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Comparison of the disposition and in vitro metabolism of 4-vinylcyclohexene in the female mouse and rat.

4-Vinylcyclohexene (VCH) is a chemical to which humans are exposed in the rubber industry. A chronic carcinogenicity bioassay conducted by the National Toxicology Program showed that oral administration of VCH induced tumors in the ovaries of mice but not in those of rats. The hypothesis tested was that the species and organ specificity of VCH toxicity was due to differences in the disposition of VCH between the female rat and mouse. Therefore, the disposition of a single oral dose of 400 mg/kg [14C]VCH was studied in female B6C3F1 mice and Fischer 344 rats. Mice eliminated greater than 95% of the dose in 24 hr, whereas rats required 48 hr to eliminate greater than 95% of the dose. The major routes of excretion of [14C]VCH-derived radioactivity were in the urine (50-60%) and expired air (30-40%). No evidence was obtained to indicate that the ovaries of either species retained VCH as a parent compound or as radioactive equivalents. A dramatic difference was observed between the rat and mouse in the appearance of a monoepoxide of VCH in blood from 0.5 to 6 hr after VCH administration (800 mg/kg, ip). VCH-1,2-epoxide was present in the blood of mice with the highest concentration at 2 hr (41 nmol/ml). The blood concentration of VCH-1,2-epoxide in rats was less than 2.5 nmol/ml at all times examined. VCH-7,8-epoxide was not present in the blood of either species at the level of detection. These findings were supported by in vitro studies of VCH epoxidation by liver microsomes. The rate of epoxidation of VCH (1 mM) to VCH-1,2-epoxide was 6.5-fold greater in mouse liver microsomes than that in rat liver microsomes. The species difference in the rate of epoxide formation by the liver may be an important factor in the species difference in susceptibility to VCH-induced ovarian tumors.

Administration, Oral↗

Temporal summation functions for detection of sine-wave gratings in young and older adults.

Temporal summation functions for 0.416 and 7.5 c/deg sinusoidal gratings were measured in young and old observers in order to test the hypothesis of a shift in sensitivity from "transient" to "sustained" channels in the aging visual system. Results failed to support the transient-shift hypothesis. Additional tests showed no age-related changes in temporal summation even within a single channel. When all observers were refracted for the test distance and matched for retinal illuminance, no age-related differences in contrast sensitivity were found.

Adult↗

A rational approach to the assessment of aluminium solubility controls in freshwaters.

The problem of assessing aluminium equilibrium solubility controls in freshwaters using thermodynamic techniques is placed in a statistical hypothesis testing framework. As an aid in interpreting field information, artificial data are generated which correspond to ideal equilibrium conditions, but which incorporate realistic analytical and temperature related uncertainties. These artificial data are then subjected to thermodynamic interpretations. The technique is useful in answering "what if" questions by showing the scatter to be expected in real data under true equilibrium conditions. Aluminium hydroxide is used as the example in this report. Reasons for discarding the conventional dependent axis plot (pAl3+ vs pH) in favour of a plot with independent or nearly independent axes are emphasized. An improved method is suggested allowing for temperature variations in the equilibrium constants when constructing stability diagrams. Also, the need for caution when regressing variables which both contain errors is noted.

Aluminum↗

Multivariate case-control study of survival following transurethral resection of prostate.

Although prevalence of perioperative mortality following transurethral resection of the prostate (TURP) has steadily declined as reported in several review studies, it has been suggested that with extended follow-up after TURP, mortality exceeds that of an age-matched population. The sample selected for this study was drawn from a data base of 2,005 men who entered a urologic health-screening program. The sample included a group of 25 patients who underwent TURP and a group of 50 age-matched control patients with symptoms of prostatism. Patients were followed for six years, a total of 450 observed person-years. Multivariate analyses based on a general linear model approach for the dependent variable of survival were used to assess gains in predictive efficiency due to combinations of TURP versus control, time, and patient variables. F-ratio hypothesis tests of coefficients of multiple determination for the models indicated that TURP did account for a significant amount of the variability of survival but only after five years of follow-up. However, a far larger proportion of the variance in survival was explained by other patient variables of age, preoperative risk, comorbidity factors, and postoperative urinary disease after all effects due to TURP, follow-up years, and operation cohort years were held constant in the survival prediction equation.

Aged↗

Effect of 17beta-estradiol on the preovulatory surge of LH in the bovine female.

The hypothesis tested was that increasing concentration of 17beta-estradiol (E(2)) subsequent to luteolysis stimulates the preovulatory surge of LH and that a decline in E(2) after the initial rise is not necessary to trigger the preovulatory surge of LH in the bovine female. Beef cows were synchronized to Day 16 of the estrous cycle. At Hour 0, all cows were ovariectomized and received one of four E(2) treatments: 1) luteal phase E(2) (LE; n=5), 2) increasing then decreasing E(2) (DE; n=5), 3) increasing and subsequent maintenance of high E(2) (IE; n=4), and 4) no E(2) (NE; n=3). Cows in the LE group received one E(2) implant at Hour 0 which provided low concentrations of E(2). Cows in the DE group received one E(2) implant at 0, 8, 16, 24, 32 and 40 hours; implants were subsequently removed at 8-hour intervals, thus mimicking the preovulatory rise and fall of E(2). Cows in the IE group were treated with the same regimen of E(2) implants as cows of the DE group, except that no E(2) implants were removed. Blood samples were collected at Hour 0 and at hourly intervals from Hour 2 through 80, for serum LH and E(2) quantification. The number of cows responding with a surge of LH was 0/3, 0/5, 4/5 and 3/4 for the NE, LE, DE and IE treatments, respectively. The proportion of cows responding with an LH surge was different (P<0.01) when data for cows in the NE and LE groups were pooled and compared with the pooled data of cows in the DE and IE groups. The mean time of the LH surge was not different (P>0.80) for cows responding with an LH surge (DE and IE treatments). Thus, increased levels of E(2) greater than luteal phase concentrations are needed to initiate preovulatory surges of LH, and it appears that concentrations of E(2) need to reach a certain level but do not need to decrease after this initial rise to stimulate a surge release of LH.

Journal Article↗

The effect of water on polymer matrix and composite wear.

OBJECTIVES: Previous studies have demonstrated increased in vitro wear of composite after long-term water exposure. The increased wear effect was not clearly related to debonding of the filler from the matrix, resulting in accelerated loss of filler particles. The hypothesis tested in this experiment was that the changes in in vitro three-body wear of a composite following water storage are caused by changes in the wear resistance of the polymer matrix. METHODS: In the in vitro wear test used, a specimen wheel was rotated against an antagonist wheel in a slurry of millet seed and water. Specimens were fabricated of composite and polymer matrix only. Specimens were wear tested after 1 wk of ambient temperature dry storage and after 14, 20, and 26 mon of water storage at 37 degrees C. RESULTS: The wear of the composite significantly increased (23%) during the 26 mon of water storage. The wear of the polymer specimens increased slightly; however, the increase was not statistically significant. SIGNIFICANCE: Analyses of the data using a series model for the wear of a composite indicated that the increase in wear of the composite was not due to changes in the wear resistance of the polymer matrix. Instead, the increased composite wear was more likely due to increases in the dislodgment rate of filler particles and the wear rate of the filler itself.

Analysis of Variance↗

Scientific inquiry in forensic psychiatry.

Forensic psychiatry and psychology, with an extensive history of clinical practice, is only recently emerging as a new scientific specialty. It is confronted with both general scientific-methodological issues, as well as unique, empirically-based psycholegal applications. Aimed towards a broader, more flexible paradigm for understanding the basis of our scientific inquiry, the paper examines various research and methodological issues. As a model for connecting and understanding these complicated and interrelated issues, Holton's explicit and useful model of scientific structure is provided. The methodology, logical and statistical analysis, and themata are explored with regards to their potential impact on scientific inquiry in forensic psychiatry. This paper argues for several considerations in furthering research. From a methodological basis, the prospective researcher has to consider (1) whether the methodology is, in part, predetermining the results; (2) whether the results are a prediction of the inclusion criteria rather than an independent finding; (3) what balance between specificity and generalizability is designed within the research study; and (4) what is the impact of various methodological artifacts on the results and conclusions of forensic psychiatric research (e.g., demand characteristics, evaluation apprehension, experimenter bias, systems influence). Further, the forensic psychiatric researcher is asked to consider the basis of the "validity" of his research findings in comparison with "objective reality" from the perspective of logical and statistical analysis. Scientists within forensic psychiatry are asked to consider (1) whether to employ "best fit" or complementarity in understanding their results; (2) how to make explicit the steps in data transformation and redefinition within their study; (3) what are the implications of exclusive use of null hypothesis testing in establishing research results; and (4) what is the comparative utility of non-parametric and multivariate statistical procedures in studying and understanding experimental variables. Finally, in acknowledging the non-linear and sometimes self-justifying aspect of science, researchers are invited to examine their basic assumptions, and the self-perpetuating and constraining nature of unacknowledged themata, as well as their impact on forensic psychiatry. This paper is conceptualized as a movement towards articulating both general methodological issues and their unique application to forensic psychiatry. The brief exposition of Holton's model and review of illustrative research in forensic psychiatry constitutes one attempt to strengthen the scientific rigor of forensic psychiatric research.

Forensic Psychiatry↗

Statistical modeling of the effects of drug combinations.

A method is described for identifying and quantitating departures from additivity (i.e., synergism and antagonism) when drugs having like effects are given in combination. It is applicable for both graded and quantal (e.g., after probit or logit transformation) responses. Log(dose)-response curves of both drugs should be linear but need not be parallel. The following model is fitted to dose-response data for both the individual drugs and combinations of drugs: Y = beta 0 + beta 1 log(A + P.B + beta 4(A.P.B)1/2) where Y is the response, A is the amount of drug A, B is the amount of drug B, and P is a relative potency of the drugs given by log(P) = beta 2 + beta 3 log(B'), in which B' is the solution to B' - B - A/P = 0. If log(dose)-response curves of the two drugs are parallel, beta 3 = 0, and P becomes a constant parameter to be estimated. A positive value of beta 4 corresponds to synergism and a negative value to antagonism. Hypothesis tests may be carried out to determine whether beta 4 is significantly different from zero.

Dose-Response Relationship, Drug↗

The European Consultation-Liaison Workgroup (ECLW) Collaborative Study. I. General outline.

Previous C-L psychiatric service research is seriously limited by its parochial nature; very few results can be generalized outside of the hospital in which the original study was performed because of differences in the nature of the hospital and the type of C-L service. This article presents the general outline and methodology of a European multicentered C-L service delivery study effected by the European Consultation-Liaison Workgroup for General Hospital Psychiatry and Psychosomatics (ECLW). The study is unique in its kind as it allows the comparison of very different C-L services; for example, some services are run by C-L psychiatrists, others are run by C-L psychosomaticists and the study encompasses a large variety of different settings. As a result, both common factors in C-L service delivery and specific local patterns can be explored. The overall hypothesis tested in this study was that the most developed services would see (as well as more patients) a wider variety of clinical problems than small services. The implication is that the absence of well-developed C-L services in a general hospital may mean that there are patients with unmet mental health needs. In separate articles the training and reliability testing of the new Patient Registration Form (PRF) and the Institutional and Provider characteristics will be described. The former includes the use of ICD-10 in the general hospital setting. This study is a collaborative effort made by 226 consultants from 56 psychiatric C-L services in 11 countries. Each consultant recorded details of 1 year's caseload leading to a thorough description of 14,717 patients collected between 1991 and 1993. The advanced methodology included a multicentered international approach, rigid training for all participating consultants, and the development and testing of new instruments. This will allow us to assess the impact of important structural and process variables on the outcome of C-L service delivery in several European countries. These results will be reported in papers both in the international and national literature of the participating countries.

Adolescent↗

Overview of chemical sampling techniques.

Although many of the ideas for sampling the chemical microenvironment of the brain were present, at least in nascent form, three decades ago or more, the last 10 years have witnessed a particularly spectacular surge of development, refinement, and use. We are now able to measure virtually any endogenous brain chemical in vivo at commendable levels of sensitivity, selectivity, and speed. The long-dreamt-of goal of being able to correlate neurochemical events with ongoing behavior and/or presentation of salient environmental cues and stimuli has already been largely achieved. Further refinements of existing techniques may well lead to levels of analysis inconceivable even a few years ago. The implications for theory-building and hypothesis-testing are enormous, particularly within such essentially virgin domains as behavioral neuroscience and biological psychiatry. These are truly exciting times.

Animals↗

REM sleep and depression: further use of computer simulation to test the phase-advance hypothesis.

A phase advance of the circadian rhythm of rapid eye movement (REM) sleep propensity relative to the sleep-wake cycle has been proposed to account for the abnormalities of REM sleep commonly found in depressed patients. One implication of this hypothesis is that a phase delay of sleep in normal subjects should produce the same abnormalities of REM sleep. The hypothesis was tested by computer simulation using equations based on data derived from normal subjects who had experienced phase shifts of their bedtime. At phase delays of between 4 and 6 hours (an estimate of the putative phase advance in depressed patients), the mean REM latency and the mean duration of the first REM period predicted by the equations did not differ significantly from those observed in depressed patients. The findings with respect to the distribution of REM latency were more equivocal.

Adult↗

Corticotropin-releasing factor modulation of the ultrasonic vocalization rate of isolated rat pups.

The effect of corticotropin-releasing factor (CRF) on ultrasonic vocalizations (USVs) and other behaviors of isolated rat pups was examined at 5/6-, 9/10-, and 13/14-days. The hypothesis tested was that central CRF affects USV rate biphasically: as endogenous CRF increases from low basal levels it initiates USV production, but at higher levels CRF diminishes USV production. As predicted, the largest doses of CRF (0.1 and 1 microgram) and of its antagonist alpha-helical CRF9-41 (aH-CRF; 20 micrograms) administered intracerebroventricularly (ICV) reduced USV rate compared to saline treatment during a 2-min isolation at ambient temperature in pups of all ages. Other behaviors were either unaffected or increased by drug treatment. Effects were not attributable to sedation or to a change in core temperature. Peripheral administration of 1 microgram CRF or 20 micrograms aH-CRF had no effect. When isolation occurred in a heated chamber containing soiled bedding from the home cage to minimize baseline USV rate, ICV-CRF (0.001, 0.01, 0.1, or 1 microgram) did not enhance the rate. The quieting ability of aH-CRF is evidence that central endogenous CRF enhances the rate of ongoing USVs during brief isolation; the quieting ability of CRF suggests that this peptide may also be responsible for the reduction in USV rate that normally occurs during more protracted isolation. However, CRF alone is not sufficient to induce vocalizing in quiet pups.

Animals↗

Early decision in clinical trials when the treatment differences are small. Experience of a controlled trial in head trauma.

In a long-term clinical trial, it is customary to review the results of the data periodically. Two possible situations suggesting a possible early decision in hypothesis testing may arise. First, the difference in outcome may be sufficiently convincing without further evidence from additional data. Second, the difference may be such that it is not likely to be significant even if additional data are collected. This article is mainly concerned with a method for reaching a decision under the second situation, in particular when inadequate patient acquisition has occurred. A predicted distribution of likely future outcomes on the basis of data already accumulated is used to evaluate what might happen if the trial were carried on to the designed end. The method is intended for the case where the outcome variable is dichotomous and the two groups are compared for the difference in proportions.

Adult↗

Optimal restricted two-stage designs.

The fixed sample p value at the final stage of a group sequential design may be "significant" while the overall p value for the trial as designed may be "nonsignificant." This can lead to confusion in reporting and interpreting final stage results. Two-stage designs are presented that allow acceptance, rejection, or continuation at the first stage while retaining the fixed sample critical value at the second stage. The designs are optimized under this restriction to minimize the expected sample size under the null hypothesis, the expected sample size under a specific alternative hypothesis, or the maximum expected sample size. These restricted designs are almost fully efficient when compared to optimal unrestricted two-stage designs. Additionally, one can interpret the results of hypothesis tests at the final stage as though a fixed sample design had been used. Examples are given which illustrate the use of these restricted plans in the design and analysis of clinical trials.

Biometry↗

World Health Organization behavioral science research: problems and prospects.

The stated goals of World Health Organization-supported behavioral research are applied: to contribute to planning and policy decision-making, and to improve health care delivery methods. The evidence suggests the organization is getting less for its behavioral research dollar than it ought to: much research has been of poor quality, and researchers often appear more concerned with research design elegance than with practical application of results. Professional and structural factors explain this picture. Physician-dominated research committees that evaluate research applications assume that quantitative hypothesis-testing investigation is the only acceptable research model. Hence, in their grant applications behavioral scientists conform to the expectations of research committees, stressing quantitative methods and slighting the qualitative approaches that often are more productive in providing operational information. Research committee members also often fail to understand the scope of behavioral research possibilities: hoped-for results are limited to information on how to change community behavior more nearly to conform to the needs of health care delivery programs. Research on organization policies and programs is viewed as irrelevant and perhaps even threatening. To improve the quality and utility of WHO-sponsored behavioral research, the author suggests a workshop of organization personnel and short-term consultants and temporary advisors with prior experience, to evaluate past research, to identify its strengths and weaknesses, and to recommend modified research support procedures to produce higher quality, operationally-useful results.

Behavioral Sciences↗

A cohort study of unemployment as a cause of psychological disturbance in Australian youth.

Data from the Australian Longitudinal Survey, conducted by the Commonwealth Department of Employment, Education and Training, were analysed to estimate relative risk of psychological disturbance accompanying unemployment in young people aged 15-24 years. Two cohorts were surveyed annually over 4 years during the mid-to-late-1980s; one from the general 15-24 year-old population (N = 8995), and the other selected from Commonwealth Employment Service records (N = 2403). Such large respondent numbers allowed control of confounding by exclusion to isolate employment transition groups suitable for hypothesis testing and quantification of causal relationships. Psychological morbidity was measured using binary outcomes of the 12 item psychological component of the General Health Questionnaire. Excluded from the analysis were those who: suffered from pre-existing physical health problems; were dissatisfied in their job; were self-employed; underwent marriage breakdown during the inter-survey period; had become widowed during the inter-survey period. A Bayesian probabilistic approach was used to calculate probabilities of psychologically normal respondents becoming psychologically morbid, given prior transition from employment to unemployment. Mantel-Haenszel analysis was utilised to estimate relative risks in comparison to a control group of those remaining employed, after controlling for age and gender. An overall relative risk of becoming psychologically disturbed as a consequence of becoming unemployed was estimated to be 1.51 (95% CI: 1.15-1.99). The overall relative risk of recovery from psychological disturbance upon re-employment in those with psychological disturbance was estimated to be 1.63 (95% CI: 1.08-2.48). Residual psychological effects of past unemployment experience and the effects of long-term unemployment were investigated, but found to be non-significant in this study. There was some evidence of psychological adaptation to unemployment, but this was statistically insignificant. Unemployment was a significant cause of psychological disturbance in young people who were initially employed, not suffering physical ill-health, and psychologically normal; conversely, re-employment reversed the effect.

Adaptation, Psychological↗

Principal components analysis of haematological data from F344 rats with bladder cancer fed N-(ethyl)-all-trans-retinamide.

Several multivariate statistical methods are available which can alleviate the problems of analysing the large volumes of data generated from toxicological experiments. One such technique, principal components analysis, provides a method for exploring the relationships between a number of variables (such as blood parameters) and for eliminating redundant data if strong correlations exist between the characters. It also provides a method for clustering individuals, which may reveal similarities between animals in a treatment group or highlight individual 'outliers'. The application of principal components analysis to a set of haematological data from a trial evaluating the efficacy of a synthetic retinoid against carcinogen-induced bladder cancer in the rat has clearly shown, in two bivariate plots, that while some animals in the carcinogen-treated groups were normal, others were anaemic and that animals fed the synthetic retinoid and killed at 1 year had a microcytic anaemia. A full exploration of the data using conventional univariate statistical analysis would have involved at least 28 graphic representations of the data, as well as the interpretation of more than 130 means and SDs. Principal components analysis provides a valuable additional tool for the statistical analysis and exploration of toxicological data, but it must be used in conjunction with univariate or other multivariate methods if hypothesis testing is required. The use of multivariate techniques in toxicology may best be assessed by their practical application to toxicological data, and this paper presents such an evaluation with the aim of encouraging further exploration of the usefulness of principal components analysis. The raw data on which most analyses have been carried out are given.

Analysis of Variance↗

Subchronic effects of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) and their reversibility in male Sprague-Dawley rats.

The hypothesis tested in this experiment is that effects of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) show identical dose-responses after subchronic as after acute exposure when the dose is corrected for toxicokinetics. Groups of male Sprague-Dawley (S-D) rats were administered orally a total dose of 0, 0.2, 2.3, 11.5, 35, 70 or 115 micrograms/kg of TCDD over a period of 10 weeks at 4 ml/kg of vehicle. Body weight was recorded weekly. One week after the last dose of TCDD one half of the rats was killed and tryptophan 2,3-dioxygenase (TdO), 7-ethoxyresorufin-O-deethylase (EROD) and phosphoenolpyruvate carboxykinase (PEPCK) activities were measured in livers, whereas tryptophan and total T4 (TT4) were determined in serum. The results show that the dose-response for decreased TdO and PEPCK activity and elevated serum tryptophan levels are similar if not the same as the dose-response for subchronic retardation of body weight increase. They also demonstrate that the dose-responses for the induction of EROD activity and the reduction of serum TT4 occurred at much lower doses than those for decreased TdO and PEPCK activities or elevated tryptophan levels and mortality. After a 6-week recovery period, PEPCK and TdO activities in liver as well as tryptophan in serum returned to near control values, whereas EROD activity and serum TT4 still displayed a dose-dependent induction and reduction, respectively, albeit both shifted to the right in accordance with toxicokinetics. These data support the notion that subchronic dose-responses of TCDD are similar to acute dose-responses when corrected for toxicokinetics and that at least some TCDD-induced effects are reversible also in accordance with toxicokinetics.

Animals↗