

Sucrose has been thought to cause dental caries; sweets and snacks being primarily responsible, together with plaque and their respective interactions. Dietary questionnaires revealed that in 3 to 5 yr olds, protein in black, colored, Indian, and white groups provided 12 to 15% of total intake, fats 10 to 17%, and carbohydrates 69 to 78%. At 16 to 17 yr old, patterns remained essentially similar. Sucrose provided about one-quarter of intake, sweets and snacks less than one-tenth, but dental caries prevalence increased rapidly from black to white. This raised several questions regarding current concepts of caries causation. Are genetic, immunological and other dietary factors also responsible for caries levels experienced?

Activator protein-2 regulates human placental lactogen gene expression.

DNase I footprint analysis of the human placental lactogen-A (hPL-A) promoter using nuclear extracts from purified human trophoblast cells and BeWo choriocarcinoma cells revealed five protected regions within the proximal 325 bp. Two of the protected regions, FP4 (-289--267) and FP5 (-167--154), are homologous to regions on the human growth hormone (hGH) promoter that bind transcription factors AP-2 and/or NFI. Competitive gel shift assays and supershift assays indicated that FP4 forms complexes with activator protein-2 (AP-2) and nuclear factor I (NFI), while FP5 forms a complex with AP-2 alone. In transient transfection studies in human trophoblast cells, hPL promoter constructs containing point mutations in the AP-2 binding sites of FP4 and/or FP5 were 60-80% less active than plasmids containing the wild-type promoter. A mutation in the NFI binding site of FP4, however, had little effect on promoter activity in these cells. Overexpression of AP-2 in HepG2 cells co-transfected with the wild-type hPL promoter resulted in a significant increase in promoter activity. Taken together, these findings suggest a critical role for AP-2 in the regulation of hPL gene expression.

Underweight, stunting and wasting in black and white South African schoolchildren: malnutrition or adaptation?

Prevalences of underweight for age in South African schoolchildren rose from seven years to reach high levels during puberty. In Black children at the height of the pubertal growth spurt, half to three-quarters were underweight for age and hence classifiable as "malnourished". However, percentages fell rapidly to one-fifth or less at 17 years. High prevalences of stunting were common in Blacks. Wasting occurred in similar proportions of urban Black compared with White children, i.e., the large majority of both Blacks and Whites were normally proportioned; younger children were more wasted than older pupils. Factors additional to nutrition appear to share in the regulation of growth. In Whites on adequate diets, there were (i) similar patterns, but smaller rises in underweight prevalences over the growth spurt, also (ii) small but not insignificant prevalences of stunting: (iii) closely similar "normal" patterns of weight for height occurred in Whites as well as Blacks, and (iv) in Blacks the sharp fall in prevalences of underweight and wasting, after the rapid growth phase, occurred without any dietary intervention. A plea is made to use not only weight, but height, particularly relative to weight, at all ages, in assessing nutritional status and "at risk" groups. The stunted and wasted child is likely to be at greater risk than a similarly stunted but normally proportioned or overweight child--both could be underweight for age. Further definitive studies are required.

Differential expression of AP-2gamma and AP-2alpha during human trophoblast differentiation.

Previous studies from our laboratory demonstrated that AP-2alpha induces the expression of the hPL and hCG genes in cultured trophoblast cells. In the current study, we have shown by transient transfection studies that AP-2gamma, which is the product of a separate gene from AP-2alpha, also stimulates hPL and hCGbeta promoter activities. However, AP-2gamma mRNA levels during in vitro differentiation of human cytotrophoblast cells were strikingly different than those of AP-2alpha mRNA levels, with AP-2alpha increasing and AP-2gamma markedly decreasing during the differentiation process. The amount of AP-2gamma protein binding to AP-2 elements on the hPL promoter, as determined by supershift assays, also markedly decreased during the differentiation process. These findings strongly suggest that AP-2gamma action in cytotrophoblast cells is repressed by a co-factor(s) that inhibits AP-2gamma action or is prevented by the absence of a co-factor(s) that is essential for AP-2gamma action.

Dental caries in rural and urban black preschoolchildren.

The dentitions of 439 rural and 192 urban black children aged 1-5 years were examined with mirror and probe. Dental caries was common and the percentage prevalence and dmft values were similar in children of 1-3 years in both groups. At 4 years of age there was a twofold increase in dental caries in the urban children to reach a dmft score significantly greater than that in the rural children (P less than 0.01). Labial caries was common in rural children but rare in urban children while rampant caries (dmft greater than or equal to 5) exhibited the opposite pattern.

Comparison of dental fluorosis and caries in primary teeth of preschool-children living in arid high and low fluoride villages.

The aim of this study was to determine the degree of fluorosis in the primary dentition and the accompanying caries patterns in groups of preschool-children in high and low fluoride areas. Among 331 coloured children, aged 1-5 years, living in an area with water F concentrations ranging from 2.2 to 4.1 parts/10(6), 82% were caries free and the dmft values ranged from 0 to 15 with a mean dmft of 0.8 +/- 2.1. Varying degrees of fluorosis in the primary teeth were present in 50.6% of the children. In 177 coloured children of similar ages from an adjacent area with 0.2 parts/10(6) F in the drinking water the dmft values ranged from 0 to 20 with a mean dmft of 5.4 +/- 5.8. Only 28% of the children were caries free. None of the children in this area had fluorosis. The caries prevalence was significantly higher in the low fluoride area than in the high fluoride area. The degree of fluorosis found in the primary dentition in the children from the high fluoride area was higher than had been anticipated and was accompanied by a very low caries prevalence.

Primary dentition caries trends, 1976-1981, in four South African populations.

This paper is a comparison of cross-sectional data on dental caries in the primary dentition undertaken between 1976 and 1981 in the Transvaal Province, South Africa, on 690 rural Black, 1463 urban Black, 870 Indian and 1622 White children aged 2-5 yr. There was a decrease in percentage dental caries prevalence in the urban White children and an increase in the other three groups, the fastest rate being seen among urban Indian children. Similar trends were noted for mean dmft. Dental caries in incisor and canine teeth remained fairly static but caries in molar teeth increased in the groups of Black and Indian children and decreased in the White children. Ratios d/dmft, m/dmft and f/dmft indicated that minimal treatment was received by all the children.

Trends in sugar intake: do these parallel changes in caries prevalence among S. African preschoolchildren?

Mean sugar intake in South Africa has fallen in Black rural groups and remained more or less constant for their urban counterparts; for Indian groups it has risen, but fallen in White groups. The amounts of sugar in mean snack/sweet intakes have not shown the same degree of fall and have remained relatively constant in all but Indian groups where there has been a definite fall in consumption. Caries prevalences (percentages of children with caries) have risen in all but White groups. It can be concluded that quantitative changes in sugar consumption and caries prevalences do not parallel each other.

Dental caries in South African white children aged 1-5 years.

The dentitions of 499 white preschoolchildren aged 1-5 years from a low fluoride area were examined with mirror and probe. The dmft values ranged from 1.0 +/- 2.0 at 1 year of age to 5.1 +/- 4.5 at 5 years of age while the overall mean for the group was 3.7 +/- 4.1. ""Rampant" caries prevalence varied according to the definition used. It is suggested that for epidemiologic studies rampant caries should be defined as a dmft value of 5 or more and that labial caries should be regarded as a specific entity.

Dental caries and dental treatment in the primary dentition in an industrialized South African community.

This paper reports an examination of dental caries in the primary dentition of 2-5-yr-old white children in an industrialized South African city, in 1981 and 1983. There was a decrease in dental caries prevalence over the 2-yr period accompanied by an increase in dental treatment in 3-5-yr-olds. Treatment, however, remains low. Socioeconomic status had a varying effect on the trends, but in general there was a greater reduction in dental caries in the lower socioeconomic areas.

Dental caries and sucrose intake in five South African preschool groups.

Dental caries, debris (DI-S) and sugar intake were determined for 766 rural Black, urban Black, coloured, Indian and White children, using standardized techniques. In general sucrose intake, both quantity and frequency was low in rural Black children yet these children had relatively few caries-free individuals and higher than expected mean dmft scores. Comparison with earlier studies in the same localities has shown a worsening of dental caries in all groups except the White, in which the situation has improved. Sucrose consumption declined in rural Black, and White groups, remained steady in urban Black children and increased in coloured and Indian groups.

Patterns of breast and bottle feeding and their association with dental caries in 1- to 4-year-old South African children. 2. A case control study of children with nursing caries.

In a case control study, 109 children with nursing caries (> or = 2 decayed, missing, or filled labial or palatal surfaces of primary incisor teeth) were matched for age, race, gender, and social class to 109 children without nursing caries from the same study areas. Mean dmfs and dmft scores were statistically higher in the nursing caries group but no statistically significant differences were found for feeding patterns between the groups in relation to the prevalence of nursing caries. In the present study nursing caries was found to be unrelated to the length of type of feeding (breast or bottle).

Patterns of breast and bottle feeding and their association with dental caries in 1- to 4-year-old South African children. 1. Dental caries prevalence and experience.

In order to study associations between breast and bottle feeding and dental caries a questionnaire on feeding habits was completed by trained interviewers for 1,263 children aged 1 to 4 years from five South African communities. Of these, 73 to 94 per cent had been breast fed for mean periods of 9 to 16 months. The types of infant feeding practised (breast, bottle or mixed) varied little within the groups although each group differed significantly from the others for the preferred feeding practice. Using responses to a dietary interview the children were subdivided into those breast fed for 12 months or longer (n = 546), those who had mixed breast and bottle feeding (n = 527) and those who were bottle fed only (n = 190). Caries prevalence increased with the age of the child, more in bottle fed than other groups. Within all feeding groups caries prevalence was lowest among white children and in social class I. The dmfs and dmft scores showed irregular patterns and were significantly influenced by feeding group and the interaction between race and social class.

PIP: The importance of breast feeding in industrialized societies is increasing. As such, it is important to establish whether or not breast feeding on demand for a prolonged period is associated with nursing caries so that the necessary prevention measures may be implemented in both developing and developed countries. The authors present findings from an investigation of breast and bottle-feeding practices and their relationships to dental caries in infants and pre-school children in the Transvaal. The relationship between feeding groups, age, race, social class, and dental decay was explored. Mothers or child carers of 1263 children aged 1-4 years from 5 South African communities were interviewed. 73-94% of the children had been breast fed for mean periods of 9-16 months. Although types of infant feeding varied little within groups, preferred feeding practice differed significantly between groups. 546 children were breast fed for 12 months or longer, 527 had mixed breast and bottle feeding, and 190 were bottle fed only. The prevalence of caries increased with the age of the child and more among the bottle fed than others. The prevalence of caries was lowest among white children and in social class I within all feeding groups.