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.

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.

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.

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.

Nutritional status and dental caries in a large sample of 4- and 5-year-old South African children.

BACKGROUND: Evidence from studies involving small samples of children in Africa, India and South America suggests a higher dental caries rate in malnourished children. A comparison was done to evaluate wasting and stunting and their association with dental caries in four samples of South African children. DESIGN: Cross-sectional study based on random sampling of birth records of two age bands. METHODS: A total of 2,728 4- and 5-year-old South African children from one rural community and three urban communities were examined for nutritional status and dental caries. RESULTS: In the total sample prevalences of wasting were mild (28%), moderate (4%) and severe (2%). For stunting the prevalences were mild (13%), moderate (3%) and severe (1%). For both conditions rural children showed higher proportions than the other groups. Statistical analysis showed statistically significant differences for wasting and stunting between the study groups. No significant association was found between the prevalence of caries and stunting or wasting, but an association was noted between wasting and decayed, missing and filled (dmf) surfaces (P = 0.003). CONCLUSIONS: In the series of children studied, nutritional status was not found to be clinically relevant to dental caries prevalence and experience.

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.

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.

The relationship between the intake frequency and the total consumption of sucrose among four South African ethnic groups.

Frequency of intake of sucrose and its total consumption have been implicated as major causative factors in the pathogenesis of dental caries. In the absence of contrary information, it seems that the figure of five sugar exposures per day is a prudent one for the practitioner to recommend to young patients.

Anthropometrically determined nutritional status and the school performance of black urban primary school children.

Anthropometric parameters (height and weight) were used to assess the nutritional status of 1407 black children in a Soweto lower primary school. Cross-sectional profiles were obtained in 1981 and 1983 as well as a longitudinal study of 362 pre-adolescent children who remained in the school over the 2-year period. The major proportion of the distribution of percentage weight-for-age and percentage height-for-age was less than 100 per cent of NCHS reference median. There was a small but significant increase in mean percentage weight-for-height between 1981 and 1983. Children who were stunted and those whose growth rate over a 2-year period was known to be reduced failed more frequently. Apart from these the general range of anthropometric findings did not clearly correlate with classroom achievement as assessed by end-of-year marks. The age ranges of children in the different grades exceeded 5 years. The highest failure rate occurred in the school entry grade (Substandard A). Only in this grade were the older boys found to be less adequately nourished than their age peers in higher standards. Untested adverse social, family and environmental effects may mask the real consequences of suboptimal growth. Without anthropometry the latter would frequently not be apparent because of the generally proportional reductions in weight and height for age.

Mortality rates among infants and young children born at home or in hospitals or clinics in rural Bophuthatswana.

Because the infant mortality rate in Gelukspan, Bophuthatswana, is relatively low, a study was conducted among 1,151 children born at home or in hospitals or clinics, to learn whether place of birth made a significant difference to any component of the infant or childhood mortality rate during neonatal (less than 1 month), infant (1-11 months) or preschool (12-59 months) periods. The rate for home births was significantly higher (P less than 0.01) when compared with that for clinic but not hospital births. The rate for neonates was significantly higher (P less than 0.05) but not for infants. This may well reflect lack of early contact with medical and paramedical staff in women delivering at home rather than at a clinic. This was not applicable to home versus hospital deliveries, but as difficult births are referred to hospital from the local clinics this may partly explain the lack of a significant difference between home and hospital deliveries. Cause of death may well be a further reason to encourage mothers to choose institutional rather than home deliveries.

Comparison of milk consumption and its contribution to total sugar intake in South African and other schoolchildren.

Mean daily milk, lactose and energy intakes were measured in groups of South African school pupils of 9-16 years. Recommended dietary allowances (RDA) were not reached by any of the groups. In comparison, groups of Canadian, Nigerian and German schoolchildren of similar ages fell into two categories, namely high milk consumers and low milk consumers. Lactose and energy intakes for high consumers were 77% of the RDA, compared with 30-40% for low consumers. The lactose contribution to daily energy intake for Canadian children was 10.7% and for South African groups about 5%. Thus for South African children lactose contribution to total sugar intake may be half that of Canadian children. Exact proportions need to be defined.