Suppression by protease-activated receptor-2 activation of gastric acid secretion in rats

Activation of protease-activated receptor-2 (PAR-2), a receptor activated by trypsin/tryptase, induces neurally mediated gastric mucus secretion accompanied by mucosal cytoprotection. In the present study, we investigated whether PAR-2 could modulate gastric acid secretion in rats. Messenger RNAs for PAR-2 and PAR-1 were detected in the gastric mucosa and smooth muscle. The PAR-2-activating peptide SLIGRL-NH(2), but not the inactive control peptide, when administered i.v., strongly suppressed gastric acid secretion in response to carbachol, pentagastrin or 2-deoxy-D-glucose in the rats with a pylorus ligation. The PAR-2-mediated suppression of acid secretion was resistant to cyclooxygenase inhibition or ablation of sensory neurons by capsaicin. Our results provide novel evidence that in addition to stimulating neurally mediated mucus secretion, activation of PAR-2 suppresses gastric acid secretion independently of prostanoid production or sensory neurons. These dual actions of PAR-2 would result in gastric mucosal cytoprotection.     

Neuritogenesis of herbal (+)- and (-)-syringaresinols separated by chiral HPLC in PC12h and Neuro2a cells

Syringaresinol isolated from Epimedium koreanum NAKA1 and Magnolia officinalis REHD. et WILS. was subjected to optical resolution by chiral HPLC to give (+)- and (-)-enantiomers. The two syringaresinol enantiomers, as well as a mixture of their glucosides, showed dose-dependent neuritogenesis in a concentration range from 0.24 to 24 microM in PC12h cells.     

Quantification of lateral ventricular subdivisions in schizophrenia by high-resolution three-dimensional magnetic resonance imaging

In vivo brain imaging and postmortem investigations have demonstrated ventricular enlargement in the brains of schizophrenic patients. However, the extent of changes in the volume of discrete ventricle subdivisions has not been clearly established. We conducted high-resolution three-dimensional magnetic resonance imaging in 40 schizophrenic patients (20 males and 20 females) and 40 healthy volunteers (20 males and 20 females). The lateral ventricle in each hemisphere was divided into the anterior horn, body, posterior horn and temporal horn. The volumes of the hemispheres, four subdivisions of the lateral ventricles and the third ventricle were measured. Compared to the control subjects, the bilateral hemisphere volumes were significantly lower in the patients than in the control subjects. In the lateral ventricular subdivisions of the male patients, the most substantial volume increase was in the left temporal horn, and volume increases were also observed in the bilateral anterior horns and the right body. The male patients also had a significantly increased volume of the third ventricle. The female patients showed similar patterns with less statistical significance. Thus, the schizophrenia patients showed ventricular enlargement, particularly in the left temporal horn, being more severely affected in the male than in the female.     

A nonsense mutation of the MASS1 gene in a family with febrile and afebrile seizures

A naturally occurring mutation of the mass1 (monogenic audiogenic seizure-susceptible) gene recently has been reported in the Frings mouse strain, which is prone to audiogenic seizures. The human orthologous gene, MASS1, was mapped to chromosome 5q14, for which we previously have reported significant evidence of linkage to febrile seizures (FEB4). We screened for MASS1 mutations in individuals from 48 families with familial febrile seizures and found 25 DNA alterations. None of nine missense polymorphic alleles was significantly associated with febrile seizures; however, a nonsense mutation (S2652X) causing a deletion of the C-terminal 126 amino acid residues was identified in one family with febrile and afebrile seizures. Our results suggest that a loss-of-function mutation in MASS1 might be responsible for the seizure phenotypes, though it is not likely that MASS1 contributed to the cause of febrile seizures in most of our families.     

Exploratory eye movements in schizophrenia

It has been reported that patients with schizophrenia show restricted eye-scanning in comparison with normal controls; however, the precise mechanism underlying the limited eye movement pattern remains unknown. The purpose of this study was to determine the factors affecting restricted eye-scanning in schizophrenic patients by examining exploratory eye movements during demonstration of two different sizes of the S-shaped figure. The second purpose was to determine the effect of the instruction for performance on the restricted viewing pattern in patients with schizophrenia. Eye movements during demonstration of the S-shaped figure of the original or half size were examined in 15 patients with schizophrenia and 15 normal controls using an infrared eye-mark recorder. The patients showed lower search scores than control subjects for both sizes of the figure. The subjects were then instructed to compare a slightly modified figure with the original one. Lower responsive search scores were found for the patients when “fixation point” was defined as a point at which a gaze was held for at least 200 ms, while the patients and control subjects performed equally at the 100-ms setting. Direct instruction to scrutinize the S-shape abolished the difference in the search scores between patients and control subjects at both the 100-ms and 200-ms settings. These findings suggest that the size of the S-figure is not a factor of restricted eye movements, and that the direct instruction improves the visual performance in patients with schizophrenia. Received: 21 February 2000 / Accepted: 15 October 2002 Correspondence to Mié Matsui, Ph. D.     

Preoperative cytodiagnosis of very small-sized peripheral-type primary lung cancer

To demonstrate the importance of preoperative diagnosis of pulmonary cancers presenting as peripheral small-sized solitary shadows we evaluated the results of morphologic definitive diagnosis together with various clinical factors in 91 tumors with less than 15-mm diameter resected surgically between 1983 and 1999. Histologically, these tumors consisted of 73 adenocarcinomas, nine squamous cell carcinomas, and nine other types. Regarding the pathologic stage, 57 tumors were classified in stage IA, three in IB, six in IIA, seven in IIIA, 14 in IIIB, and four in IV. Comparing various biopsy techniques, the sensitivity of preoperative cytodiagnosis was 43.7% for transbronchial brushing (n = 48), 52.9% for transbronchial forceps biopsy-stamp cytology (n = 51), 66.6% for transbronchial fine needle aspiration (n = 78), and 85.0% for percutaneous fine needle aspiration (n = 20). The overall sensitivity of preoperative cytodiagnosis was 79.0% for transbronchial biopsy (n = 81), and 87.3% for transbronchial and percutaneous biopsy (n = 87). Of 73 clinical N0 cases in which lobectomy was performed, 10 cases (13.6%) were diagnosed as between pathological degrees N1, N2 and N3. However, lung cancer cases with less than 10-mm diameter did not have lymph node metastasis. Our study of histologic differentiation showed that all cases of well-differentiated adenocarcinomas (n = 20) were pathological degree N0. The overall sensitivity of preoperative diagnosis increased to 89.1% in cases (n = 74) of tumors with 11-15-mm diameter. The sensitivity of cytodiagnosis for peripheral small-sized primary lung cancers is high, and we can estimate histological differentiation based on the cytological findings. Therefore, cytodiagnosis is an effective and indispensable diagnostic method for determination of the optimal treatment approach, including approaches such as intentionally limited resection.     

Evidence of neoangiogenesis and an increase in the number of proliferating cells within the bronchial epithelium of smokers

BACKGROUND: Normal bronchial epithelium gradually acquires cellular and genetic changes that result in the formation of invasive tumors. The objective of this study was to evaluate the degree of proliferative change and the amount of neovascularization in both normal and preneoplastic lesions in smokers who were at high risk for developing lung carcinoma. METHODS: The authors studied bronchial biopsy specimens from 7 nonsmokers and 52 smokers. Immunohistochemical staining of the specimens with antibodies for the presence of p53 protein, Ki-67 and CD34 antigens, and vascular endothelial growth factor was performed. The proliferation index (PI) was assessed by immunohistochemical staining for Ki-67 antigen. RESULTS: Overexpression of p53 protein was observed frequently in regions of squamous dysplasia and in squamous cell carcinoma tissue. The PI of normal epithelium from smokers was increased compared with nonsmokers, and the difference was statistically significant (P < 0.05). The microvessel count (MC) in normal mucosa obtained from smokers was higher compared with the MC in normal mucosa obtained from nonsmokers (P < 0.05). A significant difference in MC also was observed between regions of squamous metaplasia or dysplasia with projections of capillary loops into the bronchial mucosa and similar lesions without capillary loops (P < 0.005); however, there was no difference in either the PI or the incidence of p53 overexpression between these groups. CONCLUSIONS: These results show that smoking appears to induce both a proliferative response and neovascularization in bronchial mucosa. The projection of capillary loops into the bronchial mucosa also may be a result of neovascularization occurring within the lamina propria of the bronchial wall.     

A case of pulmonary adenocarcinoma accompanied by superior vena caval thrombosis in a patient with peutz-jeghers syndrome

A case of lung adenocarcinoma and extensive deep vein thrombosis in a patient with Peutz-Jeghers syndrome (PJS) is presented. A 31-year-old Chinese man complained of shoulder pain and swelling of the right arm. A series of diagnostic procedures revealed a primary adenocarcinoma in the left upper lobe with cervical and supraclavicular lymph node metastases accompanied by deep vein thrombosis in the superior vena cava and right jugular vein. In addition, typical pigmentation of the lips and oral mucosa and multiple hamartomas in the stomach, duodenum and colon led to the diagnosis of PJS. PJS is known to be associated with increased risk of malignancies, especially in the gastrointestinal tract, breast, genitals and pancreas. As bronchoscopic examination showed no hamartomatous lesions in the bronchi, the development of primary lung cancer in this young patient might be independent of any hamartomatous lesion and might be associated with some genetic factors relating to PJS.     

Comparative analysis of Helicobacter DNAs and biliary pathology in patients with and without hepatobiliary cancer

Several Helicobacter species have recently been isolated from the bile and hepatobiliary systems of murine species, and are well recognized as a pathogen of the hepatobiliary disorder. This study was planned to investigate whether Helicobacter species possess a causative potential for human hepatobiliary disease, especially for hepatobiliary carcinogenesis. Bile and hepatobiliary tissue samples from 19 patients with hepatobiliary cancer and 19 patients with benign biliary diseases were subjected to polymerase chain reaction analyses for the detection of Helicobacter DNAs. Using a proliferating cell nuclear antigen (PCNA) staining technique, we also investigated the biliary epithelial cell kinetics with special reference to the presence of Helicobacter DNAs in the hepatobiliary system. We found that Helicobacter DNAs were positive in 10 (52.6%) of the 19 patients with hepatobiliary cancer. The incidence was significantly higher than that (15.7%) in the benign cases (P = 0.03). The PCNA labeling index in the biliary epithelium in Helicobacter DNA-positive patients was statistically higher than that in Helicobacter DNA-negative ones, regardless of whether the patient was suffering from hepatobiliary cancer and/or biliary inflammation. A close correlation between the presence of Helicobacter DNAs and an elevation of the PCNA labeling index in the biliary epithelium was demonstrated by multiple regression analysis. Our findings suggest that Helicobacter species may play a role in the pathogenesis of hepatobiliary cancer through an acceleration of biliary cell kinetics.     

Biological characteristics in bladder cancer depend on the type of genetic instability.

PURPOSE: Malignant tumors show an inherent genetic instability that can be classified as microsatellite instability (MSI) or chromosomal instability (CIN). To elucidate the differences in biological characteristics of bladder cancer between the two types of genetic instability, the expression of the mismatch repair (MMR) proteins, Aurora-A and p53 proteins, the number of centrosomes, numerical aberrations of chromosomes and 20q13, and DNA ploidy were examined in 100 human urothelial carcinomas of the bladder. EXPERIMENTAL DESIGN: Expressions of the MLH1, MSH2, Aurora-A, and p53 proteins and the numbers of centrosomes were immunohistochemically assessed. Numerical aberrations of chromosomes 7, 9, 17, and 20q13 spots were evaluated by fluorescence in situ hybridization, and DNA ploidy was assessed by laser scanning cytometry. RESULTS: The expression levels of the MMR related-proteins decreased in 9 of 100 tumors. Tumors with low MLH1 or MSH2 expression (designated as MSI cancers) were not linked with centrosome amplification, Aurora-A overexpression, increased p53 immunoreactivity, 20q13 gain, DNA aneuploidy, and disease progression. MSI cancers showed a favorable prognosis. CIN cancers (49 cases), defined as tumors with a large intercellular variation in centromere copy numbers, were associated more frequently with centrosome amplification, Aurora-A overexpression, increased p53 immunoreactivity, and 20q13 gain than the others (51 cases). Tumors with disease progression were included in the CIN cancer group. CONCLUSIONS: The present observations suggest that there are differences in the biological characteristics of the two types of genetic instability.