Effects of hypoxic-ischemic encephalopathy and whole-body hypothermia on neonatal auditory function: a pilot study.

We assessed the effects of hypoxic-ischemic encephalopathy (HIE) and whole-body hypothermia therapy on auditory brain stem evoked responses (ABRs) and distortion product otoacoustic emissions (DPOAEs). We performed serial assessments of ABRs and DPOAEs in newborns with moderate or severe HIE, randomized to hypothermia ( N = 4) or usual care ( N = 5). Participants were five boys and four girls with mean gestational age (standard deviation) of 38.9 (1.8) weeks. During the first week of life, peripheral auditory function, as measured by the DPOAEs, was disrupted in all nine subjects. ABRs were delayed but central transmission was intact, suggesting a peripheral rather than a central neural insult. By 3 weeks of age, peripheral auditory function normalized. Hypothermia temporarily prolonged the ABR, more so for waves generated higher in the brain stem but the effects reversed quickly on rewarming. Neonatal audiometric testing is feasible, noninvasive, and capable of enhancing our understanding of the effects of HIE and hypothermia on auditory function.

Maintenance of phosphatidylserine asymmetry in erythroid cells during differentiation, aging, and its significance for macrophage recognition

Phosphatidylserine (PS) is distributed almost entirely in the inner leaflet of the erythrocyte membrane bilayer, and appears to be maintained by a 32 kDa integral membrane protein (PS translocase). The expression of PS on the outer leaflet may serve as a recognition signal for macrophages, since insertion of PS into erythrocytes enhances their adherence to macrophages and clearance from the circulation. Therefore I have hypothesized that erythroid cells display PS on their outer leaflet early in differentiation and upon aging. Analysis of murine erythroleukemia cells (MELC, undifferentiated erythroid progenitor cells) showed high levels of PS on the outer leaflet that decreased during differentiation, correlating with the pattern of macrophage adherence. The activity of the PS translocase during differentiation appears to be unchanged although the equilibrium distribution of PS differs. This difference may be due to qualitative changes in the PS translocase. $\sp{125}$I-Bolton/Hunter-labeled-pyridyldithioethylamine ($\sp{125}$I-B/H-PDA), a radiolabeled probe for the PS translocase, labeled a 32 kDa protein in mature erythrocytes whereas in MELC a 45 kDa protein as well as a 32 kDa protein was identified. The abundance of the 45 kDa protein in relation to the 32 kDa protein declined during differentiation, possibly indicating this protein was a precursor of the 32 kDa protein. Analysis of the 45 kDa protein by N-glycosidase F and endoproteinase cleavage suggested this protein was not a glycosylated form of the 32 kDa protein but appeared to share some structural homology. Aged murine erythrocytes had elevated levels of PS on their outer leaflet, as well as decreased PS translocase activity. $\sp{125}$I-B/H-PDA labeled a 32 kDa protein in both normal and aged erythrocytes. However, the latter cells also contained a 28 kDa protein. Experimental evidence suggests that the appearance of the 28 kDa protein may be due to increased oxidation of aged erythrocytes. Examination of PS distribution showed that the levels of PS on the outer leaflet were elevated early in differentiation, decreased during the mature state, and returned to high levels as the erythrocyte aged. In conclusion,the levels of outer leaflet PS correlated with the differentiation status and macrophage recognition of erythroid cells. ^

Zuni elders: Ethnography of American Indian aging

Problem/purpose. The specific aim of this focused ethnography was to provide insight into the experience of aging of the American Indian (AI) elder as demonstrated by one tribe, the Zuni of New Mexico. Discovering how Zuni elders construct the experience of aging and the associated behaviors allowed the researcher to deconstruct aging and then re-present it in a cogent description for this population. Such a description is lacking in the literature and will be useful in planning for culturally relevant eldercare services. ^ Methods. Ethnographic field techniques were used to sample from elders, pueblo members-at-large, activities, events and places. Over 1800 hrs were spent in the field spanning 14 months and five site visits, with the longest at almost 4 weeks. Developing codes for transcribed interviews, field notes, supplementary documents, photographs, videos, and artifacts was carried out during analysis. Categories and ultimately a cognitive map and model were developed which represented aging in Zuni Pueblo in 2000. ^ Findings. Zuni elders are aging in two worlds. Their primary world has been described as a sevenfold universe, a complicated structure with seven planes wherein the middle plane refers to themselves, a synthesis of all the other planes. The increasing influence of the white world has formed a ‘new middle’ out of which everyday aspects of aging are viewed. ^ Implications for nursing/gerontology. Nurses and others in gerontology must recognize that vast differences in worldviews are present between themselves and AI elders regarding health practices, spirituality, eating patterns, family roles, medicine, religion and countless other aspects of life. Their centuries old beliefs and practices drive these differences coupled with a collision with the white world. Making a paradigm shift using an appropriate lens with which to view these differences can only increase our understanding and efficacy in delivering culturally relevant care. ^

The construction of aging and health in older African American women

Persistence of racial and ethnic health disparities and governmental policies based on outdated ideas of aging call for inclusive approaches to the study of elder African Americans. The lived experiences of aging among urban, poor African American women, who comprise a vulnerable population, are not well known, as most studies focus on mainstream populations. Gerontological studies have tended to employ methods that collapse contextual information for ease of analysis, thus failing to capture nuanced information critically relevant to health of marginalized groups. Few researchers have been successful highlighting the importance of local knowledge, resilience, and resources for health by using participatory methods with older Black women. This study utilizes participatory principles to gather discursive data from nine older African American women, engaged in three generational cohorts: those born around World War II, women born after the great depression, and those born before the great depression. Videotaped and transcribed conversations of cohorts were analyzed in search of contextual factors that influence their experience of aging and health. As women responded to general themes that provoked their talk about their lives, they helped answer the study's questions: How do older African American women make sense of their aging experience? What are some of the important social and cultural influences that shape the construction of aging and health by these women? Are generational discourse groups an effective tool for exploring changes in the experiences of aging? A key finding demonstrated rich heterogeneity of experiences with strong generational influences on the construction of aging and health. The participants' moral orders comprised of traditional values of family, reinforced by personal experiences and the church, have guided their lives through oppression and stress but appear to be failing younger women who have greater exposure to new environmental pressures. Limited time and the size of the study were weaknesses although the women's interest in the study and their participation were gratifying. The participants served to highlight the importance of recognizing generational and other contextual factors in formation of ideas of aging and likelihood of additional challenges to the experience of old age among older, poorer, African Americans. ^

Role of telomere dysfunction, DNA damage response and p53 mutations in tumorigenesis and aging

The ends of eukaryotic chromosomes are protected by specialized ribonucleoprotein structures termed telomeres. Telomeres protect chromosomes from end-to-end fusions, inappropriate repair and degradation. Disruption of this complex activates an ATM/ATR DNA damage response (DDR) pathway. One component of the complex is the Protection Of Telomeres 1 (POT1) protein, an evolutionarily conserved protein which binds single-stranded 3' overhang and is required for both chromosomal end protection and telomere length regulation. The mouse contains two POT1 orthologs, Pot1a and Pot1b. Here we show that both proteins colocalize with telomeres through interaction with the adapter protein TPP1. In addition, compared to Pot1a, the OB-folds of Pot1b possess less sequence specificity for telomeres. Disruption of POT1 proteins result in telomere dysfunction and activation of an ATR-dependent DDR at telomeres, suggesting that this response is normally suppressed by POT1 binding to the single-stranded G-overhang. ^ Telomeres are maintained by telomerase, and its absence in somatic cells results in telomere progressive loss that triggers the activation of p53. Telomere dysfunction initiates genomic instability and induces both p53-dependent replicative senescence and apoptosis to suppress tumorigenesis. In the absence of functional p53, this genomic instability promotes cancer. It was previously not known which aspect of the p53 dependent DNA damage response is important to suppress tumorigenesis initiated by dysfunctional telomeres. The p53R172P knock-in mouse, which is unable to induce apoptosis but retains intact cell cycle arrest/cellular senescence pathways, allowed us to examine whether p53-dependent apoptosis is a major tumor suppression pathway initiated in the setting of telomere dysfunction. Spontaneous tumorigenesis remains potently suppressed in late generation telomerase null mice possessing the p53P/P mutation. These results suggest that suppression of spontaneous tumorigenesis initiated by dysfunctional telomeres requires activation of a p53-dependent senescence pathway. In addition, we used another knock-in mouse model with a p53R172H (p53H) point mutation to test the hypothesis that telomere dysfunction promotes chromosomal instability and accelerates the onset of tumorigenesis in vivo in the setting of this most common gain-of-function mutation in the human Li Fraumeni cancer syndrome. We unexpectedly observed that telomerase null mice possessing dysfunctional telomeres in the setting of the p53H/+ mutation develop significantly fewer tumors, die prematurely and exhibit higher level of cellular senescence, apoptosis and elevated genomic instability compared to telomerase intact p53H/+ and telomerase null p53+/+ mice. These contrasting results thus link cancer and aging to the functional status of telomeres and the integrity of the p53 pathway. ^

High-risk drug use and sexual behaviors among out-of-treatment drug users: An aging and life course perspective

High-risk injection drug use and the sexual behaviors that accompany it have large social and financial costs. Tailored treatments have been shown to successfully reduce high-risk behaviors. However, little is known about how age and age at first drug use are related to high-risk injection or sex behaviors. The current study draws on life course theory and hypothesizes that age will have a strong relationship with high-risk behaviors of out-of-treatment drug users. Data from the NIDA Cooperative Agreement was used to analyze the relationship between (1) age, and (2) age at first drug use with seven high-risk injection and sexual behavior variables. Negative binomial regression models revealed that high-risk sexual behavior decreases between 15.8 and 20.9% with each decade of age, while high-risk injection behavior increases between 32 and 67% with each decade of age after the addition of demographic controls. Both high-risk injection and high-risk sex behaviors are significantly reduced with a delayed age at first drug use. Previous research promotes interventions to reduce the high-risk sexual behaviors of older drug users. The current study suggests a refocusing of public health efforts on the high-risk injection habits of older drug users.^

Social support, health status and health services utilization among the noninstitutionalized elderly: An analysis of the Supplement on Aging to the 1984 national health interview survey

The association between Social Support, Health Status, and Health Services Utilization of the elderly, was explored based on the analysis of data from the Supplement on Aging to the National Health Interview Survey, 1984 (N = 11,497) using a modified framework of Aday and Andersen's Expanded Behavioral Model. The results suggested that Social Support as operationalized in this study was an independent determinant of the use of health services. The quantity of social activities and the use of community services were the two most consistent determinants across different types of health services use.^ The effects of social support on the use of health services were broken down into three components to facilitate explanations of the mechanisms through which social support operated. The Predisposing and Enabling component of Social Support had independent, although not uniform, effects on the use of health services. Only slight substitute effects of social support were detected. These included the substitution of the use of senior centers for longer stay in the hospital and the substitution of help with IADL problems for the use of formal home care services.^ The effect of financial support on the use of health services was found to be different for middle and low income populations. This differential effect was also found for the presence of intimate networks, the frequencies of interaction with children and the perceived availability of support among urban/rural, male/female and white/non-white subgroups.^ The study also suggested that the selection of appropriate Health Status measures should be based on the type of Health Services Utilization in which a researcher is interested. The level of physical function limitation and role activity limitation were the two most consistent predictors of the volume of physician visits, number of hospital days, and average length of stay in the hospital during the past year.^ Some alternative hypotheses were also raised and evaluated, when possible. The impacts of the complex sample design, the reliability and validity of the measures and other limitations of this analysis were also discussed. Finally, a revised framework was proposed and discussed based on the analysis. Some policy implications and suggestions for future study were also presented. ^

APPLICATION OF THE BRAINSTEM EVOKED RESPONSE (BER) TO NEUROTOXICITY EVALUATION OF THE AUDITORY SYSTEM: ASSESSMENT OF INORGANIC LEAD-INDUCED OTOTOXICITY

An experimental procedure was developed using the Brainstem Evoked Response (BER) electrophysiological technique to assess the effect of neurotoxic substances on the auditory system. The procedure utilizes Sprague-Dawley albino rats who have had dural electrodes implanted in their skulls, allowing neuroelectric evoked potentials to be recorded from their brainstems. Latency and amplitude parameters derived from the evoked potentials help assess the neuroanatomical integrity of the auditory pathway in the brainstem. Moreover, since frequency-specific auditory stimuli are used to evoke the neural responses, additional audiometric information is obtainable. An investigation on non-exposed control animals shows the BER threshold curve obtained by tests at various frequencies very closely approximates that obtained by behavioral audibility tests. Thus, the BER appears to be a valid measure of both functional and neuroanatomical integrity of the afferent auditory neural pathway.^ To determine the usefulness of the BER technique in neurobehavioral toxicology research, a known neurotoxic agent, Pb, was studied. Female Sprague-Dawley rats were dosed for 45 days with low levels of Pb acetate in their drinking water, after which BER recordings were obtained. The Pb dosages were determined from the findings of an earlier pilot study. One group of 6 rats received normal tap water, one group of 7 rats received a solution of 0.1% Pb, and another group of 7 rats received a solution of 0.2% Pb. After 45 days, the three groups exhibited blood Pb levels of 4.5 (+OR-) 0.43 (mu)g/100 ml, 37.8 (+OR-) 4.8 (mu)g/100 ml and 47.3 (+OR-) 2.7 (mu)g/100 ml, respectively.^ The results of the BER recording indicated evoked response waveform latency abnormalities in both the Pb-treated groups when midrange frequency (8 kHz to 32 kHz) stimuli were used. For the most part, waveform amplitudes did not vary significantly from control values. BER recordings obtained after a 30-day recovery period indicated the effects seen in the 0.1% Pb group had disappeared. However, those anomalies exhibited by the 0.2% Pb group either remained or increased in number. This outcome indicates a longer lasting or possibly irreversible effect on the auditory system from the higher dose of Pb. The auditory pathway effect appears to be in the periphery, at the level of the cochlea or the auditory (VIII) nerve. The results of this research indicate the BER technique is a valuable and sensitive indicator of low-level toxic effects on the auditory system.^