Brain-derived neurotrophic factor Val66Met genotype and ovarian steroids interactively modulate working memory-related hippocampal function in women: a multimodal neuroimaging study.

Preclinical evidence suggests that the actions of ovarian steroid hormones and brain-derived neurotrophic factor (BDNF) are highly convergent on brain function. Studies in humanized mice document an interaction between estrus cycle-related changes in estradiol secretion and BDNF Val66Met genotype on measures of hippocampal function and anxiety-like behavior. We believe our multimodal imaging data provide the first demonstration in women that the effects of the BDNF Val/Met polymorphism on hippocampal function are selectively modulated by estradiol. In a 6-month pharmacological hormone manipulation protocol, healthy, regularly menstruating, asymptomatic women completed positron emission tomography (PET) and functional magnetic resonance imaging (fMRI) scans while performing the n-back working memory task during three hormone conditions: ovarian suppression induced by the gonadotropin-releasing hormone agonist, leuprolide acetate; leuprolide plus estradiol; and leuprolide plus progesterone. For each of the three hormone conditions, a discovery data set was obtained with oxygen-15 water regional cerebral blood flow PET in 39 healthy women genotyped for BDNF Val66Met, and a confirmatory data set was obtained with fMRI in 27 women. Our results, in close agreement across the two imaging platforms, demonstrate an ovarian hormone-by-BDNF interaction on working memory-related hippocampal function (PET: F2,37=9.11, P=0.00026 uncorrected, P=0.05, familywise error corrected with small volume correction; fMRI: F2,25=5.43, P=0.01, uncorrected) that reflects differential hippocampal recruitment in Met carriers but only in the presence of estradiol. These findings have clinical relevance for understanding the neurobiological basis of individual differences in the cognitive and behavioral effects of ovarian steroids in women, and may provide a neurogenetic framework for understanding neuropsychiatric disorders related to reproductive hormones as well as illnesses with sex differences in disease expression and course.

Variation in the Williams syndrome GTF2I gene and anxiety proneness interactively affect prefrontal cortical response to aversive stimuli.

Characterizing the molecular mechanisms underlying the heritability of complex behavioral traits such as human anxiety remains a challenging endeavor for behavioral neuroscience. Copy-number variation (CNV) in the general transcription factor gene, GTF2I, located in the 7q11.23 chromosomal region that is hemideleted in Williams syndrome and duplicated in the 7q11.23 duplication syndrome (Dup7), is associated with gene-dose-dependent anxiety in mouse models and in both Williams syndrome and Dup7. Because of this recent preclinical and clinical identification of a genetic influence on anxiety, we examined whether sequence variation in GTF2I, specifically the single-nucleotide polymorphism rs2527367, interacts with trait and state anxiety to collectively impact neural response to anxiety-laden social stimuli. Two hundred and sixty healthy adults completed the Tridimensional Personality Questionnaire Harm Avoidance (HA) subscale, a trait measure of anxiety proneness, and underwent functional magnetic resonance imaging (fMRI) while matching aversive (fearful or angry) facial identity. We found an interaction between GTF2I allelic variations and HA that affects brain response: in individuals homozygous for the major allele, there was no correlation between HA and whole-brain response to aversive cues, whereas in heterozygotes and individuals homozygous for the minor allele, there was a positive correlation between HA sub-scores and a selective dorsolateral prefrontal cortex (DLPFC) responsivity during the processing of aversive stimuli. These results demonstrate that sequence variation in the GTF2I gene influences the relationship between trait anxiety and brain response to aversive social cues in healthy individuals, supporting a role for this neurogenetic mechanism in anxiety.

Brain-derived neurotrophic factor (BDNF) Val(66)Met polymorphism differentially predicts hippocampal function in medication-free patients with schizophrenia.

A Val(66)Met single-nucleotide polymorphism (SNP) in the brain-derived neurotrophic factor (BDNF) gene impairs activity-dependent BDNF release in cultured hippocampal neurons and predicts impaired memory and exaggerated basal hippocampal activity in healthy humans. Several clinical genetic association studies along with multi-modal evidence for hippocampal dysfunction in schizophrenia indirectly suggest a relationship between schizophrenia and genetically determined BDNF function in the hippocampus. To directly test this hypothesized relationship, we studied 47 medication-free patients with schizophrenia or schizoaffective disorder and 74 healthy comparison individuals with genotyping for the Val(66)Met SNP and [(15)O]H(2)O positron emission tomography (PET) to measure resting and working memory-related hippocampal regional cerebral blood flow (rCBF). In patients, harboring a Met allele was associated with significantly less hippocampal rCBF. This finding was opposite to the genotype effect seen in healthy participants, resulting in a significant diagnosis-by-genotype interaction. Exploratory analyses of interregional resting rCBF covariation revealed a specific and significant diagnosis-by-genotype interaction effect on hippocampal-prefrontal coupling. A diagnosis-by-genotype interaction was also found for working memory-related hippocampal rCBF change, which was uniquely attenuated in Met allele-carrying patients. Thus, both task-independent and task-dependent hippocampal neurophysiology accommodates a Met allelic background differently in patients with schizophrenia than in control subjects. Potentially consistent with the hypothesis that cellular sequelae of the BDNF Val(66)Met SNP interface with aspects of schizophrenic hippocampal and frontotemporal dysfunction, these results warrant future investigation to understand the contributions of unique patient trait or state variables to these robust interactions.

Fractionated Crystallization of Defect-Free Poly(3-hexylthiophene).

Fractionated crystallization (FC), a chain-sorting mechanism by length, is identified in well-defined, low molecular weight, and defect-free regioregular poly(3-hexylthiophene) by X-ray scattering and calorimetry of bulk samples. While wide-angle X-ray scattering (WAXS) qualitatively suggests that the degree of crystallinity is similar in all investigated samples, the melting enthalpies are largely different. We ascribe this to intricacies in the integration of the melting and crystallization peaks in calorimetric experiments, which is caused by FC occurring over a large temperature range. The extent of FC decreases with increasing molecular weight and increases with increasing polydispersity. The temperature-dependent investigation of the long period LP and the (100)-WAXS reflection of a sample in which FC is absent allows to disentangle effects from main-chain and side-chain crystallization.

Crystallization of a poly(ethylene-co-octene): I. A precursor structure and two competing mechanisms.

Observations of a sample of poly(ethylene-co-octene)in a polarizing optical microscope reveal peculiarities in its crystallization behavior. When cooled from the melt to a fixed crystallization temperature, at first a structure of diffuse appearance with variations on the length scale of micrometers forms rapidly. The transformation into the final semi-crystalline state then proceeds in two ways, by a continuous change of the inner structure of microm-sized objects and by the growth of spherulites. Time dependent small angle and wide angle X-ray scattering experiments corroborate the occurrence of the two crystallization mechanisms. Atomic force microscopy indicates that the change of the inner structure of the preformed objects is due to an in-filling of crystallites.

Crystallization of poly(ethylene-co-octene): II. Melt memory effects on first order kinetics.

Dilatometric and X-ray scattering experiments of the crystallization kinetics of a sample of poly(ethylene-co-octene) show pronounced melt memory effects, i.e., the shapes of isotherms and characteristic times vary systematically with the temperature of the melt prior to cooling to the crystallization temperature. The temperature range of the effect is limited; crystallization kinetics remains constant below a melt temperature T(m)l and above a melt temperature T(m)h and varies only in-between. Analysis shows that the melt memory effect is caused by a variation of the characteristic time of a first order crystallization process. The process can be assigned to the in-filling of crystallites into objects of a previously generated precursor structure.

Evidence for abnormal cortical functional connectivity during working memory in schizophrenia.

OBJECTIVE: Disturbed neuronal interactions may be involved in schizophrenia because it is without clear regional pathology. Aberrant connectivity is further suggested by theoretical formulations and neurochemical and neuroanatomical data. The authors applied to schizophrenia a recently available functional neuroimaging analytic method that permits characterization of cooperative action on the systems level. METHOD: Thirteen medication-free patients and 13 matched healthy comparison subjects performed a working memory (n-back) task and sensorimotor baseline task during positron emission tomography. "Functional connectivity" patterns, reflecting distributed correlated activity that differed most between groups, were extracted by a canonical variates analysis. RESULTS: More than half the variance was explained by a single pattern showing inferotemporal, (para-)hippocampal, and cerebellar loadings for patients versus dorsolateral prefrontal and anterior cingulate activity for comparison subjects. Expression of this pattern perfectly separated all patient scans from comparison scans, thus showing promise as a trait marker. This result was validated prospectively by successfully classifying unrelated scans from the same patients and data from a new cohort. An additional 19% of variance corresponded to the pattern activated by the working memory task. Expression of this pattern was more variable in patients during working memory but not the control condition, suggesting inability to sustain a task-adequate neural network, consistent with the disconnection hypothesis. CONCLUSIONS: Pronounced disruptions of distributed cooperative activity in schizophrenia were found. A pattern showing disturbed frontotemporal interactions showed promise as a trait marker and may be useful for future investigations.

Exercise-induced analgesia and the role of reactivity in pain sensitivity.

The present study was designed to evaluate whether pain perception and pain tolerance are altered by submaximal aerobic exercise. Sixty male volunteers were randomly assigned to one of two control or experimental groups in the first of two sessions. In session 1, baseline measures of pain tolerance and pain perception were obtained for half of the subjects in each of the experimental and control groups, respectively. In addition, all subjects completed the Reactivity Scale, followed by estimation of their maximum aerobic power (VO2 max) using the Canadian Home Fitness Test. In session 2, the subjects in the two experimental groups exercised for 12 min by climbing a double step to pre-recorded musical cadences, working on average at 63% VO2 max, whereas the subjects in the two control groups spent approximately 12 min completing two short unrelated questionnaires. Measures of pain tolerance and pain perception were obtained from all subjects after exercising or completing questionnaires. Pain tolerance was assessed by the amount of time (up to 10 min) that subjects could voluntarily endure a 2300 g pressure to the index finger of their dominant hand. Pain perception was defined by participants' intensity ratings on an 11-point scale, made at 30 and 60 s. The results showed that reactivity and exercise were significant predictors of pain tolerance, together accounting for approximately 22% of the variance. The finding that submaximal workloads produce analgesia supports the potential usefulness of exercise in therapeutic intervention.

An infectious disease day care unit--the first year.

Details are given of what is believed to be the first Day Care Unit in the U.K. for the diagnosis and treatment of infection and infectious diseases. The reaction of referring doctors and their patients has been favourable, cross-infection in the home has not been a problem and some potentially life-threatening infections have been diagnosed earlier than might otherwise have been the case. Capital and running costs were relatively small and the use of inpatient beds for infectious diseases became more efficient.

The Survey of Recent Life Experiences: a decontaminated Hassles Scale for adults.

A new decontaminated hassles measure for adults, the Survey of Recent Life Experiences, was developed and validated. An initial pool of 92 items was administered to 100 subjects along with the Perceived Stress Scale. Fifty-one items were selected, based on significant correlations with the latter scale. The alpha reliability of the resultant final form of the Survey of Recent Life Experiences and its correlation with perceived stress were both high. In a separate cross-replication sample of 136 adults, the alpha reliability of the Survey and its correlation against the Perceived Stress Scale remained acceptably high. Moreover, separate-sex analyses supported the reliability and validity of the Survey of Recent Life Experiences across gender. Factor analysis of the Survey yielded six interpretable factors. Intercorrelations among subscales based on these factors were generally modest, suggesting that the scale is relatively free from contamination by psychological distress.

Hassles, health, and personality.

College undergraduates (N = 211) responded to a "decontaminated" hassles scale plus measures of trait anxiety, reactivity, perceived stress, psychiatric symptomatology, and minor physical ailments. All but the anxiety and reactivity scales were time referenced to the past month. Major findings were as follows: (a) Hassles and trait anxiety both contributed positively to perceived stress, jointly accounting for 58% of the variance; (b) hassles and reactivity both had a significant positive impact on minor ailments, together explaining 23% of the variance; and (c) hassles and trait anxiety had a significant interactive effect on psychiatric symptomatology, which along with the nonsignificant marginal main effects accounted for 67% of the variance. The positive impact of hassles on psychiatric symptomatology increased as trait anxiety rose; likewise, the pathogenic effect of trait anxiety increased with greater exposure to hassles.

The Inventory of College Students' Recent Life Experiences: a decontaminated hassles scale for a special population.

The development and validation of a new decontaminated hassles measure, the Inventory of College Students' Recent Life Experiences, are described. An initial pool of 85 items was administered to 100 undergraduates along with the Perceived Stress Scale. Forty-nine items were selected based on significant correlations against the Perceived Stress Scale. The alpha reliability of the resultant final form of the Inventory of College Students' Recent Life Experiences and its correlation against the Perceived Stress Scale were both high. In a separate cross-replication sample of 108 undergraduates, the alpha reliability of the Inventory and its correlation against the Perceived Stress Scale showed little shrinkage. Furthermore, separate analyses for male and female subjects supported the reliability and validity of the Inventory of College Students' Recent Life Experiences across gender. Factor analysis of the Inventory yielded seven interpretable factors. Intercorrelations among sub-scales based on these factors were generally modest, though in all cases significant, suggesting that the Inventory is relatively free of contamination by psychological distress.

Protein-energy malnutrition induces changes in insulin sensitivity.

Early protein deprivation impairs glucose tolerance and insulin secretion, but the former generally recovers first. We have therefore investigated insulin sensitivity in vivo and in isolated muscle and cultured hepatocytes during protein-energy malnutrition and long-term follow-up in rats. Rats were weaned at 3 weeks onto normal rat chow (N rats) or onto 5% protein diet (LP rats). At 6 w of age LP rats were transferred to N chow. Insulin sensitivity was studied in the three systems at 3, 6, 12 and 24 w. At 6 w LP rats showed a greater and more prolonged fall in serum glucose in response to injected insulin than age--or weight--matched N, but by 12 w the difference was not significant. Similarly, soleus muscle from 6 w LP showed a higher basal rate of glucose transport and responded to a lower insulin dose than N, but there was no difference in sensitivity at 12 w. Hepatocytes from 6 w LP showed higher basal incorporation of glucose into glycogen than N, but insulin sensitivity was not different. Thymidine incorporation into hepatocyte DNA responded to lower insulin doses in 6 w LP than N. There was a decrease in insulin sensitivity with age in all experimental systems. Increased insulin sensitivity during malnutrition was seen in all tissues studied but differences between the two groups were not significant at 12 w and probably do not account for the normal glucose tolerance in the presence of low serum insulin levels previously reported.

Image reconstruction of the interior of bodies that diffuse radiation.

A method for reconstructing images from projections is described. The unique aspect of the procedure is that the reconstruction of the internal structure can be carried out for objects that diffuse the incident radiation. The method may be used with photons, phonons, neutrons, and many other kinds of radiation. The procedure has applications to medical imaging, industrial imaging, and geophysical imaging.

The social image of the young female smoker.

Community college students (N = 229) read a brief narrative about a young female college student and rated her on 14 bipolar scales. Half the subjects read a version in which the protagonist smoked, and half an otherwise identical version in which she didn't. Although most subjects recalled the protagonist's smoking status, very few recognized this as the focal variable in the experiment. Subjects rated the heroine less positively for social attractiveness (p less than 0.001) and personal resourcefulness (p less than 0.01) when she was represented as a smoker. They specifically considered the smoking protagonist more masculine (p less than 0.01), less feminine (p less than 0.001), less healthy (p less than 0.001), a poorer student (p less than 0.001), less wise (p less than 0.001), less self-disciplined (p less than 0.001), less sophisticated (p less than 0.001), and less gentle (p less than 0.02). Non-smoking subjects also rated the smoking heroine as less (physically) attractive (p less than 0.05), although smoking subjects did not discriminate significantly.