Biomedical subjects

M Kobari

Publications and source records attributed to M Kobari.

At least 73 records · Page 4Linked to original sources

PubMed1995

The time of occurrence of liver metastasis in carcinoma of the pancreas.

By measuring the doubling time of liver metastasis, the authors investigated the possibility of occult liver metastasis at the time of pancreatectomy in patients with pancreatic carcinoma. We calculated tumor doubling times of liver metastases in six patients after pancreatectomy for periampullary carcinoma and compared with cell doubling times. We also calculated the diameters of the occult liver metastases at the time of pancreatectomy on the assumption that the growth rates of liver metastasis were constant. Tumor doubling times of liver metastases in six patients were 34, 32, 318, 108, 78, and 27 d, respectively. In two of these patients, tumor doubling times, compared with cell doubling times of 51 and 52 h for PK-36 and PK-59 established from the same patients with carcinoma of the pancreas, were about 15 times as long as those of cultured cell lines. The calculated sizes of the occult liver metastases at the time of pancreatectomy in these six patients were 2.4, 0.14, 19.0, 8.2, 3.5, and 4.2 mm. In five of these six patients, the calculated sizes were in the range between 10 microns and 1 cm. These results indicated occult liver metastases had already existed in patients with carcinoma of the pancreas at the time of pancreatectomy and were too small to be detected by imaging technique. We cannot improve survival rates in carcinoma of the pancreas by surgical management alone. For further improvement in survival rate of patients with carcinoma of the pancreas to occur, effective adjuvant therapies to prevent liver metastases must complement surgical management.

Aged↗

PubMed1995

The role of angiogenesis in the tumor growth of Syrian hamster pancreatic cancer cell line HPD-NR.

BACKGROUND/AIMS: New therapeutic approach is required for pancreatic cancer, one of the most intractable malignancies. The role of angiogenesis in the tumor growth of a Syrian hamster pancreatic cancer cell line HPD-NR, which closely resembles its human counterpart, was investigated. METHODS: Angiogenic activity was measured as stimulation of growth of human umbilical vein endothelial cells (HUVEC), and angiogenic factors produced by HPD-NR cells were identified by reverse-transcription polymerase chain reaction and Northern blot analysis. Then in vitro and in vivo antitumor effects of a potent angiogenesis inhibitor, O-(chloroacetylcarbamoyl)fumagillol (AGM-1470), were examined. RESULTS: The conditioned medium of HPD-NR cells stimulated the growth of HUVEC, and four hamster angiogenic factors were detected with an overexpression of transforming growth factor alpha and vascular endothelial growth factor messenger RNAs. AGM-1470 specifically inhibited the growth of HUVEC and that of HPD-NR tumors in vivo with decreased vascularity of the tumors but not the growth of HPD-NR cells in vitro. CONCLUSIONS: The results suggest that angiogenesis plays an important role in tumor growth of HPD-NR cells and can be a new target of medical therapy for pancreatic cancer.

Animals↗

PubMed1995

Levodopa-induced local cerebral blood flow changes in Parkinson's disease and related disorders.

Local cerebral blood flow (CBF) in the steady state and after intravenous administration of levodopa (1 mg/kg) was measured by xenon-enhanced computed tomography in patients with Parkinson's disease (PD, n = 16), progressive supranuclear palsy (PSP, n = 6), olivopontocerebellar atrophy (OPCA, n = 5), and arteriosclerotic parkinsonism (AP, n = 7). Three patterns of local CBF changes following levodopa were observed: (1) diffuse CBF increases, especially in striatum and thalamus, as found in patients with PD; (2) no significant changes in CBF, as in patients with OPCA and AP; and (3) CBF reductions in basal ganglia and thalamus, as seen in patients with PSP. The CBF increases after levodopa in PD may be secondary to metabolic activation of the nigrostriatal dopaminergic system. The poor CBF responses in patients with OPCA, AP, and PSP appeared to reflect degeneration of the dopaminergic neurons and dopamine receptors to various degrees. The CBF increases, especially in striatum and thalamus, tended to be greater (not significant) among responders to oral levodopa therapy. Levodopa-induced CBF measurements may be useful for the differential diagnosis of parkinsonian syndromes of various etiologies, but are not necessarily sufficient for predicting outcomes of long-term levodopa therapy.

Adult↗

PubMed1995

Pentoxifylline ameliorates postischemic delayed hypoperfusion of the cerebral cortex following cardiac arrest in cats.

Two major events occurring in the cerebral hemodynamics after successful resuscitation from cardiac arrest are reactive hyperemia and postischemic hypoperfusion. We examined the effect of pentoxifylline on the feline cerebral hemodynamics following cardiac arrest. Fifteen cats were anesthetized and artificially ventilated. Using our photoelectric method, the local cerebral blood volume (CBV), mean transit time of blood (MTT), and cerebral blood flow (CBF) in the parietotemporal region were measured. Thoracotomy was performed, and cardiac arrest (ventricular fibrillation) was induced by direct application of a 2-V DC countershock. The heart was resuscitated with a DC countershock at 30 sec after cardiac arrest. In 9 cats, pentoxifylline (25 mg/kg) was infused into the femoral vein at 5 min before cardiac arrest (PTX group). The other 6 cats served as controls (control group). In both groups, the CBV, CBF and mean arterial blood pressure (MABP) overshot the control levels just after resuscitation, whereas the MTT was decreased. In the control group, postischemic hypoperfusion was detected at 30-180 min after resuscitation from cardiac arrest (CBF (ml/100 g/min): 51 +/- 4 (control), 38 +/- 4 (30 min, p < 0.05), and 23 +/- 3 (180 min, p < 0.05)). However, the postischemic hypoperfusion was not observed in the PTX group. Pentoxifylline ameliorated postischemic delayed hypoperfusion in the cerebral cortex after a short period of cardiac arrest. Pentoxifylline may be useful in the emergency situations following cardiac arrest.

Animals↗

PubMed1995

Effects of ventricular arrhythmia on the cerebral microcirculation in cats.

To test the widely believed but poorly proved hypothesis that the cerebral symptoms observed during ventricular arrhythmia are caused by a reduced cerebral blood supply, we examined the effects of single and multiple ectopic ventricular beats (or ventricular tachycardia of short duration) on the cerebral microcirculation. Six anesthetized cats were used. Ectopic ventricular systoles of various sequences were produced by electrically stimulating the ventricle through a bipolar needle-type electrode for 1 to 50 times at a rate of 300/min. The local cerebral blood volume (CBV) and blood flow (CBFLD) in the cortex were measured continuously employing the photoelectric and laser Doppler methods. CBV reflects the cumulative dimensions of the cerebrocortical microvessels. Ectopic ventricular contractions, as confirmed by electrocardiograms, always reduced the CBV and arterial blood pressure in a total of 104 attempts. The CBV reductions ranged from 0.20 +/- 0.03 vol% for a single ectopic beat to approximately 0.6-0.8 vol% for runs of 8 or more beats. The CBFLD reductions measured with the laser Doppler flowmeter were 10-35%. The reductions in CBV and CBFLD during the ventricular arrhythmia could be attributed to the abrupt and marked reductions in arterial blood pressure. Runs of ectopic ventricular beats have significant effects on the cerebral microcirculation, whether clinically apparent or not.

Animals↗

PubMed1995

Activated leukocytes, endothelial cells, and effects of pentoxifylline: observations by VEC-DIC microscopy.

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.

Animals↗

PubMed1995

Targeting chemotherapy using antibody-combined liposome against human pancreatic cancer cell-line.

Anti-tumor effect of Adriamycin (ADM)-encapsulated and CA19-9 antibody-conjugated artificial lipid membrane follicle liposomes against a human pancreatic cancer cell-line PK-1 was studied in vitro and in vivo. The liposome compound (lipo c ADM = Ab) showed a stronger cell damage than ADM-encapsulated liposome (lipo c ADM) and free ADM, especially when the contact time was short and the concentration was low. The intra-tumor concentration of ADM in the group of i.v. injection of lipo c ADM = Ab showed the highest value, over twice those of lipo c ADM and free ADM after 120 hr. Lipo c ADM = Ab showed a significant inhibitory effect on the tumor growth inhibition test in vivo, and the final tumor weight at the 19th day was 27% in the group of lipo c ADM = Ab and 52% in the group of free ADM as compared with the control. The targeting chemotherapy using liposomes was demonstrated to have a stronger anti-tumor effect than the administration of anti-cancer drug alone owing to enhanced tumor accessibility and good targeting.

Animals↗

PubMed1995

Hepatocyte growth factor and Met receptor expression in human pancreatic carcinogenesis.

We have used immunohistochemistry to evaluate the clinicopathological significance of hepatocyte growth factor (HGF) and Met/HGF receptor expression in ductal lesions of 46 human pancreata. Normal duct epithelium shows no significant immunoreactivity for either HGF or Met. Strong immunostaining for HGF was respectively demonstrated in hyperplastic and severely dysplastic epithelia in 35.5 and 40% of cases with such duct lesions, whereas 37% of ductal adenocarcinoma showed diffuse HGF immunostaining. Positive Met immunostaining was demonstrated in 58, 80, and 78%, respectively, of specimens demonstrating the above duct lesions. Patients with resectable ductal adenocarcinoma demonstrating diffuse Met immunostaining have a significantly longer survival than those with tumors showing negative/focal staining (19.7 versus 8.1 months at P = 0.026). In contrast, HGF immunoreactivity did not significantly correlate with the survival of the patients. The results suggest that HGF and Met expression may play significant bifunctional roles during human pancreatic ductal carcinogenesis and progression. Whereas an upregulation of Met receptor expression and HGF-Met interaction may have an important pathogenetic role during the early stages of neoplastic promotion, a lack or subsequent loss of Met expression in invasive adenocarcinoma appears to result in a more aggressive clinical behavior.

Aged↗

PubMed1995

[Transfer of carmofur (HCFU) to the serum, bile, pancreatic juice and pancreatic tumor tissue in the cases of peri-pancreatic head cancer].

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 serum > bile 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.

Administration, Oral↗

PubMed1994

Role of nitric oxide in regulation of cerebral microvascular tone and autoregulation of cerebral blood flow in cats.

The role of nitric oxide in the regulation of cerebrocortical microvascular tone and autoregulation of cerebral blood flow (CBF) was examined in 24 anesthetized cats. The local cerebral blood volume (CBV), mean transit time of blood (MTT), and CBF in the cortex were measured by our photoelectric method. CBV represents the cumulative dimensions of the cerebral microvessels. Intravenous injection of 0.35-0.7 mg/kg/min NG-monomethyl-L-arginine (L-NMMA), an inhibitor of nitric oxide synthesis, significantly increased mean arterial blood pressure (MABP; 8.4-14.1%, P < 0.01), decreased CBV (15.2-28.7%, P < 0.01), and decreased CBF (20.0-29.8%, P < 0.01) in a dose-related manner. The changes in MABP, CBV, and CBF elicited by L-NMMA were inhibited (P < 0.05) by simultaneous infusion of 35 mg/kg/min L-arginine. Autoregulation of CBF was examined during controlled hypotension of -30 to -40 mmHg (artificial bleeding) and recovery of blood pressure (reinfusion of blood). Although CBF remained constant with blood pressure changes in the control state (delta CBF/delta MABP of 0.037 +/- 0.155 with hypotension), CBF became dependent on blood pressure changes (delta CBF/delta MABP of 0.478 +/- 0.135, P < 0.05) during infusion of 0.35 mg/kg/min L-NMMA. It is concluded that nitric oxide participates in both the regulation of basal tone of cerebral microvessels and the autoregulation of CBF.

Animals↗

PubMed1994

Dilatation of cerebral microvessels mediated by endothelin ETB receptor and nitric oxide in cats.

The functional role of the endothelin (ET)B receptor in the cerebral microvessels was examined in seven anesthetized cats. The effects of intracarotidly injected IRL1620, a selective ETB receptor agonist, on the cerebral blood volume (CBV) in the cortex were examined by a photoelectric method. CBV reflects the cumulative dimensions of the cerebral microvessels. High doses of IRL1620 (0.1-1 nmol/kg) elicited a transient fall in CBV, followed by a marked and dose-related increase of CBV (P < 0.01). The CBV increase was significantly inhibited (P < 0.01) by simultaneous administration of 0.35 mg/kg/min NG-monomethyl-L-arginine (L-NMMA), an inhibitor of nitric oxide synthesis. The marked, but transient, depressor effect of IRL1620 was also attenuated (P < 0.01) by L-NMMA. The ETB receptor subtype and production of nitric oxide, probably in the endothelium, mediate the vasodilatory action of ET in the cerebral microvessels.

Animals↗

PubMed1994

Cerebral vasodilatory effect of high-dose, intravascular endothelin-1: inhibition by NG-monomethyl-L-arginine.

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.

Animals↗

PubMed1994

Constriction/dilatation of the cerebral microvessels by intravascular endothelin-1 in cats.

The effects of intracarotidly injected endothelin (ET)-1 (0.01-3 nmol) on the local cerebral blood volume (CBV) in the parietotemporal cortex were examined by the photoelectric method in 17 anesthetized cats. CBV reflects the cumulative dimensions of the cerebral microvessels. Low doses of ET-1 (0.01 and 0.1 nmol) elicited mild but significant reductions in CBV without changes in the systemic arterial blood pressure (SABP). High doses of ET-1 (3 nmol) initially induced marked declines of CBV, which were attributable to the significant falls in SABP. CBV subsequently exhibited significant increases. The CBV increases were not secondary to the accompanying elevations of SABP, since they were unaffected by inhibition of the SABP changes after preinjection of BQ-123 (1 mg/kg), an ET antagonist specific to the ETA receptors. The CBV increases, however, were prevented by continuous administration of NG-mono-methyl-L-arginine (0.35 mg/kg/min), an inhibitor of nitric oxide synthesis, plus BQ-123. We conclude that while low doses of intravascular ET-1 constrict the cerebral microvessels, high doses of ET-1 dilate the cerebral microvessels through the induction of nitric oxide probably in the cerebrovascular endothelium.

Animals↗

PubMed1994

[Time-course of adenosine deaminase activity in the cerebrospinal fluid in patients with tuberculous meningitis].

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.

Adenosine Deaminase↗

PubMed1994

[The role of intestinal flora in the pathogenesis of infection and aggravation of experimental acute pancreatitis in rats].

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.

Acute Disease↗

PubMed1994

[Effect of LAK cells and BRM on the growth of pancreatic cancer cells injected into nude mice].

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.

Animals↗

PubMed1994

Varying grades of epithelial atypia in the pancreatic ducts of humans. Classification based on morphometry and multivariate analysis and correlated with positive reactions of carcinoembryonic antigen.

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.

Carcinoembryonic Antigen↗

PubMed1993

Transient cerebral vasodilatory effect of neuropeptide Y mediated by nitric oxide.

The effects of intracarotidly injected neuropeptide Y (NPY; 0.1 micrograms/kg) on the local cerebral blood volume (CBV) and blood flow (CBF) in the parieto-temporal cortex were examined by the photoelectric method in 17 anesthetized cats. CBV reflects the cumulative crosssectional area of the cerebral microvascular beds. NPY immediately caused transient but significant increases in CBV and CBF, which lasted for less than 5 min. Thereafter, CBV returned to and remained at the control level, although CBF was decreased by 30-40% for 60 min during the monitoring period. The CBV increases after NPY were prevented by a 15-min preinjection of 0.35 mg/kg/min of NG-monomethyl-L-arginine (L-NMMA), which is a competitive blocker of nitric oxide synthesis. The CBV increases after NPY reappeared following a 15-min administration of 0.25 mg/kg/min of L-arginine, which is a precursor of nitric oxide. We conclude that NPY administered in vivo exerts a previously unreported effect of transient vasodilatation on the cerebral microvessels. This action appears to be mediated by nitric oxide, which is a major candidate as an endothelium-derived relaxing factor (EDRF).

Animals↗