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Biomedical subjects

S Wakasugi

Publications and source records attributed to S Wakasugi.

At least 37 records · Page 2Linked to original sources
PubMed1995

[Changes of liver function measured by 99mTc-GSA scintigraphy after hepatectomy].

In 14 patients with hepatic tumors, liver volume and liver function indices were studied by 99mTc-GSA liver scintigraphy before and after hepatectomy. The liver volume measured by 99mTc-GSA SPECT was significantly decreased after surgery in all 14 patients (p < 0.001). Postsurgically, 7 patients showed an increase of greater than 10% in the LU15 value, while 3 showed a decrease of 10% in the LU15 value, while 3 showed a decrease of 10%. Two patients showed a decrease of greater than 10% in the HH15 value after surgery. The changes in LU15 after surgery were inversely correlated with those in HH15. The present findings clarified that in several cases of surgically treated hepatic tumors, 99mTc-GSA indices of liver function generally thought to indicate the size of the functioning liver cell mass were distinctly improved after surgery in comparison with those before surgery, despite the postoperative decrease in the liver volume. Furthermore, the results of a 99mTc-GSA SPECT study separately measuring the volume of the unilateral hepatic lobe and its radioactivity uptake, indicated that regeneration of the functioning liver cells often occurred in the entire liver. 99mTc-GSA scintigraphy appears to be a valuable method for evaluating changes in both the liver volume and the liver function indices after hepatectomy.

Aged↗
PubMed1995

[Influence of intratumor administration of OK-432 on the tumor selectivity of 5'-DFUR].

The influence of intratumor administration of OK-432 on the tumor-selective antitumor effect of 5'-DFUR was studied in 49 patients with advanced gastric cancer. The patients were divided into 4 groups that received oral 5'-DFUR, intratumor OK-432, oral 5'-DFUR plus intratumor and intracutaneous OK-432, or no therapy before operation. Using surgical specimens, the PyNPase activity and 5-FU content were measured, and the localization of PyNPase was determined immunohistologically. The results were as follows: 1) 5'-DFUR therapy decreased intratumor PyNPase activity whereas administration of OK-432 increased it. 2) PyNPase activity was higher in cancer tissue than in normal tissue for all groups. 3) The 5-FU content of cancer tissue was higher in patients receiving OK-432 plus 5'-DFUR than in patients receiving 5'-DFUR alone. 4) In the resected tumors, PyNPase was mainly localized in the cancer cells of some patients and in the stromal cells of others. Thus, the localization of PyNPase showed two major patterns.

Antineoplastic Agents↗
PubMed1994

A novel isoform of the neurofibromatosis type-1 mRNA and a switch of isoforms during murine cell differentiation and proliferation.

Four types of cDNAs encoding the GTPase-activating protein-related domain (GRD) of the mouse neurofibromatosis type-1 gene (NF1) have been cloned. One of these isoforms was a newly identified form termed type IV. Analysis of the genomic structure of the mouse NF1-GRD revealed two exons (23A and 23B) between exons 23 and 24, leading to the production of four types of NF1-GRD cDNAs by an alternative splicing mechanism. Amino-acid sequences encoded by NF1-GRD are highly conserved between human and mouse. Analysis of the expression of these transcripts in various tissues of adult mouse revealed that the type-I transcript is predominantly expressed in neural tissues such as brain and spinal cord. Other forms, termed types II, III and IV, are also expressed in various tissues. The type-I and type-II transcripts are expressed equivalently in undifferentiated P19 mouse teratocarcinoma cells, whereas type-I expression becomes predominant during neuronal differentiation by retinoic acid treatment. Expression of type I is also shown to be correlated with cessation of cell proliferation in P19 cells, but not in NIH3T3 cells. These, together with other results, suggest that the four types of NF1-GRD transcripts generated by alternative splicing have some important biological roles in cell differentiation and proliferation.

Alternative Splicing↗
PubMed1994

Chronic active hepatitis in transgenic mice expressing interferon-gamma in the liver.

Interferon-gamma may play an important role in the immune response and in inflammatory diseases, including chronic active hepatitis. To understand the role of interferon-gamma in the regulation of inflammation and to establish a mouse model of chronic active hepatitis, we produced transgenic mice in which the mouse interferon-gamma gene was regulated by a liver-specific promoter, the serum amyloid P component gene promoter. Four transgenic mouse lines were generated, and two of these lines expressed mRNA of interferon-gamma in the liver. Levels of serum transaminases increased gradually as a function of age and were significantly higher than those of interferon-gamma-negative littermates after 4 weeks after birth. One transgenic mouse line showed a histology of chronic active hepatitis similar to that found in human patients, although cirrhotic changes such as fibrosis were scarce. Thus, the liver-specific production of interferon-gamma is sufficient to induce chronic inflammatory disease and this mouse is a transgenic model of chronic active hepatitis.

Alanine Transaminase↗
PubMed1994

[Study on intratumor administration of lentinan--primary changes in cancerous tissues].

Lentinan was administered for gastric cancer in order to determine what type of changes would occur as a consequence. In an experimental study, the intraperitoneal administration of lentinan on cancerous tissues caused a marked development of reticular fibers, along with an enhanced interstitial response. Findings which support the relationship between a marked development of reticular fibers and an anti-tumor effect, were also obtained. Furthermore, lentinan was administered for human gastric cancer to evaluate whether or not an increase in interstitial response would be observed. As a result, reticular fibers developed in tumor sites with a resultant fragmentation of cancer cell nests. Many T lymphocytes infiltrated cancer sites where the lentinan was administered. These findings suggest that the intratumor administration of lentinan enhanced an interstitial response and also activated an anti-tumor immune response in the human gastric cancer tissues.

Animals↗
PubMed1994

[Assessment of QOL in cancer drug therapy using 22-item questionnaire].

In order to integrate quality of life as the end point in the cancer drug therapy, a questionnaire form has been developed over the past four years by a Grant-in-Aid for Cancer Research from the Ministry of Health and Welfare, Japan. Fifty-one items generated by questionnaires were forwarded to oncologists, nurses, psychologists and 121 patients. Then questionnaires were scaled down to 36 items based upon factor analysis considering correlation to State-Trait Anxiety Inventory (STAI) and Self-rating Depression Scale (SDS). These 36 items were administered to 536 patients. Finally, a 22-item questionnaire was completed by rechecking correlations with PS, STAI, SDS and Cronbach's alpha. It includes such components as physical activities (6 items), psychological (5 items) and social variables (5 items), symptoms (5 items) and global well-being (1 item: face scale). In our treatment of G. I. cancer by chemotherapy, NC patients showed improvement (+1.56 score), especially in physical functions (+2.43 score), but with slight deterioration (-0.25 score).

Female↗
PubMed1993

An efficient gene-trap method using poly A trap vectors and characterization of gene-trap events.

New trap vectors (U1 and U2) have been developed to trap genes in murine embryonic stem (ES) cells. The polyA addition signal of the neomycin phosphotransferase II (neo) gene was removed from these vectors so that they needed to trap an endogenous polyA signal for expression of the neo gene. The frequency of gene-trap events of these vectors was about five times higher than with the vector containing the polyA signal, and only one copy of the trap vector was integrated in most cases. Four out of five 5'-flanking regions of the integrated vector in ES cell lines were found to be novel endogenous promoters, suggesting that this method is efficient for trapping genes in ES cells. In two cases analyzed, large deletions or rearrangements spanning more than 10 kb were found in the 3'-flanking region of the trap vector introduced by electroporation. This result suggests that phenotypes observed in homozygotes with a mutated allele could be due to the disruption of a gene adjacent to the trapped gene, but not of the trapped gene.

Animals↗
PubMed1993

Metaiodobenzylguanidine: evaluation of its potential as a tracer for monitoring doxorubicin cardiomyopathy.

We evaluated alterations in cardiac adrenergic neuron activity and progression of left ventricular dysfunction in comparison with the severity of structural changes using a rat model of adriamycin cardiomyopathy. Rats were treated with adriamycin (2 mg/kg s.c. once a week) for 6, 7, 8 and 9 wk. Accumulation of 125I-metaiodobenzylguanidine (MIBG) 4 hr after intravenous administration was determined and left ventricular ejection fraction (LVEF) was calculated from gated blood-pool images. H & E and Masson-Trichrome stained specimens of the myocardium were examined by light microscopy. Histopathologic examination demonstrated dose-dependent myocyte damage, although there were no differences between the 8-wk and 9-wk groups. LVEF did not differ between controls and the 6-wk group (81.3% +/- 5.5% versus 82.1% +/- 4.8%, p = ns). LVEF began to decrease slightly in the 7-wk group (75.0% +/- 5.7%, p < 0.05) and showed a remarkable decrease in the 8-wk group (53.7% +/- 2.6%, p < 0.001). In the 9-wk group, LVEF diminished to 47.9% +/- 3.1% (p < 0.001), accompanied by massive pleural effusions and ascites. MIBG accumulation in the heart (%ID/heart) significantly and progressively diminished; 1.42% +/- 0.15% in the 6-wk group, 1.06% +/- 0.16% in the 7-wk group, 0.77% +/- 0.13% in the 8-wk group and 0.34% +/- 0.11% in the 9-wk group, respectively p < 0.001, compared to controls (1.99% +/- 0.30%). These results demonstrate that MIBG accumulation in the heart showed a greater and more linear dose-dependent decrease than LVEF. Furthermore, MIBG uptake was significantly reduced in the 6-wk group where only mild myocyte damage (isolated vacuolation or myofibrillar loss) was observed. Thus, MIBG may be a sensitive biochemical marker of adriamycin cardiomyopathy.

3-Iodobenzylguanidine↗
PubMed1993

Myocardial substrate utilization and left ventricular function in adriamycin cardiomyopathy.

We evaluated alterations of substrate utilization in a rat model of adriamycin cardiomyopathy with deteriorating left ventricular function. Rats were treated with adriamycin (2 mg/kg), once a week for 6, 8, 9 and 10 wk. Fluorine-18-F-deoxyglucose (18F-FDG) and 125I-beta-methyl-branched fatty acid (125I-BMIPP) were used as tracers of glucose and fatty acid metabolism and 99mTc-hexakis (2-methoxyisobutyl-isonitrile) (99mTc-MIBI) was used as a myocardial blood flow tracer. Left ventricular ejection fraction (LVEF) calculated from gated blood pool images was used as an indicator of cardiac function. LVEF was normal in the 6-wk group (78.0% +/- 4.8%), abruptly decreased in the 8-wk group (43.1% +/- 10.1%) and further deteriorated in the 9-wk group (27.6% +/- 13.4%). Accumulation of 18F-FDG (%kgID/g) in the hearts of adriamycin treated animals progressively decreased compared to controls (2.19% +/- 0.38%); 1.47% +/- 0.42% (p < 0.01) at 6 wk, 1.22% +/- 0.27% (p < 0.001) at 8 wk, 0.69% +/- 0.56% (p < 0.001) at 9 wk and 0.50% +/- 0.08% (p < 0.001) at 10 wk. This decrease occurred earlier than the deterioration in LVEF. Myocardial accumulation of 125I-BMIPP decreased in the advanced stages of adriamycin cardiomyopathy and was well correlated with the decrease in 18F-FDG accumulation. However, the decrease was less profound than for 18F-FDG; 53.7% +/- 9.8% versus 31.6% +/- 25.4% of control at 9 wk (p = NS), 49.5% +/- 15.3% versus 22.6% +/- 3.5% of control at 10 wk (p < 0.05). Accumulation of 99mTc-MIBI did not differ between controls and the adriamycin treated groups. There were no differences in blood glucose levels between controls and adriamycin treatment groups. Both glucose and fatty acid utilization are decreased in adriamycin-induced cardiomyopathy and these critical impairments in energy metabolism are associated with heart failure. Impaired myocardial glucose utilization measured with 18F-FDG may be a particularly sensitive marker of adriamycin cardiomyopathy.

Animals↗
PubMed1992

Thrombin-induced calcium oscillation in human platelets and MEG-01, a megakaryoblastic leukemia cell line.

Digital imaging microscopy revealed that human platelets show periodic intracellular Ca++ elevation in response to 0.01 U/ml thrombin. MEG-01, a megakaryoblastic leukemia cell line, also responded with oscillatory intracellular Ca++ elevation (0.7-1 times/min) to thrombin (0.001-0.003U/ml). Ca++ transients appears to be fused with higher thrombin doses. With extracellular Ca++ concentrations of 0.1 mM or less, Ca++ oscillation could not be elicited, or even when present, it disappeared after a few spikings of [Ca++]i. Extracellular Ca++ concentrations of 0.3 mM or more were required to facilitate ongoing Ca++ oscillation, suggesting an important role of Ca++ influx for Ca++ oscillation.

Blood Platelets↗
PubMed1992

Detection of abnormal cardiac adrenergic neuron activity in adriamycin-induced cardiomyopathy with iodine-125-metaiodobenzylguanidine.

Radiolabeled metaiodobenzylguanidine (MIBG), an analog of norepinephrine (NE), serves as an index of adrenergic neuron integrity and function. Using a rat model of adriamycin-induced cardiomyopathy, we tested the hypothesis that abnormal cardiac adrenergic neuron activity may appear and be exacerbated dose-dependently in adriamycin cardiomyopathy. The degree of vacuolar degeneration of myocardial cells was analyzed in relation to the duration of adriamycin treatment (2 mg/kg, once a week). There were no abnormalities or only isolated degeneration in the 1- or 2-wk treatment groups, isolated or scattered degeneration in half of the 3-wk group, frequent scattered degeneration in the 4-wk group, scattered or focal degeneration in the 5-wk group, and extensive degeneration in the 8-wk group. Myocardial accumulation of [125I]MIBG 4 hr after intravenous injection did not differ between the controls and the groups treated 3 wk or less. However, the 4-wk group had a slightly lower accumulation in the right ventricular wall (82% of the control) and significantly lower accumulation in the left ventricular wall (about 66% of the control: p less than 0.05). In the 5-wk group, MIBG accumulation in the right and left ventricular wall was 35% and 27% of that in controls, respectively (p less than 0.001). In the 8-wk group, MIBG accumulation in the right and left ventricular wall was 18% and 14% of that in controls, respectively (p less than 0.001). Thus, MIBG accumulation in the myocardium decreased in an adriamycin dose-dependent manner. The appearance of impaired cardiac adrenergic neuron activity in the presence of slight myocardial impairment (scattered or focal vacuolar degeneration) indicates that MIBG scintigraphy may be a useful method for detection of adriamycin-induced cardiomyopathy.

3-Iodobenzylguanidine↗
PubMed1991

Role of serum amyloid P component for systemic amyloidosis in transgenic mice carrying human mutant transthyretin gene.

The role of serum amyloid P component (SAP) for systemic amyloidosis in a transgenic mouse model for an autosomal dominant disease, familial amyloidotic polyneuropathy (FAP), was examined. For this purpose, two lines of transgenic mouse were produced by introducing the human mutant transthyretin (TTR) gene and the human SAP gene, respectively. Two lines of transgenic mice were mated to produce double transgenic mice carrying both human mutant TTR gene and human SAP gene. The serum concentration of human SAP in these transgenic mice was about 42 micrograms/ml and was about equal to that in human control serum. In case of single transgenic mice carrying human mutant TTR gene, amyloid deposition starts at around 6 months of age, and the amount of amyloid deposition increases gradually with age. Amyloid deposition is observed in many tissues including heart, kidney and thyroid gland, where amyloid deposition is commonly observed in FAP patients. In double transgenic mice, onset, progression and tissue distribution of amyloid deposition were the same as those in single transgenic mouse. These results clearly suggest that SAP is not important for the initiation and progression of amyloid deposition.

Age Factors↗
PubMed1991

Systemic amyloidosis in transgenic mice carrying the human mutant transthyretin (Met30) gene. Pathologic similarity to human familial amyloidotic polyneuropathy, type I.

To analyze the pathologic processes of amyloid deposition in type I familial amyloidotic polyneuropathy (FAP), mice were made transgenic by introducing the human mutant transthyretin (TTR) gene. In these transgenic mice, amyloid deposition started in the gastrointestinal tract, cardiovascular system, and kidneys 6 months after birth and extended to various other organs and tissues with advancing age. At age 24 months, the pattern of amyloid deposition was similar to that observed in human autopsy cases of FAP, except for its absence in the choroid plexus and in the peripheral and autonomic nervous systems. Amyloid deposition was shown to be composed of human mutant TTR and, in addition, mouse serum amyloid P component. These results clearly indicate that human variant TTR produced in transgenic mice deposits is a major component of amyloid fibrils in various organs and tissues. Thus this animal model is useful for analyzing how amyloid deposition initiates and proceeds in FAP.

Amyloid↗
PubMed1989

Liver-specific and high-level expression of human serum amyloid P component gene in transgenic mice.

To analyze the regulation of human serum amyloid P component (SAP) gene expression, we have produced seven transgenic mice. The 3.3 kb human SAP genes containing about 0.8 kb of 5' and 1.5 kb of 3' flanking region were injected into fertilized eggs of C57BL/6 mice. In five of the seven transgenic mice, human SAP was detected in the sera and serum concentrations were higher than that of human serum in three lines. The human SAP gene was expressed only in the liver. Amounts of human mRNA in the liver and serum concentrations of human SAP were roughly proportional to the copy number of the integrated gene. Human SAP production lowered the serum levels of mouse endogenous SAP. With the intraperitoneal administration of lipopolysaccharide, the mRNA levels in the liver and serum levels of mouse SAP increased several-fold in both the control and transgenic mice. On the other hand, neither the mRNA nor the serum levels of human SAP increased significantly.

Animals↗
PubMed1989

Transgenic mouse model of familial amyloidotic polyneuropathy.

Familial amyloidotic polyneuropathy (FAP) is a dominantly inherited disorder, characterized by the extracellular deposition of amyloid fibrils composed of variant transthyretin (TTR), and by prominent peripheral nerve involvement. We demonstrate that the main cause of this disease is the presence of a point mutation in the TTR gene. However, neither the time of onset nor the clinical course is predictable. To elucidate the molecular pathogenesis of this disease, we constructed transgenic mice carrying and expressing the human mutant TTR gene. In these mice, amyloid is deposited in the alimentary tract as early as age six months, and becomes more remarkable with aging. These transgenic mice should be useful in elucidating factors which modulate the time of onset and the clinical course of FAP, and in establishing therapy for this intractable disorder.

Amyloidosis↗
PubMed1988

An autosomal dominant mutation of facial development in a transgenic mouse.

We have created a transgenic mouse which showed an autosomal dominant mutation of facial development. This facial malformation was characterized by a short snout and a twisted upper jaw. All offspring showing the dysmorphic phenotype carried the injected gene. In order to analyze the primary cause of this mutation, newborn mice and embryos were examined. The outcome was that the malformation of nasal and premaxillary bone was not the primary defect but was a secondary event. The primary cause of this dysmorphism was a developmental defect in the first branchial arch. Genomic DNA fragments flanking the insertion site of this mutant mouse were cloned. Using these fragments, we have assigned the integration site to chromosome 13. The gene responsible for a previously reported mutant mouse, one which also has a short snout, is also reported to be on chromosome 13. In the fragments flanking the insertion site of the transgenic mouse, at least one fragment was highly conserved in mammals. These results indicate that this malformation is due to the insertional disruption of a host gene. However, the possibility that this mutation is caused by an inappropriate expression of the injected gene still remains to be investigated.

Animals↗
PubMed1988

Expression of tissue-specific genes in transgenic mice.

The ability to introduce cloned genes into mouse germ line has been used for analyzing cis-acting DNA sequences involved in tissue-specific and developmental regulation of the introduced gene. Using this system we have attempted to produce a transgenic mouse model for human dominantly inherited disease, familial amyloidotic polyneuropathy. Recently the mutant transthyretin gene which is considered to be responsible for this disease has been cloned and well characterized at molecular level. We have produced transgenic mice by microinjecting human mutant gene. Amyloid deposition was observed in the mucosa of alimentary tract and renal glomeruli, suggesting that this approach is successful in establishing the mouse model for human genetic disease. In addition, these experiments suggest that the expression of the mutant gene is regulated normally during developmental process and that the cause of adult onset is not due to the dysregulation of this gene expression.

Amyloidosis↗