Search

Matrix metalloproteinase (MMP) plays an important role in extracellular matrix degradation associated with cancer invasion. An expression of MMP-1 (interstitial collagenase), MMP-2 (72-kDa type IV collagenase) and MMP-3 (stromelysin-1) was investigated in squamous cell carcinoma (SCC) and its precancerous condition, actinic keratosis (AK), using in situ hybridization techniques. MMP-1 mRNA was detected in tumour cells and/or in stromal cells in all cases of SCC, four of six AKs adjacent to SCC and four of 16 AKs. MMP-2 and MMP-3 mRNAs were detected in SCC but not in AK. The expression of MMP-3 correlated to that of MMP-1 (P = 0.03) localized at the tumour mass and stroma of the invasive area, while MMP-2 mRNA was detected widely throughout the stroma independent of MMP-1 expression. Our results indicated that the expression of MMP-1, -2 and -3 showed different localization patterns, suggesting a unique role of each MMP in tumour progression. Moreover, MMP-1 expression could be an early event in the development of SCC, and AK demonstrating MMP-1 mRNA, might be in a more advanced dysplastic state, progressing to SCC. © 1999 Cancer Research Campaign

SUT-8701 is a cholecystokinin octapeptide (CCK8) analog and a more lipophilic peptide than CCK8. We previously demonstrated that intra-ventricularly administered CCK8 protected against the degeneration of the cholinergic neurons in the cortex of the nucleus basalis magnocellularis (nbm)-lesioned rat. We determined whether SUT-8701 and CCK8 have the ability to protect against cholinergic degeneration in the cerebral cortex of nbm-lesioned rats. Systemically administered SUT-8701 (0.1-1 micrograms/day/animal, s.c.) preserved choline acetyltransferase activity and K(+)-evoked acetylcholine release in nbm-lesioned rats. SUT-8701 was more potent than CCK8. However, SUT-8701 was much less potent than CCK8 in satiety action. The affinity of SUT-8701 to the cholecystokinin (CCK) receptors assessed by using [125I]-CCK8 was almost the same as that of CCK8 in the mouse cerebral cortex, but was 107 times less than that of CCK8 in guinea pig pancreas. These results suggest that SUT-8701 may be effective in slowing down the degenerative processes in Alzheimer's disease by preserving the integrity of cholinergic neurons in the nucleus basalis.

Amyloid beta protein (beta/A4) is deposited in senile plaques of patients with Alzheimer's disease. This protein is derived from a larger membrane-associated protein, termed amyloid precursor protein (APP). The constitutive processing of APP occurs at the central portion of beta/A4, resulting in the release of large N-terminal peptides. We have purified these peptides from the culture medium of cDNA-transfected COS-1 cells. Some of the isoforms contain the Kunitz-type protease inhibitor (KPI) domain and strongly inhibit trypsin, chymotrypsin and plasmin, but do not inhibit kallikrein, prolyl endopeptidase or granzyme A. The peptides also do not inhibit cysteine proteases such as cathepsin B or calpain. Soluble APPs lacking the KPI domain fail to inhibit any of these proteases. The results indicate that the KPI domain in soluble APPs has protease inhibitory activity against certain serine proteases.

Background: Fukuyama-type congenital muscular dystrophy (FCMD) is an autosomal recessive disorder characterized by severe dystrophic muscle wasting from birth or early infancy with structural brain abnormalities. The gene for FCMD is located on chromosome 9q31, and encodes a novel protein named fukutin. The function of fukutin is not known yet, but is suggested to be an enzyme that modifies the cell-surface glycoprotein or glycolipids. Objective: To elucidate the roles of fukutin gene mutation in skeletal and cardiac muscles and brain. Methods: Immunohistochemical and immunoblot analyses were performed in skeletal and cardiac muscles and brain tissue samples from patients with FCMD and control subjects. Results: The authors found a selective deficiency of highly glycosylated α-dystroglycan, but not β-dystroglycan, on the surface membrane of skeletal and cardiac muscle fibers in patients with FCMD. Immunoblot analyses also showed no immunoreactive band for α-dystroglycan, but were positive for β-dystroglycan in FCMD in skeletal and cardiac muscles. Conclusion: The current findings suggest a critical role for fukutin gene mutation in the loss or modification of glycosylation of the extracellular peripheral membrane protein, α-dystroglycan, which may cause a crucial disruption of the transmembranous molecular linkage of muscle fibers in patients with FCMD.

Acorn worms are hemichordate deuterostomes that have remarkable gills thought to be homologous to pharyngeal gills in urochordates and cephalochordates, and pharyngeal pouches in vertebrates. In search of molecular keys to analyzing the origin and evolution of the anterior gut and neck region of the chordate body, the present study isolated cDNA clones for six gill-specific genes, designated PfG1 to PfG6, from Ptychodera flava using differential screening of a cDNA library of RNA from gills. Northern blotting confirmed that these genes were all expressed only in the gills. In situ hybridization showed that the expression of these genes is limited to the endodermally derived columnar epithelium of the pharynx. PfG1 encodes a 42-kDa polypeptide containing sequence similar to D-domains, protein domains characteristic of extracellular proteins. Expression of PfG1 is localized in a delimited pattern along the columnar epithelium of the inner gill apparatus. Expression in the epibranchial ridge appears as two stripes running longitudinally in the epithelium just lateral of the midline. A stripe of expression also appears in a slightly posterior portion on the curve of each band of columnar epithelium on the pharyngeal surface of the secondary gill bars. The five other gill-specific genes, PfG2 to PfG6, encode a family of C-type lectin polypeptides that appear to be secreted proteins. PfG2 to PfG6 are also expressed in the columnar epithelium of the epibranchial ridge as two parallel stripes, but at the lateral margin of the ridge. One of the genes, PfG6, is additionally expressed in the innermost curve of the epithelium on the pharyngeal surface of each secondary gill bar. The localization of expression of PfPax1/9, a gill-specific transcription factor gene, was examined and shown to also be primarily in the endodermal columnar epithelium on the pharyngeal faces of the gill bars. On the secondary gill bars, where PfG1 and PfG6 are also expressed in the columnar epithelium, PfPax1/9 is expressed in the anterior and posterior portions but signal is not evident in the epithelium on the central, innermost curve of the gill bar. The anterior domain of PfPax1/9 expression is more extensive but overlaps the anterior domain of PfG1 expression, whereas its posterior domain of expression is more posterior and complementary to that of PfG6.

An ipsilateral neck dissection is mandatory during initial treatment stages II-IV oral carcinomas. However, no consensus exists whether or not to perform an elective contralateral neck dissection.Five hundred thirteen consecutive cases of squamous cell carcinoma (269 tongue, 135 floor of the mouth, 44 inferior gingiva, 65 retromolar trigone) were reviewed. Tumor stages were: 69 T1, 227 T2, 217 T3-T4, 263 N0, 250 N1-N3. A total of 563 neck dissections were performed in 448 patients. Univariate and multivariate analysis of risk factors were performed using logistic regression.Two hundred twenty-three patients (49.8%) had positive nodes in the specimen (182 ipsilateral, 36 bilateral, 5 contralateral). Contralateral neck recurrences occurred in 38 cases (33 not submitted to a contralateral neck dissection initially). Multivariate logistic regression analysis demonstrated that clinical stage (p = .0001), tumor crossing midline (p = .0011), and floor of the mouth involvement (p = .0236) were the most important predictors of contralateral metastasis.The contralateral side of the neck is a common and potentially preventable site of recurrence in tumors of the oral cavity. The multivariate model obtained discriminates patients with low and high risk (more than 20%) of contralateral metastasis. The application of this mathematical model can be useful for the indication of contralateral neck dissections, because not all tumors crossing midline are associated to a high risk (stages I and II tumors not involving the floor of the mouth) and not all tumors not crossing midline are at low risk (stages III and IV tumors involving the floor of the mouth).

We studied on the prevalence of drug-resistance among 65 homeless cases who were admitted and treated for active tuberculosis at the Nakano National Chest Hospital during the period from 1990 to 1992 and at the International Medical Center of Japan during the period from 1993 to 1994. Resistance to one or more first line antituberculous drug were revealed in 14 cases out of 65 (21.5%) in initially treated cases 6 out of 43, and in retreated cases 8 out of 22. The prevalence of drug resistance in this study was significantly higher compared with 2 out of 39 cases (5.1%) in our previous report during the period from 1986 to 1988. In these drug-resistant cases, multidrug-resistant cases, namely, resistant to at least 2 drugs including both INH and RFP were founded in 6 cases (9.2%). Compared with drug-sensitive cases, the negative convertion rate of bacilli was lower and the number of defalters was significantly larger. It was suggested that higher prevalence of drug-resistance and defalting from the adequate treatment in homeless cases of tuberculosis possibly makes the prognosis of drug-resistant tuberculosis worse and treatment of such cases more difficult.

For the purpose to compare the effectiveness of SM and EB as a third drug in the standard regimens and to know whether the addition of SM twice weekly to INH and RFP could be acceptable for the treatment of pulmonary tuberculosis, the efficacy, adverse effects and results of long-term follow-up of the groups consisting of 105 patients treated with SM twice weekly for 6 months in addition to INH and RFP for 9 months (S2 group) and 107 patients treated with EB for 6 months in addition to INH and RFP for 9 months (E group) were observed. The speed of negative conversion of sputum and that of X-ray findings improvement were slightly faster in S2 group than E group but the difference was statistically not significant. The incidence of adverse effects such as elevation of serum transaminase values, gastrointestinal troubles, drug allergy and others was not similar in two groups. The relapse was observed in 2 cases of S2 group and 5 cases of E group. We concluded that SM twice weekly to INH and RFP is similarly effective as EB in combination with INH and RFP, and the this regimen could be used as standard regimen for pulmonary tuberculosis.

A 62-year-old man was found to have recurrent hepatocellular carcinoma (HCC) 2 cm in diameter in the left lobe in June 1990. After right lobectomy of the liver which contained the tumors of S6 2 cm and S8 3 cm in diameter 7 months before, the patient was treated with hepatic arterial embolization (TAE) combined with infusion of anti-cancer drug (ADM, CDDP) four times since June 1990. HCFU 300 mg per day was administered orally since June 1990. Since the 3rd TAE in December, 1990, the tumor stain in the left lobe disappeared for 10 months till October, 1991. No remarkable side effect of HCFU was noticed during this period. HCFU administration combined with TAE effectively prevented post-surgical recurrence of HCC in this case.

Histopathologic examination was done on 18 cases after percutaneous ethanol injection therapy (PEIT) for hepatocellular carcinoma. In eight cases, the lesion was treated by PEIT alone; in the other ten cases, PEIT was combined with transcatheter arterial embolization. The lesion was completely necrotic in 13 cases, 90% necrotic in four cases, and 70% necrotic in the rest. In addition, PEIT seemed to be effective against intercapsular, extracapsular, and vascular invasions. In the four cases of incomplete necrosis, the viable cancer tissue remained in small tumor nodules around the main tumor, in portions isolated by septa, or along the edge of the lesion. Therefore, ethanol should be injected not only into the center of the lesion, but also into sites close to its edge. Ethanol did not damage noncancerous liver parenchyma distant from injected sites. Local dissemination of the cancer cells was not found in any case. Therefore, PEIT seems to be a valuable therapy and may be an alternative to surgery in some cases.

A total of 1744 HBsAg carriers were investigated to determine whether there are clinical differences among HBsAg subtypes or not. Although adr was more predominant than adw in 1078 asymptomatic carriers as well as in 666 carriers with liver dysfunction, the adr carriers had liver dysfunction more frequently than the adw carriers (p = 0.005). In addition, the adr carriers were more often positive for HBeAg and less often positive for anti-HBe than the adw carriers (p less than 0.001). Multivariate analyses indicated that the HBsAg subtypes were associated with liver dysfunction not directly but through the relationship between the HBsAg subtypes and HBeAg/anti-HBe status. HBeAg/anti-HBe status of each age bracket in the adr carriers and in the adw carriers suggested that adr carriers are seroconverted later than adw carriers. In conclusion, HBsAg subtypes may affect the development of chronic liver disease, through their association with HBeAg/anti-HBe status.

In this study, we examined a possibility that epidemiological factors or suspected risk factors of liver dysfunction could account for the different HBeAg/anti-HBe status or the different prevalence of liver dysfunction between the adr and adw carriers. A total of 428 HBsAg carriers were surveyed of their age, sex, racial background, socioeconomic status, place of residence, birthplace, alcohol consumption, smoking habit, and history of blood transfusion as epidemiological factors or suspected risk factors of liver dysfunction. Adjustment for those variables using multivariate analyses did not substantially affect the association of the HBsAg subtypes with either prevalence of liver dysfunction or HBeAg/anti-HBe status. HBsAg subtypes seem to directly affect HBeAg/anti-HBe status and consequently influence development of chronic liver disease.

A phase 1 study of etoposide for hepatocellular carcinoma and cholangiocarcinoma was undertaken by single arterial infusion (9 cases; range of doses levels; step 1: 50 mg/m2, step 2: 75 mg/m2, step 3: 120 mg/m2). Mild leukopenia (2500/mm3 in step 2 and 2400/mm3 in step 3) was observed in 2 cases. Thrombocytopenia or anemia was not observed in these doses. Hypotension was experienced 2 hrs. after infusion in one case of step 2. The post-infusion plasma decay of etoposide was biphasic with t1/2 alpha ranging from 0.59 approximately 0.63 h and t1/2 beta ranging from 5.40 approximately 6.57 h. AUC0-24 increased in association with the increase of the doses. Hepatic artery infusion of etoposide was performed without serious complication and the dose limiting toxicity was leukopenia.

Using positron computed tomography (PCT) and the 15O labeled gas steady-state inhalation technique, regional cerebral blood flow (rCBF), cerebral oxygen consumption (rCMRO2), and oxygen extraction fraction (rOEF) can be measured quantitatively in humans. We quantitatively examined the relationship between focal ischemic lesions and intact regions as detected by X-ray CT in such areas as the territory of the contralateral middle cerebral artery (MCA), thalami, pons, and cerebellar hemispheres. Twenty-three PCT measurements in 13 patients with unilateral ischemic infarction in the MCA territory as detected by X-ray CT were performed. Remote effects from cerebral infarction of the MCA territory were observed in the contralateral MCA territory, ipsilateral thalamus, brainstem, and contralateral cerebellar hemisphere. Slight depression of rCBF and rCMRO2 was also observed in the contralateral thalamus and ipsilateral cerebral hemisphere; rOEF was normal in these areas. Though the depression of rCBF and rCMRO2 due to remote effects was detected in all periods, it was mildly observed 0 to 6 days after onset. The reduction of rCBF and rCMRO2 due to remote effects was less than the morphological as well as the functional threshold. The phenomenon is probably caused by neuronal deactivation, and the regions with depressed blood flow and metabolism may be in a "resting" state.

HBs antigen subtypes were determined among 137 acute hepatitis patients in Japan. The distribution among the 99 male patients was 40 adr, 37 adw, one ayw, and 21 undetermined while that among the 38 female patients was 19 adr, 11 adw, and eight undetermined. The distribution among the male patients was different from that among HBs antigen carriers in Japan, suggesting that they were exposed not only to domestic HBs antigen carriers, but also to other sources. Thirty-one (29 males and two females) of the 137 patients (22.6%) were found to have been abroad at some time during the incubation period. The distribution among them was seven adr, 21 adw, and three undetermined. The majority had the same subtypes that are prevalent in the countries they visited, supporting the hypothesis that most of them had contracted the disease overseas. The remaining 106 patients had a distribution of the subtypes similar to that of domestic HBs antigen carriers. "Imported hepatitis" would be an important cause of acute type B hepatitis in Japan.

Using positron emission tomography, the regional cerebral blood flow (CBF), oxygen extraction fraction (OEF) and oxygen consumption (CMRO2) were studied in 21 patients with hypertensive intracerebral hematomas. The study showed a very localized decrease of CBF and CMRO2 around a hematoma, and revealed in two cases (9.1%) distinct luxury perfusion around it. There was diffuse reduction of CBF with increased OEF in hematomas larger than 4.5 cm in diameter. The results suggested that surgical evacuation should be considered for hematomas with a diameter exceeding 4.5 cm.

In recent years, prosopagnosia is defined as the "loss of ability to recognize the well-acquainted persons like the family members by their physiognomy." There are many reports based on this definition. However, from the viewpoint of symptomatology, there are many problems not entirely solved yet. And the mechanism of its manifestation is not clearly explained. Topographic disorientation, which often accompanies prosopagnosia, is studied even less. From the results of the postmortem examination in the literature, bilateral occipito-temporal lesions have been known to cause prosopagnosia. However, the recent radiographical examination by the computed tomography revealed that the prosopagnosia is also caused by the right occipito-temporal lesions only. We experienced a case with prosopagnosia and topographic disorientation which were considered to be caused by infarction in the territory of the right posterior cerebral artery. Detailed symptomatological, morphological and functional examinations were carried out by means of various psychological testing, X-ray computed tomography (CT), magnetic resonance imaging (MRI) and positron emission tomography (PET). The patient was a 70-year-old right-handed man who suffered from sudden visual loss on both eyes, and was admitted to our hospital after four weeks. On examination, a decrease of visual acuity and right homonymous hemianopsia were recognized. When visual acuity was recovered, he was unable to recognize the faces of his relatives and friends, with whom he has been well acquainted for many years. He also found his own house, the buildings and streets around it as entirely unfamiliar. Seven months after the onset of the disease, examination showed he had definite prosopagnosia and topographic disorientation.(ABSTRACT TRUNCATED AT 250 WORDS)

In 24 patients with subarachnoid hemorrhage (SAH) who were admitted within 48 hours after the onset, the activity of dopamine-beta-hydroxylase (DBH) in peripheral venous plasma was analyzed applying the method described by Nagatsu and Udenfriend (Clin. Chem., 18: 980-983, 1972) with a minor modification. Plasma samples were serially collected every a few days for three days to four weeks after the onset. DBH activity in peripheral venous plasma increased markedly after the onset, reaching the highest level within 48 hours, and thereafter declined time-dependently for about two weeks. There was no significant difference in the plasma DBH activities on admission between patients with and without cerebrovascular spasm revealed by angiography. The decline of the activity was significantly remarkable in patients with spasm compared with those without spasm. The difference was most prominent around the 7th day after the onset when spasm was shown most frequently. Neurosurgery or administration of analgesics and/or sedatives had little effect on the changes in plasma DBH activity in acute SAH. The activity correlated with the pressure of cerebrospinal fluid (r = 0.587, P less than 0.05), when it was higher than the normal range. With these results we obtained following: 1) The activity of sympathetic nervous system increases following SAH for a week after the onset. 2) The activity declines more rapidly in patients with cerebrovascular spasm than those without spasm, when it was judged from the activity of plasma DBH activity.

In the present paper we report that 3, 4 dihydroxyphenylalanine (DOPA), dopamine (DA) and noradrenaline (NA) in guinea pig brain can be easily separated by Duolite C-25 resin column and measured fluorimetrically. Using the present method, the quantitative assays of these catechol compounds were carried out in brain of guinea pigs treated with reserpine. It has been well known that catecholamines (CA) such as NA and DA are formed even in brain tissue and peripheral sympathetic nervous tissue besides in adrenal grand (1-3). We have also demonstrated CA were synthesized from DOPA in guinea pig brain and investigated intracellular localization of the enzyme activities related to the formation of CA. The activities of enzyme related to the formation and inactivation of CA in brain of guinea pigs were activated by the intraperitoneal injections of reserpine. It is suggested that the action of reserpine is not only limited to its releasing action (4-6) but also it has a dynamic effect on the enzym systems.