Human circadian rhythms in continuous darkness: entrainment by social cues.

Three groups of two subjects each were kept in underground chambers, first for 4 days in an artificial light-dark cycle, and thereafter for 4 days in complete darkness. They lived on a rigorous time schedule. Physiological as well as psychological functions were measured at 3-hour intervals. There were no differences in the results between the two sections of the experiment. Social cues are sufficient to entrain human circadian rhythms, and absence of light has no immediate effect on the functions measured.

Further studies on sex hormones in male homosexuals.

Plasma estrone, dihydrotestosterone, luteinizing hormone (LH), and percentage-free testosterone levels were determined in 26 predominantly or exclusively homosexual males (20 to 33 years of age) and in an age-matched control group. Although the homosexual and control groups showed a broad overlapping for all hormonal factors measured, highly significant differences between the groups were found without exception. The medians of the homosexual group (control group) and the significance levels for the two-sample rank tests were as follows: estrone 3.07 (2.43) ng/100 ml, P less than .01; dihydrotestosterone 66.0 (49.2) ng/100 ml, P less than .01; percentage-free testosterone 10.7% (9.7%), P less than .02; LH 35.1 (24.9) ng/ml, P less than .001. These findings can in part be explained by the higher LH secretion in the homosexual subjects.

Cortisol-induced suppression of plasma testosterone in normal adult males.

The response of plasma testosterone, LH and FSH to oral administration of cortisol or dexamethasone was studied for 26 h in 6 groups of 12 normal adult males. Twenty-four hour treatment with cortisol (60 mg at 1000 h, followed by 30 mg at 2 h intervals) or with dexamethasone (6 mg at 1000 h, followed by 3 mg at 6 h intervals) was without effect on testosterone during the day but suppressed the nocturnal rise completely. LH and FSH did not decrease at any time during the day and showed a highly significant increase during the second part of the night. Short-term treatment (1000-1600 h, 1600-2200 h or 2400 h-0800 h) with cortisol was less effective in suppressing the nocturnal rise in testosterone. It was concluded that administration of cortisol leading to plasma levels as seen under treatment with ACTH suppresses testosterone by abolishing or flattening the nocturnal rise. This effect was not mediated by changes in LH or FSH. Our data suggest that the ACTH-induced suppression of testosterone is due to an action of cortisol.

Neuroendocrinological and neurophysiological studies in major depressive disorders: are there biological markers for the endogenous subtype?

The possibility of characterizing subgroups of depressive disorders by biological markers was studied by means of the dexamethasone suppression test (DST), the 24-hr urinary free cortisol (UFC), the growth hormone response to the insulin tolerance test (ITT), and polygraphic sleep recordings. Forty-five hospitalized patients suffering from a moderate to severe nonpsychotic major depressive disorder were clinically subdivided into three groups: endogenous (n = 20), neurotic (n = 19), and "ambiguous" (n = 6). These clinical diagnoses were supplemented by operational diagnostic tools, namely, the Research Diagnostic Criteria (RDC) and the Newcastle Scale. The different diagnostic procedures exhibited a high degree of correspondence. Whereas the results of the ITT were normal in almost all patients, 20% of all patients were dexamethasone nonsuppressors and more than half of the patients showed a shortened REM latency. Both markers did not reveal any specificity for the endogenous subtype. A significant influence of weight loss on the DST and the excretion of UFC was evident.

Temporal coordination of rest-activity cycle, body temperature, urinary free cortisol, and mood in a patient with 48-hour unipolar-depressive cycles in clinical and time-cue-free environments.

During medication-free observation a 66-year-old male patient showed an almost strict alternation of days with depressed mood and days with normal mood. The experiment consisted of two parts; the first was 4 weeks' observation in the psychiatric ward, while the second was 2 weeks' observation in an experimental unit where the patient was deprived of all known information on local time. In the psychiatric ward the observed circadian rhythms, i.e., the rest-activity cycle, the body temperature, the urinary free cortisol, and the mood rhythm, were all synchronized with the geophysical day. Under isolation from time cues the average rest-activity cycle duration was reduced to about 19.5 hr, whereas the body temperature and the urinary free cortisol continued to show rhythms with near-24-hr periods. The main finding of the study is the persistence of a near-48-hr periodicity in the mood fluctuation under isolation from time cues. Besides this, in the time course of body temperature and urinary free cortisol evoked components correlating with the mood cycles were found.

Efficacy and side effects of haloperidol in psychotic patients: oral versus intravenous administration.

It is a commonly held view among clinicians that intravenously administered haloperidol has a greater antipsychotic effect than oral haloperidol. To test this hypothesis, the authors carried out a double-blind study on patients with acute schizophrenia and patients with schizophreniform or schizoaffective (with manic features) psychoses. Using biologically equivalent doses, they found that intravenously administered haloperidol was slightly more effective during the first 3 hours; thereafter the route of administration did not make a difference in effectiveness.

The effects of in vitro cocaine exposure on human sperm motility, intracellular calcium, and oocyte penetration.

OBJECTIVE: To determine if cocaine exposure affects human sperm motility, intracellular calcium level, and fertilizing capability. DESIGN AND METHODS: Human semen samples were treated with 1 to 1,000 microM cocaine hydrochloride for up to 2 hours in vitro. Sperm motion kinematics were measured by computer-assisted semen analysis (CASA). Spermatozoan intracellular calcium was determined by laser cytometry. The sperm fertilizing capability was assessed using the zona-free hamster oocyte penetration test. RESULTS: After a short exposure (15 minutes) to cocaine, the sperm motion kinematic parameters, straight line velocity and linearity, were decreased in the high concentration groups. However, after a longer exposure (2 hours) to cocaine, the differences were no longer significant. Cocaine treatment did not alter spermatozoa intracellular calcium levels. Most importantly, human sperm treated with cocaine at a high concentration were fully capable of penetrating zona-free hamster oocytes. CONCLUSION: Human spermatozoa acutely exposed to high concentrations of cocaine initially demonstrate a decrease in two motion kinematics, straight line velocity and linearity. However, overall, cocaine exposure had no significant effects on sperm motility and fertilizing capability.

Relationship between mood changes and adrenal cortical activity in a patient with 48-hour unipolar-depressive cycles.

A 66-year-old patient with 48-hour unipolar-depressive cycles was studied in the hospital for one month and in an isolation unit for two weeks. At 3-hour intervals during the day and once at night the mood state was assessed by two self-rating scales and urine was collected for the determination of urinary free cortisol (UFC). In the hospital there was a regular alternation between 'good' and 'bad' days. Without exception the switch from normal to depressive mood occurred between 22:00 and 2:30, when the patient was sleeping. The switch from depressive to good mood was variable and occurred in the late morning or in the afternoon. On a 24-hour basis a highly significant correlation was seen between the mood state and the UFC excretion: r = 0.73, P less than 0.001 (hospital); r = 0.82, P less than 0.01 (isolation unit). The shape of the 24-hour profile for the UFC excretion was similar on good and bad days, with a maximum between 2:30 and 7:00 and a minimum between 19:00 and 2:30. However, on bad days UFC was elevated at all clock times. A decrease in adrenal cortical activity preceded or was parallel to substantial improvement in the mood state. Internal desynchronization occurred in the isolation unit but not in the hospital, with a rest-activity period of 18.6 h and a period close to 24 h for UFC excretion. Changes in mood were associated with both cycles, and a very close link between the switch from normal to depressive mood and the sleep state could be demonstrated.

Circadian rhythms in endogenous depression.

A comprehensive study of circadian rhythms was carried out in 16 drug-free patients with endogenous depression, 10 of whom were reinvestigated after clinical remission, and 10 healthy controls. No free-running periods were observed in body temperature, urinary excretion of potassium and free cortisol, or any other variable. Moreover, there was little, if any, indication of phase-advance. The circadian variation of several variables was reduced during depression, e.g., motor activity, body temperature, and (less markedly) urinary potassium, but not cortisol. The circadian worsening of mood tended to occur around the time of awakening during depression, i.e., several hours later than after remission or in normal controls. In patients with circadian variation of self-rated mood, the acrophase of this variable correlated significantly with that of urinary free cortisol. This indicates an entrainment of the disease process to the circadian rhythm of cortisol secretion, probably via circadian variations of neurotransmitters in the hypothalamus. The other circadian phenomena observed in depression can adequately be explained by masking effects (negative or positive) of psychopathological symptoms (e.g., early morning awakening) on overt circadian rhythms.

Factors associated with dental anxiety.

This study assessed dental anxiety in adults living in the Detroit tricounty area and identified factors associated with it. The prevalence of dental anxiety was 10.0 percent. Regression analysis revealed six factors associated with dental anxiety: unfavorable attitudes toward dentists, infrequent checkups, dissatisfaction with one's month, small numbers of filled surfaces, being female and lower income. Dentists should be aware of these factors when assessing dental anxiety in their patient populations.

Isolation of Mycoplasma gallopavonis from free-ranging wild turkeys in coastal North Carolina seropositive and culture-negative for Mycoplasma gallisepticum.

Serum samples and choanal cleft swabs were collected from livetrapped and hunter killed wild turkeys (Meleagris gallopavo) from Martin and Bertie counties, North Carolina (USA). Sera were tested for antibodies to Mycoplasma gallisepticum, Mycoplasma synoviae and Mycoplasma meleagridis by hemagglutination inhibition (HI). Sera from 33% (five of 15) of livetrapped turkeys were positive for antibodies to M. gallisepticum by HI, and all were negative for antibodies to M. synoviae and M. meleagridis. Choanal cleft swabs from 22 livertrapped and five hunter killed wild turkeys cultured in Frey's broth medium resulted in 23 mycoplasma isolations. Using direct immunofluorescence, 74% (17/23) were M. gallopavonis, and 26% (six of 23) were unidentified; no isolate was identified as M. gallisepticum, M. synoviae or M. meleagridis.

Recurrent aphthous stomatitis.

Etiology and Epidemiology: The Greek term aphthai was initially used in relation to disorders of the mouth and is credited to Hippocrates (460-370 BC). Today, recurrent aphthous ulceration, or recurrent aphthous stomatitis (RAS), is recognized as the most common oral mucosal disease known to human beings. Considerable research attention has been devoted to elucidating the causes of RAS; local and systemic conditions, and genetic, immunologic, and infectious microbial factors all have been identified as potential etiopathogenic agents (Table 1). However, to date, no principal etiology has been discovered. Epidemiologic studies indicate that the prevalence of RAS is between 2% and 50% in the general population; most estimates fall between 5% and 25%. In selected groups, such as medical and dental students, it has been observed with a frequency as high as 50% to 60%. The peak age of onset for RAS is between 10 and 19 years. After childhood and adolescence, it may continue throughout the entire human lifespan without geographic or age-, sex-, or race-related preference.

The value and benefits of the International Conference on Harmonisation to drug regulatory authorities: advancing harmonization for better public health.

The International Conference on Harmonisation (ICH) is an unparalleled undertaking, which has brought together drug regulatory authorities and pharmaceutical trade associations from Europe, Japan, and the United States, to discuss the scientific and technical aspects of medical product registration. Launched in 1990, the value and benefits of ICH to regulators are being realized. ICH has harmonized submission requirements and created a harmonized submission format that is relieving both companies and regulatory authorities of the burdens of assembling and reviewing separate submissions for each region. As more countries embrace ICH guidelines, we anticipate additional benefits, including the promotion of good review practices and, ultimately, a common regulatory language that will facilitate further interactions among global drug regulatory authorities.

Radioimmunoassay of oestrone in plasma. A comparison of different methods with respect to the relation between assay specificity, sample purification and antibody specificity.

A radioimmunoassay (RIA) for oestrone (Oe1) in plasma was developed using an ether extraction, a partition between NaOH and light petroleum, and a TLC as sample purification and an antiserum cross-reacting with Oe2 for the final assay (Method A1). The reliability criteria are given in detail. In order to simplify this method a highly specific antiserum was developed by using Oe1-3-hemisuccinate-BSA as an antigen. Using this antiserum for the final assay but omitting the TLC (Method B) the Oe1 concentration in male plasma was 76% overestimated (Method B compared with Method A1). In pregnancy plasma Oe1 could specifically be determined after a simple ether extraction (Method C). It was concluded that the use of a highly specific antiserum (as determined by cross-reaction studies) for the final assay does not necessarily imply that a chromatographic sample purification can be omitted without loss in assay specificity. This appears to be true mainly in cases where the steroid concentration of the sample is low. Normal values of Oe1 from 80 healthy adult males were ascertained by Method A1. Age group I (22-61 years, n = 48) ranged from 1.22-5.60 ng/100 ml, median 2.81; age group II (67-90 years, n = 32) from 1.55-6.40, 100 median 3.41. The small increase of Oe1 with age was highly significant.