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Muscarinic action of acetylcholine in the rat ventromedial thalamic nucleus.

Several lines of evidence suggest a role for ACh in the mediation of cerebello-thalamic transmission. The physiological, pharmacological and biochemical experiments described were designed to test this hypothesis for the rat cerebello-thalamic pathway. Unilateral electrolytic lesions of the superior cerebellar peduncle resulted in modest falls of CAT from both ventromedial thalamic nuclei (contralateral 35%, ipsilateral 15%). Iontophoretic application of ACh to relay cells evokes three types of response (i) excitation (ii) inhibition (iii) polyphasic combinations of (i) and (ii). The type of response evoked was directly related to the firing pattern of the cell. Thus, for example, excitatory responses were never recorded during high-frequency bursting but were easily evoked following a switch to tonic, single-spike activity. All responses to ACh and synaptic responses to cerebellar stimulation were sensitive to muscarinic but not to nicotinic cholinergic antagonists. The nicotinic antagonist mecamylamine was a potent blocker of excitant amino acid responses but had no effect on cerebellar-evoked synaptic responses. Cholinergic and anticholinergic agents had a profound action on relay cell firing pattern. ACh promoted single-spike activity whereas atropine promoted high-frequency bursting. The actions of ACh are discussed with reference to recently discovered voltage-sensitive ionic conductances. Because of the modulatory action of ACh on relay cell firing pattern and excitability no firm conclusion can be reached concerning the hypothesis under test here. We tentatively suggest a dual role for ACh as both neurotransmitter and neuromodulator.

Acetylcholine↗

An electrophysiological assessment of X and Y cells as pattern and flicker detectors in the dorsal lateral geniculate nucleus of the cat.

We tested the hypothesis that geniculate X cells are the neural substrate of psychophysically identified pattern channels and that geniculate Y cells are the neural substrate of psychophysically identified flicker channels. The hypothesis was tested by measuring the relative sensitivity of isolated X and Y cells in the dorsal lateral geniculate nucleus of the cat to counterphase and on-off grating presentations. The fundamental and second harmonic responses of X and Y cells to sinusoidal counterphase and on-off temporal modulation were measured at a number of spatial frequencies using two contrasts, 0.1 and 0.4. The fundamental responses of both X and Y cells to sinusoidal counterphase were greater relative to on-off responses. The second harmonic responses of Y cells to counterphase were larger at high spatial frequencies. Contrast sensitivity also was measured. At all spatial frequencies, both X and Y cells were slightly more sensitive to counterphase than to on-off presentations. Since flicker sensitivity in humans is twice as high for counterphase as for on-off presentations across all spatial frequencies, whereas pattern sensitivity is equal for the two presentations, we conclude that X and Y cells do not subserve uniquely pattern and flicker sensitivity, respectively. This conclusion is based on the result that differences between X and Y cells to counterphase and on-off presentations were inconsistent with the differences observed for pattern and flicker sensitivity. We suggest then that a spatial/temporal dichotomy does not seem to accurately characterize the functional roles of X and Y cells.

Animals↗

GABA can improve acoustic contrast in the rat ventral cochlear nucleus.

The effect of microiontophoretically applied gamma-aminobutyric acid (GABA) and its agonists and antagonists on the response pattern of single units in the ventral cochlear nucleus (VCN) of the rat was examined in order to study GABA's physiological function in auditory processing. The effects of the drugs were judged by changes of spontaneous and sound-evoked activity in peristimulus-time histograms (PSTHs) of at least 20 consecutive presentations of acoustic stimuli. GABA inhibited the discharge activity of the majority of neurons. All response types found in the VCN except onset-I responders were sensitive to GABA. The GABAergic inhibition is most probably mediated by GABAA receptors, since the GABAA-receptor agonist muscimol, but not the GABAB-receptor agonist baclofen, mimicked the effect of GABA. The GABAA-receptor antagonists, bicuculline and picrotoxin, had an excitatory effect on the neurons' spontaneous activity, suggesting a tonic endogeneous release of GABA which exerts a permanent inhibition on VCN neurons. Although inhibitory, iontophoresis of GABA emphasized the response to stimulus onset in the PSTHs by means of a stronger inhibition of spontaneous activity. When using iontophoretical currents which did not suppress the neuronal activity completely, a strong inhibition of spontaneous activity was accompanied by only a small inhibition of tone-evoked activity. Under these conditions, the response to tone onset was frequently not inhibited at all. Therefore, GABA's physiological function is possibly to improve the contrast between transient acoustic signals and ongoing background activity. In order to test this hypothesis, the test tone was masked by continuous background noise. Indeed, GABA reduced the noise-evoked discharge more than the tone-evoked discharge, leaving the onset peak in the PSTHs almost unchanged. Thus, GABAergic input improves the signal-to-noise ratio for acoustic transients in VCN neurons. Our data suggest that a functional role of GABA in the VCN is to act as a transmitter within a descending inhibitory feedback loop of the auditory brainstem which serves to improve the transmission of relevant acoustic signals in constant background noise.

Animals↗

Characterization of the distribution of sister chromatid exchange frequencies: implications for research design.

Mitoses from 21 individuals were examined to characterize the within and between subjects distributions of sister chromatid exchange (SCE) frequencies. The importance of accounting for both the within subjects and between subjects variability in the design and interpretation of research is demonstrated. A computer simulation study was performed to evaluate the estimate of an individual's mean SCE rate. A power analysis was performed using our transformed descriptive data to determine the percentage difference in SCE which could be detected between two groups (with 95% probability) as a function of both the number of mitoses per individual and the number of individuals in each group. Tables are provided as guidelines. Conclusions from our work include: (1) The empirical distribution of SCEs within an individual is best described by a negative binomial distribution; (2) The predominant source of variability in baseline SCE rates is between cells within a given individual rather than between individuals and can be accounted for in experiments by counting adequate numbers of mitoses per individual; and (3) There is a systematic relationship between the mean and SD for SCEs which should be removed prior to hypothesis testing by taking either a logarithmic transformation or square root transformation of the data.

Analysis of Variance↗

Arthritis diagnosis based upon the near-infrared spectrum of synovial fluid.

Synovial fluid aspirates have been characterized by measuring their visible/near-infrared spectra (400-2500 nm). The hypothesis tested in this study is that the spectra contain sufficient information to serve as an aid in the diagnosis and/or staging of arthritic disorders. The concentrations of all major constituents are carried implicitly in the spectra, and in this sense this approach is similar in spirit to conventional synovial fluid analysis. The distinguishing feature of this method is that we have not converted the raw data (spectra) explicitly to analytical information. Rather, we have used automated pattern recognition methods to identify significant characteristics of the spectra themselves. A total of 109 spectra were measured and split into three classes according to the disease (osteoarthritis, rheumatoid arthritis, or spondyloarthropathy) affecting the patient from whom the synovial fluid sample was taken. An automated classification method was then trained by correlating features derived from these spectra to the clinical diagnoses. The robustness of the classification was validated using the leave-one-out cross-validation method, i.e., by training on all but one of the spectra and using the resulting model to predict the classification for the spectrum that is left out. The result derived by following this procedure for each of the spectra was that 105 of the 109 predicted classifications correctly matched the clinical diagnosis. These results suggest that the near-infrared spectrum of synovial fluid is sufficient to allow diagnosis of the disease affecting the joint from which the aspirate is drawn.

Arthritis, Rheumatoid↗

The significance of luminance on visual evoked potentials in diagnosis of MS.

In view of the fact that with psychophysical methods monocular luminance changes may increase the detection rate of pathological interocular-latency differences in MS patients, we studied the influence of stimulus luminance on the detection rate of MS using checkerboard visual evoked potentials. Decrements of stimulus luminance covering a range of three log units were unable to increase the detection rate of VEP. Regression coefficients of the luminance-latency functions did not differ in MS patients and normals. Contrary to the hypothesis tested, the diagnostic significance of VEP decreases with decreasing stimulus intensity.

Adult↗

Childhood victimization: desensitization effects in the later lifespan.

The hypothesis tested in this study was that young adults who report having been abused by parents or guardians as children would report less concern when confronted with hypothetical situations similar to the type of abuse they had reportedly experienced during childhood. In our study of nonclinical adults those who reported childhood victimization experiences showed diminished concern toward the specific kind of abuse situation encountered earlier in their lifespan.

Adolescent↗

Social relationships and health-related behavior.

The relationship of social ties to health behavior is studied in this paper. The general hypothesis tested is that those with social relationships are more likely to avoid health damaging behavior. Patterns regarding specific social ties and particular health behaviors are examined. Findings indicate the relationships of spouse, organization member, and friend are related to preventive health behavior; spouses are less likely smokers, drinkers, and heavy drinkers. The friend relationship is related to decreased smoking behavior, while the employee relationship is related to increased drinking. A consistent predictor of health behaviors is the social tie of organization member. People with relationships as organization members are more likely always to wear seat belts, smoke and drink less, and consume lower amounts of these substances.

Adult↗

Mental health status among Puerto Ricans, Mexican Americans, and non-Hispanic whites: the case of the misbegotten hypothesis.

Challenged Shrout et al.'s (1992) comparisons of mental health characteristics of island Puerto Ricans to Mexican Americans and non-Hispanic whites from the Los Angeles Epidemiological Catchment Area Study. The hypothesis tested by Shrout et al.--higher symptom counts but lower DSM-III prevalence rates among Puerto Ricans--was misattributed to Rogler (1989). We also question the validity of assessing lifetime prevalence and reaffirm the need for psychiatric epidemiological research to consider the role of culture in diagnostic criteria.

Cross-Cultural Comparison↗

The population pharmacokinetics of theophylline in neonates and young infants.

The population pharmacokinetics of theophylline were evaluated using 391 theophylline serum concentration measurements from 108 neonates and young infants (postnatal age 0-26 weeks), who received theophylline for the treatment of neonatal apnea. A one-compartment pharmacokinetic model with first-order elimination was used, with intravenous aminophylline and oral theophylline administration modeled as zero-order infusions. The effect of a variety of developmental and demographic factors on clearance (CL) and volume (V) were investigated. Hypothesis testing to evaluate potentially significant factors produced a final model in which clearance was based on weight (kg) raised to an exponential power and postnatal age (weeks), with CL (ml/hr) = 17.5 (weight)1.28 + 1.17 (postnatal age). Clearance was reduced by 12% for patients receiving parenteral nutrition. Volume of distribution in this population was adequately described using only weight, with V (L) = 0.858 L/kg. Bioavailability of orally administered drug was not significantly less than unity. Interindividual variability in clearance was modest, with a coefficient of variation for clearance of 16%. An estimate of interindividual variability in volume could not be obtained. As a measure of residual variability in theophylline serum concentrations, the coefficients of variation for theophylline serum concentrations of 5.0, 10.0, and 13.0 mg/L were found to be approximately, 25, 12, and 9%, respectively. The identification of influential patient factors and the quantification of their influence on theophylline disposition allow for a priori estimates of theophylline pharmacokinetic parameters in these patients.

Aging↗

An evaluation of point and interval estimates in population pharmacokinetics using NONMEM analysis.

In a simulation study of the estimation of population pharmacokinetic parameters, including fixed and random effects, the estimates and confidence intervals produced by NONMEM were evaluated. Data were simulated according to a monoexponential model with a wide range of design and statistical parameters, under both steady state (SS) and non-SS conditions. Within the range of values for population parameters commonly encountered in research and clinical settings, NONMEM produced parameter estimates for CL, V, sigma CL, and sigma epsilon which exhibit relatively small biases. As the range of variability increases, these biases became larger and more variable. An important exception was bias in the estimate for sigma V which was large even when the underlying variability was small. NONMEM standard error estimates are appropriate as estimates of standard deviation when the underlying variability is small. Except in the case of CL, standard error estimates tend to deteriorate as underlying variability increases. An examination of confidence interval coverage indicates that caution should be exercised when the usual 95% confidence intervals are used for hypothesis testing. Finally, simulation-based corrections of point and interval estimates are possible but corrections must be performed on a case-by-case basis.

Computer Simulation↗

Application of NONMEM to routine bioavailability data.

Although NONMEM has been proposed as a modeling tool for sparse data sets, little work has described its application to pharmacokinetic data which is also amenable to typical evaluations. An analysis was performed with NONMEM using plasma concentration data obtained during the development of liquid and capsule extended-release (ER) pseudoephedrine products. A total of four studies (single dose and steady-state studies for both the liquid and capsule formulations) were evaluated, each with an immediate-release (IR) control, and consisting of 18 to 20 subjects. NONMEM analyses provided additional information which could not be obtained through traditional means. Specifically, NONMEM provided not only estimates of residual error from single dose and steady-state studies but also a stochastic measure of bioinequivalence and dose-dumping. It permitted hypothesis testing in the same process as pharmacokinetic parameter estimation, such as contrasting absorption rates from capsule and suspension ER products. A less biased estimate of absorption rate was obtainable for ER formulations by utilizing IR runs. Finally, these NONMEM runs confirmed that, even when data are plentiful and amenable to two-stage analyses, NONMEM provides estimates that may in fact be more meaningful and less susceptible to assay or residual variability. Fundamental differences between population and two-stage approaches are discussed.

Analysis of Variance↗

Logic as a tool for clinical training in social work.

The paper is an attempt to illustrate the usefulness of logic as a technique in the clinical training of mental health professionals. The specific concepts that are examined include the nature of deductive and inductive reasoning, hypothesis testing, necessary and sufficient conditions, "if-then" propositions, and the nature of clinical evidence. Knowledge and use of these concepts was tested in a tutorial program directed toward students who were beginning graduate studies in the field of social work. Some of the difficulties encountered by these students, especially in the clinical aspects of their training, were directly related to an inadequate understanding of these logical forms of reasoning. It is suggested that a portion of the clinical training in mental health fields be directed towards a deeper understanding and utilization of these basic concepts.

Curriculum↗

Frequency domain models of the EEG.

The structure of the normal resting EEG crosspectrum SVV(omega) is analyzed using complex multivariate statistics. Exploratory data analysis with Principal Component Analysis (PCA) is followed by hypothesis testing and computer simulations related to possible neural generators. The SVV(omega) of 211 normal individuals (ages 5 to 97) may be decomposed into two types of processes: the xi process with spatial isotropicity reflecting diffuse, correlated cortical generators with radial symmetry, and processes that seem to be generated by more spatially concentrated, correlated sources. The latter are reflected as spectral peaks such as the process. The eigenvectors of the xi process are the Spherical Harmonic Functions which explains the recurring pattern of maps characteristic of the spatial PCA of qEEG data. A new method for estimating sources in the frequency domain which fits dipoles to the whole crosspectrum is applied to explain the characteristics of the localized sources.

Age Factors↗

Prediction of preschool social behavior from social-emotional development at one year.

In an attempt to directly investigate later consequences of the early mother-infant relationship, several measures of social-emotional and cognitive-motivational development at 12 months of age were correlated with two measures of preschool adjustment for 26 children. Results indicated that both of our measures of early social functioning were related to more optimal adjustment in a peer-setting at three-and-a-half years of age. Taken together, the results of the study provide empirical support for the widely held, but seldom tested, hypothesis that the quality of the early mother-infant tie has important consequences for the child's subsequent development in most areas.

Attention↗

A comparison of professionally employed lesbians and heterosexual women on the MMPI.

The hypothesis tested is whether lesbianism implies psychopathology. The MMPI was given to 26 nonpatient lesbians who were professionally employed full time, and the results were compared to those for a group of 29 similarly employed heterosexual women. With the exception of the Sc scale, no difference was found on the clinical scales. The lesbian group achieved a significantly higher elevation than the nonlesbians on the Mf and Sc scales. Further analysis of the data on the Sc subscales indicated no difference on the pathological part of the scale, but rather a difference in degree of social alienation. Analysis of the data according to a second variable, living status, found significant differences and has important implications for future studies of the lesbian population. Single women, regardless of sexual orientation, scored significantly higher on scales K and Pa and on the Pa subscale naivete. A significant interaction between sexual orientation and living status was achieved on one scale, the F scale.

Female↗

[Modeling residential mobility: the example of Le Havre].

The author describes a model based on input-output models that considers out-migration from a particular system. "These movements have important effects on population distribution and the stock of dwellings, and start new vacancy chains, just like new constructions. [By]...incorporating these movements into a model,...vacancies created by out-migration or obtained by new constructions in a given period are both reallocated by the model in the ensuing period. It thus becomes a better tool for decision-making, hypothesis testing, simulation and forecasting, taking account of the state of the housing market and the urban situation in general." Data are for the French city of Le Havre. (SUMMARY IN ENG)

Demography↗

Clinical aspects of trial design: what can we expect from the cardiac arrhythmia suppression trial?

The controlled clinical trial, i.e., a prospective study that compares the effect of one or more interventions against a control in human subjects, is the most definitive method to determine the benefit/risk ratio for a treatment. Some of the elements are a clear statement of the primary and secondary hypothesis, carefully defined end points, randomization, double blinding, and concomitant controls for the experimental treatment using either placebo or standard treatment. Randomization tends to produce study groups that are comparable with respect to both known and unknown factors that influence the outcome, and also removes bias in the assignment of subjects to treatments to ensure that statistical hypothesis testing will have valid significance levels. An adequate sample size is critically important for a successful trial. The Cardiac Arrhythmia Suppression Trial (CAST) is a randomized, placebo-controlled, double-blind, international, multicenter clinical trial to determine whether suppression of ventricular arrhythmias after myocardial infarction with long-term antiarrhythmic drug treatment will reduce arrhythmic death. Survivors of myocardial infarction who are less than 80 years of age and have greater than or equal to six ventricular premature depolarizations (VPD) per hour on a 24-hour continuous ECG recording obtained between 6 days and 2 years after myocardial infarction are eligible for CAST.(ABSTRACT TRUNCATED AT 250 WORDS)

Anilides↗