Morphological characterisation of glial and neuronal tau pathology in globular glial tauopathy (Types II and III).

AIMS: Globular glial tauopathy (GGT) is a new category within the 4-repeat tauopathies that is characterised neuropathologically by tau-positive globular glial inclusions (GGIs), namely, globular oligodendrocytic and astrocytic inclusions (GOIs and GAIs). Occurrence of tau-positive neuronal cytoplasmic inclusions (NCIs) is also a feature. GGT is classified into three pathological subtypes (Types I, II and III). We studied the tau pathology in 6 cases of GGT (Type II, n = 3; Type III, n = 3), with special reference to GAIs and NCIs. METHODS: Neuropathological examinations were conducted, along with immunohistochemistry, morphometry and three-dimensional imaging, and biochemical and genetic analysis of tau. RESULTS: The cortical GAIs in Type II and those in Type III were distinguishable from each other. In the motor cortex, GAIs were much more numerous in Type III than in Type II. Prominent occurrence of perikaryal globular structures was a feature of GAIs in Type III. By contrast, prominent occurrence of radiating process-like structures was a feature of GAIs in Type II. Overall, the GAIs were significantly smaller in Type III than in Type II. NCIs were divisible into three subgroups in terms of shape: diffuse granular, thick cord-like, and round/horseshoe-shaped structures. In all cases, NCIs were a feature of the upper and lower motor neurons. Interestingly, the round/horseshoe-shaped NCIs were observed only in Type III cases. CONCLUSIONS: These findings, which characterised GAIs and NCIs, indicated that Type II and Type III constitute two distinct pathological subtypes, and also further strengthen the concept of GGT as a distinct entity.

Use of endoscopy to determine the resection margin during laparoscopic gastrectomy for cancer.

BACKGROUND: It can be difficult to determine the transection line during totally laparoscopic surgery for early gastric cancer owing to lack of tactile feedback. This retrospective cohort study aimed to assess the role of intraoperative endoscopy in determining the resection margin in totally laparoscopic gastrectomy. METHODS: Consecutive patients with histologically confirmed gastric cancer who underwent laparoscopic gastrectomy between March 2012 and July 2015 were eligible. Preoperative placement of marking clips and intraoperative endoscopy were performed to determine the resection margin. Frozen-section analyses were also performed to confirm the absence of cancer cells at the surgical margin. Success was defined as the proportion of specimens with all clips present and by the proportion of resections with a negative surgical margin following initial transection. RESULTS: Total laparoscopic gastrectomy with intraoperative endoscopy was performed in 522 patients; a total of 662 surgical margins were analysed. The overall success rate was 99·8 per cent (661 of 662 margins). The success rate of achieving a negative surgical margin during the initial transection was 98·9 per cent (550 of 556 margins). CONCLUSION: Preoperative placement of marking clips and intraoperative endoscopy is helpful in the determination of a safe surgical margin in patients with gastric cancer who undergo laparoscopic gastrectomy.

[Rheumatic disease and depression].

We reviewed depressive symptoms in rheumatic disease. In systemic lupus erythematosus(SLE), depressive symptoms are frequently mentioned with the prevalence rate about 30% and usually respond to antidepressant. The duration of symptoms is within two months in most patients. Antibodies to ribosomal P protein appear to be a specific marker for SLE with depression. Single photon emission tomography but magnetic resonance imaging may also be useful for predicting the development of depressive symptoms. We also reported a patient of dermatomyositis with manic-depressive state who showed decreased cerebral blood flow in the left frontal and temporal regions during depressive state.

Nucleotide sequence analysis of the binding site on the inositol 1,4,5-trisphosphate type-1 receptor in bipolar disorder -- a negative study.

Pharmacological studies of bipolar disorder suggest that dysfunction of calcium mobilization via phosphatidylinositol-mediated transduction may be involved in its pathogenesis. The present study tests the hypothesis that dysfunction of calcium mobilization in bipolar disorder is due to the mutation of the nucleotide sequence in the FKBP12 binding site on the inositol 1,4,5-trisphosphate type-1 receptor (IP(3)R1). Nucleotide sequence analysis of the FKBP12 binding site on IP(3)R1 was performed using reverse transcription-polymerase chain reaction and DNA sequencing. The nucleotide sequence in this region was preserved in all subjects. This finding suggests that IP(3)R1 dysfunction through the FKBP12 binding site is not involved in the pathogenesis of bipolar disorder.

Apoptotic neurons in Alzheimer's disease frequently show intracellular Abeta42 labeling.

It is widely accepted that Abeta plays a pivotal role in the pathogenesis of Alzheimer's disease (AD) [27]. Attention has been focused mainly on how extracellular Abeta exerts its effects on neuronal cells [7,11,16,32]. However, neuronal degeneration from an accumulation of intracellular Abetax-42 (iAbeta42) occurs in presenilin 1 (PS1) mutant mice without extracellular Abeta deposits [5]. In the present study, intracellular deposits of iAbeta42 are correlated with apoptotic cell death in AD and PS-1 familial AD (PS1 FAD) brains by means of triple staining with antibodies to Abeta, TUNEL, and staining with Hoechst 33342. Neurons simultaneously positive for iAbeta42 and the TUNEL assay were significantly more abundant in AD brains than in controls. The number of apoptotic neurons with intracellular neurofibrillary tangles (iNFTs) was insignificant. Our results indicate that intraneuronal deposition of a neurotoxic form of Abeta seems to be an early event in the neurodegeneration of AD.

Clomipramine treatment of delusional disorder, somatic type.

Four patients of delusional disorder, somatic type, were treated with clomipramine 60-120 mg/day. All patients showed marked clinical improvement after 27-57 days of clomipramine treatment. In one case, previous treatments by various antipsychotic drugs including pimozide had been unsuccessful. This report suggests that clomipramine is effective at least for some patients with delusional disorder, somatic type, including pimozide-resistant cases. It is also suggested that there is some association between delusional disorder, somatic type, and serotonergic dysfunction.

Possible association between delusional disorder, somatic type and reduced regional cerebral blood flow.

1. A 78-year-old female with DDST and pain disorder was treated by clomipramine 20-100 mg/day. The hypochondriacal delusion was completely resolved, while the pains were partially resolved. 2. The SPECT using Xe-133 taken at the early stage of clomipramine treatment, when she still had hypochondriacal delusions, showed markedly reduced rCBF in the temporal and parietal lobes, with predominance on the left hemisphere. Meanwhile, the SPECT taken after resolution of the hypochondriacal delusions showed a marked improvement in the reduced rCBF. 3. This report suggests that DDST has some association with reduced rCBF in the temporal and parietal lobes.

Carboxyl-terminal fragments of presenilin-1 are closely related to cytoskeletal abnormalities in Alzheimer's brains.

To clarify the role of presenilin-1 (PS-1) in the pathology of Alzheimer's disease (AD), we tested four antisera to PS-1. The specific antisera to the N-terminus (HSN-2) and C-terminus (HS-C) of PS-1 detected a 44/40kD holoprotein, a 25kD N-terminal fragment (NTF) and a 16kD C-terminal fragment (CTF) of PS-1 in COS-7 cells. The 25kD NTF and 16kD CTF were observed in human brains, and their amounts were not significantly different between the control and AD brains. The antibody HS-C labeled extensive neurofibrillary tangles, dystrophic neurites and curly fibers in the AD brains. In the paired helical filament (PHF) fraction containing A68 protein from AD brains, a smear pattern of CTFs was revealed. Antisera (HS-L292 and HS-L300) to cleavage sites of PS-1 also revealed immunoreactive neurofibrillary tangles in the AD brain sections and the smear pattern of CTFs of A68 protein fraction. The CTFs of PS-1 accumulate with PHF tau, suggesting a close relationship between PS-1 and cytoskeletal abnormalities in AD brains.

[Discrepancy between 99mTc-HMPAO and 99mTc-ECD in Alzheimer's disease: does the retention mechanism depend on the disease?].

The discrepancy between 99mTc-hexamethyl-propyleneamine oxime (HMPAO) and 99mTc-ethyl cysteinate dimer (ECD) in Alzheimer's disease (AD) was investigated and compared with in cerebral ischemic disease (CID). The subjects were fourteen AD and thirty-one CID patients with clinically reasonable rCBF reduced lesion on 133Xe SPECT. The subjects did not include the cases of acute and subacute CID. These SPECT were performed within two weeks by ring-type dynamic SPECT (HEADTOME, Shimadzu, Japan). In the CID group, both of HMPAO and ECD SPECT could hardly detect the mildly reduced rCBF lesion on 133Xe SPECT but normal on X-CT. In the case of AD group, the rCBF-reduced lesion on 133Xe SPECT could be detected well by ECD SPECT, but the HMPAO hardly detected the reduced lesion. This discrepancy between HMPAO and ECD may be due to the difference of the retention mechanism. In the case of AD, the injury of esterase activity that participates with the ECD retention may be more notable than that of glutathione activity for the HMPAO retention. These results suggest suggest that the reduction of ECD or HMPAO density depends directly on the insufficiency of retention mechanism rather the than rCBF reduction. And the insufficiency of this retention mechanism depends on also type of the disease i.e. AD or CID.

Changes in regional brain activity in major depression after successful treatment with antidepressant drugs.

Relative regional cerebral blood flow was measured with single photon emission computed tomography (SPECT) using 99mTc-hexamethylpropyleneamine oxime (99mTc-HMPAO) in 16 patients with major depression while they were in the depressed state as well as in remission. All patients were closely matched with regard to medication status. In the depressed state, significant reductions in tracer uptake were found in the left superior frontal, bilateral parietal and right lateral temporal cortex. During remission, significant increases in uptake were found in the left superior frontal, right parietal and right lateral temporal cortex. There were no significant differences in tracer uptake between patients in remission and controls. These findings suggest that the regional decreases in tracer uptake observed in the depressed state might be a state-related abnormality.

Effects of genetic defects in the CYP2C19 gene on the N-demethylation of imipramine, and clinical outcome of imipramine therapy.

The relationship between the genetic polymorphism of S-mephenytoin 4'-hydroxylation catalyzed by CYP2C19 and the N-demethylation of imipramine was examined in 10 Japanese depressed patients. Five patients, who were poor metabolizers of S-mephenytoin, were determined to be either homozygous for a mutation in exon 5 or heterozygous for mutations in exon 4 and exon 5 of the CYP2C19 gene. In contrast, five patients, who were extensive metabolizers, had no mutations. The demethylation index (the desipramine/imipramine ratio) was significantly lower in patients with genetic defects. Plasma levels of imipramine and 2-hydroxyimipramine normalized by the daily dose (mg) per weight (kg) were significantly higher in patients with genetic defects. This suggests that the N-demethylation of imipramine is impaired in patients with genetic defects in the CYP2C19 gene, and that genotype determination may be useful in preventing side effects induced by unexpectedly elevated levels of imipramine.

Sequence analysis of presenilin-1 gene mutation in Japanese Alzheimer's disease patients.

The mutations of presenilins (PSs) gene and their clinicopathological correlations to Alzheimer's disease (AD) have lately attracted considerable attention. In this report we analyzed fifteen Japanese familial Alzheimer's disease (FAD) including 12 early-onset FAD and 13 sporadic AD patients for the mutation of PS-1 gene by direct sequence analysis. We found the mutations, G384A, E280A in two FAD and H163R in one sporadic AD patient, and no N1411 or M239V mutation in PS-2 gene, and no mutation in exons 16 and 17 in amyloid precursor protein (APP) gene. Families in which we failed to find the mutation by this screening may have mutations elsewhere in PSs or in APP gene, or yet unidentified other AD loci may exist. This is the first report to find a sporadic AD patient having PS-1 mutation.

Steady-state plasma concentrations of imipramine and desipramine in relation to S-mephenytoin 4'-hydroxylation status in Japanese depressive patients.

The steady-state plasma concentrations of imipramine and desipramine were measured after a more than 2-week treatment with 0.39 to 1.39 mg/kg/day of imipramine hydrochloride in 28 Japanese patients with major depression who had been phenotyped simultaneously with mephenytoin (for CYP2C19-related status) and with metoprolol (for CYP2D6-related status) before initiating the antidepressant therapy. Patients consisted of five poor metabolizers (PMs) of CYP2C19 with an extensive metabolizer (EM) phenotype of CYP2D6, whereas the remainder were EMs for both of the phenotypes. The mean respective concentrations (corrected by mg/kg) of imipramine and the sum of imipramine plus desipramine were 2.4 and 1.8 times greater in the CYP2C19-related PM than in the EM group, and these two variables correlated with the log10 urinary excretion of 4'-hydroxymephenytoin (rs = -0.73 and -0.64, both p < 0.01, respectively), but not with the metabolic ratio (MR) of metoprolol/alpha-hydroxymetoprolol. The mean N-demethylation index (MR of desipramine/imipramine) was significantly (p < 0.01) less in the PM than in the EM group. This index correlated with the 4'-hydroxylation of S-mephenytoin (rs = -0.51, p < 0.01), but not with the alpha-hydroxylation of metoprolol, implying that imipramine N-demethylation is under a coregulatory pharmacogenetic control of CYP2C19, but not of CYP2D6. In conclusion, by taking into account that the incidence of the PMs of CYP2C19 is much greater (18-23%) than that of CYP2D6 (< 1%) in Japanese population, the individually predetermined assessment of the CYP2C19-mediated metabolic capacity of imipramine would be more valuable than that of the CYP2D6-mediated capacity for forecasting the steady-state concentrations of imipramine and desipramine in Japanese depressive patients, thereby attaining an individualized optimization of imipramine therapy. Obviously, a pharmacodynamic assessment study conducted simultaneously with predetermined CYP2C19 status is required for supporting this contention.

[Xe-133 inhalation single photon emission computerized tomography in manic-depressive illness].

We measured regional cerebral blood flow (rCBF) in depressed patients using Xe-133 inhalation single photon emission computerized tomography (SPECT; HEADTOME). Thirty-two medicated mildly depressed patients, six bipolar (BP) and 26 unipolar (UP), and 20 control subjects participated in the study. Compared to the controls, UP patients showed a significant decrease of rCBF in the bilateral frontal and the parietal regions, which were dominant in the left hemisphere, while BP patients showed no decrease of rCBF and mean CBF. Comparison of rCBF between before and after treatment with antidepressants in 8 depressed patients revealed an increased rCBF after the improvement in the left superior frontal, the left parietal and the right temporal regions which are critical areas for the development of depression.

[A clinical investigation of the role of allergic factors in the severity of bronchial asthma].

In order to study whether allergic factors have role in the severity of asthmatic attack, two hundred and forty adult asthmatics were clinically investigated (142 male, 98 female, aged 36.5 +/- 14.3). Fifty-seven extrinsic asthmatics were selected from the adult asthmatic group. The relationship between the total serum IgE levels, RAST scores, intracutaneous reactions to the twenty antigens, and the severity of bronchial asthma categorized according to the guidelines of the Japanese Society of Allergology, and methacholine bronchial responsiveness (Dmin(u)) were determined. In extrinsic asthma, there was a significant correlation between the severity of bronchial asthma, the intensity of asthmatic attack and bronchial responsiveness. However, there was no significant correlation between the severity of asthma, the Dmin(u) values and the total serum IgE levels, RAST scores, and the intensity of intracutaneous reaction, although there was a significant correlation between the Dmin(u) values and the numbers of positive intracutaneous reactions. In conclusion, it is suggested that there is no direct correlation between allergic factors and the severity of bronchial asthma in adult asthmatics.

Acetylcholinesterase activities and monoamine metabolite levels in the cerebrospinal fluid of patients with Alzheimer's disease.

We measured cholinesterase (ChE) activity and monoamine metabolite levels in the cerebrospinal fluid (CSF) of 22 patients with early-onset Alzheimer type dementia (Alzheimer's disease; AD) and of 32 controls. Acetylcholinesterase (AChE) activity, 5-hydroxyindoleacetic acid (5-HIAA), and homovanillic acid (HVA) levels were significantly lower in AD patients than in controls. However, there was an overlap in values of each CSF parameter. The measurement of various CSF parameters rather than one alone was more useful as a diagnostic aid. CSF ChE activities correlated with scores on the GBS rating scale, Hasegawa dementia scale, and Wechsler Adult Intelligence Scale, but the monoamine metabolite levels did not. Although cholinergic and monoaminergic deficits may coexist in AD patients, cholinergic deficits tend to be more often associated with cognitive decline than the monoaminergic deficits.

Correlation of regional cerebral blood flow with performance on neuropsychological tests in schizophrenic patients.

Regional cerebral blood flow (rCBF) was determined by the 133Xe inhalation technique (Headtome II: ring detection SPECT) in 53 DSM-III schizophrenic patients. The rCBF values were corrected by using end-tidal carbon dioxide concentration values (PECO2). After rCBF measurement, neuropsychological tests--Word Fluency Test, Maze Test and Wisconsin Card Sorting Test--were performed. There were significant correlations between frontal rCBF and scores on each neuropsychological test. In particular, a moderate correlations between the frontal rCBF and the performance on the Wisconsin Card Sorting Test was noted. It seems likely that decrease of rCBF in prefrontal regions at rest reflects a disturbance of frontal lobe function in schizophrenic patients.

Frontality, laterality, and cortical-subcortical gradient of cerebral blood flow in schizophrenia: relationship to symptoms and neuropsychological functions.

According to the three hypotheses on the regional brain dysfunction in schizophrenia that have received some support in studies of cerebral blood flow (CBF) and cerebral metabolic rate, we calculated eight CBF measurement indices in 59 schizophrenic patients; frontality, laterality, cortical to subcortical gradients and superior to inferior difference. Four factors were selected from these eight indices, treated by principal component factor analysis (factor 1: cortical to subcortical gradient; factor 2: inferior frontality; factor 3: superior frontality; factor 4: laterality). We investigated their correlations with clinical and demographic characteristics. Factor 1 correlated with duration of illness. Factor 2 related most highly to numbers of perseverative errors on the Wisconsin Card Sorting Test and moderately to anhedonia. Factor 4 related to attentional impairment score of the Scale for the Assessment of Negative Symptoms. The schizophrenia specific symptom score calculated from the Brief Psychiatric Rating Scale did not relate to any of these factors. It seemed that there were various dimensions of neural deficits in schizophrenia, corresponding to various aspects of symptomatology or neuropsychological functions.

[Effect of breathing fluctuations on cerebral blood flow in demented patients and its correction method using end-tidal CO2 concentration].

During mouthpiece respiration of Xe-133 for a measurement of regional cerebral blood flow (rCBF), the breathing pattern of patients fluctuated and it caused a change of end-tidal CO2 concentration that had an excellent correlation with PaCO2 in patient without respiratory disease. The end-tidal CO2 concentration of demented patients varied within lower ranges than senile control group. The range of fluctuation on the end-tidal CO2 concentration was dependent on the type and the degree of dementia, and it fluctuated most widely at the middle stage of Alzheimer disease. Mean cerebral blood flow increased by 13.9% for each 1% increase in end-tidal CO2 concentration (3.6%/mmHg PaCO2) in the case of demented patients without cerebrovascular disease. To improve the reliability of rCBF in demented patients, especially in Alzheimer disease, the correction of rCBF data for end-tidal CO2 concentration should be performed.

Assessment of demented patients by dynamic SPECT of inhaled xenon-133.

We studied the potential for using dynamic single photon emission computed tomography of inhaled xenon-133 (133Xe) gas in the assessment of demented patients. An advanced ring-type single photon emission computed tomography (SPECT) "HEADTOME" with improved spatial resolution [15 mm in full width at half maximum (FWHM)] was used for tomographic measurement of regional cerebral blood flow (rCBF). All 34 patients underwent a detailed psychiatric examination and x-ray computed tomography scan, and matched research criteria for Alzheimer's disease (n = 13), senile dementia of the Alzheimer type (n = 9), or multi-infarct dementia (n = 12). In comparison with a senile control group (n = 7), mean CBF of both the whole brain and the temporo-parietal region was significantly less in the Alzheimer's disease and senile dementia Alzheimer type groups, but no significant difference was seen between the senile control group and multi-infarct dementia group. The correlation was 0.72 (p less than 0.004) between the mean CBF of the whole brain and the score of Hasegawa's Dementia Scale, and 0.94 (p less than 0.0001) between rCBF of the temporo-parietal region and the scale in Alzheimer's disease. In the senile dementia Alzheimer type group, the correlations were 0.77 (p less than 0.01) and 0.83 (p less than 0.004) respectively. No significant correlations were found in the multi-infarct dementia group. A temporo-parietal reduction in the distribution of the rCBF characteristic in the Alzheimer's disease group and a patchy whole brain reduction characteristic in the multi-infarct dementia group was detected. The ability of our improved SPECT to provide both quantitative measurement of rCBF and characteristic rCBF distribution patterns, makes it a promising tool for research or routine examination of demented patients.