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The metastable zone width (MSZW, Δ T m ) and induction time ( t ind ) were determined with computer simulation for seeded batch crystallization of potassium sulfate from aqueous solution. The MSZW and induction time determined with simulation showed the same behavior as experimental values reported in the literature; log (Δ T m ) increased linearly with an increase in log R ( R : cooling rate) and t ind decreases in proportion to (Δ T ) − n (Δ T : supercooling, n: nucleation order in the secondary rate expression of B = k n (Δ T ) n ). The secondary nucleation parameters ( k n and n ) were deduced both from the simulated MSZW and induction times by using the previously proposed model [J. Cryst. Growth, 2010, 312, 548–554]. The secondary nucleation rate calculated with the deduced parameters was in agreement with that calculated with the parameters input for simulation.

Seventeen patients with pancreatic carcinoma were treated with intraoperative radiation therapy (IORT) combined with hyperthermia. Their treatment results were compared with those of 56 patients treated with the IORT alone (control group). The pain relief rate and the local tumor control rate of the hyperthermia group were slightly better than the control group. The survival rate of all patients was 13.7% at one year, 1.4% at two years (median, 5.0 months). The survival of the hyperthermia group was marginally better than that of the control group. Only 29% of the patients of the hyperthermia group was successfully heated, and if hyperthermia were given successfully to all patients, their prognoses would have been possibly improved.

We report a case of HTLV-1 associated myelopathy (HAM) with pseudopseudohypoparathyroidism (PPHP). A 57-year-old woman, without a history of blood transfusion, was admitted with numbness and pain in her legs. Pain sensation in both legs was reduced and tendon reflexes were exaggerated. She exhibited spastic gait. The diagnosis of HAM was made because of positive antibody for HTLV-1 in blood and CSF. She also had features of Albright syndrome (short stature, round face, and short fourth metatarsals) without abnormal calcium and phosphorus metabolism, leading to the diagnosis of PPHP. Brain CT revealed bilateral calcification of the basal ganglia. Although HAM rarely accompanies pseudohypoparathyroidism (PHP), there are few reported cases of HAM associated with PPHP. The exact mechanism of HAM is not known, but it is thought to involve an immune-related process. Since PHP is considered to induce a state of mild immunosuppression through reduction of 1,25-dihydroxyvitamin D3, it is possible that susceptibility to HAM could be augmented in the presence of PHP. If PPHP should be an incomplete form of PHP, a similar mechanism may be involved in the association of PPHP and HAM.

In order to elucidate the cerebral hemodynamic changes that occur in Suzuki's six angiographic stages of moyamoya disease, local cerebral blood flow (LCBF) during the stable state and CO2 responsiveness of LCBF (L-CO2R: delta %LCBF/delta PaCO2) were measured by the Xenon CT-CBF method. Nineteen patients with moyamoya disease (mean age: 36.8 +/- 11.6 years) and 11 age-matched normal volunteers were studied. The LCBF during the steady state at all stages was not significantly different from that in normal volunteers. At stage 6, however, the LCBF was slightly decreased in the anterior part of the brain, resulting in loss of "hyperfrontality." On the other hand, the L-CO2R in the anterior part of the brain tended to diminish with progression through the stages. Especially in the frontal cortex, the L-CO2R at stage 5 was significantly less than that in normal volunteers (p0.01) or at stage 3 (p0.05). In conclusion, the cerebrovascular reserve in the anterior circulation became insufficient after stage 4, although the posterior circulation was well maintained. Revascularization surgery involving the anterior circulation may be crucial to prevent ischemic events.

Despite the poor prognosis of pancreatic carcinoma patients, surgical resection remains the only potentially curative treatment. As it has been demonstrated that extended radical surgery does not lead to a better prognosis, accurate staging to select those patients who may benefit from resection is essential. According to the report of a national survey of pancreatic cancer in 1997, patients with S0 or S1, RP0 or RP1, and N0 or N1 disease have longer survival periods compared with patients with S2, RP2, and N2 disease. Therefore patients classified as Stage I, Stage II, or Stage III are recognized as candidates for surgical resection. Patients classified as Stage IVb because of positive P factor or positive H factor are selected for conservative treatment such as chemotherapy and irradiation. It remains to be clarified whether patients classified as Stage IVa should undergo surgical resection or not. Future prospective randomized studies of patients with Stage IVa disease will reveal whether surgical resection or chemoradiation is effective. Helical CT is useful to evaluate S and RP factors for definitive preoperative staging. CT-AP can reveal occult metastases to the liver. These preoperative evaluations should be evaluated along with histological findings.

It is well-known that the patients with pancreatic cancer are vulnerable for recurrence such as local relapse and liver metastasis after surgical resection. We revealed that a patient with local relapse without liver metastasis showed better prognosis as compared with a patient having liver metastasis. We usually adapt further therapeutic intervention for local recurrence using external radiation therapy accompanied with 5FU infusion as a radiosensitizer, if the patient is not revealed with liver metastasis. On the other hand, there is no effective intervention for liver metastasis accompanying pancreatic cancer, as small lesions of multiple liver metastases progress rapidly. We insert the tip of catheter in proper hepatic artery in order to infuse MMC once a week at outpatient clinic. However, we were not yet able to evaluate the effect of arterial infusion therapy.

Experimental evidence has directly implicated matrix metalloproteinases (MMPs) in the remodeling of the stromal tissue surrounding tumors. Thus, MMP inhibitors could limit the expansion of both neoplastic cell compartment and endothelial cell compartment of a tumor. Much of the work on the role of MMP inhibitors has concentrated on their inhibitory effects on tumor cell invasion. We have examined the effects of a new MMP inhibitor, KB-R7785 (acting on MMP-1, MMP-3, and MMP-9), on tumor angiogenesis and metastasis of murine colon adenocarcinoma (C-26) in two tumor models in BALB/c mice (transparent chamber model and lung colonization model). KB-R7785 has not shown inhibitory effects on in vitro growth of either C-26 or KOP2.16 murine endothelial cells. In vivo, KB-R7785 administrated twice daily for 15 days (100 mg/kg, i.p.), starting the day of tumor inoculation (5 x 10(5) C26 cells) in transparent chamber, has resulted in 88.2% suppression of tumor growth, compared with that in vehicle-administered mice (controls). Tumors grown in controls have doubled their area in 3.3 days, whereas those treated by KB-R7785 progressed almost four times slower (tumor area doubling time, 12 days). KB-R7785 rendered centrally avascular tumors with only a rim of peripheral neovasculature, which had significant lower functional vascular density and vascular area than the corresponding parameters in control tumors 10 days after inoculation [79.9+/-6.7 cm/cm2 versus 164.1+/-10.1 cm/cm2 (P0.01) and 19.8+/-1.5% versus 42.6+/-2.7% (P0.01), respectively]. In the lung colonization model (tail vein inoculation of 5 x 10(5) C-26 cells), administration of KB-R7785 (100 mg/kg, i.p.) twice daily for 20 days has reduced the number of surface metastasis by 85.8% and abolished the tumor burden, as compared with controls. The few metastatic colonies found in the lungs of KB-R7785 treated mice appeared to be dormant (i.e., staining with von Willebrand factor antibody revealed few, if any, positive cells within the metastatic foci from MMP inhibitor-treated lungs, whereas terminal deoxynucleotidyl transferase-mediated nick end labeling showed a 4-fold increase in the rate of tumor cell apoptosis compared with controls. The fact that KB-R7785 interferes with early steps of angiogenesis and cancer spread suggests that MMP inhibitors may control both primary and secondary tumor growths by limiting the expansion of endothelial cells, as well as cancer cells, composing the tumors.

Cytogenetic and molecular studies demonstrated that pancreatic cancer frequently shows specific chromosomal abnormalities, such as losses of 9p, 17p, and 18q, and gains of 8q and 20q. We have analyzed alterations in the copy number of specific chromosomal regions in cells from the pancreatic juices of 32 patients with various pancreatic disorders by fluorescence in situ hybridization (FISH) technique to pursue the possible clinical use of early diagnosis of pancreatic cancer. None of the chromosomal abnormalities were found in 13 specimens from individuals who had no neoplastic lesions. On the other hand, 12 specimens (63%) derived from the remaining 19 patients who had neoplastic lesions showed at least one chromosomal abnormality. Ten of these specimens were from pancreatic cancer patients; 7 cases (70%) showed chromosomal abnormalities. All but one of the 12 tumors with chromosomal abnormalities had loss of 18q. Furthermore, we detected a tumor in one patient in whom the routine cytological method and endoscopic retrograde chorangiopancreatography found nothing. Based on the results by FISH, we performed endoscopic ultrasonography and found a small serous cystadenoma in this patient. These results indicate that: (a) FISH analysis of cells from pancreatic juices obtained during endoscopic retrograde chorangiopancreatography is quite useful for detecting pancreatic ductal tumors; and (b) loss of chromosome 18q is one of the early genetic changes that provide very useful information in diagnosing pancreatic neoplasias.

Using the method of microsatellite analysis, we studied 40 tissues with pancreatic ductal adenocarcinoma and identified two commonly deleted regions on the long arm of chromosome 12. One (region A) was found between D12S81 and D12S1719 at 12q21 at a frequency of 67.5%, and the other (region B) was located between D12S360 and D12S78 at 12q22-q23.1 at a frequency of 60%; the latter was reported previously (M. Kimura, et al. Genes Chromosomes Cancer, 17: 88-93, 1996). The results of microsatellite analyses were verified by fluorescence in situ hybridization. We further analyzed 19 pancreatic cancer cell lines by fluorescence in situ hybridization and found that 10 of them showed allelic loss at D12S81 and 6 showed allelic loss at D12S360. Yeast artificial chromosome contigs were constructed to cover the deleted regions. Region B was completely covered by a 650-kb yeast artificial chromosome clone. The frequently deleted regions in chromosome 12q in pancreatic cancer that were identified here may provide new avenues for isolating novel tumor suppressor genes.

The role of Frey's operation as extended pancreatic duct drainage operation was evaluated in patients with chronic pancreatitis.206 patients with chronic pancreatitis were surgically treated, evaluated and followed for a minimum period of 6 months, in order to ascertain the status of pancreatic function and pain relief for both pancreatic duct drainage operations, including Frey's operation, and pancreatectomy.Pain relief was established in 62 out of 86 patients (72.1%) undergoing pancreas duct drainage operation, in 51 out of 65 patients (78.5%) undergoing pancreatectomy. Fourteen out of 16 patients undergoing standard pancreaticojejunostomy with either persistent or alleviated pain had impacted calculi or pseudocysts in the pancreatic head and uncinate process preoperatively. Seventeen patients (16.3%) maintained normal glucose tolerance. Improvement was noted in 15 patients (14.4%) and in 27 patients the condition worsened (26.0%). The 10 years survival ratio in patients with diabetes mellitus preoperatively was 67.5% significantly lower than in patients without diabetes mellitus, 81.3% (p = 0.0029). Frey's operation was performed in 11 patients, providing satisfactory pain relief and preserving pancreatic exocrine and endocrine function.Frey's procedure should be considered as a new standard procedure in patients with pancreatic head complications and ductal dilatation in chronic pancreatitis.

A 45-year-old woman was incidentally suspected to have megacolon. Chest X-rays showed elevated left diaphragm due to colonic gas, and the heart was deviated to the midline. Barium enema revealed marked dilation of the sigmoid colon, confirming the diagnosis of megacolon. Maximal diameter of the sigmoid colon was 23 cm, but she had no gastrointestinal symptoms. During the work up for megacolon, the presence of myotonic dystrophy was suspected. She had hatchet face, but was not bald. Muscles of the neck and extremities were slightly atrophic. There was percussion myotonia of the tongue and both hands, and grip myotonia of the hands. Laboratory examinations showed impaired glucose tolerance and low level of serum IgG. EMG showed myotonic discharges and myopathic units in the limbs. Brain CT imaging revealed a thick skull. Cases of myotonic dystrophy associated with marked megacolon are rare in Japan. Megacolon presents a high risk for ileus, volvulus, and rupture, and myotonic dystrophy is associated with a high operative and anesthesic risk. Megacolon, therefore, is an important complication to look for in the management of myotonic dystrophy.

We evaluated the clinical features of 5 cases of tuberculous meningitis who had been admitted to our department from 1987 to 1994. Three patients were male and two were female. Their age ranged from 17 to 74 years old. All cases were examined by both CT and MRI before and during antituberculous treatment. Before the treatment, CT scan revealed abnormal findings such as nodular lesion suggesting tuberculoma, subarachnoid contrast enhancement or cerebral infarction in 2 cases, while MRI revealed abnormal findings such as inflammatory lesions with Gd-enhancement in 4 out of 5 patients. During the treatment, all abnormal findings except cerebral infarction disappeared. No abnormal findings were detected by CT. MRI and SPECT in one case who showed right hemiparesis and motor aphasia. In summary, CT scan could demonstrate abnormal findings in only a small portion of patients with tuberculous meningitis. One the other hand, MRI revealed various abnormal findings in most patients, and could reveal some lesions which could be responsible for the symptoms of patients. In a few patients, however, MRI could not show any lesion in spite of obvious focal neurological signs. MRI is considered to be useful for detecting the lesions in most patients with tuberculous meningitis, although its findings are not always specific for the disease.

We discussed the possibility of the screening programs for the early detection in carcinoma of the pancreas. Several trials of screening have been conducted for the outpatients with diabetes mellitus, jaundice or upper abdominal pain by means of serum erastase-1, amylase and CA19-9 levels and the ultrasonography. The trials could detect 37 patients of 4250 (1.3%), 47 of 423,905 (0.011%) and 89 of 3585 (2.4%) with carcinoma of the pancreas. Despite effective screening program is not available, the screening carries the potential for improvement of the resectability and the mortality in the patients with carcinoma of the pancreas.

We retrospectively evaluated the clinical findings of 10 cases of tuberculous meningitis who had been admitted to our department from 1987 to 1994. Four patients were male and six were female. All of them were Japanese, and their age ranged from 17 to 74 years old. Regarding the patient's delay, nine patients visited a doctor in 1 to 20 days after the onset of headache, and one patient visited a doctor in 14 days after the onset of general malaise. It is suggested that the patient's delay could not be longer than 3 weeks because of progressively worsening symptoms of tuberculous meningitis such as severe headache and fever. The time interval between the first contact of the patient to a doctor and the commencement of antituberculous therapy (doctor's delay), ranged from 14 to 66 days. When the diagnosis of meningitis was obtained based on the findings of the cerebrospinal fluid (CSF), focal neurological signs including psychological symptoms, cranial nerve palsies and seizure were noted besides meningeal signs or the disturbance of consciousness in 4 patients. The CSF revealed an increase in cell counts with mononuclear cell dominance in 9 patients, but the findings typical for tuberculous meningitis such as increase in total protein content and a decrease in glucose concentration were obtained in only 5 patients. Mycobacterium tuberculosis had not been detected in all cases when the antituberculous chemotherapy was started. Later, it was found to be positive in the CSF sample from only three patients by culture or polymerase chain reaction (PCR) method. When the antituberculous therapy was completed, meningitis was cured without remaining any symptom or sign in all patients. All patients had no active pulmonary tuberculosis when the meningitis was diagnosed, and only one of them had sequels of lung tuberculosis. Four patients had the past history of tuberculosis, and 1 had the familial history of pulmonary tuberculosis. At the first contact to a doctor, seven patients were diagnosed as having common cold or headache related with fever because of the lack of typical signs of meningitis. Similarly three other patients were initially diagnosed as having meningitis due to viral infection or unknown etiology. In summary, it was difficult to obtain the solid diagnosis of tuberculous meningitis at the initial stage of this disease, since the symptoms and signs at its onset often similar to those of common cold or non-specific headache. Therefore, when we see the patients with subacute onset of headache and fever followed by the meningeal signs, tuberculous meningitis should always be included in the list of diseases requiring differential diagnosis. In addition, when tuberculous meningitis is suspected, the antituberculous therapy should be started without any delay.

Differences in the clinical staging in Japan from that of the Union Internationale Contre le Cancer (UICC) staging system may account for discrepancies in the prognosis of carcinoma of the pancreas between Japan and the United States of America.This study compares the usefulness of Japanese staging with the UICC staging in 1,689 patients who underwent resection for carcinoma of the pancreatic head registered with the Japan Pancreas Society.The survival rate was correlated with the Japanese stage classification. The survival rate of patients with T4 tumors was surprisingly better than for those with T2 or T3 tumors. The extent of lymph node involvement and of extrapancreatic tissue invasion reflected the prognosis. The UICC staging system did not reflect differences in prognosis among the four stages, especially between stages II and III.To establish a more practical and universal staging system for carcinoma of the pancreas, the Japanese system may offer improvements in predicting the prognosis of American or European patients with this disease.

The concentrations of carmofur, 1-hexyl-carbamoyl-5-fluorouracil (HCFU), in the serum, bile, pancreatic juice and pancreatic tumor tissue were studied in 18 cases of peri-pancreatic head cancer with drainages of the pancreatic and biliary ducts after pancreatico-duodenectomy. As a result, high concentrations of HCFU and 5-FU were detected in the serum, bile and pancreatic juice after a per-oral administration of HCFU, 200 mg: HCFU was high in the order of serumbile and pancreatic juice, and 5-FU in the order of bile, serum and pancreatic juice. Two hours after administration, 5-FU concentration in the bile and serum attained to the maximum levels of 0.45 and 0.19 micrograms/ml, respectively, which demonstrated a lasting transfer of 5-FU to the bile at high concentration. HCFU and 5-FU levels in the tumor tissue were 0.079 and 0.024 micrograms/g, respectively. In conclusion, antitumor effect against the malignant tumors of the pancreatobiliary system can be expected by peroral administration of carmofur.

In the absence of causative therapy of acute pancreatitis the management of the disease focus on treatment and prevention of complications and symptoms. In mild acute pancreatitis intravenous fluid administration, analgetics and avoidance of oral fluid or food intake is sufficient in most cases. The treatment of severe pancreatitis involves identification of pancreatic and peripancreatic necroses, best demonstrated and evaluated by contrast-enhanced computerized tomography (CT). Infection of such necroses is the most common cause of death from acute pancreatitis. Recent data suggest that antibiotic prophylaxis is worthwhile and it should therefore always be instituted in the severe form of the disease. Careful monitoring of vital functions is mandatory and early treatment with assisted ventilation and renal dialysis is advised. Adequate volume replacement and nutritional support is important. The role of the gut in the development of infected necroses is becoming increasingly obvious. Also, the absence of food in the intestine may increase the intestinal barrier damage. Therefore, enteral nutrition is discussed as a logical step in pancreatitis treatment. However, the food should be delivered below the ligament of Treitz (below the area of the cholecystokinin (CCK) cells) as CCK stimulation probably worsen the course of the disease.

Using video-enhanced contrast (VEC)-differential interference contrast (DIC) microscopy, ultrastructural observations were made of the activation of polymorphonuclear leukocytes (PMNLs), the interaction between activated PMNLs and endothelial cells (ECs), and the effects of pentoxifylline (PTX). The ECs were obtained from a commercial source as human umbilical cord vein endothelial cells (HUVECs) or were obtained from pig or rat brains. They were cultured on a coverglass with DMEM for about 1 week. The human PMNLs were obtained from the authors' venous blood. The control appearance of the PMNLs resembled an elastic ball covered with fine villi. The PMNL was activated spontaneously and became flattened on the glass surface within 10 min in the observation chamber. The activation of the PMNLs was estimated arbitrarily from the polymorphous changes in cell shape, agitation of the intracellular granules, and apparent increase in adhesiveness. Preadministered PTX prevented such PMNL activation, and the PMNLs remained round for more than 15 min. PMNL activation was accelerated by chemoattractants (PAF, fMLP, and PMA). In one case, a PMNL that had been activated by PMA tended to recover its round shape with PTX, but finally ended by swelling and bursting. When PMNLs were introduced into the EC-containing chamber, they became entrapped by the ECs and activated, with degranulation followed by release of a smoke-like material. After about 3 h, the EC with an attached PMNL shrank and fell into a state of coagulation necrosis. When PTX was introduced at the time of adhesion of the flattened PMNL, the PMNL appeared to be deactivated, becoming smaller and assuming its previous round shape, and detached from the EC. PTX prevented the spontaneous activation of PMNLs, and of deactivated PMNLs even after their adherence to the endothelium.

The level of adenosine deaminase (ADA) activity in the cerebrospinal fluid is used as a supportive diagnostic measure for tuberculous meningitis. However the time-course of adenosine deaminase activity of the cerebrospinal fluid in patients with tuberculous meningitis remains unknown. The present study describes 4 patients with tuberculous meningitis in whom ADA activity in the cerebrospinal fluid was serially determined in order to clarify the effects of anti-tuberculous chemotherapy on ADA activity in the cerebrospinal fluid. In two of these patients the ADA did not show a high activity in the early stage of the disease. But in all cases the ADA showed a high activity after all, and gradually declined and reached the normal level at approximately 1 month after the initiation of chemotherapy. It seems that the decrease in the ADA activity was seen when T cells in the cerebrospinal fluid returned to a static state upon removal of mycobacterial antigen by the treatment. The level of ADA in the cerebrospinal fluid is considered to be one of the useful measures for diagnosis and follow-up in patients with tuberculous meningitis.

The effects of intracarotid administration of endothelin-1 on the cerebral microvessels were examined in anesthetized cats. The local cerebral blood volume in the cortex, which reflects the cumulative dimensions of the cerebral microvessels, was measured by our photoelectric method. A low dose of endothelin-1 (0.1 nmol) elicited mild but significant declines in cerebral blood volume. Following a high dose of endothelin-1 (3 nmol), the cerebral blood volume was initially reduced, probably due to the marked fall in arterial blood pressure, but was subsequently increased significantly. The increase in cerebral blood volume was not secondary to the rise in blood pressure, since it was unaffected by inhibition of the blood pressure changes with BQ-123 (1 mg/kg), an endothelin antagonist. However, the cerebral blood volume increase was prevented by continuous administration of NG-monomethyl-L-arginine (0.35 mg/kg per min), an inhibitor of nitric oxide synthesis, plus BQ-123. BQ-123 itself had no significant effects on cerebral blood volume or blood pressure. We conclude that while a low dose of intravascular endothelin-1 steadily constricts the cerebral microvessels, a high dose dilates the cerebral microvessels through the induction of nitric oxide synthesis, probably in the endothelium.

This study was undertaken to determine the role of bacterial translocation in the pathogenesis of infection and aggravation of the course of experimental acute pancreatitis in rats. Acute pancreatitis was induced by the injection of 3% sodium taurocholate. The rats were divided into following 3 groups: acute pancreatitis only (AP), total colectomy + pancreatitis (TCAP), acute pancreatitis with ED preparation (EDAP). The positive rate of bacteriological culture of pancreatic tissue was 40.7% at 24 hours in AP group and 50.0% in EDAP group, but in TCAP group, pancreatic tissue was sterile at 6.12 hours and at 24 hours positive rate was only 6%. There was a significant reduction of bacterial contamination in TCAP group compared with AP and EDAP groups. In the bacteriological culture of the liver, spleen and MLN, bacterial contamination was reduced in TCAP group. Blood endotoxin level elevated gradually compared to the level before induction of acute pancreatitis. At 24 hours, there was a significant difference between TCAP group and EDAP group. In TCAP group, survival rate was improved at 24 hours compared to AP group and EDAP group. Infectious complication during the experimental acute pancreatitis in rats can be explained by the bacterial translocation of intestinal flora, especially colonal bacteria, which may result in aggravation of pancreatitis.

Effect of lymphokine activated killer (LAK) cells induced by in vitro or in vivo stimulation with biological response modifier (BRM) such as recombinant interleukin-2 (rIL-2) or OK-432 on the growth of pancreatic cancer cells injected into nude mice were studied. Human rIL-2 stimulated spleen cells from BALB/c nu/nu mice were used as effector LAK cells. Human pancreatic cancer cell lines PK-1 and PK-9 were used as target for cytolytic activities against pancreatic cancer. Cytolysis was estimated by 51Cr release assay in vitro, and tumor growth inhibition was estimated by Winn assay in vivo. NK, LAK and pancreatic cancer cell killing activities of LAK cells were elevated to significantly high level of 82%, 70% 51% (PK-1) and 33% (PK-9) respectively on the 2nd day after cultivation with rIL-2. Significantly high level of tumor inhibition rate (98%) was obtained when PK-1 cells were injected into nude mice subcutaneously with LAK cells compared with injection of PK-1 cells only (control). Spleen cells induced from nude mice injected intraperitoneally with rIL-2 or OK-432 showed significantly high cytolytic activities. These results indicate that LAK cells induced by in vitro or in vivo stimulation with BRM could inhibit the growth of pancreatic cancer.

To establish an adequate statistical classification of epithelial atypia in the pancreatic duct, a total of 78 areas of duct epithelia with varying grades of atypia were subjected to nine-parameter morphometry and nine-dimensional multivariate cluster analysis. The material was derived from 53 pancreases resected for various epithelial tumors or acute or chronic pancreatitis. The result was correlated with immunohistochemical findings in which the pattern of intraepithelial distribution of carcinoembryonic antigen changed with the degree of ductal atypia. Finally, atypical cells classified by cluster analysis and immunohistochemistry were subjected to computer-aided three-dimensional mapping to visualize their distribution in the ductal tree. Cluster analysis demonstrated that the various epithelial forms were classifiable into Clusters 1, 2, and 3, representing ordinary epithelia and mild and severe dysplasias, respectively. The last category was created so as to include not only in situ and invasive carcinoma but the so-called borderline atypical lesions. The reproducibility of this classification was proved by two sorts of discriminant analyses. Also, the grades of atypia shown by the clustering proved to correlate with the reaction patterns for carcinoembryonic antigen. In the computer-aided three-dimensional mapping, severely dysplastic areas were shown surrounded by zones of mild dysplasia, justifying the assumption of a stepwise carcinogenesis in the pancreatic ducts.

CT images of leuko-araiosis in brain slices were quantified according to volumes of reduced Hounsfield units in frontal periventricular white matter in groups of elderly patients with multi-infarct dementia (MID, n = 23) and dementia of the Alzheimer type (DAT, n = 16). Volumes of leuko-araiosis, estimates of atrophic cerebral tissue, and local cerebral perfusion utilising inhalation of xenon gas as the indicator were correlated on the same CT slices. Ratios of frontal leuko-araiosis to total brain tissue volume were similar for patients with MID and DAT (mean 5.7 (SD 2.1)% v 6.5 (3.2%)), and both were significantly greater than ratios in elderly normal volunteers (3.1(1.3)%, 0 < 0.001). Cerebral atrophy (measured as the ratio of volumes of cerebrospinal fluid to total brain area) for DAT patients was 17.0 (6.7)%, which was greater than for MID patients (12.5 (5.4)%; p < 0.05) and both types of patients showed more cerebral atrophy than did age matched, elderly normal subjects. Cerebral perfusion was decreased in all regions measured in patients with MID and DAT compared with elderly normal subjects. Multi variate regression analyses correlated frontal leuko-araiosis with reductions of local cerebral blood flow in subcortical grey matter (p < 0.025) in patients with vascular dementia but not in those with DAT. These quantitative measures implicate decreased perfusion due to atherosclerosis in territories supplied by the deep penetrating cerebral arteries in the pathogenesis of leuko-araiosis in patients with vascular dementia, but suggest a different pathogenesis for leuko-araiosis in Alzheimer's disease.

A successful surgical case of malignant undifferentiated (embryonal) sarcoma of the liver (USL), a rare tumor normally found in children, is reported. The patient was a 21-year-old woman, complaining of epigastric pain and abdominal fullness. Chemical analyses of the blood and urine and complete blood counts revealed no significant changes, and serum alpha-fetoprotein levels were within normal limits. A physical examination demonstrated a film, slightly tender lesion at the liver's edge palpable 10 cm below the xiphoid process. CT scan and ultrasonography showed an oval mass, confined to the left lobe of the liver, which proved to be hypovascular on angiography. At laparotomy, a large, 18 x 15 x 13 cm tumor, found in the left hepatic lobe was resected. The lesion was dark red in color, encapsulated, smooth surfaced and of an elastic firm consistency. No metastasis was apparent. Histological examination resulted in a diagnosis of undifferentiated sarcoma of the liver. Three courses of adjuvant chemotherapy, including adriamycin, cis-diaminodichloroplatinum, vincristine and dacarbazine were administered following the surgery with no serious adverse effects. The patient remains well with no evidence of recurrence 12 months after her operation.

By measuring the doubling time both of clinical liver metastases and cultured human pancreatic cancer cell lines, we studied the possibility of occult liver metastases at the time of pancreatectomy in patients with pancreatic cancer. Doubling times of 3 pancreatic cancers were obtained from the measurements of size of liver metastases after pancreatectomy and those were compared with those of cultured human pancreatic cancer cell lines established from two of these cases. Doubling time of liver metastases were about fifteen times as long as those of cultured cell lines. On the assumption that growth rates of liver metastases were constant, the size of liver metastases at the time of pancreatectomy was calculated in three cases. The calculated sizes of these liver metastases were 140 microns, 2.4 mm, and 8.3 mm respectively. These results indicate that occult liver metastases have already existed in patients with pancreatic cancer even though they were clinically undetectable at the time of operation. And some adjuvant therapies against occult liver metastases are necessary for achievement of the better prognosis.

Sensitivities to anti-tumor drugs, mitomycin C (MMC), aclarubicin hydrochloride (ACR), doxorubicin hydrochloride (ADR), cisplatin, and 5-fluorouracil (5FU), were examined using PK-1, -8, -9, -12, -14, and -16 cell lines derived from human pancreatic cancer. These cell lines showed different sensitivities to each of the above anti-tumor drugs. The concentrations required for 50% growth-inhibition (IC50) after 2 hours of exposure were 0.096 to 0.35 micrograms/ml for MMC, 0.0074 to 0.0076 micrograms/ml for ACR, 0.033 to 0.23 micrograms/ml for ADR, 0.35 to 1.9 micrograms/ml for cisplatin, and 21 to 42 micrograms/ml for 5FU, IC50 of each anti-tumor drug decreased significantly after 48 hours of exposure. The combination of any two out of MMC, ACR, and 5FU showed synergistic inhibition of the growth of PK-1 and PK-8 cell lines. These results show that MMC, ACR, ADR, cisplatin, and 5FU have sufficient anti-tumor effect against six human pancreatic cancer cell lines even at clinically achievable concentrations and exposure times, and chemotherapy for pancreatic cancers requires naturally effective drug delivery into cancer tissues.

The effectiveness of continuous arterial infusion of protease inhibitor on acute experimental pancreatitis was investigated. Acute hemorrhagic pancreatitis was induced by closed duodenal loop obstruction using mongrel dogs. The obstruction was released at 16 hr, and dogs were divided into three groups; Group I: non-treated control, Group II: nafamostat mesilate (FUT-175) was admitted intravenously (5 micrograms/kg/min), Group III: FUT-175 was admitted via celiac artery. At 24 hr, the concentration of FUT-175 in the pancreatic tissues in group II and III were 905 and 4453 ng/g, respectively. The trypsin like activities in the pancreatic tissues in group I, II and III were 2.1, 1.4 and 0.7 nmol/min/mg protein, and the extent of necrosis of pancreatic parenchyma in each group were 49.5, 25.6 and 12.4%, respectively. Serum calcium, amylase and lipase levels were significantly improved in group III. These results suggest that continuous arterial infusion of protease inhibitor markedly decreases the extent of pancreatic necrosis in severe acute pancreatitis.

This study was designed to examine the combined ototoxic effects of cisplatin, an antitumor platinum compound, administration and electron beam irradiation on the inner ear of guinea pigs, histopathologically. One group received saline solution 4 ml/kg/day and the other group received cisplatin of 2 mg/4 ml/kg/day for five consecutive days. The right temporal bones of all animals of both groups were exposed to the electron beam of 14 Gy/day 3 hours after the daily injection of saline or cisplatin. All animals were sacrificed for inner ear histopathological findings 21 days after the last injection. A combination of cisplatin administration and electron beam irradiation produced a severe potentiation of the outer hair cell damage with no inner hair cell damage. Therefore, in treatment of head and neck carcinomas, it is important to pay attention to inner ear damage caused by combination therapy of cisplatin and electron beam irradiation which involves the inner ear.

Experimental chronic pancreatitis model were made in five dogs with chronic pancreatic fistula by injection of microspheres into peripheral pancreatic duct. Sequential changes of pancreatic exocrine and endocrine functions also with morphology were studied. Significant decrease of volume, bicarbonate output, and amylase output of pure pancreatic juice (PPJ) separately collected with stimulation of secretin were detected. While, viscosity of PPJ was significantly increased with concomitant increase of hexosamine concentration. Chronic pancreatitis was demonstrated morphologically also. These results suggest that concentrated PPJ caused by decrease in volume in PPJ and increase in viscosity of PPJ with concomitant increase in hexosamine concentration bring about the progression of chronic pancreatitis in this experimental model.

The effect of ethanol on pancreatic exocrine secretion and intraduodenal pH was investigated in 3 dogs, after making pancreatic, gastric, and jejunal fistula. After intragastric and intrajejunal administration of ethanol the intraduodenal pH went down and pancreatic juice, pancreatic bicarbonate output was increased. The integrated value of pancreatic juice, pancreatic bicarbonate and pancreatic protein output was greater in case of intrajejunal administration rather than intragastric administration of the ethanol. After intragastric and intrajejunal administration of the ethanol the plasma concentration of CCK was unchanged. The decrease of intraduodenal pH and increase of pancreatic exocrine secretion was though be mainly due to the secondary action of gastric acid secretion stimulated by ethanol.

Hypodense periventricular white-matter lesions detected by CT (leukoaraiosis) and high-intensity T2 signals detected by MR imaging were correlated with measurements of local cerebral blood flow (LCBF), cerebral atrophy, and cognitive performance. Subjects studied included elderly volunteers who were neurologically normal (n = 6), patients with chronic cerebral infarctions and intact cognition (n = 2), patients with multiinfarct dementia (n = 14), and patients with Alzheimer dementia (n = 9). Leukoaraiosis correlated with periventricular high-intensity lesions detected by MR, LCBF reductions, cognitive impairments, and cerebral atrophy. Moderate to severe leukoaraiosis was associated with LCBF reductions in the cortex, basal ganglia, and frontal white matter. Periventricular MR lesions correlated with cerebral atrophy but not with cognitive impairments or reductions in LCBF. The exquisite sensitivity of MR revealed small lesions that did not correlate with LCBF reductions and cognitive impairments. Remote subcortical white-matter lesions detected by MR did not correlate with periventricular MR lesions, leukoaraiosis, LCBF, cerebral atrophy, or cognitive performance, indicating little clinical relevance. We concluded that diffuse cerebral hypoperfusion, particularly in combination with the poor collateral circulation of white matter surrounding the lateral ventricles, is responsible for leukoaraiosis.

The effect of glycerol on the hemodynamics of ischemic areas of the brain was examined. Employing a photoelectric apparatus, the CBV (vol%), mean transit time of blood(s), and CBF (ml/100 g/min) in the cortex of the left ectosylvian gyrus were determined in 16 anesthetized cats before, at 1 hr, and at 2 hr after left MCA occlusion. In 10 cats, 10% glycerol in 5% fructose saline was intravenously administered at a speed of 5 ml/kg/hr at 1 hr after MCA occlusion. The other animals served as the control. In the group given glycerol, the relation between the values of CBF at 1 hr after MCA occlusion (X) and those at 2 hr after MCA occlusion (Y) was curvilinear and could be expressed by the regression curve, Y = 0.04X2 - 0.26X + 7.68 (R2 = 0.86). In the control group without glycerol, however, a linear relation expressed by the equation, Y = 0.76X + 5.96 (R2 = 0.94), was obtained. Comparison between the two relations indicated that glycerol improved the hemodynamics in the mild ischemic area with a relatively higher CBF. Severely ischemic areas showed no improvement.

High-resolution, color-coded images of local cerebral blood flow (LCBF) were made utilizing stable xenon-enhanced computed tomography among patients with common migraine (n = 18), classic migraine (n = 12) and cluster headache (n = 5). During spontaneously occurring headache in common and classic migraine patients, LCBF values for cerebral cortex and subcortical gray and white matter were diffusely increased by 20-40% with the exception of the occipital lobes. LCBF increases involved both hemispheres whether the head pain was unilateral or bilateral. No significant differences were noted in the degree or pattern of LCBF increases during headaches of common and classic migraineurs. Similar cerebral hyperperfusion of greater magnitude was observed during cluster headaches but was more prominent on the side of the head pain. Present observations do not support the hypothesis of spreading cortical depression as a cause of classic migraine. From a hemodynamic viewpoint, LCBF increases during headaches of common or classic migraine or cluster appear similar. Evidence is adduced that sympathetic hypofunction with denervation hypersensitivity of cerebral vessels plays a role in the cerebral hyperperfusion of migraine headaches. More pronounced unilateral autonomic derangements appear to account for the symptoms and cerebral hyperperfusion associated with cluster headaches.

The mechanical filtration coefficient (Lp) of the membrane of cultured glioma cells was determined from the rate of swelling of the cells. The swelling was induced by exposing the cells to distilled water. Assuming that cells swell in a symmetrical manner, Lp was 2.2 x 10(-8) cm/s.mmHg, or 1.7 x 10(-4) microns/s.cmH2O when calculated from changes of the cell diameter.

Glycerol is administered to reduce intracranial pressure by clinically enhancing cerebral edema. In this study, the effect of glycerol on ischemic edema was evaluated in 34 cerebral infarct patients by serial SEP. Evoked potentials were obtained by stimulating the hemiparetic median nerve 60 times with duration of 0.1 msec. N20 wave of SEP was analyzed by signal processor. SEP was monitored every 30 min for 3 hr after glycerol administration. Improvements of CCT, which means interpeak latency between N13 and N20, were observed in 14 patients. In seven patients, N20 waves were observed after IV administration of glycerol even though N20 waves were not observed before glycerol administration. The patients in acute stage or with the small infarction of basal ganglia showed these electrophysiological improvements. No CCT changes were observed in nine patients, and no N20 waves were obtained in two patients even after glycerol administration. In conclusion, electrophysiologically, glycerol effect on ischemic edema was well recognized in acute staged infarct patients and the patients with small infarction of basal ganglia.

Results of measurements of LCBF and L lambda values utilizing optimal CT-CBF methods under resting conditions are reported among thirty-two neurologically normal volunteers aged between 20 and 88 years. Measurements were made during inhalation of 26-30% stable xenon gas for 8 min and serial scanning utilizing a state-of the-art CT scanner with both eyes closed and ears unplugged. LCBF values for cortical gray matter were lowest in occipital cortex and highest in frontal cortex. Gray matter flow values were also high in subcortical structures with highest values measured in the thalamus. For white matter, highest flow values were measured in the internal capsule. Changes in LCBF and L lambda values were analyzed with respect to advancing age. Significant age-related declines in LCBF values were observed in occipital cortex and frontal white matter. Significant age-related increases in L lambda values were measured in frontal and temporal cortex, caudate nucleus and thalamus. Possible explanations are offered for these age-related increases in L lambda values for gray matter, such as accumulation of lipofuscin in neurons and relative compacting of gray matter with advancing age. The latter increases the numbers of nerve cells sampled per volume of gray matter measured.