Characteristic regional cerebral blood flow patterns in anorexia nervosa patients with binge/purge behavior.

OBJECTIVE: The authors' goal was to investigate the effect of imagining food on the regional cerebral blood flow (rCBF) of anorexia nervosa patients with and without habitual binge/purge behavior. METHOD: The subjects included seven female patients with purely restrictive anorexia, seven female patients with anorexia and habitual binge/purge behavior, and seven healthy women. Single photon emission computed tomography examination was performed before and after the subjects were asked to imagine food. Changes in rCBF count ratios (percent change) were then calculated and compared. The subjects were also asked to assess their degree of fear regarding their control of food intake. RESULTS: The anorexia nervosa patients with habitual binge/purge behavior had a significantly higher percent change in the inferior, superior, prefrontal, and parietal regions of the right brain than the patients with purely restrictive anorexia and the healthy volunteers. The patients with habitual binge/purge behavior also had the highest level of apprehension in regard to food intake. CONCLUSIONS: Specific activation in cortical regions suggests an association between habitual binge/purge behavior and the food recognition process linked to anxiety in patients with anorexia nervosa.

4-N-hydroxy-L-2,4-diaminobutyric acid. A strong inhibitor of glutamine synthetase.

Analogues of glutamic acid were synthesized and evaluated for their inhibitory activity toward glutamine synthetase (EC 6.3.1.2; GS). The title compound, 4-N-hydroxy-L-2,4-diaminobutyric acid (NH-DABA), showed a potent inhibitory activity against GS from both sheep brain and soybean. The inhibition is competitive with respect to glutamic acid and the Ki values of sheep brain GS and soybean GS for NH-DABA are 0.007 mmol and 0.021 mmol, respectively. The activity of inhibition is comparable to those of L-methionine sulfoximine and 2-amino-4-(hydroxymethyl-phosphinyl)butyric acid (phosphinothricin).

Mechanism of action of cerulenin on fatty acid synthetase. Effect of cerulenin on iodoacetamide-induced malonyl-CoA decarboxylase activity.

Cerulenin, an antibiotic with the structure of (2R)(3S)-2,3-epoxy-4-oxo-7,10-dodecadienoylamide, irreversibly inactivates yeast fatty acid synthetase. Of all catalytic activities of the synthetase, only the condensation reaction is inhibited by cerulenin. At 0 degrees C and pH 6.5, the second-order rate constant of k = 88 M-1 . S-1 was obtained for the inactivation by cerulenin. This value was about 90-times greater than the rate constant for the inactivation of the enzyme by iodoacetamide. The enzyme was protected against the action of cerulenin by prior treatment with acetyl-CoA but not malonyl-CoA. Treatment of the enzyme with iodoacetamide, while impairing the synthetase activity, induced malonyl-CoA decarboxylase activity [Kresze, G.-B., Steber, L., Oesterhelt, D., and Lynen, F. (1977) Eur. J. Biochem. 79, 191-199]. Cerulenin had no effect on the malonyl-CoA decarboxylase activity of the iodoacetamide-treated enzyme. N-Ethylmaleimide, in contrast, inhibited the iodoacetamide-induced malonyl-CoA decarboxylase activity. When the enzyme was preincubated with cerulenin, malonyl-CoA decarboxylase activity could not be detected even after treatment of the enzyme with iodoacetamide. These results indicated that the reaction of cerulenin with the peripheral SH-groups of the synthetase is responsible for the inactivation.

5-HT2A promoter polymorphism is not associated with anorexia nervosa in Japanese patients.

Genetic factors have been implicated in playing a significant role in susceptibility to anorexia nervosa (AN). Among many candidate genes for AN, an association with the A allele of the -1438G/A polymorphism in the promoter region of the 5-HT2A receptor has been reported. However, these findings are controversial and all patients studied to date have been Caucasian. This study was designed to determine whether this association is reproducible in Japanese subjects. This case-control study of a cohort of 75 female Japanese AN sufferers and 127 normal female control subjects revealed no significant association between the 5-HT2A promoter polymorphism and AN. Thus, at least for Japanese subjects, the A-allele of the -1438G/A polymorphism in the promoter region of the 5-HT2A receptor gene does not contribute to a predisposition to AN.

Analysis of tumor necrosis factor-alpha gene promoter polymorphisms in anorexia nervosa.

Elevated plasma tumor necrosis factor-alpha (TNFalpha) levels and enhanced spontaneous TNFalpha release from peripheral blood mononuclear cells in patients with anorexia nervosa (AN) have been reported. TNFalpha activates the hypothalamic-pituitary-adrenal axis and reduces food intake, which is characteristic of eating disorders. Recently, three novel polymorphisms in the 5'-flanking region of the TNFalpha gene were reported at positions -1031 (T --> C substitution), -863 (C --> A) and -857 (C --> T). Differences in these alleles are reportedly related to altered TNFalpha-transcriptional promoter activity. Therefore, we performed a case-control association analysis to determine whether any of those three polymorphisms in the TNFalpha promoter region were involved in a predisposition to AN. The results of our analysis of a cohort of 79 female Japanese AN sufferers and 127 normal female control subjects provide no support for the hypothesis that -1031T/C, -863 C/A and -857C/T polymorphisms in the TNFalpha gene promoter region influence the susceptibility to AN.

Pharmacological properties of alpha-mangostin, a novel histamine H1 receptor antagonist.

In the isolated rabbit thoracic aorta and guinea-pig trachea, alpha-mangostin inhibited histamine-induced contractions in a concentration-dependent manner in the presence or absence of cimetidine, a histamine H2 receptor antagonist. But KCl-, phenylephrine- or carbachol-induced contractions were not affected by alpha-mangostin. The concentration-contractile response curve for histamine was shifted to the right in a parallel manner by alpha-mangostin. In the presence of chlorpheniramine, a histamine H1 receptor antagonist, alpha-mangostin did not affect the relaxation of the rabbit aorta induced by histamine. In the guinea-pig trachea, alpha-mangostin had no effect on the relaxation induced by dimaprit, a histamine H2 receptor agonist. alpha-Mangostin caused a concentration-dependent inhibition of the binding of [3H]mepyramine, a specific histamine H1 receptor antagonist to rat aortic smooth muscle cells. Kinetic analysis of [3H]mepyramine binding indicated the competitive inhibition by alpha-mangostin. These results suggest that alpha-mangostin is a novel competitive histamine H1 receptor antagonist in smooth muscle cells.

Gamma-mangostin, a novel type of 5-hydroxytryptamine 2A receptor antagonist.

Gamma-mangostin, purified from the fruit hull of the medicinal plant Garcinia mangostana caused a parallel rightwards shift of the concentration/response curve for the contraction elicited by 5-hydroxytryptamine (5-HT) in the rabbit aorta (pA2 = 8.2) without affecting the contractile responses to KCl, phenylephrine (alpha1) or histamine (H1). The perfusion pressure response of rat coronary artery to 5-HT (5-HT2A) was reduced concentration dependently by gamma-mangostin (IC50 = 0.32 microM). 5-HT amplified, ADP-induced aggregation of rabbit platelets (5-HT2A) was inhibited by gamma-mangostin (IC50 = 0.29 microM), whereas that induced by thrombin was not affected, nor did gamma-mangostin affect 5-HT-induced contraction of the guinea-pig ileum (5-HT3)in the presence of 5-HT1, 5-HT2 and 5-HT4 receptor antagonists. Furthermore, 5-HT-induced contraction of the rat fundus (5-HT2B) and 5-HT-induced relaxation of the rabbit aorta in the presence of ketanserin (5-HT1) and carbachol-induced contraction of the guinea-pig ileum (muscarinic M3) were not affected by gamma-mangostin (5 microM). Gamma-mangostin inhibited [3H]spiperone binding to cultured rat aortic myocytes (IC50 = 3.5 nM). The Kd for [3H]spiperone binding was increased by gamma-mangostin (3 nM) from 11.7 to 27.4 nM without affecting Bmax. These results suggest that gamma-mangostin is a novel competitive antagonist, free from a nitrogen atom, for the 5-HT2A receptors in vascular smooth muscles and platelets.

Comparison of regional cerebral blood flow in patients with eating disorders.

We used single photon emission computed tomography (SPECT) with Tc-99m-HMPAO to examine the characteristics of regional cerebral blood flow (rCBF) in five patients with bulimia nervosa (BN), eight patients with anorexia nervosa (AN), and in nine healthy controls. The SPECT examinations were performed before and after food intake stimulus, and the values of the corrected ratio (R) for rCBF in 10 cerebral cortical regions before (Rbefore) and after eating (Rafter) were calculated. The asymmetry indices (AI) of the R values for the left and right side of each cortical region and the percent change from Rbefore to Rafter (%change) were computed. In comparison with the other two groups, BN patients showed significantly higher Rbefore values in the bilateral inferior frontal and left temporal regions. The AN patients showed significantly lower Rbefore values in the left parietal region than the control group. There were no significant differences in Rafter values among the three groups. The %change values in the AN group showed the greatest increase in 9 out of the 10 regions. In contrast to the positive values obtained from the 10 regions observed in the AN group, 5 out of the 10 regions in the BN group showed negative values. Among the three groups, significant differences in %change were observed on both sides of the inferior frontal, temporal, parietal, and occipital regions. These findings indicate that differences in cerebral function of BN and AN patients can be characterized through SPECT imaging.

Changes in taste responsiveness in patients with anorexia nervosa during behavior therapy.

We evaluated the changes in taste responsiveness of anorexia nervosa (AN) patients during behavior therapy. Taste responsiveness of AN patients was lower at admission when compared to controls but it improved significantly over the course of treatment (p < 0.01). Taste responsiveness improved prior to increase in body weight. No significant correlation was noted between weight gain and improvement in taste responsiveness. The period required to reach a food intake of 1600 Kcal/day and the duration of hospitalization were highly correlated (r = 0.72, p < 0.05). Those who reached 1600 Kcal/day earlier showed more rapid improvements in taste responsiveness. These results suggest that decreased taste responsiveness in AN patients can rapidly improve and such early improvement may result in better progression of treatment.

Psychosocial and clinical factors predicting resumption of work following acute myocardial infarction in Japanese men.

We investigated psychosocial and clinical factors related to work resumption, delay in returning to work and level of work activity after an acute myocardial infarction in Japanese male patients. A total of 111 married male patients experiencing a first acute myocardial infarction, aged less than 66 years and in full-time employment participated. Interviews and questionnaires were administered during hospitalization to assess potential predictors of work-related outcomes, with follow-up (81.6%) after an average of 8 months. We found that failure to return to work was predicated independently by older age (P=0.019), an introverted personality (P=0.011) and the presence of depressive symptoms during hospitalization (P=0.031). Delay in returning to work was predicted by greater concerns about health (P=0.011), low social support (P=0.021), and a failure to recognise a link between stress, coping style and illness (P=0.001). Resuming work at a lower activity level than before infarction was associated with older age (P=0.008), higher health concerns (P=0.012), and patients' predictions of their lower work activity (P=0.001). Clinical indices of infarction size and disease severity did not predict work-related outcomes. We conclude that psychosocial factors are associated with work resumption in Japanese men characterised by a job-centred lifestyle, with different factors being important for different work outcomes. The psychosocial factors found to be important are similar to those identified in Western societies.

Clinical features of patients with anorexia nervosa: assessment of factors influencing the duration of in-patient treatment.

We investigated that factors affecting the duration of in-patient treatment of patients with anorexia nervosa by comparing pretreatment clinical features with the length of hospitalization in 55 patients. Only patients who had completed the entire course of treatment were included in our analysis. Longer hospitalization was correlated with: poor social adaptation; anxiety and/or personality disorders before onset; older age at onset; older age at admission to our hospital; lower minimum body weight after onset; lower body weight at admission; longer duration of illness; frequent previous hospital treatment and/or history of in-patient treatment for anorexia nervosa or other somatic disorders after onset; habitual stimulant (alcohol, coffee and/or cigarettes) abuse; and a history of stealing after onset. Step-wise regression analysis revealed that minimum body weight after onset and age at admission explained 47% of the variance in the duration of in-patient treatment. We also describe the nature of in patient treatment typically offered to patients with anorexia nervosa in Japan.

Evaluation of depression in rats exposed to chronic (unpredictable) electric shock.

The present study was undertaken to evaluate the applicability of a proposed behavioral stress paradigm as an animal model for depression. Rats were trained to press a lever under a fixed ratio (FR) 5 schedule in a Skinner box for 10 days and were subsequently exposed to a daily regimen of 20 cycles of FR 5 and 10 cycles of variable ratio (VR) 10 for about a week. This exposure resulted in a reduction of the number of lever presses and successful escapes compared to the level achieved after training. In addition, weight gain was significantly suppressed compared with other treatments. Acute and chronic administration of psychotropic drugs (imipramine and chlordiazepoxide) showed that treatment with imipramine increased both the number of lever presses and successful escapes while chlordiazepoxide increased only the number of lever presses. The results suggest that this simplified animal model utilizing chronic unpredictable electric shock may be useful in the study of human depression.

Decreases in blood perfusion of the anterior cingulate gyri in Anorexia Nervosa Restricters assessed by SPECT image analysis.

BACKGROUND: It is possible that psychopathological differences exist between the restricting and bulimic forms of anorexia nervosa. We investigated localized differences of brain blood flow of anorexia nervosa patients using SPECT image analysis with statistic parametric mapping (SPM) in an attempt to link brain blood flow patterns to neurophysiologic characteristics. METHODS: The subjects enrolled in this study included the following three groups: pure restrictor anorexics (AN-R), anorexic bulimics (AN-BP), and healthy volunteers (HV). All images were transformed into the standard anatomical space of the stereotactic brain atlas, then smoothed. After statistical analysis of each brain image, the relationships among images were evaluated. RESULTS: SPM analysis of the SPECT images revealed that the blood flow of frontal area mainly containing bilateral anterior cingulate gyri (ACC) was significantly decreased in the AN-R group compared to the AN-BP and HV groups. CONCLUSIONS: These findings suggest that some localized functions of the ACCare possibly relevant to the psychopathological aspects of AN-R.

Biosynthesis of brefeldin A. Introduction of oxygen at the C-7 position.

The biosynthetic introduction of oxygen in position 7 of brefeldin A, a structurally unique macrolide with an alicyclic ring, was studied. [4-2H]Brefeldin C was prepared efficiently from brefeldin A. A high incorporation ratio of the labeled brefeldin C into brefeldin A by Eupenicillium brefeldianum clearly indicates that the oxygen in position 7 of brefeldin A does not contribute to the cyclopentane ring formation but is introduced during the last step of brefeldin A biosynthesis.

Psychobehavioral and immunological characteristics of HTLV-1 carriers and non-carriers with persistently low natural killer cell activity.

OBJECTIVE: To clarify the differences in immunological and psychobehavioral characteristics of HTLV-1 carriers and non-carriers with persistently low natural killer (NK) cell activity. METHODS: The individuals with persistently low NK cell activity were divided into HTLV-1 carriers and non-carriers. NK cell activity, lymphocytic proliferation, lymphocyte subsets (CD4+, CD8+, CD16+, CD20+, CD56+), and psychobehavioral responses were examined. PATIENTS: Of 296 outpatients with physical complaints, 30 patients with persistently low NK cell activity (10 HTLV-1 carriers and 20 HTLV-1 non-carriers) and 20 healthy controls negative for HTLV-1 antibody and with normal NK cell activity were randomly selected. RESULTS: In HTLV-1 carriers with persistently low NK cell activity, no significant differences were observed in NK cell subsets (CD16+ and CD56+) and psychobehavioral responses compared with the healthy controls. In HTLV-1 non-carriers, NK cell subsets were significantly low, and depression, anxiety and fatigue were significantly greater than in healthy controls. CONCLUSIONS: These findings suggest that persistently e low NK cell activity in HTLV-1 carriers might be reduced due to the HTLV-1 infection. On the other hand, the reduction in the NK cell activity in HTLV-1 non-carriers appears a to be related to depression, anxiety, and fatigue.

Percutaneous intracavitary antifungals for a patient with pulmonary aspergilloma; with a special reference to in vivo efficacies and in vitro susceptibility results.

A 61-year-old man with pulmonary aspergilloma received two antifungals intracavitarily. Although clinical, serological and roentgenographic improvement were observed with fluconazole therapy, bronchial secretions continuously yielded Aspergillus fumigatus. When fluconazole was switched to amphotericin B, the pathogen was eradicated immediately. The minimal inhibitory concentrations (MICs) of the isolate were 400 micrograms/ml for fluconazole, and 0.2 microgram/ml for amphotericin B. Although the discrepancy between in vitro and in vivo efficacy of antifungals has been argued, it was suggested the drug of choice should be selected on the basis of the MIC results at least in the intracavitary antifungal therapy for pulmonary aspergilloma.

I-123 iomazenil SPECT in patients with mental disorders.

The purpose of this study is visual evaluation of the distribution of I-123 iomazenil in the brains of patients with various types of mental disorder and to examine whether chronic administration of a clinical dose of benzodiazepine (BZ) affects the binding of I-123 iomazenil to BZ receptors (BZR). The subjects were 10 patients with mental disorders (3 males and 7 females) with a mean age of 26.8 yrs (range 19-39 yrs). Four of 10 patients were administered BZ for over 3 months and the other six were free of BZ for over one month. The SPECT images were obtained at 5-25 min (early) and 170-190 min (delayed), after the bolus i.v. injection of 167 MBq of I-123 iomazenil, with a triple-head gamma camera. The images were visually evaluated and the washout ratios of each region were calculated. In visual analysis, abnormalities were recognized in 5 patients on the delaye SPECT. The abnormalities were recognized more frequently in the superior frontal lobe. The washout ratio was higher in the BZ (+) patient group than in the BZ (-) patient group. I-123 iomazenil is useful, because the SPECT image with I-123 iomazenil reflects the distribution of BZR on the brain and provides the different information from that obtained with perfusion SPECT, X-ray CT or MRI. The rapid washout of I-123 iomazenil from the brains of BZ (+) patients suggests that chronic administration of a clinical dose of BZ affects the binding of I-123 iomazenil to BZR.

[Absolute configuration of the diastereoisomer of 2-amino-3-(1,2-dicarboxyethylthio) propanoic acid from Amanita pantherina].

Four stereoisomers of 2-amino-3-(1,2-dicarboxyethylthio) propanoic acid were prepared by reaction of L- and D-cysteine with fumaric acid. The absolute configuration of the diastereoisomer of 2-amino-3-(1,2-dicarboxyethylthio) propanoic acid from Amanita pantherina were assigned as (2R, 1'R) and (2R, 1'S) by analysis of the optical properties. Pharmacological tests showed that all of the four stereoisomers inhibited the depolarization of NMDA on spinal motorneurones in newborn rats, The inhibition intensity of L-A, D-A and D-B were higher than that of L-B.

[Anorexia nervosa (AN)--epidemiology, cause, therapy, outcome].

The number of patients suffering from anorexia nervosa is rising steadily. More than 90 percent of patients are female in preadolescents or adolescents. AN is characterized by abnormal eating behavior and excessive loss of weight. The self-esteem is highly dependent on their body shape and weight. The purposes of behavior therapy for AN are to remove various types of avoidance behavior, to reestablish desirable eating behavior and social skill behavior. The course and outcome of AN are variable. Of patients admitted to our hospital to receive behavior therapy, 60 percent are mostly recovered, 30 percent exhibit a fluctuating pattern of weight gain followed by relapse, and 10 percent are chronically deteriorating course of the illness over many years. The long-term mortality from AN is about 6 percent.