Dual modulation by thrombin of the motility of rat oesophageal muscularis mucosae via two distinct protease-activated receptors (PARs): a novel role for PAR-4 as opposed to PAR-1.

Since protease-activated receptors (PARs) are distributed throughout the gastrointestinal tract, we investigated the role of PARs in modulation of the motility of the rat oesophageal muscularis mucosae. Thrombin produced contraction of segments of the upper and lower part of the smooth muscle. Trypsin contracted both the muscle preparations only at high concentrations. SFLLR-NH(2) and TFLLR-NH(2) (PAR-1-activating peptides), but not the PAR-1-inactive peptide FSLLR-NH(2), evoked a marked contraction. In contrast, the PAR-2 agonist SLIGRL-NH(2) and the PAR-4 agonist GYPGKF-NH(2) caused no or only a negligible contraction. In oesophageal preparations precontracted with carbachol, thrombin produced a dual action i.e. relaxation followed by contraction. TFLLR-NH(2) further contracted the precontracted preparations with no preceding relaxation. GYPGKF-NH(2), but not the inactive peptide GAPGKF-NH(2), produced marked relaxation. Trypsin or SLIGRL-NH(2) caused no relaxation. The PAR-1-mediated contraction was completely abolished in Ca(2+)-free medium and considerably attenuated by nifedipine (1 microM) and in a low Na(+) medium. The PAR-4-mediated relaxation was resistant to tetrodotoxin (10 microM), apamin (0.1 microM), charybdotoxin (0.1 microM), L-N(G)-nitroarginine methyl ester (100 microM), indomethacin (3 microM), propranolol (5 microM) or adenosine 3', 5'-cyclic monophosphorothioate, 8-bromo, Rp-isomer (30 microM). Thus, thrombin plays a dual role in modulating the motility of the oesophageal muscularis mucosae, producing contraction via PAR-1 and relaxation via PAR-4. The PAR-1-mediated effect appears to occur largely through increased Na(+) permeability followed by activation of L-type Ca(2+) channels and subsequent influx of extracellular Ca(2+). Our data could provide evidence for a novel role of PAR-4 as opposed to PAR-1, although the underlying mechanisms are still open to question.

Autopsy study of Alzheimer's disease brain pathology in schizophrenia.

The brains of 125 schizophrenic patients (DSM-IV criteria) without other major diseases likely to affect brain morphology were examined at autopsy in our hospital for an evaluation of the number of neurofibrillary tangles (NFT) and senile plaques (SP) as indicators of the incidence of Alzheimer's disease (AD) brain pathology. The clinical degree of dementia and the presence or absence of delirium and Parkinsonism were determined in a review of the patients' charts. No significant difference in the degree of AD brain pathology between the 12 schizophrenics more than 75 years old and 12 age-matched normal controls was present. We conclude that AD pathology seems to be no more frequent among schizophrenic patients than in the normal population, and that the severe cognitive impairment observed in schizophrenics is based on neither neuronal degeneration nor neuronal loss like that occurring in AD. We believe that future morphological studies of cognitive impairments in schizophrenics will require a more detailed investigation at the receptor level.

1H-MR spectroscopy and gray matter volume of the anterior cingulate cortex in schizophrenia.

Schizophrenic and normal control subjects were examined using both H-magnetic resonance spectroscopy (MRS) and structural MR imaging, in order to accurately assess the partial volume within the spectroscopic volume of interest (VOI) in the anterior cingulate cortex. The gray matter volume within VOI correlated positively with the N-acetyl-aspartate (NAA) to choline (Cho) ratio in schizophrenics only, not in controls. Schizophrenic patients had a reduced NAA/Cho ratio and an elevated Cho/creatine ratio compared to controls after the partial volume effect was eliminated. There was a significant negative correlation between the NAA/Cho ratio and the severity of blunted affect symptom in schizophrenics. These results provide further support to the idea that the measures of H-MRS indicate not only neuronal loss but also neuronal dysfunction in schizophrenia.

Argyrophilic glial inclusions in the midbrain of patients with Parkinson's disease and diffuse Lewy body disease are immunopositive for NACP/alpha-synuclein.

Argyrophilic glial inclusions occur in the midbrain of patients with Parkinson's disease (PD) and diffuse Lewy body disease (DLBD). These inclusions are immunohistochemically positive for NACP/alpha-synuclein but negative for tau protein. The results of the present study suggest that a primary degenerative process involves NACP/alpha-synuclein in PD and DLBD and that the process takes place not only in neurons but also in glial cells. Argyrophilic cytoplasmic inclusions, both glial and neuronal, in a variety of degenerative diseases may be grouped into two major categories; one related to aggregates of abnormally phosphorylated tau protein and the other to unusual accumulations of NACP/alpha-synuclein.

Morphological changes in neuropeptide Y-positive fiber in the hippocampal formation of schizophrenics.

1. The authors observed NPY-positive fibers in the CA4 area of the hippocampus from schizophrenics and normal controls using immunohistochemical techniques. 2. Positive fibers followed a straight course and were oriented to exit the CA4 region of hippocampus in normal controls. 3. Many NPY-positive fibers in the CA4 area appeared coiled or helix-like or appeared wasted and thread-like in schizophrenic brains, compared to those of normal controls. 4. These findings may indicate a dysfunction of the interneuron in the schizophrenic brain and support the hypothesis of developmental impairments of the CNS in schizophrenia, and these morphological changes in fibers may relate to schizophrenic symptoms such as memory or/and learning deterioration.

Calbindin immunoreactivity in the hippocampal formation and neocortex of schizophrenics.

1. The authors studied the morphology of CalbindinD28K (CaBp) immunoreactive cells and processes in the hippocampal formation and the prefrontal cortex of schizophrenics using the immunohistochemical technique of avidin-biotin-complex method (ABC method), and the results were compared with those from normal human brains. 2. In the hippocampal formation area CA2 of schizophrenics, many CaBp-immunopositive cell bodies and fibers were disordered in their arrangement compared to normal control brains. 3. In the prefrontal cortex (Brodmann area 9) of schizophrenics, many immunopositive cell bodies were exhibited irregular axis arrangement and fiber disarray. 4. The altered distribution pattern of CaBp-immunopositive structures in the hippocampal formation and the prefrontal cortex might indicate the existence of GABA(gamma-aminobutyric acid)ergic dysfunction in the brain of schizophrenic patients.

Characterization of the protease-activated receptor-1-mediated contraction and relaxation in the rat duodenal smooth muscle.

Activation of protease-activated receptor-1 (PAR-1) produces a dual action, apamin-sensitive relaxation followed by contraction, in the rat duodenal smooth muscle, which is partially dependent on activation of L-type Ca2+ channels, protein kinase C (PKC) or tyrosine kinase (TK), and resistant to tetrodotoxin. The present study further characterized the PAR-1-mediated duodenal responses. Removal of extracellular Ca2+ as well as SK&F96365 reduced the contraction due to the PAR-1 agonist TFLLR-NH2 (TFp-NH2) by 60-80% that was similar to the extent of the inhibition by nifedipine. Lowering of the extracellular Na+ concentration, but not IAA-94, a Cl- channel inhibitor, reduced both the PAR-1-mediated contraction and relaxation by about 50%. U73122, a phospholipase C (PLC) inhibitor, or wortmannin, a phosphatidyl inositol 3'-kinase (PI3K) inhibitor, significantly reduced the PAR-1-mediated contraction, but not the relaxation, by itself, as the PKC inhibitor GF109203X and the TK inhibitor genistein did. U73122 or wortmannin, like GF109203X, when applied in combination with genistein, significantly reduced the PAR-1-mediated relaxation. The relaxation was resistant to antagonists of PACAP receptors, VIP receptors and P2 purinoceptors. Thus, the PAR-1-mediated contraction is considered to be dependent on intracellular and extracellular Ca2+, the influx of the latter being induced through activation of L-type Ca2+ channels triggered by the enhanced Na+ permeability, and that PLC and PI3K, in addition to PKC and TK, are involved in the PAR-1-mediated dual responses. Furthermore, non-adrenergic, non-cholinergic nerve neurotransmitter candidates that may modulate K+ channels do not appear to contribute to the relaxation by PAR-1 activation.

[An elderly patient with progressive supranuclear palsy without neurological signs].

We report an elderly patient with progressive supranuclear palsy (PSP) who showed no neurological signs clinically. A 70-year-old man presented with irritation and poor hygiene, thereafter he showed excitement and violence. A cranial CT scan revealed bilateral moderate atrophy of the temporal lobes and slight enlargement of the lateral ventricle. The brain stem was slightly atrophic. Although he died at the age of 80 years, he had no neurological signs throughout the clinical course. Neuropathological study showed typical findings of PSP, neuronal loss with gliosis and neurofibrillary tangles in the basal ganglia, amygdala, midbrain, pons, dentate nucleus and inferior olivary nucleus. Staining by Gallyas-Braak methods revealed argyrophilic and tau-positive glial fibrillary tangles in the cerebral cortex. Neurofibrillary tangles showed greater frequency than usual for the physiological level in that age group in the hippocampus regions as well as in the amygdala. The possibility that the psychotic symptoms, mainly personality change, are connected with the degeneration of limbic system is indicated. Since there have not been any previous reports of PSP without neurological signs, this case represents an important in terms of clinico-pathological variation of PSP. We suggest that there is discrepancy between symptomatic and neuropathological aspects in elderly patients with PSP.

[An autopsy case of "diffuse neurofibrillary tangles with calcification", multiple infarctions and hyaline arteriosclerosis].

"Diffuse neurofibrillary tangles with calcification (DNTC)" is a slowly progressive form of presenile dementia characterized by localized temporal atrophy, pronounced calcareous deposits and numerous neurofibrillary tangles (NFTs) without senile plaques. We report a 70-year-old woman with DNTC, multiple infarctions and hyaline arteriosclerosis. This case was clinically characterized by persistent delusional ideas and personality changes. Intellectual deterioration was mild, and no focal manifestations were noted. Neuropathologically, numerous NFTs were seen distributed primarily in the hippocampal region, and massive calcareous deposits were observed in the cerebrum, basal ganglia and cerebellum. There were no senile plaques. Although the findings in this case were compatible with a diagnosis of DNTC, certain additional findings were also noted. The first was the presence of multiple infarctions in the basal ganglia and hyaline arteriosclerosis. Although these lesions may have been induced by hypertension, our review of previous reports of DNTC revealed a high incidence of arteriosclerosis. The second was the absence of lobar atrophy, which may have been due to the cerebral edema caused by the subdural hemorrhage or related to the relatively short duration of the illness. The dilatation of the temporal horn of the lateral ventricle and prominent NFTs in the hippocampal region indicate the initial occurrence of the disease in this region.

[Regional cerebral blood flow in diabetic patients].

N-isopropyl-p-123I-iodoamphetamine (IMP) was used to quantify the regional cerebral blood flow (r-CBF) in 11 diabetic patients (average age; 67.9 years) and 12 non-diabetic subjects (average age; 67.4 years), none of whom had CVD (Cerebrovascular disease) on CT studies. A reference sampling method by continuous arterial blood sampling was used to quantify r-CBF. There were no significant differences in physiological or laboratory data between diabetic and non-diabetic groups except for fasting plasma glucose and HbA1C levels. The average of r-CBF in each region of cerebrum and cerebellum was significantly lower in diabetic group than that in the control group (p < 0.01). These observations show that r-CBF of diabetic patients is reduced, even in the absence of findings of CVD on a CT study.

Nuclear thioredoxin peroxidase Dot5 in Saccharomyces cerevisiae: roles in oxidative stress response and disruption of telomeric silencing.

The DOT5 gene was originally cloned as one of the DOT (disrupter of telomeric silencing) genes; and later it was re-discovered as a nuclear thioredoxin peroxidase in Saccharomyces cerevisiae. Here, we demonstrate that the telomeric-silencing disruption activity of Dot5 is independent of thioredoxin peroxidase activity. In addition, Dot5 cannot suppress the increased susceptibility to peroxides of mutants defected in cytosolic thioredoxin peroxidase, even when Dot5 is expressed in the cytoplasm. Furthermore, Dot5 does not affect redox regulation of the Yap1 transcription factor. These results suggest that Dot5 is less important as an antioxidant in yeast cells.

Application of psychoimmunotherapy in patients with alopecia universalis.

Mental stress and immunological abnormality have recently been listed as causes of alopecia universalis. This disease is difficult to treat with only ordinary pharmacotherapy. Thus, from the standpoint of psychoneuroimmunology, stress was relieved by relaxation and image therapy, and administration of small doses of a strong immunosuppressant was effective, leading to clinically favorable results. In addition, changes were recognized in the subpopulation of peripheral lymphocytes and in beta-endorphin before and after relaxation and image therapy. The treatment of alopecia universalis favorably changed the subpopulations of T cells. A patient suffering from alopecia is always under stress. Alleviating this stress facilitates recovery of immunological competence. Our method was effective in 5 of 6 cases with refractory alopecia universalis.

Interrater reliability of the Japanese version of the Positive and Negative Syndrome Scale and the appraisal of its training effect.

The purpose of the present study is to test interrater reliability of the Japanese version of the Positive and Negative Syndrome Scale (PANSS) and to examine factors possibly affecting the reliability. The study group conducted the PANSS rating on 20 patients with DSM-IV schizophrenia. For the analysis of interrater reliability, intraclass correlation coefficient (ICC) was calculated. The ICC for individual items of the PANSS ranged from 0.26 to 0.92, and those for the positive, negative, and general psychopathology subscales were 0.85, 0.83 and 0.75, respectively. The Cronbach's alpha coefficient for the subscales were 0.84, 0.87 and 0.76, respectively. The interrater reliability and the internal consistency were satisfactory and similar to those obtained in the antecedent studies. No salient training effect was found in a sequential analysis of the concordance rate. It is concluded that the Japanese version of the PANSS is a reliable and efficient tool for comprehensive assessment of the schizophrenic syndrome.

Circadian rhythms of sterol 12alpha-hydroxylase, cholesterol 7alpha-hydroxylase and DBP involved in rat cholesterol catabolism.

Circadian rhythms of important enzymes involved in the conversion of cholesterol to bile acids [sterol 12alpha-hydroxylase (12alpha-hydroxylase) and cholesterol 7alpha-hydroxylase (7alpha-hydroxylase)] and an albumin site D-binding protein (DBP) were examined in rats. When the animals were fed freely, they usually ate in the dark and the circadian rhythms of activities of 12alpha-hydroxylase and 7alpha-hydroxylase showed the same peaks (at 10 p.m.) and lows (at 2 p.m.). Their mRNA levels were determined at four timepoints: 3 a.m., 10 a.m., 3 p.m. and 10 p.m. A maximum of the rhythm of 12alpha-hydroxylase was observed at 3 p.m. and the minimum at 3 a.m. These results are distinct from those of 7alpha-hydroxylase, whose maximum point was at 10 p.m. and minimum at 3 p.m. When the rats were fed only in the day-time (from 9 a.m. to 5 p.m.), a marked shift of the activity and mRNA rhythms was observed with both enzymes. The circadian rhythms of the activities of both enzymes showed the same peaks (at 3 p.m.), but the mRNA levels of 12alpha-hydroxylase were distinct from those of 7alpha-hydroxylase, whose maximum point was at 3 a.m. and minimum at 10 p.m. Differences between the maximum and the minimum points of each enzyme mRNA level were statistically significant (P < 0.01 for 12alpha-hydroxylase and 0.05 for 7alpha-hydroxylase). Moreover, circadian rhythms of DBP were also markedly shifted with the change of feeding period. The maximum mRNA level was observed at 10 p.m. instead of 10 a.m. and the minimum was at 10 a.m. instead of 10 p.m.

Intersegmental connection with aberrant hepatic duct.

A 66-year-old Japanese woman whose cystic duct drained into an aberrant bile duct was found to have an intersegmental connection bridging the right anterior and posterior ducts. The patient had cholelithiasis but no history of hepatic trauma, lending support to congenital etiology for the intersegmental duct. In the presence of aberrant bile ducts, a meticulous search may reveal such biliary communications.