Dopamine-modulated aversive emotion processing fails in alcohol-dependent patients.

Negative mood states after alcohol detoxification may enhance the relapse risk. As recently shown in healthy volunteers, dopamine storage capacity (V d) in the left amygdala was positively correlated with functional activation in the left amygdala and anterior cingulate cortex (ACC) during an emotional task; high functional connectivity between the amygdala and the ACC, a region important for emotion regulation, was associated with low trait anxiety. Based on these findings, we now tested whether detoxified alcohol-dependent patients have a disrupted modulation of the anterior cingulate cortex activation in response to aversive stimuli by amygdala dopamine. Furthermore, we asked whether disrupted functional coupling between amygdala and ACC during aversive processing is related to trait anxiety.We used combined 6-[18F]-fluoro-l-DOPA positron emission tomography (PET), functional magnetic resonance imaging (fMRI) and Spielberger's state-trait anxiety questionnaire (STAI) in 11 male detoxified alcohol-dependent patients compared to 13 matched healthy controls.Unlike healthy controls, patients showed no significant correlation between our PET metric for dopamine storage capacity (FDOPA V d), in left amygdala and activation in left ACC. Moreover, the functional connectivity between amygdala and ACC during processing of aversive emotional stimuli was reduced in patients. Voxel-based morphometry did not reveal any discernible group differences in amygdala volume.These results suggest that dopamine-modulated corticolimbic circuit function is important for responding to emotional information such that apparent functional deficits in this neuromodulatory circuitry may contribute to trait anxiety in alcohol-dependent patients.

Increasing blood oxygen increases an index of 5-HT synthesis in human brain as measured using alpha-[(11)C]methyl-L-tryptophan and positron emission tomography.

The main objective of this investigation was to test the hypothesis that brain serotonin (5-HT) synthesis, as measured by trapping of alpha-[(11)C]methyl-L-tryptophan (alpha-MTrp) using positron emission tomography (PET), can be modulated by changes in blood oxygen. The study involved six healthy participants (three male and three female), who breathed a 15% or 60% oxygen mixture starting 15 min before the injection of tracer and continuing during the entire acquisition period. Participants were injected with up to 12m Ci of alpha-MTrp. Two sets of PET images were acquired while the participants were breathing each of the oxygen mixtures and, after reconstruction, all images were converted into brain functional images illustrating the brain trapping constant K(*) (microL/g/min). The K(*) values were obtained for 12 regions of interest outlined on the magnetic resonance images. The K(*) values obtained at high and low blood oxygen content were compared by paired statistics using Tukey's post hoc correction. As there were no difference in plasma tryptophan concentrations, these K(*) values are directly related to regional 5-HT synthesis. The results showed highly significant increases (50% on average) in brain serotonin synthesis (K(*) values) at high (mean value of 223+/-41 mmHg) relative to low (mean value 77.1+/-7.7 mmHg) blood oxygen levels. This suggests that tryptophan hydroxylase is not saturated with oxygen in the living human brain and that increases in blood oxygen can elevate brain serotonin synthesis.

The effects of the 5-HT3 antagonist, alosetron, on brain serotonin synthesis in patients with irritable bowel syndrome.

Serotonin (5-HT) plays an important role in the pathophysiology of irritable bowel syndrome (IBS). Using alpha-[(11)C]methyl-L-tryptophan-positron emission tomography (PET), it was demonstrated that brain 5-HT synthesis is increased in patients with IBS, in a gender-specific manner. The aims of the study were to evaluate the effects of alosetron on brain 5-HT synthesis in patients with IBS. Six male and five female non-constipation-predominant IBS patients were enrolled. The subjects received alosetron or a placebo for 14 days, separated by a 2-week washout period. On day 14, rectal distensions commenced just prior to the PET scan (which was performed for 80 min), and continued for 20-min periods. The functional images were analysed with SPM99. Alosetron vs placebo treatments, in a randomized, double-blinded, crossover manner, were studied. 5-HT synthesis was greater in several regions in the males than in the females during the alosetron treatment, whereas there was no region in which the females had greater synthesis. There were significant gender-treatment interactions of synthesis in the cingulate gyrus, caudate nucleus, globus pallidus, and cerebellum. The gender differences in the effect of alosetron on brain 5-HT synthesis may be related to the gender differences in the efficacy of alosetron.

Levodopa effect on [18F]fluorodopa influx to brain: normal volunteers and patients with Parkinson's disease.

OBJECTIVES: Levodopa is the immediate precursor of dopamine and the substrate for DOPA decarboxylase, an enzyme subject to regulation in living brain. To test whether this regulation changes in disease, we used Positron Emission Tomography (PET) with parametric mapping to measure the effect of levodopa on the net clearance of [(18)F]fluorodopa to brain (K, ml/g/min). METHODS: Five patients with early Parkinson's disease with pause of medication for 3 days and six age-matched healthy volunteers were studied in a baseline condition and after levodopa challenge. RESULTS: Levodopa (200 mg as Sinemet) increased the magnitude of the net clearance K in the left and right putamen of the healthy volunteers by 11% relative to the baseline condition. In contrast, resumption of medication with levodopa did not significantly alter the magnitude of K in putamen of the Parkinson's disease patients. Compartmental analysis was used to probe the physiological basis of the activation of K: levodopa treatment increased by 15% the apparent distribution volume of [(18)F]fluorodopa in cerebellum (, ml/g) of both patients and control subjects, without significantly altering the unidirectional blood-brain clearance (, ml/g/min) or the relative activity of DOPA decarboxylase (, min(-1)) in putamen. CONCLUSION: We conclude that levodopa treatment increases the distribution volume of [(18)F]fluorodopa in brain, increasing its availability for utilization in dopamine terminals. We speculate that levodopa act as a direct beta-adrenergic agonist at receptors regulating the permeability of the blood-brain barrier to levodopa. However, the PET analytical method was without sufficient power to detect the consequent increase in magnitude of K in brain of only five Parkinson's disease subjects.

Change in apoptosis in the gastric surface epithelium and glands after eradication of Helicobacter pylori.

BACKGROUND: Change in apoptosis in gastric glands after eradication of Helicobacter pylori has never been reported. AIMS: The purpose of this paper is to investigate the change in apoptosis in gastric glands after eradication of Heliobacter pylori. PATIENTS AND METHODS: We studied 23 Heliobacter pylori-positive patients with duodenal and gastric ulcers, who were monitored for 6-12 months after eradication, and eight controls. Biopsies were taken from the antrum and body. Apoptosis was evaluated immunohistochemically using anti-single stranded DNA antibody. Apoptotic index was calculated by counting immunostained cells in surface epithelial and glandular cells. RESULTS: In the surface epithelium, Apoptotic indexes were significantly higher in patients than in controls. In the upper portion of fundic glands, apoptotic indexes were significantly higher in patients with gastric ulcers (14.2% (9.3, 17.8)) (median (1st quartile, 3rd quartile)) than in controls (8.0% (2.0, 9.0), p < 0.01) and decreased significantly after eradication (3.4% (2.0, 5.3)), p < 0.01). In pyloric glands, apoptotic indexes were no different between patients and controls. In the lower portion of fundic glands, apoptotic indexes were very low, both in patients and in controls. CONCLUSIONS: Our results showed that apoptosis, not only of surface epithelial cells but also of glandular cells in the upper portion of fundic glands, increased in Heliobacter pylori-positive patients with gastric ulcers and decreased to normal levels after eradication of Heliobacter pylori.

Alpha-[11C] methyl-L-tryptophan and glucose metabolism in patients with temporal lobe epilepsy.

OBJECTIVE: To determine whether metabolism in the brain serotonergic system, including the kynurenine pathway, is involved in temporal lobe epilepsy (TLE). METHODS: The authors studied 14 patients with intractable TLE by PET using alpha-[11C] methyl-L-tryptophan (alpha-MTrp) and 2-[18F]-fluoro-deoxy-glucose (FDG) and compared results with 21 healthy control subjects who had alpha-MTrp PET studies. Seven patients had unilateral hippocampal atrophy (HA), and seven had normal hippocampal volumes (NV). The regional uptake constant (K*) for alpha-MTrp and regional FDG uptake were calculated in regions with high serotonergic innervation, including the hippocampus, amygdala, lateral temporal lobe, frontal lobe, thalamus, lenticular nucleus, and cingulate cortex. RESULTS: A significant increase of alpha-MTrp uptake was observed in the hippocampus ipsilateral to the seizure focus in seven TLE patients with NV compared to seven patients with HA as well as to healthy controls. In patients with TLE, glucose utilization in the lateral temporal lobe ipsilateral to the seizure focus was correlated negatively with K* for alpha-MTrp in the ipsilateral hippocampus and positively with K* in the ipsilateral lenticular nucleus and cingulate cortex. Glucose utilization in the frontal lobe ipsilateral to the seizure shows a reduction in the glucose utilization which relates to the increase in the alpha-MTrp uptake in the ipsilateral lateral temporal lobe. CONCLUSION: This study demonstrates dysfunction of the serotonergic system, which could include metabolism through the kynurenine pathway in TLE patients with normal hippocampal volumes. alpha-MTrp PET studies might be useful for lateralizing the epileptic focus in TLE patients with normal hippocampal volumes.

p53 expression in the gastric mucosa before and after eradication of Helicobacter pylori.

BACKGROUND: Accumulation of p53 has been recognized in the gastric mucosa infected with Helicobacter pylori. We investigated the prevalence of p53-positive cells in the gastric mucosa before and one month after eradication of H. pylori and the relationship between p53 positivity and inflammation and cell proliferation. METHODS: The subjects included 24 H. pylori-positive patients. They achieved eradication one month after anti-H. pylori therapy. Biopsies were taken from the greater curvatures of the antrum and middle body. H. pylori status was assessed using culture and tissue section (Giemsa stain). Serial sections were used for examination of gastritis (hematoxylin and eosin stain) and for immunostaining of p53, Ki-67 and myeloperoxidase (MPO). p53 index and Ki-67 labeling index (LI) were calculated by counting p53-positive and Ki-67-positive cells in the entire gastric pits longitudinally sectioned and expressing them as a percentage of the total cells in a gastric pit. In the neck regions with and without p53-positive cells, polymorphonuclear leukocytes (PMNs) were counted in the corresponding area (/50 x 50 microm2) of the sections stained both with p53 and MPO. RESULTS: p53-positive cells decreased significantly after eradication of H. pylori. Before eradication, the number of PMNs was significantly higher in the neck regions with p53-positive cells than in those without. CONCLUSIONS: In the gastric mucosa infected with H. pylori, p53-positive cells were found in the neck region infiltrated with PMNs. p53 expression decreased significantly one month after eradication of H. pylori.

Cortical activation in reading assessed by region of interest-based analysis and statistical parametric mapping.

Reanalysis of our positron emission tomography study on the reading of Japanese Kanji (morphograms) and Kana (phonograms) with Statistical Parametric Mapping (SPM) Version 96 (Cogn. Brain Res. 9 (2000) 111) were described in comparison with our previous region of interest (ROI)-based analysis. Some areas were activated in one analysis but not in the other, which was due to the methodological differences. Furthermore, we conducted cognitive subtraction analysis between Kanji and Kana and between Kana words and nonwords and confirmed that Kana words activated the lateral occipital gyri more extensively than Kanji words.

[Triple therapy regimens involving H2 blockaders for therapy of Helicobacter pylori infections].

Comparison of ranitidine and lansoprazole in short-term low-dose triple therapy for Helicobacter pylori infection. To evaluate the efficacy and safety of two 1-week low-dose triple-therapy drug regimens involving antisecretory drugs for Helicobacter pylori infection, 99 patients with H. pylori infection were treated with either lansoprazole (LPZ) or ranitidine (RNT) used together with clarithromycin (CAM) and metrinidazole (MTZ). The drug combination and administration periods in the PPI group were LPZ 30 mg, CAM 400 mg, MTZ 500 mg (LCM group). The ranitidine group received RNT 300 mg, CAM 400 mg, MTZ 500 mg (RCM group). The cure rate of H. pylori infection was 88% in the LCM group; 95% CI 79-97 and 92% in the RCM group; 95% CI 84-99.

[Analysis of cerebral blood flow SPECT imaging on standard brain atlas in patients with dementia of Alzheimer type].

Statistical parametric map (SPM) has been developed by Friston et al. to analyze focal changes in rCBF induced by brain activation. This automated and objective approach has the potential of being applied to SPECT image data sets. This study evaluated an automated analysis of brain SPECT imaging in patients with dementia of Alzheimer type (DAT) using SPM95. Seventeen patients with clinically diagnosed moderate to severe DAT and nine normal control subjects were studied. The SPECT device used was a triple-headed rotation gamma camera GCA9300A/HG. All images were transformed into the standard anatomical space of the stereotactic brain atlas of Talairach and Tournoux, and then smoothed. Statistical analysis was made between DAT and normal control groups. SPM analysis of SPECT images revealed that the parieto-temporal areas and posterior cingulate gyrus of both cerebral hemispheres were significantly decreased in DAT patients compared to normal controls. In conclusion, SPM analysis of SPECT images proved to be useful in the evaluation of abnormal perfusion areas of demented patients.

A pilot study on modified endoscopic variceal ligation using endoscopic ultrasonography with color Doppler function.

OBJECTIVE: The purpose of the study was to evaluate feasibility of modified endoscopic variceal ligation (EVL), namely the "intensive ligation" method, using endoscopic ultrasonography with color Doppler function (EUS-CD). METHODS: Forty-five patients with esophageal varices were treated by modified EVL. Variceal hemodynamics in 38 patients were examined using EUS-CD, which showed abdominal hemodynamics in detail under physiological conditions before and after the modified procedure. RESULTS: 1) The median number of treatment sessions was 3.2, and 41 O-rings on average were required per individual patient. 2) The median nonrecurrence period after treatment was 18 months (Kaplan-Meier method). 3) Nine patients with a good response to modified EVL did not have recurrences for 16.9+/-2.8 months, and five with a poor response had recurrences at 5.8+/-2.2 months. Gastric varices were related to the response to modified EVL (p < 0.05, Mann-Whitney's U test). 4) Minor complications in modified EVL as well as standard EVL were experienced; however, we had a patient with the development of meningitis, which was a major septic complication. 5) Before modified EVL, EUS-CD demonstrated that good responders had undeveloped (grade I) gastric varices in five of nine (56%); however, poor responders had developed (grade III) gastric varices in four of five (80%) (p < 0.05, Mann-Whitney's U test]. 6) After modified EVL, EUS-CD revealed that six of nine (67%) good responders and one of five (20%) poor responders showed a decrease in color signals in supplying veins; however, none of the former (0%) and three of the latter (60%) showed an increase (p < 0.05, Mann-Whitney's U test]. CONCLUSION: Modified EVL was safe and effective, at least with regard to intermediate-term outcome, especially when treating patients with undeveloped gastric varices revealed by EUS-CD. Both good and poor responders showed no exacerbation of gastric varices after the modified procedure, ultrasonographically as well as endoscopically.

[Stepwise analysis of cerebral blood flow SPECT imaging on standard brain atlas in patients with dementia of Alzheimer's type].

Statistical parametric mapping (SPM) has been developed by Friston et al. to analyze focal changes in regional cerebral blood flow (rCBF) induced by brain activation. This automated and objective approach has the potential of being applied to single photon emission computed tomography (SPECT) image data sets. This study evaluated an automated analysis of N-isopropyl-p[123I]iodoamphetamine SPECT (123I-IMP) imaging in patients with dementia of Alzheimer's type (DAT) using statistical parametric mapping '95 (SPM'95). Eighteen patients with clinically diagnosed mild to severe DAT who were classified into two groups and ten normal control subjects were studied. The SPECT device used was a triple-headed rotation gamma camera. All images were transformed into the standard anatomical space of the stereotaxic brain atlas of Talairach and Tournoux, and then smoothed. Statistical analyses were made between severe DAT, mild DAT and normal control groups. SPM analysis of 123I-IMP SPECT images revealed that the parietotemporal association areas and posterior cingulate gyri of both cerebral hemispheres were significantly decreased in CBF in mild DAT group compared to normal controls. In comparison of DAT groups, the right hippocampal area and basal forebrain were significantly decreased in CBF in severe DAT group. In conclusion, these results obtained by SPM analysis of SPECT images suggested that the right hippocampal area and basal forebrain followed the parietotemporal association areas and posterior cingulate gyri in the reduction of the rCBF in patients with DAT.

[Fluorine-18 labeled 6-fluoro-L-dopa: systematization and evaluation of its usefulness].

6-[18F]Fluoro-L-dopa (L-3,4-dihydroxy-6-[18F]fluorophenylalanine; 6-[18F]FDPA) is useful to assess presynaptic dopamine metabolism in central nervous system. In this paper, we report on the usefulness of the 6-[18F]FDOPA synthesis system developed for the routine synthesis. This system consists of the 6-[18F]FOPA synthesis and the separation units in conjunction with controller using a personal computer. The synthesis time of 6-[18F]FDOPA was 73 minutes. The typical yield and specific activity were 1.4-2.4 GBq and 244-270 MBq/mumol at the end of synthesis, respectively, under the irradiation condition of 50 microA for 130 minutes. The radiochemical yields of 6-[18F]FDOPA were 31.3-38.7% based on the [18F]acetylhypofluorite, and the results were affected with the condition of potassium acetate (AcOK) to produce gaseous [18F]acetylhypofluorite. This system is useful for the routine production of 6-[18F]FDOPA because of its high yield and high specific activity while maintaining AcOK in good condition, and decreasing the radiation exposure for chemist.

[Progress and clinical usefulness of color Doppler method in diagnosing abdominal diseases].

We report the clinical usefulness of extracorporeal color Doppler ultrasonography (CDUS), color Doppler endoscopic ultrasonography (CDEUS), and recent progress in diagnosing abdominal diseases by the color Doppler method. CDUS has the advantage of being able to be performed repeatedly and noninvasively, it is thought to be useful for the evaluation of tumor vascularity and diagnosis of vascular tumor invasion and analysis of hemodynamics in abnormal vessels found in several abdominal diseases. CDEUS, which is performed under endoscopic ultrasonography (EUS), can evaluate the hemodynamics more minutely and visualize small vessels more clearly than conventional CDUS. Recent progress in the color Doppler method, such as US color angiography and the use of contrast agents is expected to lead to a higher resolution of visualization and easier detection of abdominal vessels.

Radiation therapy for patients with xeroderma pigmentosum.

Our experience reported here, as well as a review of the literature, suggests that radiation therapy can be used in the palliative treatment of XP-related malignancy. However, radiation therapy should be used with caution in XP patients with an anticipated prolonged life expectancy, because the late side effects of ionizing radiation in XP are not well known.

Age-related changes in the microvessels of the human stomach: an ultrastructural study.

The ultrastructure of microvessels in the gastric mucosa of patients with atrophic gastritis was investigated. In the gastric mucosa of atrophic gastritis, the endothelial cells of microvessels were irregularly swollen and subendothelial spaces were enlarged. The basement membrane underlying the endothelium was thickened. Degeneration of smooth-muscle cells was also evident in the media. These changes appear to correspond to sclerosis or aging of the microvessels. Such sclerotic changes in microvessels may initiate deterioration of the microenvironment in the gastric mucosa and may consequently affect metabolic activity of the gastric mucosal cells. Those sequences might induce degeneration or abnormal differentiation of mucosal cells. Such vascular changes may advance slowly and increase in intensity with advancing age. The final result would be the histologic changes associated with atrophic gastritis.