Biomedical subjects
Publications and source records attributed to Y Fukuda.
We performed laparoscopic survey and treatment on a 17-year-old girl who was diagnosed as having complete midgut nonrotation. The Ladd procedure was successfully performed laparoscopically. The patient was discharged 6 days after the operation. Laparoscopic operation is a useful tool for the correct diagnosis and treatment of intestinal malrotation disease in the adult patient.
We performed transhiatal subtotal esophagectomy under laparoscopic guidance to reduce the invasiveness of subtotal esophagectomy while preserving dissectional accuracy. In six cases of advanced thoracic esophageal cancer with distant metastasis, we used a special type of handpiece of ultrasonic surgical aspirator (CUSA) for laparoscopic surgery to dissect the esophagus from surrounding tissues and to isolate vessels entering it while viewing with the video monitor. Hemostasis of isolated vessels was effected by clips or electrocoagulation. There was no massive bleeding from the mediastinum during the operation, nor was there postoperative bleeding or infection. All patients regained normal swallowing ability and were discharged. Transhiatal esophagectomy under laparoscopic guidance is considered a safe, less invasive operative treatment for patients who are suffering from advanced thoracic esophageal cancer.
A 43-year-old woman was admitted to our hospital for sigmoid colon cancer with multiple liver metastasis (H3). As preoperative CTAP (CT during arterial portography) examination showed 23 metastatic nodules in the whole liver, hepatic resections were not indicated. Angiographic findings showed that right and left hepatic arteries branched separately from the celiac artery. Sigmoid colon resection with D3 lymph node dissection and catheterization to the right hepatic artery via gastroduodenal artery were undertaken as a first operation. Continuous hepatic artery infusion chemotherapy with MMC, 5-FU oriented by in vitro chemosensitivity test (SDI test: Succinic Dehydrogenase Inhibition test) of primary tumor was performed 7 days after the first operation. After administration of MMC (40 mg) and 5-FU (16,500 mg), metastatic nodules in the right lobe almost disappeared except for the one tumor of S7, but the size and number of the nodules in the left lobes increased. At 10 months after the first operation, the left hepatic lobectomy and extirpation of only one tumor in the right lobe (S7) underwent. This case showed the usefulness of continuous hepatic artery infusion chemotherapy oriented by in vitro chemosensitivity test for multiple liver metastasis from colon cancer.
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As a nature of central neurons, retinal ganglion cells (RGCs) of adult mammals cannot regenerate spontaneously, but rather, degenerate retrogradely after optic nerve (ON) transection. Recent studies have clarified that some RGCs survive axotomy and regrow their axons through the graft when the peripheral nerve is transplanted to the cut stump. However, the numbers of regenerated fibers are still quite small and a great majority of RGCs die after axotomy. Studies on the rodent and cat retinas have revealed that vulnerability to axotomy differs among RGC types. Especially in the cat retina, X/beta cells are more vulnerable to axotomy than other cells. Several neurotrophic factors such as brain-derived neurotrophic factor (BDNF) and neurotrophin-4 or 5 (NT-4/5) are effective to rescue RGCs from retrograde cell death, and promote growth of intraretinal axons. Localization of their receptors is also demonstrated in RGCs. On the other hand, evidence has been accumulated that regenerated ON fibers reform functional synapses with central visual neurons and thereby axotomized RGCs survive longer. These reformed retino-collicular synapses enabled the animals to recover the ability of light-dark discrimination.
The mammalian cell cycle is controlled by regulators of the G1 to S transition such as tumor suppressor proteins, p53 and retinoblastoma (RB); cyclin D1 and cyclin-dependent kinase 4; and inhibitor of cyclin dependent kinase, p16INK4A. Recently, aberrations of these cell cycle-related genes have been reported to contribute to the formation and development of cancer. In human hepatocellular carcinoma (HCC), high frequencies of aberration have been detected in the p53 and RB genes. Loss of heterozygosity (LOH) of chromosome 13q was detected in 35% of HCC and LOH on chromosome 17p was detected in 49%. Mutation of the p53 gene was also detected in 32%. The aberrations of these genes were observed more frequently in poorly differentiated and in advanced HCCs. On the other hand, genetic alterations of the cyclin D1 and p16INK4A genes were not so frequent, but appeared to be associated with the aggressive behavior of the tumor, which suggests that disruption of the cell cycle-related genes results in the progression of HCC. Further study with a substantial number of cases is required to determine the actual frequency of the aberrations of the G1 controlling genes in hepatocarcinogenesis.
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Preservation with University of Wisconsin (UW) solution can maintain liver graft function and produces survival rates of recipients higher than that with Euro Collins (EC) solution. To explore the underlying mechanisms, we transplanted rat livers following cold preservation with EC or UW solution for 18 hr, and measured hepatic adenine nucleotide levels, the percentage of water content, lactate levels, and endogenous antioxidant levels (alpha-tocopherol [alpha-Toc], reduced coenzyme Q9 [CoQ9H2], reduced coenzyme Q10, [CoQ1OH2] and reduced glutathione [GSH] during preservation and after transplantation. The adenosine triphosphate levels of the liver grafts preserved with UW solution recovered after reperfusion more rapidly and reached a higher level than those preserved with EC solution. UW solution caused a reduction in hepatic water content during preservation. Conversely, EC solution induced remarkable tissue edema. In addition, UW solution reduced the rate of hepatic lactate production both during preservation and after reperfusion. The concentrations of hepatic GSH, alpha-Toc, CoQ9H2, and CoQ1OH2 immediately after the graftectomy, and after the 18 hr of preservation with both EC and UW solutions, did not differ from those in the normal liver, and decreased only after transplantation. However, UW solution suppressed significantly the reduction in hepatic GSH, alpha-Toc, and CoQ9H2 after reperfusion, compared with EC solution. These results suggest that long-term cold storage induces tissue edema, reflecting a disturbance of the microcirculation during preservation, followed by parenchymal cell damage mediated by free radicals after reperfusion. The protective effects of UW solution could be attributable to the inhibition of free radical production after reperfusion.
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Peripheral nerve (PN) was grafted to sectioned optic nerve and was bridged to the superior colliculus in adult rats. To test functional recovery of restored retinocollicular pathway, we examined cortical electroencephalogram (EEG) and behavioral arousal responses to light stimuli. In eight of 10 recording trials in PN grafted rats (n = 6) and in all of eight trials in normal rats (n = 5), cortical EEGs showed desynchronization to light stimuli. On the other hand, after bilateral sections of the optic nerve (n = 3) EEG desynchronization to light disappeared while it was induced by a white noise. Mean threshold duration of light for EEG desynchronization was significantly longer in the PN grafted rats (440 ms) than in normal rats (173 ms). In three of six trials in PN grafted rats (n = 4), and in four of eight trials in normal rats (n = 4), EEG desynchronization elicited by light stimulus was accompanied by behavioral arousal responses, whereas no behavioral arousal could be induced by light in blind rats (n = 3). These results strongly suggest that visual information processed through the restored retinocollicular pathway was further transmitted to the cerebral cortices and ultimately resulted in behavioral arousal of the PN grafted rats.
STUDY DESIGN: This study investigated the effects of hypoxia and glucose on motor functions of spinal cord, monitoring ventral root motor-evoked potential in the in vitro cervical cord preparations. OBJECTIVE: To study ischemia-induced changes in ventral root motor-evoked potential of spinal cord. SUMMARY OF BACKGROUND DATA: Previous studies demonstrated ischemic changes caused by local circulatory impairment might be a major pathophysiologic basis of neuron damage in cord compression. METHODS: Ventral root motor-evoked potential elicited by stimulation of ventrolateral funiculus was recorded from the ventral root in the isolated spinal cord preparations obtained from a newborn rat. The preparations were exposed to artificial cerebrospinal fluid equilibrated with severe or mild hypoxia for 90 minutes. Inhibitory and excitatory neurotransmitter antagonists were added to artificial cerebrospinal fluid to investigate synaptic transmission. The artificial cerebrospinal fluids containing various concentrations of glucose were used to study the glucose's effects. RESULTS: Ventral root motor-evoked potential consisted of the early and late components, which were excitatory transsynaptic potentials. The amplitudes were increased in the early phase of severe hypoxia and declined in the prolonged exposure. In mild hypoxia, there was a sustained increase of the amplitudes. The application of inhibitory neurotransmitter antagonists abolished the augmentation of the amplitudes in the early phase of severe hypoxia. Hypoxia without glucose accelerated hypoxic change. CONCLUSION: Inhibitory synaptic transmission was depressed preferentially in the early phase of severe hypoxia or in mild hypoxia. Excitatory and inhibitory transmissions were suppressed in prolonged severe hypoxia. Glucose deficiency aggravated hypoxic inhibition of synaptic transmissions.
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Hemophiliac patients with chronic hepatitis C might be exposed to and become infected with multiple hepatitis C virus (HCV) strains by means of frequent use of blood products, even if they are infected with a single subtype of HCV. To test this hypothesis, we analyzed the genetic diversity of hypervariable region 1 (HVR1) of HCV in chronically infected hemophiliacs and in patients with chronic posttransfusion hepatitis with a single HCV inoculation. The diversity of nucleotide sequences in HVR1 of serum HCV RNA was compared between 21 hemophiliacs infected with a single HCV subtype and 16 patients with posttransfusion HCV infection. The number of HCV quasispecies was determined by fluorescence single-strand conformation polymorphism (SSCP) analysis. Direct sequencing was performed to determine the diversity in HVR1. The number of HCV quasispecies in the blood was 5.2 +/- 2.0 clones in hemophiliacs and 4.0 +/- 2.3 clones in posttransfusion patients, a nonsignificant difference (P = .0943). The number of sites at which the nucleotide was not homogenous in all quasispecies was significantly higher in hemophiliacs (13.0% +/- 7.4%) than in posttransfusion hepatitis patients (2.7% +/- 2.8%; P < .0001). In conclusion, there was a high degree of genetic variation in HVR1 of HCV specimens isolated from hemophiliacs compared with posttransfusion patients. These findings indicate the possibility that multiple infections of a single HCV subtype may occur among patients frequently exposed to blood products; single HCV subtypes may therefore derive from multiple origins.
Polyclonal antibody against human natriuretic peptide receptor B (NPR-B) was produced using as immunogen a soluble chimeric protein consisting of the extracellular domain of the receptor fused with Fc portion of human IgG. The antibody was purified with protein A column, and then subjected to an adsorption of anti-Fc antibody using IgG column. The purified antibody recognized human NPR-B but not the related receptor NPR-A. The antibody inhibited C-type natriuretic peptide (CNP)-mediated intracellular cGMP accumulation in a dose-dependent manner. With regard to specific activity for the neutralization, the antibody purified with IgG column was significantly stronger than that before the adsorption step, indicating that the purification of the antibody with IgG column was extremely effective to remove the contaminating anti-Fc antibody from anti-NPR-B antibody. Western blot analysis using the purified antibody revealed that while the native NPR-B exists as an oligomer, the truncated NPR-B lacking most of its cytoplasmic domain is a monomer. This finding suggests that the cytoplasmic region may be involved in the oligomerization of the receptor. The results in this study demonstrate that soluble IgG fusion protein is very effective and useful for generating specific antibodies to the proteins expressed on cell surface.
Two groups of rats received different amounts of peripheral deafferentations; one group received sections of sciatic nerve (S-rats) and the other received sections of sciatic and saphenous nerves (SS-rats). In Experiment 1 the occurrence of autotomy was compared between S- and SS-rats for up to 70 days after the surgery. Autotomy in SS-rats frequently recurred until 40 days after denervation whereas in S-rats it scarcely recurred. In Experiment 2 spontaneous activity was recorded from the spinal cords in S- and SS-rats, and the proportion of burst firing cells (B-cells), characterized by periodic and high frequency bursts, was compared. In both S- and SS-rats with fresh wounds the occurrence of B-cells was high until 40 days after denervation. However, B-cells were still frequently observed in SS-rats with old wounds until 40 days after denervation, whereas B-cells were scarcely found in S-rats with similar old wounds. This finding corresponded well with the behavioral observation in Experiment 1. The data strongly suggests that the continuance of a high proportion of B-cells in the spinal cord plays an essential role for the induction of recurrent autotomy.
We examined the genomic status of the p16INK4A (inhibitor of cyclin-dependent kinase 4 A) and cyclin-dependent kinase 4 (CDK4) genes in 62 human hepatocellular carcinomas (HCCs), 5 cholangiocellular carcinomas and 6 cell lines derived from human liver cancers. Although no samples showed the homozygous deletion of the p16INK4A gene, we detected intragenic mutations of the p16INK4A gene in 3 HCCs and one HCC cell line, which led to an amino-acid substitution or a frameshift. In 2 HCC samples with mis-sense mutations of the p16INK4A gene, loss of heterozygosity on 9p22 was also detected, suggesting that the loss of function of p16 was induced during hepatocarcinogenesis. On the other hand, amplification or rearrangement of the CDK4 gene was not detected in any samples examined in this study. These results indicated that the mutations or deletions of the p16INK4A gene are not frequent, but may play a role in a sub-set of human HCC.
The stage-specific embryonic Ag-1 (SSEA-1) is a carbohydrate Ag and regarded as an onco-developmental Ag. Sialyl SSEA-1 Ag, the sialylated form of SSEA-1, is frequently expressed in human cancer cells as well as in murine cancer cells. A mAb, FH-6, was shown to specifically recognize the Ag. We have generated five anti-Id Abs directed to the paratope-related idiotopes of the FH-6 Ab. One of these anti-Id Abs, Id-F2, increased the survival of host mice that were inoculated with Meth-A cells expressing the sialyl SSEA-1 Ag. To clarify the exact mechanism underlying the antitumor effect of the anti-Id Ab, we established a T cell line that recognized Id-F2 in association with MHC class II molecules. The T cell line was CD4+V beta 8+, and produced IL-2, exhibiting helper activity for B cells. The VH CDR2 region of the Id-F2 amino acid sequences turned out to be strongly immunogenic to T cells. When the immune complexes, consisting of the sialyl SSEA-1 Ag, FH-6, and Id-F2, were formed at the Meth-A cell-surface, the T cell line showed a strong proliferative response. The possible roles played by such T cell subsets in the anti-tumor effect are discussed.
The state of DNA methylation in the c-fos gene was examined in human livers of different ages, cirrhosis and hepatocellular carcinoma. The degree of methylation in the intron 1 to exon 4 region increased with age, whereas all of the 10 cirrhosis samples revealed a decrease in methylation when compared to normal livers of similar ages. The 11 hepatocellular carcinomas showed varied alterations suggesting that the alteration of the c-fos gene methylation is related to aging as well as to early-step of hepatocarcinogenesis.