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.

Evaluating a federated medical search engine: tailoring the methodology and reporting the evaluation outcomes.

BACKGROUND: Federated medical search engines are health information systems that provide a single access point to different types of information. Their efficiency as clinical decision support tools has been demonstrated through numerous evaluations. Despite their rigor, very few of these studies report holistic evaluations of medical search engines and even fewer base their evaluations on existing evaluation frameworks. OBJECTIVES: To evaluate a federated medical search engine, MedSocket, for its potential net benefits in an established clinical setting. METHODS: This study applied the Human, Organization, and Technology (HOT-fit) evaluation framework in order to evaluate MedSocket. The hierarchical structure of the HOT-factors allowed for identification of a combination of efficiency metrics. Human fit was evaluated through user satisfaction and patterns of system use; technology fit was evaluated through the measurements of time-on-task and the accuracy of the found answers; and organization fit was evaluated from the perspective of system fit to the existing organizational structure. RESULTS: Evaluations produced mixed results and suggested several opportunities for system improvement. On average, participants were satisfied with MedSocket searches and confident in the accuracy of retrieved answers. However, MedSocket did not meet participants' expectations in terms of download speed, access to information, and relevance of the search results. These mixed results made it necessary to conclude that in the case of MedSocket, technology fit had a significant influence on the human and organization fit. Hence, improving technological capabilities of the system is critical before its net benefits can become noticeable. CONCLUSIONS: The HOT-fit evaluation framework was instrumental in tailoring the methodology for conducting a comprehensive evaluation of the search engine. Such multidimensional evaluation of the search engine resulted in recommendations for system improvement.

DNA from bird-dispersed seed and wind-disseminated pollen provides insights into postglacial colonization and population genetic structure of whitebark pine (Pinus albicaulis).

Uniparentally inherited mitochondrial (mt)DNA and chloroplast (cp)DNA microsatellites (cpSSRs) were used to examine population genetic structure and biogeographic patterns of bird-dispersed seed and wind-disseminated pollen of whitebark pine (Pinus albicaulis Engelm.). Sampling was conducted from 41 populations throughout the range of the species. Analyses provide evidence for an ancestral haplotype and two derived mtDNA haplotypes with distinct regional distributions. An abrupt contact zone between mtDNA haplotypes in the Cascade Range suggests postglacial biogeographic movements. Among three cpSSR loci, 42 haplotypes were detected within 28 cpSSR sample populations that were aggregated into six regions. Analysis of molecular variance (amova) was used to determine the hierarchical genetic structure of cpSSRs. amova and population pairwise comparisons (FST ) of cpSSR, and geographical distribution of mtDNA haplotypes provide insights into historical changes in biogeography. The genetic data suggest that whitebark pine has been intimately tied to climatic change and associated glaciation, which has led to range movements facilitated by seed dispersal by Clark's nutcracker (Nucifraga columbiana Wilson). The two hypotheses proposed to explain the genetic structure are: (i) a northward expansion into Canada and the northern Cascades in the early Holocene; and (ii) historical gene flow between Idaho and the Oregon Cascades when more continuous habitat existed in Central Oregon during the late Pleistocene. Genetic structure and insights gained from historical seed movements provide a basis on which to develop recovery plans for a species that is at risk from multiple threats.

Activation of the hypothalamic-pituitary-adrenal axis with repetitive umbilical cord occlusion in the preterm ovine fetus.

OBJECTIVE: To determine whether repeated hypoxic insults with umbilical cord occlusion over 4 days will lead to activation of the hypothalamic-pituitary-adrenal (HPA) axis altered adrenocortical responsiveness in the preterm ovine fetus. METHODS: Umbilical cord occlusions of 90 seconds duration were performed every 30 minutes for 3 to 5 hours each day (experimental group n = 7, control group n = 7; at 112-116 days' gestation, term = 147 days). Arterial blood was sampled at predetermined times for blood gases and pH, plasma ACTH, and cortisol. Pituitary proopiomelanocortin (POMC) and glucocorticoid receptor (GR) mRNA also were localized and quantified by in situ hybridization. RESULTS: During umbilical cord occlusions fetal arterial oxygen pressure (approximately 17 mmHg) and pH (approximately 0.05) decreased, and carbon dioxide pressure increased (approximately 8 mmHg) as measured on days 1 and 4, but with no cumulative blood gas or pH change over successive occlusions for any of the 4 study days. Plasma ACTH increased, as measured after cord occlusion and over the course of successive cord occlusions on days 1 and 4, and returned to control values by the next day. The cumulative increase in ACTH was much less on day 4 than day 1 (15 +/- 3 compared with 101 +/- 25 pg/mL, P <.05). Plasma cortisol increased, as measured after cord occlusion and over the course of successive cord occlusions on day 4 only (2.7 +/- 0.4 to 4. 7 +/- 0.3 ng/mL, P <.05). POMC mRNA increased 2.5-fold in the pars distalis of the pituitaries from cord occlusion compared to control fetuses, but was unchanged in the pars intermedia. GR mRNA, which was detected in the pars distalis only, was unaltered. CONCLUSION: Repetitive umbilical cord occlusion in the preterm ovine fetus resulted in the activation of the HPA axis, with increased adrenocortical responsiveness over time, and involved differential regulation of POMC mRNA expression in the pars distalis and pars intermedia of the pituitary, but with no change in GR.

Cell-free human immunodeficiency virus type 1 in breast milk.

Breast-feeding may be an important route of human immunodeficiency virus type 1 (HIV-1) vertical transmission in settings where it is routinely practiced. To define the prevalence and quantity of HIV-1 in cell-free breast milk, samples from HIV-1-seropositive women were analyzed by quantitative competitive reverse transcription-polymerase chain reaction (QC-RT-PCR). HIV-1 RNA was detected in 29 (39%) of 75 specimens tested. Of these 29 specimens, 16 (55%) had levels that were near the detection limit of the assay (240 copies/mL), while 6 (21%) had >900 copies/mL. The maximum concentration of HIV-1 RNA detected was 8100 copies/mL. The prevalence of cell-free HIV-1 was higher in mature milk (47%) than in colostrum (27%, P = 0.1). Because mature milk is consumed in large quantities, these data suggest that cell-free HIV-1 in breast milk may contribute to vertical transmission of HIV-1.

The effects of bronchodilators on spontaneous ventilation and oxygen consumption in rhesus monkeys.

The effects of breathing normal saline, salmeterol, fenoterol, ipratropium bromide, or formoterol, and of i.v. infusion of theophylline on oxygen consumption (VO2), carbon dioxide production (VCO2), minute ventilation (VE), heart and respiratory rates, and end-tidal carbon dioxide tension (P(ET)CO2) have been defined in 10 anesthetized, intubated rhesus monkeys (mean age 7.0 y, weight 10.2 kg). VO2 increased over control by + 17.1% after salmeterol (p < 0.001), +33.3% after fenoterol (p < 0.001), +23.7% after formoterol (p < 0.001), +3.9% after theophylline (p < 0.01), but did not change after ipratropium bromide and normal saline. VE increased by 63.0% after fenoterol (p < 0.001), 49.8% after formoterol (p < 0.001), 31.7% after salmeterol (p < 0.01), and 29.7% after theophylline (p < 0.001), but not after ipratropium bromide or normal saline. Heart rate response was greatest after fenoterol, formoterol, and salmeterol, respectively. P(ET)CO2 dropped dramatically after theophylline (-15.7%, p < 0.001), but not at all with any of the inhaled beta2-adrenoceptor agonists. In seven animals, salbutamol (albuterol) caused an increase in V(E) and VO2 of 50.1% and 45.9%, respectively, whereas in the presence of a beta2-adrenoceptor antagonist [racemic or (+/-)-propranolol (0.1 mg/kg i.v.)], inhaled salbutamol (2.5 mg/mL for 10 min) could not increase V(E) (+6.2%, p > 0.05) and VO2 (+1.6%, p > 0.05). The increase in VO2 and V(E) after administration of beta2-agonists may be partly the result of direct stimulation of the respiratory center and partly a response to increased metabolic rate. The dramatic increase in VO2 and V(E) after salbutamol was suppressed in the presence of propranolol, which is consistent with a beta-receptor-mediated mechanism.

A study of milk and calcium supplement intake and subsequent preeclampsia in a cohort of pregnant women.

To test the hypothesis that high calcium intake protects against preeclampsia, the relation between milk intake and preeclampsia was examined in a cohort of 9,291 pregnant women (7,104 white women and 2,187 black women) selected from the Child Health and Development Study population assembled by the University of California, Berkeley, during 1959-1966. Exposure was based on glasses of milk per day with and without calcium supplements. Data from both white and black women displayed a U-shaped distribution of preeclampsia risk in relation to milk and milk plus supplement intake. Logistic regression analysis showed that women who drank two glasses of milk per day had the lowest risk (reference category). The relative risk (RR) for those drinking one glass of milk per day was similarly low (RR = 1.2; 95 percent confidence interval (CI) 0.7-2.0), but risk for those drinking less than one glass of milk per day was substantially higher (RR = 1.9; 95 percent CI 1.2-2.9). Women drinking three or more glasses of milk per day also showed increased risk (RR = 2.0; 95 percent CI 1.2-3.4) as did those drinking four or more glasses per day (RR = 1.8; 95 percent CI 1.1-3.0). The increased risk associated with low milk intake is consistent with studies showing reduced blood pressure with increased calcium intake. The increased risk with high milk intake has not been demonstrated previously.

Prompted voiding therapy for urinary incontinence in aged female nursing home residents.

A study of 85 incontinent female nursing home residents explored the effects of two nursing interventions (prompted voiding and socialization) on incontinence. Findings indicate that a controlled prompted voiding programme is useful in decreasing incontinent episodes. Positive effects of prompted voiding were noted over a 5-week experimental period. It is suggested that nursing homes incorporate prompted voiding into their care. Nursing homes adopting this protocol should be encouraged to keep data that will contribute further to knowledge in this area. Recommendations for additional research are made.

Self-hypnosis training in anxiety reduction.

Twenty three adult patients with problems of anxiety in a suburban general practice were invited to participate in a study to determine the effectiveness of self-hypnosis training in reducing anxiety levels. In an initial interview (T1), Experimenter 1 gave subjects two C-60 cassette tapes for home use. These contained the voice of Experimenter 2 who was unknown to the subjects, instructing them in self-hypnosis. After six weeks (T2), measures by Experimenter 1 of both psychological anxiety and blood pressure showed significant reduction (with the exception of systolic blood pressure), and in some cases subjects reduced their anxiolytic medication. A follow-up nine months later of as many subjects as were available (12) showed that these desirable effects were still detectable to a significant degree. It is suggested that audiotaped training in self-hypnosis represent a valid non-pharmacological method for anxiety reduction.

The functional significance of sodium channels in pancreatic beta-cell membranes.

1. The existence and functional significance of Na channels in pancreatic beta-cell membranes were investigated by studying the effects of the plant alkaloid veratridine on the temporal release of insulin from perfused isolated rat islets of Langerhans.2. 100 muM veratridine evoked a sustained threefold increase in insulin release which was almost completely inhibited by 3 muM tetrodotoxin (TTX). This action of TTX was rapidly reversible.3. The simultaneous presence of 100 muM propranolol, 100 muM phenoxy-benzamine and 10 muM atropine did not alter the magnitude of the response to 100 muM veratridine, indicating that the action of veratridine on the beta-cells was direct and was not mediated via the release of neurotrans-mitters from nerve endings within the islets.4. (45)Ca uptake by isolated islets in static incubation was increased almost threefold by 100 muM veratridine. This increase was completely inhibited by the simultaneous presence of 3 muM TTX.5. Replacement of Na(o) by choline caused a transient fourfold increase in insulin release which was associated with an increase in the uptake of (45)Ca from the extracellular space of similar magnitude. Subsequent exposure of islets to 100 muM veratridine still evoked some insulin release but this only achieved 32% of that secreted by islets exposed to veratridine in medium of normal [Na](o).6. The addition of 2.5 mM CoCl(2) to the medium caused a 62.5% inhibition of veratridine-mediated insulin release.7. In Ca-free medium supplemented with 1 mM EGTA, 100 muM veratridine evoked insulin release of equal magnitude and of similar temporal relationship to that obtained in the presence of normal [Ca](o).8. A twofold increase in insulin release that occurred in the 15 min period immediately following exposure to 1 mM ouabain was completely independent of [Ca](o). Subsequent ouabain-evoked release became increasingly dependent on [Ca](o).9. Tetrodotoxin (3 muM) inhibited the first phase of insulin release evoked by 16.7 mMd-glucose by 37% and the second phase by 20%.10. Both Na and Ca appear capable of entering through Na channels opened in the beta-cell membrane by veratridine. The increase in [Na](i), resulting from the veratridine mediated increase in P(Na+), causes depolarization of the beta-cell membrane with a consequent opening of voltage-sensitive, Co(2+)-blockable channels for additional Ca entry. An increase in [Na](i) also increases [Ca](i) by altering the equilibria of intracellular Ca-sequestering mechanisms. The small but significant reduction of glucose-mediated insulin release by TTX indicates that glucose has a rather weak action on the Na channel and a more pronounced effect on the voltage-dependent Co(2+)-blockable Ca channel.

Complementary idiotypy in the regulation of the immune response.

A new concept is presented for the interactions of two complementary antibodies in the immune response. These antibodies bind to each other by means of their variable sequence determinants and therefore are designated as complementary idiotypes. Under certain conditions, both complementary idiotypes are produced by the same animal at the same time. An idiotype can drastically affect the expression of the complementary idiotype in the animal, inducing a peripheral quench effect of antibody-binding activity and a central effect on the immunocompetent cell, which produces the complementary idiotype. It is proposed that complementary idiotypes might be induced during every immune response, thus playing an essential role in the regulation of the immune response.

Growth of Chlorella sorokiniana at hyperbaric oxygen pressures.

The growth rate of Chlorella sorokiniana decreased in a linear fashion as the partial pressure of oxygen was increased from 711 to 1,478 mm of Hg. Under two atmospheres of oxygen pressure, growth ceased after 10 to 12 hr. This cessation of growth was not due to any permanent injury, as growth resumed when oxygen partial pressure was reduced to ambient levels. The inhibition occurred under both autotrophic and heterotrophic growth conditions and was not accompanied by an increase in cell size. The results indicated that the tolerance of Chlorella cells to elevated oxygen pressures was not an absolute immunity, and that inhibition of growth at very high oxygen pressures cannot be accounted for by an inhibition of photosynthesis alone.