Cognitive and behavioral performance among FMR1 high-repeat allele carriers surveyed from special education classes.

The fragile X syndrome is caused by an unstable CGG repeat sequence in the 5' untranslated region of the X-linked, FMR1 gene. When the number of repeats exceeds 200, the region is hypermethylated and the gene is silenced. The lack of the protein produced by the FMR1 gene, FMRP, causes the fragile X syndrome. Recent evidence suggests that FMR1 alleles with unmethylated long repeat tracks (40-200 repeats) may cause a specific somatic phenotype in women, premature ovarian failure, and may cause variation in the levels of FMR1 mRNA and FMRP. Because FMR1 is known to be involved in the regulation of subset of genes expressed in the brain, we investigated the variation in cognitive and/or behavioral performance among carriers of high repeat alleles. Specifically, we administered cognitive, behavioral, and adaptive performance tests to children identified with high repeat alleles who attended special education classes in Atlanta, Georgia public schools and to those with < 40 repeats drawn from the same population. Overall, we found no significant effect of repeat size and the psychometric measures in our test battery after adjustment for multiple comparisons. All scales were found to be within 1 SD standard deviation of the mean. We did find an intriguing, albeit marginally statistically significant, association in the cognitive profile among males and not females, consistent with an X-linked effect. After adjusting for the overall cognitive abilities score, Verbal Ability scores decreased and Nonverbal Reasoning scores increased with repeat number to a greater extent in males than females. Spatial Ability scores were not associated with repeat number.

Effects of morphine on T-cell recirculation in rhesus monkeys.

A 2-yr study on effects of morphine on lymphocyte circulation in rhesus monkeys (Macaca mulatta) showed that, over time, a well-maintained morphine-dependency caused biphasic depressive effects on circulating lymphocyte levels. Depression of T cell circulation by opiates actually was a relative effect. Morphine exposure basically stabilized T cell circulation in the context of concurrent increases in controls. Biphasic effects of morphine were attributable to distinctions in circulation kinetics of CD4+/CD62L (+ & -) T cells. That is, levels of CD4+/CD62L+ T cells were selectively depressed by opiates through the first 32wk after initiation of drug, and levels of CD4+/CD62L- T cells were selectively depressed thereafter. Regression analyses also showed that morphine stabilized lymphocyte recirculation. Circulating levels of resting and activated-memory types of T cells were positively correlated in opiate-exposed monkeys during the first 32wk after opiate exposure--an effect not seen with control monkeys. Considerations of changes in the types of experimental stressors extant during the study suggested that temporally differential effects of opiates on T cell recirculation were connected with changes in the stress environment and the ability of morphine to modulate these changes. Thus, morphine, and by inference the endogenous opioid system, are involved in homeostasis of lymphocyte recirculation, probably through effects on central mediation of the stress axis.

Placebo-controlled study of fluvoxamine in the treatment of patients with compulsive buying.

Compulsive buying is a syndrome characterized by the impulsive and/or compulsive buying of unneeded objects that results in personal distress, impairment in vocational or social functioning, and/or financial problems. Results from a two-site, double-blind, placebo-controlled 13-week trial of fluvoxamine are presented. Subjects had problematic buying behavior that they could not control for the previous 6 months or longer and met DSM-IV criteria for impulse control disorder-not otherwise specified (ICD-NOS) and the University of Cincinnati criteria for compulsive buying. Assessments included clinician-rated scales-the Yale-Brown Obsessive Compulsive Scale modified for compulsive buying, the Clinical Global Impression Scale, the Global Assessment of Functioning, and the Hamilton Rating Scale for Depression-and patient self-reports using daily diaries, which measured episodes of compulsive buying. Forty-two subjects gave informed consent, with 37 subjects providing evaluable information and 23 completing the study. Current or past psychiatric comorbidity was present in 74% of subjects. Intent-to-treat and completer analyses failed to show a significant difference between treatments on any measures of outcome. A high placebo-response rate, possibly from the behavioral benefits of maintaining a daily diary, prevents any definitive statement on the efficacy of fluvoxamine in treating compulsive buying.

A placebo-controlled trial of cognitive-behavioral therapy and clomipramine in trichotillomania.

BACKGROUND: The major treatments reported to be effective in the treatment of trichotillomania are cognitive-behavioral therapy (CBT) with habit reversal and serotonin-norepinephrine reuptake inhibitors such as clomipramine. However, the 2 treatments have not been previously compared with each other. This study examines the efficacy of CBT and clomipramine compared with placebo in the treatment of trichotillomania. METHOD: Twenty-three patients with trichotillomania as determined by the Structured Clinical Interview for DSM-III-R entered and 16 completed a 9-week, placebo-controlled, randomized, parallel-treatment study of CBT and clomipramine. Efficacy was evaluated by the Trichotillomania Severity Scale, the Trichotillomania Impairment Scale, and the Clinical Global Impressions-Improvement scale, which were conducted by an independent assessor blinded to the treatment condition. RESULTS: CBT had a dramatic effect in reducing symptoms of trichotillomania and was significantly more effective than clomipramine (p = .016) or placebo (p = .026). Clomipramine resulted in symptom reduction greater than that with placebo, but the difference fell short of statistical significance. Placebo response was minimal. CONCLUSION: Clinicians should be aware of the potential treatments available for trichotillomania. A larger and more definitive study comparing CBT and a serotonin-norepinephrine reuptake inhibitor is indicated.

Hyperintense lesions on magnetic resonance images in bipolar disorder.

BACKGROUND: To examine the magnetic resonance (MR) images of bipolar patients across a wide age range for the presence of hyperintense lesions compared to age- and gender-matched control subjects. METHODS: Consecutive admissions to a mood disorders unit over a 2-year period were evaluated retrospectively for the presence of bipolar disorder by DSM-III-R criteria and whether they received an MR scan. Bipolar patients (n = 70, mean age = 49.9 +/- 19.7 years) were age- and gender-matched to control subjects (n = 70, mean age = 53.2 +/- 18.1 years) and the MR scans were rated to assess for the presence of hyperintensites. RESULTS: Compared to control subjects, the bipolar patients demonstrated hyperintense lesions in the subependymal region, subcortical gray nuclei, and the deep white matter. CONCLUSIONS: Hyperintense lesions in bipolar patients are found in both the subcortical white matter and gray nuclei and may play an important role in the etiology of bipolar illness.

Whole-blood serotonin and cognitive functioning in autistic individuals and their first-degree relatives.

The relationship between cognitive-intellectual abilities and whole-blood serotonin (5-hydroxytryptamine; 5-HT) in 18 autistic probands and their first-degree relatives (n = 21 parents, n = 13 siblings) was investigated. Whole-blood 5-HT was significantly negatively associated with verbal-expressive/symbolic abilities for the entire sample. The proportion of variance in cognitive-intellectual performances attributable to whole-blood 5-HT was substantial in the context of variance attributable to familial classification. The relationship between verbal-expressive abilities and whole-blood 5-HT, adjusted for race and familial classification, was noteworthy. Simple correlations between 5-HT and cognitive-intellectual performances were conducted. However, bias related to covariance attributable to race seriously limits such findings. The issue of bias and its relevance to previous research is discussed further.

Pharmacokinetically designed double-blind placebo-controlled study of nortriptyline in 6- to 12-year-olds with major depressive disorder.

A random assignment, double-blind, placebo-controlled study of nortriptyline in 50 prepubertal 6- to 12-year-olds with Research Diagnostic Criteria and DSM-III major depressive disorder was performed. The protocol included a 2-week placebo wash-out phase and an 8-week double-blind, placebo-controlled phase with weekly plasma level monitoring. Active subjects had their plasma level pharmacokinetically placed at 80 +/- 20 ng/ml by using previously developed tables to determine the starting dose from a plasma level 24 hours after a single dose administered at baseline. The mean plasma level was 89.9 ng/ml. The study population was severely depressed, had a chronic, unremitting course of long duration before the study, had a high percentage of family histories with affective disorder, alcoholism and suicidality, and had a high rate of comorbidity. None of the subjects had ever received tricyclic antidepressants before this study. There was a poor rate of response in both treatment groups (30.8% active, 16.7% placebo). Active subjects did not evidence the anticholinergic side effects reported in adult samples. The implications of these findings for future pharmacotherapy studies of depressed children are discussed.

The assessment of suicidal behavior in adolescents.

All available assessment instruments (N = 29) used to study suicidal behaviors in adolescents and young adults (age 12-20) were collected and reviewed. Instruments were found to vary substantially in purpose, format, informat, and theoretical orientation. The items from these tools (N = 461) were categorized according to behavior type (thoughts, feelings, or actions) and content categories (death/life-related, disease-promoting/preventing, injury-producing/reducing, person-reducing/enhancing, and factual information). The majority of the items were found to assess thoughts and were focused on death-related content. Recommendations include the need for more rigorous validation of instruments, clearer operational definitions, additional normative information, and expansion of the pool of available items to encompass a broader array of self-destructive behaviors.

A longitudinal study of depressive symptomatology in young adolescents.

As part of a longitudinal study of depression in adolescents, the Center for Epidemiologic Studies Depression Scale (CES-D) was administered to 550 students 3 times, at the beginning of the seventh, eighth, and ninth grades. Blacks and females had higher scores than did whites and males. Scores of blacks and males declined more over the 3 year period than did those of females and whites. The stability of individual students' depression scores was less consistent than the overall distributions with 1 and 2 year correlations reaching only 0.53 and 0.36, respectively. The best predictor of subsequent year CES-D scores was the previous year's score. Undesirable life events and family adaptability were significant but less important predictors.

Double-blind placebo-controlled study of nortriptyline in depressed adolescents using a "fixed plasma level" design.

We performed a random assignment, double-blind, placebo-controlled study of nortriptyline (NT) in postpubertal 12- to 17-year-olds with Research Diagnostic Criteria (RDC) and DSM-III major depressive disorder. The protocol included a 2-week placebo washout phase and an 8-week double-blind, placebo-controlled phase with weekly plasma level monitoring. Active subjects had their plasma level placed at 80 +/- 20 ng/ml by using previously developed tables to determine the starting dose from a plasma level drawn 24 hours after a single dose administered at baseline. The study population was severely depressed and had a chronic, unremitting course prior to study; a high percentage of family histories with affective disorder, alcoholism, and suicidality; and a high rate of comorbidity. Of the 52 subjects enrolled, there were 17 placebo washout responders, 4 dropouts, and 31 completers (12 active and 19 placebo). Only one active subject responded; therefore, the study was terminated early. The mean NT plasma level was 91.1 (18.3 SD) ng/ml. The two treatment groups had similar postprotocol severity ratings. Subjects on active drug did not evidence the anticholinergic side effects reported in adult samples. The negative outcome in this study is similar to the findings in our previously reported NT study in prepubertal 6- to 12-year-olds.

Reproductive responses to variation in temperature and food supply by house mice. I. Mating and pregnancy.

The effects of food restriction upon mating and pregnancy of female house mice were studied at a warm (21 degrees C) and a cold (5 degrees C) temperature to examine the hypothesis that the effects of temperature and food availability are not independent. Analyses of the data showed significant interaction between temperature and food availability for virtually all variables measured, supporting the initial hypothesis. Contingency analysis of mating, fertility, and litter survivorship showed that the interaction influenced not only the percentage of females successfully producing litters, but also the timing of abandonment of reproductive effort by those females that did not have surviving litters. The percentage of females who mated was reduced only in food-restricted females under cold conditions. Both low temperature and food restriction reduced the percentage of mated females that became pregnant. Food-restricted females under cold conditions who did become pregnant tended to kill their litters at birth. The net effect was an interaction between temperature and food restriction that resulted in females reducing or abandoning reproductive effort at progressively earlier stages of the reproductive cycle. The interaction between temperature and food restriction was further displayed in the growth curves of pregnant females, with the reduction of growth by food restriction being greater in the cold.

Reproductive responses to variation in temperature and food supply by house mice: II. Lactation.

Lactating HS/Ibg house mice housed at 21 degrees C and 5 degrees C were assigned to 3 feeding regimes: ad libitum, daily rations of 80% of ad libitum, or 60% of ad libitum beginning on the day that they bore litters. Significant interaction between temperature and food restriction was found for litter survivorship, pup survivorship, litter size, female body weight, and cumulative biomass production. The interaction was due to a magnification of the effects of food restriction at the colder temperature: i.e. mice fed ad libitum were similar at the two temperatures, mice fed the 80% ration differed, and mice fed the 60% ration differed to a greater extent. The dominant response to food restriction was cannibalism by females, which might be associated with the rate of loss in body weight by the female on the days preceding cannibalism of one or more pups. Incidents of cannibalism tended to involve a limited number of pups and to be repeated until a sustainable litter size was reached. In 3 of the food-restricted treatments, females weaned relatively large litters of relatively small pups, but in the most severe treatment (in the group fed the 60% ration at 5 degrees C), the females weaned small litters of large pups. The patterns of cannibalism and variable relative investment in individual pups reflect the aggressive breeding strategy of this classic colonizing species.

Effect of short-term food deprivation on reproduction in female mice.

CF-1 female mice were subjected to 24 or 48 h of food deprivation beginning when they were in estrus or diestrus, or when they were 2 or 12 days pregnant, or on Days 2 or 12 of lactation. Ovulation was delayed by a week or more when 48 h of food deprivation was initiated when the female was in diestrus; lesser delays occurred when food deprivation began in estrus. There was little effect of acute food deprivation on pregnancy. Most females deprived of food beginning on Day 2 of lactation ate their young, but females deprived on Day 12 of lactation rarely did so. These results are discussed in terms of the complexity of interacting factors that determine the degree to which each stage of the female's reproductive cycle is susceptible to disruption by acute food deprivation.

The relationship between the dwarfing gene and E. coli infection in two populations of chickens.

Resistance to an E. coli challenge was studied in the 6th, 7th, and 8th backcross generations after the introduction of the sex-linked recessive dwarf gene (dw) into two populations of White Plymouth Rock chickens that had undergone bidirectional selection for juvenile body weight. In the B6 and B8 generations, the dwarf genotype from the HW line had significantly higher mortality and/or heart lesions than the heterozygotes while the homozygous normal chickens were intermediate. No association between the dwarf allele and the incidence of E. coli infection was observed in the HW line in any generation, but genotypes in the LW lines were influenced by social environment in susceptibility to the E. coli challenge. Under low social strife, the dwarf and heterozygote genotypes were more susceptible than the normal genotype to the E. coli challenge, while under a high social strife there were no differences among genotypes. Since the genotypes in the LW line responded differently to the disease challenge than those in the HW line, it was concluded that a line-dwarf genotype interaction was present.

Antibody production and Escherichia coli resistance in socially stable flocks of dwarf and nondwarf chickens.

Dwarf and normal pullets from lines that had undergone selection for divergence in juvenile body weight were maintained in cages as socially stable flocks. Antibody titers were measured at 6 and 14 weeks of age and an Escherichia coli challenge was administered at 16 weeks of age. There was a significant line by dwarf genotype interaction with dwarfs having lower antibody titers than normal pullets in the low weight line and higher antibody titers in the high weight line. The mortality of dwarfs from the low weight line to an Escherichia coli challenge was much higher than that of any other group. These results were consistent with those from previous experiments where the Escherichia coli challenge was given to hens in single cages.

Agonistic behavior, the development of the social hierarchy and stress in genetically diverse flocks of chickens.

The agonistic behavior and development of the social hierarchy of juvenile pullets were studied in two lines of chickens which had been divergently selected for juvenile body weight and in which the dwarf gene (dw) was segregating. The lines differed significantly in both the frequency and intensity of agonistic encounters. Dwarf and normal genotypes differed in the frequency of encounters in both lines, whereas for the intensity of encounters, the difference was only in the high weight line. Although the frequency was more important than the intensity of encounters in determining social rank, agonistic behaviors accounted for only 20% of the variation in rank. The stability of the social orders increased slightly between 6 and 10 weeks of age. Although the correlations between behavioral and physiological variables agreed in sign with those predicted of stressors, their values were low. Therefore, it was concluded that the pullets were only minimally stressed by normal agonistic activity during the development of the social hierarchy.