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.

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.

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.

Vasopressin: action on WRK-1 rat mammary tumor cells.

WRK-1, a cell line in long-term culture derived from a 7, 12-dimethylbenz[a]anthracene-induced rat mammary tumor, responds to physiologic concentrations of vasopressin with increased precursor incorporation into phospholipids and with increased protein accumulation. Because vasopressin has been reported to be a potent mitogen for Hela cells and 3T3 cells, a study was conducted to determine whether it could act as a mitogen for WRK-1 cells. Under no conditions was a clear-cut mitogen response to vasopressin demonstrated.

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.

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.

Fetal cerebrohepatorenal (Zellweger) syndrome: dysmorphic, radiologic, biochemical, and pathologic findings in four affected fetuses.

Four fetuses with positive family histories for cerebrohepatorenal (Zellweger) syndrome (CHRS) underwent diagnostic amniocentesis or chorionic villus biopsy. Cultured amniocytes or fibroblasts from all of the fetuses displayed abnormal fatty acid ratios, and the parents elected therapeutic abortions. Dysmorphic features in one fetus consisted of micrognathia, proximal implantation of toes, and bilateral talipes equinovarus. Radiologic examination of the fetus confirmed the dysmorphic features and revealed foci of mineralization in the patellae. Biochemical analysis of three of the fetuses demonstrated markedly increased levels of very-long-chain fatty acids, both saturated and monounsaturated, in liver, kidney, adrenal, and brain. Pathologic findings consisted of premature mineralization of patellae; renal cystic tubular dilations; striated cells in adrenal fetal zone and testicular interstitium; dysplastic alterations of inferior olivary nuclei, dentate nuclei, and cerebral cortex; equivocal increases in portal fibrous tissue; and abnormal cytosomes in fetal zone adrenocortical cells, testicular and renal interstitial cells, and brain macrophages. Iron deposition, probably physiologic, was observed only in liver tissue. Distributions of immunoreactive catalase were identical in the fetuses with CHRS and age-matched control subjects. These findings document the accuracy of the prenatal diagnostic test and provide insights into the morphogenesis and pathogenesis of CHRS.

Pulmonary injury following exposure to chlorine gas. Possible beneficial effects of steroid treatment.

Two sisters were exposed to chlorine gas in toxic quantities in the same room of their home during an industrial accident. One was hospitalized and treated with corticosteroids and oxygen therapy, while the other received evaluation in the emergency room, and brief oxygen therapy and was released without corticosteroid therapy. Pulmonary physiologic studies have been performed on both patients at intervals following the exposure. The treated patient was stable, with normal results on studies of pulmonary function at the end of two years, while the sibling not treated with corticosteroids had demonstrable abnormalities of gas exchange which persisted during 55 months of observation. This "natural experiment" gives evidence of prolonged detrimental effects of sublethal exposure to chlorine gas on human pulmonary function in some patients. The effect of the differences in treatment between the two siblings cannot be definitely assessed in this single situation.

Chromosomal instability in ataxia telangiectasia.

We have examined various aspects of lymphocyte chromosomal instability in three families comprised of five individuals affected with ataxiatelangiectasia (AT), their obligate heterozygous parents, and their unaffected sibs. We found that neither baseline sister chromatid exchanges (SCEs) nor mitomycin-C-induced increments in SCEs showed any significant differences among family members or between AT heterozygotes or homozygotes. Chromosome breakage in first-division metaphases was found to be moderately elevated in three of the five AT homozygotes (range 1-12%); breakage in the six AT obligate heterozygotes was within normal limits (0-4%). Analysis of Giemsa-banded metaphases indicated the presence of a clone bearing a paracentric inversion of chromosome #14 in addition to other chromosome #14 abnormalities in one AT homozygote. The same inversion was also found in this individual's affected sister and his obligate heterozygous father. A discussion regarding the relationship of the specificity of breakage and reunion of bands q12 and q23 on chromosome #14 and the high incidence of malignancy in AT is included.

Sex differences in the marital functioning of treated alcoholics.

Fifty-five treated alcoholics (31 males and 24 females) were matched with a control group of social drinkers on four dimensions: sex, age, level of education and number of children. Spouses of alcoholic and non-alcoholic respondents were also sampled (total n = 199). Respondents and spouses completed the following questionnaires: The Dyadic Adjustment Scale (DAS), the Areas of Change Questionnaire (AC), and the Marital Status Inventory (MSI). Major results were as follows: (1) Alcoholics reported poorer marital functioning than non-alcoholics. (2) Male alcoholics described less troubled relationships than did female alcoholics. (3) However, spouses of alcoholics described strained marriages in both cases. (4) Alcoholic couples were less congruent than control couples on conscious decisions regarding marital dissolution. (5) Alcoholic wives had taken more steps towards marital dissolution than their husbands had, whereas alcoholic husbands had taken fewer steps than their wives had. It was suggested that male alcoholics externalize their drinking and deny its impact on their marriages, whereas female alcoholics acknowledge their drinking and take the blame for their marital problems. Therapeutic and research implications were discussed.

Sensation seeking, augmenting-reducing, and the perceived and preferred effects of drugs.

The following measures were administered to 78 undergraduates: the General and Disinhibition subscales of Zuckerman's (1971) Sensation-Seeking Scale; the Reducer-Augmenter Scale (RAS; Vando, 1970, 1974); self-reported use of alcohol, tobacco, and cannabis; the degree of attribution of stimulant, depressant, and neutral effects to these drugs; and desirability ratings of stimulant and depressant effects ascribed to various drugs. Major findings were as follows: (a) On the RAS, reducing correlated positively with both sensation-seeking measures. (b) Seven of the nine personality-versus-drug-use correlations were positive and significant. (c) Generally, the effects attributed to drugs did not differ by sex, personality, or use. (d) However, frequent drinkers attributed stimulant effects to alcohol more strongly than depressant effects, whereas infrequent drinkers did the opposite. (e) The mean desirability ratings of stimulant and depressant drug effects correlated positively. (f) High disinhibitors rated drug effects of both kinds more favorably than did lows. (g) A similar, more favorable evaluation by high than by low general sensation seekers was significant for male subjects only. (h) Score on the Reducer-Augmenter Scale was not significantly predictive of subjects' desirability ratings.

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.

Sensation seeking, augmenting-reducing, and absolute auditory threshold: a strength-of-the-nervous-system perspective.

The following measures were obtained from 42 student volunteers: the General and the Disinhibition subscales of the Sensation Seeking Scale (Form IV), the Reducer-Augmenter Scale, and the Absolute Auditory Threshold. General sensation seeking correlated significantly with the Reducer-Augmenter Scale, r(40) = .59, p less than .001, and the Absolute Auditory Threshold, r(40) = .45, p less than .005. Both results proved general across sex. These findings, that high-sensation seekers tend to be reducers and to lack sensitivity to weak stimulation, were interpreted as supporting strength-of-the-nervous-system theory more than the formulation of Zuckerman and his associates.

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.

Sister chromatid exchange in cancer.

Sister chromatid exchange (SCE) techniques have been shown to have great potential for use in the in vitro screening of suspected mutagens and carcinogens. Application of these techniques to bone marrow cells and/or lymphocytes from patients with various hematologic malignancies has demonstrated significant abnormalities in SCE frequencies in some of these diseases, as well as showing drug treatment effects. Interpretation of abnormal SCE findings in cancer patients is currently hindered by the lack of a clear understanding of the basic molecular and biochemical mechanisms involved in SCE formation. The potential practical use of SCE techniques in the diagnosis and treatment of cancer can not adequately be appreciated until this basic understanding is achieved.

Wine, women, suspiciousness and advertising.

Women college students (N = 66) viewed videotapes of a soap opera episode and a rock music program, ostensibly to evaluate the appeal of such material to college women. Different versions of the videotape included zero, three or nine wine commercials. Refreshments, including white wine, were available to the subjects. Suspiciousness about the experiment was evaluated through an open-ended questionnaire, responses to which were independently content-analyzed by two scorers. Major findings were as follows: Women exposed to nine wine commercials consumed more wine than those exposed to three. Twelve women were judged suspicious about the experiment, but none showed continued specific awareness of the study's true purpose. The differential consumption patterns of women in the three-wine-commercial and nine-wine-commercial conditions were exaggerated among suspicious women. These findings, in light of previous observations, suggest opposite reactions to soft-sell versus hard-sell persuasive appeals by men and women, notably ones predisposed to be suspicious about the purpose of experiments.

The impact of television advertising on alcohol consumption: an experiment.

A videotaped indoor soccer game was shown to 125 men college students, ostensibly to evaluate the sport's televiewing appeal. Different versions of the videotape included zero, four or nine beer commercials. Refreshments, including beer, were available to the subjects. Half the subjects had immediate access to beer, and half had access delayed by one half hour. Exposure to the first few commercials increased consumption; however, continued exposure did not. Over the entire experiment, advertising had no significant effect on total beer consumption. Delayed access to beer led to compensatory beer consumption, notably in the third half hour. The results of the present study were interpreted as not supporting strong concern about television advertising's impact on immediate consumption of available alcohol. The results suggest that experiments on alcohol advertising are likely to produce negative results where drinking is measured over a substantial period (e.g., an hour or more), and positive results where drinking is measured over a brief period (e.g., half an hour or less).

[Prophylactic effect of isosorbide dinitrate on postoperative cardiac complications (author's transl)]. / Prophylaktische Wirkung von Isosorbiddinitrat auf postoperative kardiale Komplikationen

Isosorbide dinitrate (ISD) was administered before, during and after 178 operations performed on 127 patients with arterial occlusive disease. Its influence on postoperative myocardial infarction, heart failure and mortality was tested by comparison with 188 operations performed on 140 patients with hypertension and/or old myocardial infarction receiving no ISD prophylaxis. Risk of cardiac complications was similar in both groups. Mortality in the ISD-treated group was significantly lowered as compared with the control group and was about half of the overall mortality in patients with arterial occlusive disease operated on at our hospital over the past 10 years. This difference depended partly on the influence of ISD on cardiac complications. Post-operative myocardial infarction during ISD prophylaxis occurred in 0.6% of cases as compared with 3.7% in the control group (p less than 0.05), whilst the respective values for postoperative heart failure were 5.7% and 18.2% (p less than 0.001). Both complications are related to absolute or relative hypoxia during the post-operative stress period. ISD is effective by lowering cardiac preload and afterload and thereby diminishing myocardial oxygen demand. ISD is the drug of choice for surgical patients since it provides a steady and long-lasting effect after sublingual absorption. ISD prophylaxis during the perioperative period is indicated in cases with coronary artery disease and with increased cardiac preload or afterload.