Biomedical subjects

Y Oshiro

Publications and source records attributed to Y Oshiro.

At least 37 records · Page 2Linked to original sources

PubMed2001

Morphological transformation of Syrian hamster embryo cells at pH 6.7 by bemitradine, a nongenotoxic carcinogen.

Bemitradine is a compound that was intended for use as a diuretic antihypertensive drug. In the preclinical safety assays, it was found to be nongenotoxic in five in vitro assays (Ames, mouse lymphoma, CHO/HGPRT, CHO chromosome aberration, and UDS) and in one in vivo assay (mouse bone marrow micronucleus). In a subsequent long-term bioassay using Sprague-Dawley rats, this compound was found to be a rodent carcinogen at multiple sites. Because of the carcinogenicity, further development of this compound as a drug was halted. Because the Syrian hamster embryo (SHE) cell transformation assay at pH 6.7 has been demonstrated to be a good predictor of carcinogenic activity in animals, this nongenotoxic compound was used to determine if this in vitro assay system could be utilized to predict the potential for the carcinogenicity in rodents. The SHE cell transformation assay was validated initially for use in this laboratory using genotoxic and nongenotoxic carcinogens including benzo(a)pyrene, 20-methylcholanthrene, 2-acetylaminofluorene, methapyrilene, and phenobarbital. Each of these chemicals induced a statistically significant increase in morphological transformation frequency. Bemitradine was initially tested in a range-finding cytotoxicity assay at 10-250 microg/mL for treatment periods of 7 days. Doses used in the 7-day treatment transformation assay were 1.25, 2.5, 5.0, 7.5, and 10.0 microg/mL. Statistically significant increases in morphological transformation frequencies were observed at 1.25, 2.5, and 7.5 microg/mL, indicating a positive response. The experiment was repeated with similar results confirming the previous conclusion. These data provide additional evidence that the pH 6.7 SHE cell transformation assay may be a valuable in vitro tool to detect nongenotoxic rodent carcinogens.

Animals↗

PubMed2001

Pleomorphic leiomyosarcoma: clinicopathologic and immunohistochemical study with special emphasis on its distinction from ordinary leiomyosarcoma and malignant fibrous histiocytoma.

Pleomorphic leiomyosarcoma (PLMS) was recently described as a morphologic variant of leiomyosarcoma; however, its diagnostic criteria, as shown by morphologic features and biologic behavior, remain controversial. We describe 28 cases of pleomorphic sarcoma with pleomorphic areas in more than two thirds of the tumor and an ordinary leiomyosarcomatous fascicular area covering less than one third as PLMS. PLMS comprised 8.6% of all the leiomyosarcomas (322 cases) registered in our institute. Patients ranged in age from 31 to 89 years (average, 57.9 years). Seventeen patients (60.7%) were male and 11 were female. Tumor location was as follows: the extremities in 17 cases, the retroperitoneum or abdominal cavity in 7 cases, the chest/abdominal wall in 3 cases, and the scalp in 1 case. Histologically, all cases showed at least small foci of fascicles consisting of smooth muscle tumor cells, in addition to pleomorphic areas mimicking storiform-pleomorphic malignant fibrous histiocytoma. The border between pleomorphic and leiomyosarcomatous fascicular areas was sharp in 3 cases, gradual in 2 cases, and blending in 23 cases. Sixteen cases (57.1%) showed a typical storiform pattern, 6 cases revealed extensive stromal hyalinization, 6 cases showed a chronic inflammatory infiltrate, 2 cases had the foci of foamy xanthomatous cells, and 7 cases contained myxoid malignant fibrous histiocytoma-like areas covering less than 50% of the tumor. The tumors had a tendency to be of a morphologically higher grade (10 tumors were French Federation of Cancer Centers grade 2, 18 were grade 3). Five of 28 cases (18%) showed rhabdoid features. Immunohistochemically, all of the 28 tumors examined showed a positive reactivity for at least one smooth muscle marker (desmin, muscle-specific actin, and alpha-smooth muscle actin) in the leiomyosarcomatous fascicular areas. In the pleomorphic areas the expression of smooth muscle markers (desmin 10 of 28, muscle-specific actin 13 of 28, and alpha-smooth muscle actin 14 of 28) was significantly reduced, compared with that in leiomyosarcomatous fascicular area (desmin 18 of 28, muscle-specific actin 26 of 28, and alpha-smooth muscle actin 24 of 28). No significant difference was observed between the MIB-1 labeling index in the leiomyosarcomatous fascicular areas (26.10 on average) and that in the pleomorphic areas (26.17 on average). However, the MIB-1 labeling index in PLMS was significantly higher than that in ordinary leiomyosarcoma (n = 20, 12.86 on average) or storiform-pleomorphic malignant fibrous histiocytoma (n = 16, 16.63 on average). In 23 patients follow-up data were available with a duration of 1-239 months. Eleven patients developed metastases, and lung accounted for the most common site of metastasis (9 cases). Fifteen of 23 patients (65.2%) died of disease. Our results indicate that PLMS should be differentiated from ordinary leiomyosarcoma because of its high proliferative activities and rather aggressive biologic behavior.

Adult↗

PubMed2001

CD3- bone marrow cells augment the generation of cytotoxic T lymphocytes showing a preference for the X-chromosome linked gene product of stimulator cells.

Responder cells, composed of both a limited number of nylon wool-passed lymph node (NW-LN) cells and an excess number of CD3+ cell-depleted bone marrow (CD3- BM) cells from the same strain of mice, were stimulated with allogeneic spleen cells in vitro. The CD3- BM cells augmented the generation of allogeneic major histocompatibility complex (MHC) class I specific cytotoxic T lymphocytes (CTL) from NW-LN cells. C3H/He (H-2k, C3H background) responder cells were stimulated with either B10.D2 (H-2d, B10 background) or BALB/c (H-2d, BALB background) spleen cells. In the former stimulation, the CTL induced lysed B10.D2 target cells more efficiently than the BALB/c cells. Furthermore, these CTL lysed more (B10.D2 x BALB/c) F1 male target cells than (BALB/c x B10.D2) F1 male. In the latter stimulation, the CTL lysed more BALB/c than B10.D2 cells, and more (BALB/c) x B10.D2) F1 male than (B10.D2 x BALB/c) F1 male. The reciprocal mixed lymphocyte cultures (MLC) were carried out, in which BALB/c responder cells were stimulated with either C3H/He or B10.BR (H-2k, B10 background) spleen cells. In the former stimulation, the CTL induced lysed more C3H/He or (C3H/He x B10.BR) F1 male target cells than B10.BR or (B10.BR x C3H/He) F1 male, and in the latter, the reciprocal results were obtained. These results suggested that the CTL induced had a preference for the X-chromosome linked gene products (Xlgp), besides the specificity for the allogeneic MHC class I, of the mice used as stimulator.

Animals↗

PubMed2001

Cytokeratin subunits of inclusion bodies in rhabdoid cells: immunohistochemical and clinicopathological study of malignant rhabdoid tumor and epithelioid sarcoma.

Extrarenal malignant rhabdoid tumor (MRT), which is recognized as being histologically similar to renal MRT, is characterized by the presence of "rhabdoid cell" (RC) and a highly aggressive biological behavior. Recently it has been proposed that "proximal variant" of epithelioid sarcoma (ES), whose morphology is similar to that of MRT, actually has a more aggressive clinical course than classical type ES. Detailed immunohistochemical analysis of cytokeratin (CK) subunits was performed in 3 cases of extrarenal MRT, 3 cases of renal MRT, and 11 cases of ES comprising 2 "proximal variants" and 9 classical types. Renal and extrarenal MRTs showed positive immunoreactivity for both CK8 and CK18. Classical type ESs were diffusely positive, not only for CK8 and CK18, but also for other cytokeratin subunits including CK4, 6, 10, 13, 16, 17, and "high-molecular-weight" CKs (CK1, 5, 10, and 14). On the other hand, proximal ES revealed limited immunohistochemical reactivity for cytokeratins, compared with classical ES. In conclusion, the inclusion bodies of RCs show immunoreactivity confined to CK8, CK18, and vimentin. Furthermore, ES has additional CK expressions, while proximal ES possesses characteristics intermediate between those of classical ES and those of external MRT.

Adult↗

PubMed2000

Overexpression of cathepsin B and urokinase plasminogen activator is associated with increased risk of recurrence and metastasis in patients with chondrosarcoma.

BACKGROUND: Deregulation of the cellular protease network has been shown to be responsible for aggressive clinical behavior in several common human malignancies. In the current study, the authors evaluated the expression patterns of proteases in patients with chondrosarcoma of bone and correlated these patterns with clinical outcome. METHODS: The expression levels of urokinase plasminogen activator; matrix metalloproteinase types-1, -2, and -9; and cathepsins B and L were determined immunohistochemically in 114 cases of chondrosarcomas of bone and were correlated with their clinicopathologic parameters as well as with long term follow-up data. RESULTS: Overexpression of cathepsin B was associated with a high rate of local recurrence (P = 0.006) and a decreased recurrence free survival (P = 0.005). Overexpression of urokinase plasminogen activator was associated with an increased rate of metastasis (P = 0. 013), a decreased metastasis free survival (P = 0.016), and a decreased 5-year overall survival rate (P = 0.048). The univariate Cox model showed that tumor extension into soft tissue, high histologic grade, and overexpression of cathepsin B were predictors of adverse outcome. Multivariate analysis showed only overexpression of cathepsin B and tumor extension into soft tissue to be independent predictors of local recurrence. CONCLUSIONS: Overexpression of cathepsin B and urokinase plasminogen activator can be used to identify those patients with chondrosarcoma of bone who have an increased risk of local recurrence and distant metastases.

Adult↗

PubMed2000

Effects of stimulus rate on the auditory cortex using fMRI with 'sparse' temporal sampling.

The purpose of this study was to evaluate the effects of the auditory stimulus presentation rate on signal response during fMRI with a minimal effect of scanner acoustic noise. Six subjects received auditory stimulus with a pure tone (1000 Hz, 30 ms duration) at presentation rates of 0.5, 2, 5, 10 and 20 Hz. Echo planar images were obtained with a long TR of 12 s and clustered multi-slice acquisition. The number of activated pixels and percentage signal change were measured in the transverse temporal gyri, which revealed that these values at 5 Hz were significantly greater than those at 0.5 Hz and at 20 Hz.

Acoustic Stimulation↗

PubMed2000

3,4-dihydro-2(1H)-quinolinone as a novel antidepressant drug: synthesis and pharmacology of 1-[3-[4-(3-chlorophenyl)-1-piperazinyl]propyl]-3,4- dihydro-5-methoxy-2(1H)-quinolinone and its derivatives.

To develop a novel antidepressant drug with central nervous system-stimulating activity, we prepared a series of 1-[omega-(4-substituted phenyl-1-piperazinyl)alkyl]-3, 4-dihydro-2(1H)-quinolinone derivatives and examined their activities by their effects at 30 and 100 mg/kg po on the sleeping time of mice anesthetized with halothane and on the time required for recovery from coma induced in mice by cerebral concussion. We examined their binding affinities for sigma receptors by evaluating their ability to inhibit [(3)H]-1,3-di(o-tolyl)guanidine ([(3)H]DTG) binding to the rat whole brain membrane in comparison with three putative sigma receptor agonists: 1,3-di(o-tolyl)guanidine (DTG, 66), (+)-1,2,3,4,5,6-hexahydro-6,11-dimethyl-3-(2-propenyl)-2, 6-methano-3-benzazecin-8-ol (SKF10,047, 67), and (+)-1,2,3,4,5, 6-hexahydro-6,11-dimethyl-3-(3-methyl-2-butenyl)-2, 6-methano-3-benzazecin-8-ol (pentazocine, 68). Among the series of derivatives, 1-[3-[4-(3-chlorophenyl)-1-piperazinyl]propyl]-3, 4-dihydro-5-methoxy-2(1H)-quinolinone hydrochloride (34b) and its mesylate (34c), at a dose of 30 mg/kg po, reduced the sleeping time and the time for recovery from coma and they inhibited [(3)H]DTG binding for sigma receptors. The putative sigma receptor agonists reduced the sleeping time and the time for recovery from coma whereas two sigma receptor antagonists, alpha-(4-fluorophenyl)-4-(5-fluoro-2-pyrimidinyl)-1-piperazinebutanol hydrochloride (BMY14802, 69) and cis-9-[3-(3, 5-dimethyl-1-piperazinyl)propyl]carbazole dihydrochloride (rimcazole, 70), were inactive in the two tests. Preadministration of the putative sigma receptor antagonists 69 (3 mg/kg po) and 70 (30 mg/kg po) completely antagonized the actions of 34b and the sigma receptor agonists in the test for recovery from coma. These results suggested that 34b and 34c are sigma receptor agonists. Furthermore, a single administration of 1 and 10 mg/kg po 34b and 34c showed antidepressant-like activity by reducing the immobility time in the forced-swimming test with mice, while a tricyclic antidepressant, 10, 11-dihydro-N,N-dimethyl-5H-dibenz[b,f]azepine-5-propanamine hydrochloride (imipramine, 1) (10 and 30 mg/kg po), did not reduce the time after a single administration. 1 reduced the time after repeated administration of 30 mg/kg po once a day for 4 days. The structure-activity relationship of the series of compounds is also discussed.

Animals↗

PubMed2000

Rhabdoid features in leiomyosarcoma of soft tissue: with special reference to aggressive behavior.

The presence of rhabdoid cells has been reported in various types of malignant neoplasms and has been determined to be a predictor of aggressive behavior of neoplasms regardless of tumor histogenesis. One hundred and thirteen cases of leiomyosarcoma, selected from 1800 soft tissue sarcomas, were reviewed on hematoxylin and eosin sections, and immunohistochemical staining when available, and seven cases with rhabdoid features were retrieved. Clinicopathologic differences were analyzed to compare between cases with rhabdoid features and those without rhabdoid features. In the seven cases with rhabdoid features, two were intra-abdominal, and the others arose in external soft tissues including muscle, subcutis, and cutis. Patient age ranged from 33 to 84 years, three were female, and four were male. Tumor size ranged from 3 to 22 cm. Clinical evidence showed no differences from those cases without rhabdoid features. Histologically, one of the abdominal cases was epithelioid leiomyosarcoma. Two of the 7 cases were better subclassified as pleomorphic leiomyosarcoma, in which rhabdoid cells are diffusely scattered. In cases other than those with pleomorphic leiomyosarcomas, foci of anaplastic areas were observed, and collections of rhabdoid cells were present in those areas. Immunohistochemical examination of the cases confirmed myogenic differentiation, and showed rhabdoid cells being positive for vimentin and desmin in the inclusion bodies, and diffusely so for muscle actin in the cytoplasm. After dividing all the cases of leiomyosarcoma by their location, prognostic analysis was performed. Leiomyosarcoma of external soft tissue with rhabdoid cells showed a tendency for poorer prognoses than cases without rhabdoid features. On the contrary, retroperitoneal cases did not. This study indicates that rhabdoid features are associated with aggressive biological behavior in leiomyosarcoma of the external soft tissue.

Adult↗

PubMed1999

Long-term follow up of pure myxoid liposarcomas with special reference to local recurrence and progression to round cell lesions.

Myxoid and round cell liposarcomas cytogenetically share the t(12;16)(q13;p11) translocation, and represent a continuous morphological spectrum including pure myxoid liposarcoma (PML), mixed (myxoid/round cell) liposarcoma (MXL) and pure round cell liposarcoma (RCL). It has been documented that a critical amount of RC lesion in low-grade, MXL is associated with poor prognosis. The present long-term follow-up study examined the factors that influence the progression of PML to RCL and several other prognostic factors and compared the results with those of liposarcomas initially diagnosed as MXL. Using 34 primary PML and their local recurrences after curative resection, and two initially diagnosed MXL, the appearance of RC lesion in PML was examined, and the prognostic significance of the local recurrence rate (times/month), tumor size, infiltrative proliferation (defined as entrapping of striated muscle fibers in the tumor), tumor necrosis and mitotic figures. The follow-up period ranged from 19 to 378 months (mean, 173.4 months). Based on Cox's proportional hazards regression model, a recurrence rate >/= 0.01 in 24 PML with recurrences (P = 0.037) and the presence of infiltrative proliferation in 34 PML (P = 0.043) were significant independent factors associated with poor prognosis. Round cell lesions were detected in the last recurrences of two surviving PML. These results indicate that through their recurrence, PML might potentially become malignant, independent of the proportion of RC lesions in the tumor. The appearance of RC lesions in subsequent recurrences may indicate a progression from PML to MXL.

Adult↗

PubMed1998

Altered p53 is associated with aggressive behavior of chondrosarcoma: a long term follow-up study.

BACKGROUND: p53 is a major tumor suppressor gene that has been implicated in the biology of a variety of human neoplasms, including some that affect the skeleton. Recent studies based on small numbers of cases have shown that overexpression or alteration of the p53 gene is frequently present in high grade, clinically aggressive chondrosarcomas of bone. In this study, the authors addressed the relation between overexpression and alteration of the p53 gene and the clinical aggressiveness of chondrosarcoma in a large series of patients for whom long term follow-up data were available. METHODS: The authors analyzed the expression and/or alteration of the p53 gene in 158 cases of chondrosarcoma of bone using immunohistochemistry, single-strand conformation polymorphism, and direct sequencing. They then related the findings to various clinicopathologic parameters and long term follow-up data. RESULTS: The presence of overexpression and/or structural alterations of the p53 gene was documented in 38.1% of chondrosarcomas of bone. A statistically significant correlation was observed between overexpression or alteration of the p53 gene and both the histologic grade of the tumor and the presence of metastasis. The probability of local recurrence free, metastasis free, and overall survival was significantly higher for patients with no overexpression or alteration of p53 than for patients with p53 overexpression or alteration. CONCLUSIONS: Overexpression or alteration of the p53 gene is an important predictor of aggressive clinical behavior in chondrosarcoma of bone.

Adolescent↗

PubMed1998

Functional mapping of pain-related activation with echo-planar MRI: significance of the SII-insular region.

Activation in numerous regions of the brain is likely to be involved in the complex neural network function of pain perception. To detect the cortical representation during nonpainful and painful stimuli, which were presented using electrical finger stimulation in six normal right-handed male volunteers, we performed echo-planar functional magnetic resonance imaging (fMRI). Using a 1.5-T MR system that scanned the supratentorial region of the brain, we obtained multislice BOLD-based functional MR images with single-shot gradient-echo echo-planar imaging (EPI). The data show that dispersed brain regions are activated during painful stimulation, and especially demonstrate the significance of the SII-insular region in pain perception.

Adult↗

PubMed1998

Novel antipsychotic agents with dopamine autoreceptor agonist properties: synthesis and pharmacology of 7-[4-(4-phenyl-1-piperazinyl)butoxy]-3,4-dihydro-2(1H)-quinolinone derivatives.

To develop a novel antipsychotic agent which is an agonist of dopamine (DA) autoreceptors and an antagonist of postsynaptic DA receptors, a series of 7-[4-[4-(substituted phenyl)-1-piperazinyl]butoxy]-3,4-dihydro-2 (1H)-quinolinones was synthesized and their dual activities were examined. The postsynaptic DA receptor antagonistic activities of the compounds were evaluated by their ability to inhibit stereotypy induced by apomorphine in mice, and the autoreceptor agonist activities were determined by their effects on the gamma-butyrolactone (GBL)-induced increase in L-dihydroxyphenylalanine (DOPA) synthesis in the mouse brain. Many compounds inhibited the stereotypic behavior, and several compounds reversed the GBL-induced increase in the DOPA synthesis. Among them, 7-[4-[4-(2,3-dichlorophenyl)-1-piperazinyl]-butoxy]-3,4-dihydro-2 (1H)-quinolinone (28, aripiprazole, OPC-14597) was found to have these two activities. This compound reversed the GBL-induced DOPA synthesis (ED50 values of 5.1 mumol/kg p.o.) and inhibited the APO induced stereotypy (ED50 values of 0.6 mumol/kg p.o.). Compound 28 induced catalepsy at 10 times higher dose than that required for the antagonism of APO-induced stereotypy (ED50 value of 7.8 mumol/kg p.o.).

4-Butyrolactone↗

PubMed1998

Malignant mesothelioma originating in the hepatic falciform ligament: report of a case.

We report herein what to our knowledge is the first documented case of malignant mesothelioma arising from the falciform ligament. A 65-year-old woman was admitted to our department for the evaluation of an epigastric mass. An abdominal computed tomography scan, magnetic resonance imaging, and celiac angiogram showed a tumor originating in the falciform ligament. The tumor was subsequently resected, and pathological examination confirmed a diagnosis of malignant mesothelioma originating in the falciform ligament. A metastatic liver tumor was detected 3 years after this operation and a partial liver resection was performed. She is currently off therapy, and no clinical or radiologic evidence of disease has been found for 1 year since her second operation.

Aged↗

PubMed1998

Direct effects of thyroid hormones on rat coronary artery: nongenomic effects of triiodothyronine and thyroxine.

To determine whether thyroid hormones, triiodothyronine (T3) and thyroxine (T4), have any direct, nongenomic effects on vascular smooth muscle cells, we evaluated the effects of these hormones on rat coronary arteries. Bolus injection of T3 or T4 elicited a transient, dose-dependent decrease in coronary perfusion pressure (CPP), as well as an increase in arterial vasodilation. Vasodilation occurred immediately after injection, peaked at 15 seconds, and lasted 80 seconds. Reverse T3 had no effect on CPP or vasodilation. The rapidity of these effects suggests that they are not mediated by the T3-nuclear receptor, but are direct, nongenomic effects of thyroid hormones. Our results also suggest that thyroid hormones may play a role in preventing myocardial ischemia by inducing coronary artery vasodilation.

Animals↗

PubMed1998

Tumor localization studies and surgical treatment in patients with insulinoma.

In the present study, we retrospectively reviewed thirteen consecutive patients with insulinomas including 2 reoperations at our department for insulinomas, from the viewpoint of preoperative localization studies, surgery and long term follow-up. The results of the preoperative localization studies proved to be percutaneous transhepatic portal venous sampling (PTPVS) 6/7, angiography 8/15, ultrasonography (US) 6/11, endoscopic ultrasonography (EUS) 4/4, computed tomography (CT) 3/10, and magnetic resonance imaging (MRI) 2/2. The tumor was visualized by intraoperative ultrasonography (IUS) in 6 of 6 patients (100%). Six patients underwent enucleation, 6 patients underwent distal pancreatectomy, 2 patients underwent subtotal (80%) distal pancreatectomy, and one patient a pylorus preserving pancreaticoduodenectomy (PPPD). Two patients, one of whom belonged to the MEN-I group, underwent reoperations because they had multiple adenomas. The development of iatrogenic diabetes occurred in the case of 3 patients. These results suggest that the use of selected preoperative localization studies (PTPVS and probably EUS) may be very helpful for detecting insulinoma, and that IUS is an essential part of the operative exploration for insulinoma. Our data may further indicate the need for an aggressive surgical procedure in the case of multiple adenoma or insulinoma in MEN-I.

Adult↗

PubMed1998

Effect of the angiotensin-converting enzyme inhibitor enalapril on post-transplant erythrocytosis.

Post-transplant erythrocytosis (PTE) is increasingly recognized as a complication of kidney transplantation. In this study we report the effect of the angiotesin-converting enzyme (ACE) inhibitor enalapril on hematocrit (Ht) and erythropoietin in four patients with PTE. Four renal allograft recipients with Ht greater than 51% were studied. Treatment was initiated with enalapril administered orally at a dose of 2.5 mg/day. All the patients had an increase of hemoglobin (Hb) (17.7 +/- 0.64 g/dl), Ht (54.5 +/- 1.29%) and red blood cell count (RBC) (584 +/- 19.2 x 10(4)/microliter). All patients responded to enalapril in 8 weeks with a significant decrease of Hb, Ht, and RBC. In one patient, the downward trend was more rapid and sustained, and treatment had to be discontinued to prevent the development of anemia. Serum erythropoietin showed normal in all four patients and remained unchanged during the study, even after discontinuation of enalapril treatment. Serum creatinine remained relatively stable throughout the study. These results suggest that PTE may not be dependent upon circulating erythropoietin and that enalapril treatment may be an effective treatment of PTE without renal dysfunction.

Adult↗

PubMed1997

Protective effect of monoclonal antibodies to adhesion molecules on rat liver ischemia-reperfusion injury.

BACKGROUND: The source of reactive oxygen species in the liver remains to be elucidated. The present study was undertaken to determine whether polymorphonuclear neutrophils (PMNs) can contribute to hepatic ischemia-reperfusion injury, and pretreatment with monoclonal antibodies (mAbs) to intercellular adhesion molecule-1 (ICAM-1), lymphocyte function associated antigen-1 (LFA-1), and CD 18 could improve energy metabolism and prolong the viability of the organ. METHODS: Male Wistar rats were used. Rat liver ischemia was induced by clamping blood vessels supplying median and left lateral hepatic lobes. Monoclonal antibodies to ICAM-1, LFA-1, or CD18 were injected intravenously 5 minutes before inducing ischemia. To determine the effect of mAbs on the survival rate, total hepatic ischemia was induced by clamping the hepatic artery, portal vein, and bile duct after making a portafemoral shunt. RESULTS: Although ischemia of the liver for 90 minutes did not permit survival of the animals, pretreatment with mAbs to ICAM-1 plus LFA-1 increased the survival rate to 57%. Pretreatment with mAb to ICAM-1 failed to increase the survival rate. The number of PMNs in the liver increased continually up to 24 hours after reperfusion after 90 minutes of ischemia, and the expression of ICAM-1 was enhanced 4 hours after reperfusion. This is accompanied by a low recovery of hepatic adenosine triphosphate and, on the contrary, a marked increase in lipid-peroxide in the reperfused liver. Pretreatment with mAbs suppressed the infiltration of PMNs and the elevation of lipid peroxide and enhanced the recovery of hepatic adenosine triphosphate 6, 12, or 24 hours after reperfusion. Pretreatment with mAbs also prevented the rise in serum alanine aminotransferase level after reperfusion. CONCLUSIONS: These results suggest that PMNs contribute to ischemia-reperfusion injury in the liver 4 hours and more after reperfusion, and pretreatment with mAbs to adhesion molecules is useful for the prevention of ischemic liver cell injury.

Adenine Nucleotides↗

PubMed1997

TNF-alpha release from human peripheral blood mononuclear cells to predict the proinflammatory activity of cytokines and growth factors.

Therapeutic applications of novel growth factors and cytokines can be limited due to the oftentimes severe inflammatory reactions that are encountered in patients following parenteral administration. These inflammatory responses, hallmarked by fever, headache, and chills are mediated by the release of inflammatory cytokines following administration of protein-based therapeutics. TNF-alpha appears to be one of the most potent and pleiotropic inflammatory cytokines released during the early stages of an inflammatory response. In the present study, we have explored the use of an in vitro assay system to determine whether the release of TNF-alpha from human PBMC could be correlated with documented inflammatory activity in humans. The cytokines tested included rhGM-CSF, rhIL-2, rhIL-3, and rhIFN-gamma, rhG-CSF, which has been shown to lack substantial proinflammatory activity in humans, was also tested. The potent macrophage activator and inflammatory agent, LPS, was used as a positive control. Results of this study demonstrate and confirm an association between the inflammatory activity of cytokines observed in patients and the stimulation of TNF-alpha release from PBMC in vitro. This assay system can be used as a predictive tool in determining the inflammatory potential of novel growth factors and cytokines.

Cytokines↗