The aggregated form of an AAMP derived peptide behaves as a heparin sensitive cell binding agent.

A peptide termed P189, derived from the sequence of a newly discovered protein, AAMP (angio-associated migratory cell protein), contains a motif that is predicted to a bind heparin. It occurs near the amino terminal end of AAMP. Previous studies have shown that in its solubilized form P189 (RRLRRMESESES) binds heparin and melanoma cells. The peptide is bipolar in that it contains positive charges at its amino end and negative charges at its carboxyl end. It forms strongly aggregated particles that require exposure to 50% DMSO and 100 degrees C for solubilization to occur. Now heparin and cell binding (heparin sensitive) are also demonstrated for the peptide in its particular form. Cell binding/clustering to the peptide particles is strong and resists exposure to various reagents (sugars and inhibitors of glycolysis and protein synthesis) except heparin. Tumor cell migration is partially inhibited by the presence of the peptide. On electron photomicrographs the peptide is seen in close apposition to cell membranes. Heparin sensitivity of the cell binding indicates that cell surface glycosaminoglycans are involved. The aggregated peptide binds heparin in a saturable manner with a dissociation constant, K(d), of 306 pmol. Cell binding/clustering studies using peptide variants of P189, which have substitutions in either the charged and/or nonpolar residues, show that the specific sequence of P189 optimizes heparin-sensitive cell aggregation. (c) 1997 John Wiley & Sons, Inc. Biotechnol Bioeng 54: 365-372, 1997.

Effects of meta-chlorophenylpiperazine infusions in patients with seasonal affective disorder and healthy control subjects. Diurnal responses and nocturnal regulatory mechanisms.

BACKGROUND: Multiple lines of evidence suggest that brain serotonergic systems may be disturbed in seasonal affective disorder (SAD). Previously, we found that the serotonergic agent meta-chlorophenylpiperazine (m-CPP) produced increases in activation and euphoria in depressed patients with SAD, but not in patients with SAD following light treatment or in the summer, nor in healthy control subjects in any condition. In the present study, we attempted to replicate and extend this finding using better methods. METHODS: Seventeen outpatients with SAD and 15 control subjects underwent successive 3-week periods of bright light treatment and light avoidance in a randomized order. During the third week of each condition, on 2 different occasions, subjects were admitted to the hospital for a night of sleep (core temperatures were recorded), followed by infusions of m-CPP (0.08 mg/kg) or placebo the next morning. Dependent measures included the 24-item National Institute of Mental Health Self-Rating Scale, plasma corticotropin, cortisol, prolactin, growth hormone, and norepinephrine concentrations, and core temperatures. RESULTS: Meta-chlorophenylpiperazine produced (1) significant increases in "activation-euphoria" ratings only in depressed patients with SAD in the untreated condition and (2) blunted corticotropin and norepinephrine responses in patients with SAD compared with controls across both light treatment conditions. In both groups, light treatment was associated with significant reductions in nocturnal core temperatures, which were correlated with similarly significant reductions in mean diurnal growth hormone concentrations. In patients with SAD, (1) the reductions in nocturnal core temperatures also were correlated with the reductions in baseline depression ratings and (2) the reductions in mean growth hormone concentrations were significantly smaller compared with controls. CONCLUSIONS: The abnormal m-CPP-induced activation-euphoria responses represent a replicated state marker of winter depression in patients with SAD. The blunted m-CPP-induced responsiveness of the hypothalamic-pituitary-adrenal axis and the sympathetic nervous system may represent traitlike abnormalities. The improvements in mood following light treatment in patients with SAD seem to be associated with the lowering of nocturnal core temperatures. The findings, although not easily explained based on a uniform abnormality of serotonin receptors, are nonetheless compatible with the notion that selected regions of the central nervous system are deficient in serotonin transmission during winter depression.

Suppression of men's responses to seasonal changes in day length by modern artificial lighting.

We recently reported that humans have conserved mechanisms, like those that exist in other animals, which detect changes in day length and make corresponding adjustments in the duration of nocturnal periods of secretion of melatonin and of other functions. We detected these responses in individuals who were exposed to artificial "days" of different durations. The purpose of the present study was to determine whether men who are exposed to natural and artificial light in an urban environment at 39 degrees N are still able to detect and respond to seasonal changes in duration of the natural photoperiod. We measured profiles of circadian rhythms during 24-h periods of constant darkness (< 1 lx) and found no summer-winter differences in durations of nocturnal periods of active secretion of melatonin, rising levels of cortisol, high levels of thyrotropin, and low levels of rectal temperature. The results of this and our previous study suggest that modern men's use of artificial light suppresses responses to seasonal changes in the natural photoperiod that might otherwise occur at this latitude.

A controlled trial of levodopa plus carbidopa in the treatment of winter seasonal affective disorder: a test of the dopamine hypothesis.

The objectives of this study were to test the hypothesis that a dopaminergic deficiency plays a role in the pathogenesis of winter seasonal affective disorder (SAD) and to test the efficacy of levodopa plus carbidopa as a treatment for SAD. Two weeks of double-blind placebo washout were followed by random assignment to parallel treatments for 2 weeks with levodopa and carbidopa versus placebo. Observations were made during weekly outpatient visits. All subjects met criteria for SAD. Fifty patients entered the study. Twenty-four were significantly depressed after the washout period and were randomly assigned to medication or placebo. Twenty-three completed the study. Twelve patients received placebo capsules four times a day during the 2-week drug comparison period. On an identical schedule, 11 patients received capsules containing levodopa (up to 7 mg/kg per day by the end of the second week) and carbidopa (100 mg/day). Twenty-one item Hamilton Rating Scale for Depression scores were used to determine antidepressant efficacy. No differences were found in the rates of response. There is no evidence to support the use of levodopa for the treatment of SAD patients in general. A model of systemic dopaminergic deficiency does not readily explain the pathology of SAD.

Exposure to ambient light in patients with winter seasonal affective disorder.

In a study of the quantitative relationship between ambient light and depression in winter seasonal affective disorder, 13 outpatients and 13 normal comparison subjects each wore a light monitor for 1 week. The patients and normal subjects showed similar light exposure profiles; among the patients, severity of depression was inversely related to photoperiod, and there was a trend toward a correlation between greater severity of depression and later time of onset of morning light exposure. These findings suggest that vulnerability to short photoperiods may be related to depression in winter seasonal affective disorder.

High titers of anti-Epstein-Barr virus DNA polymerase are found in patients with severe fatiguing illness.

Forty-one patients with chronic fatigue syndrome (CFS), 76 healthy controls matched with the patient group for age range, sex, race, and socioeconomic class, and 22 symptomatic patients with seasonal affective disorder (SAD) had serum sampled for antibodies against 2 Epstein-Barr virus (EBV) replicating enzymes. Abnormal titers of antibodies were found twice as often in CFS patients as controls (34.1% vs. 17.1%), with SAD patients having an intermediate frequency (27.3%). Stratifying for disease severity sharpened the differences considerably, with the sicker CFS and SAD patients having 52% and 50% abnormal tests, respectively; more mildly afflicted CFS and SAD patients had a frequency of abnormal tests in the normal range. Antibodies to EBV DNA polymerase (DNAP) were the more sensitive of the two tests in that they were positive in all cases but one. These findings suggest that antibodies against EBV DNAP may be a useful marker in delineating a subset of patients with severe fatiguing illness for appropriate treatment trials and for monitoring their outcomes.

Effects of phototherapy on electrooculographic ratio in winter seasonal affective disorder.

Low electrooculographic (EOG) ratios have been reported in patients with seasonal affective disorder (SAD). This study was undertaken to replicate these results and to consider the effects of light therapy on the EOG in SAD patients. Sixteen outpatients with SAD and 16 age-, sex-, and medication-matched control subjects had EOG testing before and after 1 week of light therapy during the winter. The EOG ratios in the SAD patients were only marginally lower than those in the normal control subjects. These differences persisted after light therapy. Although the slightly decreased EOG ratios in SAD patients might have resulted from an artifact of test variability, drowsiness, or other confounding factors, the difference between patients and control subjects raises the possibility of retinal abnormality in SAD.

Conservation of photoperiod-responsive mechanisms in humans.

In animals, circadian pacemakers respond to seasonal changes in day length by making corresponding adjustments in the durations of diurnal and nocturnal periods of circadian rhythms; these adjustments mediate effects of photoperiod on breeding and other seasonally recurring phenomena. Little is known about photoperiod responses of human circadian pacemakers. To investigate this question, we recorded and compared circadian rhythm profiles of 15 individuals after chronic exposures to short (8 h) and long (14 h) nights. As occurs in animals, durations of nocturnal periods of active melatonin secretion (11.9 +/- 1.6 vs. 10.3 +/- 1.3 h, df = 14, t = 4.583, P < 0.0005, paired t test), high prolactin secretion (12.9 +/- 2.1 vs. 9.9 +/- 2.2 h, df = 11, t = 2.917, P < 0.01), and sleep (10.6 +/- 0.8 vs. 7.6 +/- 0.4 h, df = 14, t = 17.122, P < 0.0005) were longer after exposure to long nights than after short ones. Durations of nocturnal periods of low rectal temperature (11.6 +/- 2.3 vs. 9.5 +/- 1.6 h, df = 12, t = 3.912, P < 0.001) and rising cortisol secretion (10.8 +/- 1.6 vs. 9.3 +/- 1.9 h, df = 14, t = 3.130, P < 0.005) were also longer. Some of these differences persisted during 24-h periods of enforced wakefulness in constant dim light, indicating that prior exposure to the two regimes induced abiding changes in the timing of internal processes, such as circadian pacemaker oscillations, that control the durations of nocturnal and diurnal periods of the rhythms.

Side effects of light therapy in seasonal affective disorder.

The authors report the frequency of side effects of light therapy in 105 patients with seasonal affective disorder treated with three intensities of light. Common symptoms to emerge during treatment were headache (19%), eyestrain (17%), and feeling "wired" (14%). There was no relationship between side effects and intensity of light used.

Spontaneous eye blink rate in winter seasonal affective disorder.

We investigated spontaneous eye-blink rates in 19 drug-free patients with winter seasonal affective disorder (SAD) and 18 normal control subjects. At baseline, there were no significant differences between the two groups (mean +/- SD blink rate: 15/minute +/- 8 vs. 15/minute +/- 7). Light therapy (10,000 lux: 1 hour each morning for 1 week) produced no significant change in mean (+/- SD) blink rates either in 10 SAD patients (13/minute +/- 8 vs. 10/minute +/- 7) or in 12 normal control subjects (15/minute +/- 6 vs. 14/minute +/- 6). A post hoc exploratory analysis of the effect of light therapy on premenopausal female subjects (5 patients and 9 control subjects) showed a significant decrease in mean (+/- SD) blink rate in the patients after treatment (17 +/- 6 vs. 12 +/- 8 compared with 15 +/- 7 vs. 16 +/- 5). These results do not support the idea that an elevated blink rate may be a general biological marker in SAD, but they suggest a possible link between light treatment and mechanisms that regulate blink rate in premenopausal SAD patients.

A clinical trial of sleep deprivation in combination with antidepressant medication.

The literature suggests that sleep deprivation can potentiate the effect of antidepressant medication in depressed patients. However, the clinical efficacy of sleep deprivation has not been demonstrated definitively, in part because it is difficult to design an adequate control condition. We conducted a trial of sleep deprivation in 26 depressed patients who remained symptomatic despite 3 months of treatment with antidepressant medication. Since the literature indicates that early sleep deprivation (ESD), carried out in the first half of the night, is a less effective antidepressant than late sleep deprivation (LSD), carried out in the second half of the night, we designed a study that attempted to use ESD as a control condition for LSD. Patients were randomly assigned to ESD or LSD, received a total of 4 nights of sleep deprivation over 2 weeks, and were followed in clinic for the 3 subsequent weeks. ESD proved to be as effective an antidepressant as LSD, with the overall sample showing a mild, but statistically significant, response. There was a significant correlation between patients' acute response at the time of the first course of sleep deprivation treatments and their improvement over the course of the study. There were significant changes in plasma levels of thyroid stimulating hormone, free triiodothyronine, prolactin, and cortisol measured at 8 a.m. before and after sleep deprivation, and in the followup period, but there were no significant correlations between changes in hormonal levels and either acute or chronic response to sleep deprivation.

A multicenter study of the light visor for seasonal affective disorder: no difference in efficacy found between two different intensities.

Fifty-five patients with winter seasonal affective disorder (SAD) were treated with a light visor, a newly developed portable light-delivery system, in a controlled parallel design. A dim (400 lux) visor was compared with a bright (6000 lux) visor for either 30 or 60 minutes in the morning for 1 week. Response rates for these two treatments were 36% and 56%, respectively; the duration of treatment sessions did not affect outcome. There was no evidence that the brighter visor was superior in efficacy to the dimmer one. Significantly greater relapse occurred following withdrawal of the dimmer visor. Alternative explanations for these findings are that the light visor is acting as a placebo or that it is equally effective over a wide range of intensities.

Depressive symptoms and the self-reported use of alcohol, caffeine, and carbohydrates in normal volunteers and four groups of psychiatric outpatients.

OBJECTIVE: The authors examined the relationship between depressive symptoms and the self-reported use of alcohol, carbohydrates, and caffeine in normal volunteers and four groups of psychiatric outpatients. METHOD: Outpatients and normal volunteers were given a questionnaire asking about their use of each of the three substances in response to each of the 14 depressive symptoms on the Hamilton Rating Scale for Depression. They also rated how much each substance improved each symptom. Twenty-six normal volunteers, 35 patients with major depression, 117 patients with seasonal affective disorder, 16 patients with alcohol dependence, and 24 patients with comorbid primary depression and secondary alcohol dependence completed the questionnaire. Test-retest reliability was established. Analysis of variance and stepwise multivariate discriminant function analyses were used to determine if diagnostic groups differed in the reported use and effect of each of the three substances. RESULTS: The responses concerning use and effect of alcohol of patients with alcohol dependence with or without depression were indistinguishable from each other. The responses of the patient groups regarding caffeine and carbohydrate use did not differ from each other, but all differed significantly from the responses of normal volunteers. Discriminant function analysis distinguished alcoholics from nonalcoholics in the relationship between drinking and the symptoms of anger and anhedonia. CONCLUSIONS: The relationship between symptoms and substance use varied depending on the substance. Alcoholics without depression were as likely to report drinking in response to depressive symptoms as were those who had had depression. Patients of all diagnostic groups were more likely than normal volunteers to report using caffeine and carbohydrates in response to depressive symptoms.

Light visor treatment for seasonal affective disorder: a multicenter study.

The effectiveness of light therapy in seasonal affective disorder (SAD) was evaluated in 105 subjects across five centers. Three intensities of light (60 lux, 600 lux, and 3500 lux) were used in a 2-week randomized, parallel design. There was no significant difference in antidepressant efficacy of the three intensities of light. All three intensities produced a similar frequency of antidepressant response to each other and to that reported in previous studies. There were site differences in the severity of depression during light treatment, but diagnosis and medication status did not affect antidepressant response. These findings suggest that light therapy has an antidepressant action by a nonspecific effect or that light is biologically active in the treatment of SAD across a wide range of intensities.