Differential behavioral syndrome evoked in the rats after multiple doses of SSRI fluoxetine with selective MAO inhibitors rasagiline or selegiline.

This study investigated whether rasagiline and selegiline (MAO-B inhibitors) induce serotonin syndrome in fluoxetine-treated rats. Rats received rasagiline (0.1, 0.5, 2.0 mg/kg), or selegiline (0.8, 4.0, 16.0 mg/kg) (doses reflecting the clinical ratio of 1:8 base) in drinking water for 28 days. During the last 21 days, they received injections of fluoxetine 10 mg/kg (controls received water only, then saline injections; a fluoxetine only group received water only then fluoxetine). Serotonin syndrome was assessed using neurological severity score (NSS), food intake and weight gain. Mean NSS significantly increased, and weight and food consumption significantly decreased in rats receiving fluoxetine alone compared with controls. Selegiline 16 mg/kg but not rasagiline (regardless of dose) exacerbated these effects. We concluded that selegiline's amphetamine-like metabolites may increase synaptic cathecholamines and possibly serotonin, aggravating fluoxetine's effect. Rasagiline is devoid of this effect and may therefore be safer for use with serotonergic drugs in parkinsonian patients.

Rasagiline is neuroprotective in an experimental model of brain ischemia in the rat.

The neuroprotective effects of intravenous rasagiline were investigated in a rat model of stroke. Middle cerebral artery (MCA) occlusion was performed in male rats and the short- (neurological severity score [NSS], infarct size), intermediate- (cognition) and long-term (necrotic area) effects were assessed. A bolus (3 mg/kg) of rasagiline followed by a 3-h infusion (3 mg/kg/h), initiated immediately after MCA occlusion, reduced infarct size by 48.6% and NSS by 32.7% relative to saline treatment. Cognitive function, tested in a water maze 2-3 weeks after occlusion, also significantly improved compared with saline-treated controls. Necrotic brain area was 35-50% smaller with rasagiline than with saline following a single bolus dose. The single bolus rasagiline dose was as effective as a rasagiline bolus followed by rasagiline infusion in short-term outcomes. The neuroprotective effect of rasagiline was fully reproducible when administered at 2 h following occlusion but not after 4 h.

Luminescent yeast cells entrapped in hydrogels for estrogenic endocrine disrupting chemical biodetection.

In the construction of luminescent yeast cell based fibre-optic biosensors, we demonstrate a novel approach for estrogenic endocrine disrupting chemical (EDC) biodetection by entrapping genetically modified Saccharomyces cerevisiae cells, containing the estrogen receptor alpha-mediated expression of the luc reporter gene, in hydrogel matrices based on calcium alginate or PVA. In order to insure a significant signal, an optimal immobilization ratio of 1:2 alginate 3% (w/v): 5 x 10(6) [cells/ml], respectively, was used with the highest 17-beta-estradiol (beta-E2) induction factor after 2.5 h of incubation with 10[nM] beta-E2. It was shown that biocompatible alginate beads, 4.27-4.55 x 10(5) [CFU/bead], which were characterized by a detection limit of 0.08[microg l(-1)] and an EC50 of 0.64[microg l(-1)] for beta-E2, retained their viability for luminescence measurements after 1 month of storage at -80 degrees C slow freeze condition, and thus repeated cell cultivations were not required. The assay reproducibility for each tested EDC, represented by the coefficients of variation (CV), ranged from 4.35 to 18.47%. An alternative immobilization method, based on a room temperature partial drying of polyvinyl alcohol (PVA) solution (LentiKat Liquid) and cell suspension mix, was investigated with only a slightly lower detection limit for beta-E2 than that reported with alginate beads. Alginate yeast based hydrogels may also be applicable to the analysis of environmental water samples since the trend of detected estrogenic activities with alginate beads roughly correlated with LC-MS-MS analytical results.

Parameter convergence and learning curves for neural networks.

We revisit the oft-studied asymptotic (in sample size) behavior of the parameter or weight estimate returned by any member of a large family of neural network training algorithms. By properly accounting for the characteristic property of neural networks that their empirical and generalization errors possess multiple minima, we rigorously establish conditions under which the parameter estimate converges strongly into the set of minima of the generalization error. Convergence of the parameter estimate to a particular value cannot be guaranteed under our assumptions. We then evaluate the asymptotic distribution of the distance between the parameter estimate and its nearest neighbor among the set of minima of the generalization error. Results on this question have appeared numerous times and generally assert asymptotic normality, the conclusion expected from familiar statistical arguments concerned with maximum likelihood estimators. These conclusions are usually reached on the basis of somewhat informal calculations, although we shall see that the situation is somewhat delicate. The preceding results then provide a derivation of learning curves for generalization and empirical errors that leads to bounds on rates of convergence.

Neural-network design for small training sets of high dimension.

We introduce a statistically based methodology for the design of neural networks when the dimension d of the network input is comparable to the size n of the training set. If one proceeds straightforwardly, then one is committed to a network of complexity exceeding n. The result will be good performance on the training set but poor generalization performance when the network is presented with new data. To avoid this we need to select carefully the network architecture, including control over the input variables. Our approach to selecting a network architecture first selects a subset of input variables (features) using the nonparametric statistical process of difference-based variance estimation and then selects a simple network architecture using projection pursuit regression (PPR) ideas combined with the statistical idea of slicing inverse regression (SIR). The resulting network, which is then retrained without regard to the PPR/SIR determined parameters, is one of moderate complexity (number of parameters significantly less than n) whose performance on the training set can be expected to generalize well. The application of this methodology is illustrated in detail in the context of short-term forecasting of the demand for electric power from an electric utility.

The 'anatomy' of research funding of mental illness and addictive disorders.

To assess the level and sources of research funding for mental illness and substance abuse fields, we undertook a systematic survey of public and private funding entities. Applying standard definitions, we found that research support in these fields totaled approximately $859 million in fiscal 1988. This level of research support for mental illness and substance abuse is extremely limited and disproportionate to the overall costs to society by these disorders. Mental disorders and substance abuse accounted for $66.8 billion in health care costs in 1988; in the same year, research on these disorders represented only 4.7% of all health research support nationwide. The three institutes of the Alcohol, Drug Abuse, and Mental Health Administration (ADAMHA) (namely, the National Institute of Mental Health [NIMH], the National Institute of Drug Abuse [NIDA], and the National Institute on Alcoholism and Alcohol Abuse [NIAAA]) support 64% of all mental illness and substance abuse research; other federal agencies add little more than 7.5%, with the Department of Veterans Affairs the largest at 2%. The pharmaceutical and hospital industries account for another 17% of all support; state funding is 8%, which is particularly surprising in light of the states responsibility for the chronically mentally ill. While there has been recent significant growth in the research budgets of the NIMH, the NIDA, and the NIAAA, other sectors have not grown commensurately, leaving the field vulnerable to the funding vicissitudes of these institutes. Greater coalition building and advocacy are necessary to expand the breadth and depth of research resources for the field.(ABSTRACT TRUNCATED AT 250 WORDS)

Restricting environmental stimulation influences levels and variability of plasma cortisol.

Restricting stimulation from the environment has been shown to alter psychological and physiological states. The present study of 27 healthy subjects examines the effects of restricted environmental stimulation technique (REST) on plasma levels of cortisol and variability in plasma cortisol levels across repeated REST sessions. The REST environment consisted of a 1.2 X 1.2 X 2.4-m ovoid chamber containing 25 cm of saturated MgSO4 solution (sp gr 1.28) maintained at 34.5 degrees F. The buoyant supinely floating subject experienced a minimum of light, sound, and temperature awareness and spatial orientation. The non-REST environment was a cushioned reclining chair in a quiet dimly lit room. The 5-wk protocol consisted of four visits for blood sampling during a 2-wk baseline followed by eight REST or non-REST sessions, 40 min each, with blood samples taken on four nonsession days between sessions 5 and 8. Variability in plasma cortisol was expressed in terms of standard deviation. REST was associated with across-session decreases of 21.6% in plasma cortisol and 50.5% in plasma cortisol variability, whereas no changes in these measures occurred in non-REST. It is concluded that REST influences both static and dynamic aspects of adrenocortical function, possibly altering the feedback monitoring of plasma cortisol.

The presence or absence of light during flotation restricted environmental stimulation: effects on plasma cortisol, blood pressure, and mood.

This study examined the effect of light on relaxation associated with flotation restricted environmental stimulation therapy (REST), as measured by plasma cortisol, mean arterial pressure, and psychometric parameters. Twenty-one subjects were paired by baseline cortisol levels into two groups: one experiencing flotation REST in the presence of light (REST-L) and one experiencing flotation REST in the absence of light (REST-D). Subjects were 15 male and 6 female students aged 22-28 in normal health who had not experienced REST. Repeated flotation REST (8 sessions) either with light or without light was associated with a decrease in plasma cortisol and a decrease in mean arterial pressure, with no differences in effectiveness between groups. The psychometric assessment of mood, using the POMS scale, before and after sessions 1 and 8 revealed mood state improvement in both REST-L and REST-D groups. These data suggest that the presence of light did not compromise the flotation REST experience, as evidenced by the lack of difference between REST-L and REST-D groups.

Factors that influence state funding for mental health research.

A 50-state survey was conducted to identify the extent of and the factors associated with states' funding of mental health research. Of the 49 states responding, 28 funded mental health research. Funds for research represented about .3 percent of total state expenditures for mental health. More populous states were more likely to fund mental health research. A moderately high correlation was found between state funding for research and federal research funding, and a modest but statistically significant correlation was found between state funding for research and total state expenditures for mental health. No correlation was found between state mental health research funding and state per capita mental health expenditures. Political environments supportive of mental health research were characterized by budget stability, articulate and committed leaders, and active citizen advocacy.

Models of state funding for mental health research.

Twenty-eight of 49 states that responded to a survey supported mental health or substance abuse research through at least one of four funding mechanisms--the joint state-university research unit, research grants, state in-house research, and contracts. The authors illustrate the use of these mechanisms with examples from the states. The events leading to the establishment of the new Oklahoma Mental Health Research Institute are described.

Foundation funding and psychiatric research.

Support for psychiatric research is limited to a relatively small number of funding sources. Foundations--nonprofit entities that support a variety of social, medical, educational, and other activities--are a potentially important source. The authors describe the role and structure of foundations, discuss historical trends in foundation support for research in mental illness, and present the results of a study of the extent to which foundations support mental health research. The results of this study confirm the paucity of foundation support for mental health research but show important differences and similarities among the foundations that support research in this field.

Effects of relaxation associated with brief restricted environmental stimulation therapy (REST) on plasma cortisol, ACTH, and LH.

Restricted Environmental Stimulation Therapy (REST), which involves placing an individual into an environment of severely reduced stimulation for brief periods, has been subjectively reported to produce deep relaxation. The present study determines the effects of REST-assisted relaxation on plasma cortisol, ACTH, and luteinizing hormone (LH). These parameters were also measured in a group exposed to a similar relaxation paradigm, but without REST (non-REST). Each subject experienced two baseline sessions (1 and 2), four REST (or non-REST) relaxation sessions (3, 4, 5, 6), and two follow-up sessions (7 and 8). Pre- and postsession plasma hormone levels were measured in sessions 1, 2, 5, and 8. Both REST and non-REST subjects reported that the experience was relaxing. During the treatment period (session 5) pre- to postsession changes in cortisol and ACTH, but not in LH, were significantly greater for the REST group than for the non-REST group. Plasma cortisol level also decreased across sessions in the REST group, with levels in sessions 5 and 8 significantly lower than the baseline (sessions 1 and 2). Non-Rest subjects showed no change in plasma cortisol across sessions. No significant change in plasma ACTH or LH occurred across sessions in the REST or non-REST groups, although ACTH showed a decreasing trend. These data demonstrate that repeated brief REST-assisted relaxation produces a relaxation state associated with specific decreases in pituitary-adrenal axis activity.

The effect of biofeedback-assisted relaxation training on blood pressure and selected biochemical parameters in patients with essential hypertension.

The effect of EMG biofeedback-assisted relaxation on blood pressure and selected biochemical parameters was evaluated in 38 patients with essential hypertension. Training consisted of 8 weeks of biofeedback and home practice of relaxation exercises. Mean blood pressure decreased in the experimental group from 144/90 to 133/84 mm Hg while the control group remained unchanged. Statistically significant decreases in the experimental group also occurred in muscle tension levels, in plasma aldosterone, and in urinary cortisol. Both aldosterone and cortisol are secreted by the adrenal cortex. It was concluded that the technique taught to the experimental group produced a reduction in skeletal muscle tension and a decrease in stress responding mediated by the adrenal cortex.

A method for using reversible hydrocolloid at high altitudes.

This study has shown that high-altitude boiling of reversible hydrocolloid in water alone is inadequate. It must be liquefied at a temperature of at least 100 degrees C. (212 degrees F). The use of propylene glycol alone in the liquefying bath or as an additive to water is effective in attaining this temperature. A microwave oven did not liquefy the reversible hydrocolloid adequately.

Doubly multiplexed dispersive spectrometers.

We analyze the performance of a dispersion instrument in which light is multiplexed both in the entrance and exit slit positions. This double multiplexing scheme allows one to recover both Fellgett's advantage and the high throughput advantage normally attributed only to interferometric spectrometers. The spectrometer's performance is evaluated for a number of binary cyclic coding schemes. Optical limitations on doubly multiplexed instruments are discussed, and we show that such spectrometers compare favorably with Michelson interferometric spectrometers. Some first results obtained with a laboratory pilot model are presented.

Codes for multiplex spectrometry.

A number of binary cyclic coding schemes for multiplex spectrometry are discussed and evaluated in terms of a linear, least mean square, unbiased estimate. The optical realization of such codes in dispersion instruments is briefly discussed. We show that there are many advantages both in the construction of the instrument and in its operation which accrue from cyclic codes.