Biomedical subjects
Publications and source records attributed to H Wada.
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Three cases are reported who received brachytherapy with external irradiation for inoperable lung cancer and have shown long-term remission. The diseases were adenoid cystic carcinoma, recurrent adenocarcinoma and squamous cell carcinoma. The associated symptoms were severe cough and dyspnea in all 3 cases. They received 60 Gy of external irradiation. After an interval of 2 weeks, 6 Gy at a radius of 1 cm from the center of the source was delivered by iridium-192. They received 2-4 fractions at 1-week intervals. On termination of brachytherapy, complete response was observed in all cases. In 1 case, bronchial stenosis due to radiation-induced fibrosis was observed, but was successfully treated by bronchial stent. Cough and dyspnea disappeared, and all patients have been rendered asymptomatic for the last 2 years. Local disease was well controlled in 2 cases; however, minimal local recurrence was observed after a 2-year follow-up in 1 case.
Excessive procoagulant activity in the alveolar space may play a relevant role in the pathogenesis of pulmonary fibrosis. Hypercoagulability results from the disruption of the balance between the procoagulant and anticoagulant factors. The aim of this study was to assess the levels of molecular markers of the anticoagulant protein C (PC) pathway in the bronchoalveolar lavage fluid (BALF) and plasma of 11 patients with idiopathic pulmonary fibrosis (IPF), 14 with sarcoidosis and 16 with collagen vascular disease (CVD)-associated interstitial lung disease (CVD-ILD). Six healthy nonsmoking volunteers served as control subjects. BALF concentrations of the marker of clotting activation, thrombin- antithrombin III complex (TAT), in patients with sarcoidosis and CVD-ILD were significantly greater than those in control subjects. PC levels in BALF were markedly higher in patients with IPF (610 +/- 150 ng/ml), sarcoidosis (680 +/- 170 ng/ml), and CVD-ILD (1,580 +/- 600 ng/ml) than in control subjects (230 +/- 140 ng/ml). BALF concentrations of activated PC-PC inhibitor (APC-PCI) complex were significantly decreased in IPF (0.46 +/- 0.16 ng/ml), sarcoidosis (0. 43 +/- 0.11 ng/ml), and CVD-ILD (0.50 +/- 0.15 ng/ml) patients as compared with control subjects (1.08 +/- 0.23 ng/ml). APC-PCI/PC ratios were significantly lower in patients with IPF (2.70 +/- 1.74 ng/microg), sarcoidosis (1.94 +/- 0.82 ng/microg), and CVD-ILD (1.89 +/- 0.68 ng/microg) than in control subjects (15.91 +/- 8.45 ng/microg). Plasma levels of APC- PCI and the APC-PCI/PC ratio were also significantly decreased in patients with CVD-ILD as compared with control subjects. Overall, these findings suggest that decreased PC activation with increased procoagulant activity occurs in patients with ILD.
Ascidians and vertebrates belong to the Phylum Chordata and both have dorsal tubular central nervous systems. The structure of the ascidian neural tube is extremely simple, containing less than 400 cells, among which less than 100 cells are neurons. Recent studies suggest that, despite its simple organization, the mechanisms patterning the ascidian neural tube are similar to those of the more complex vertebrate brain. Identification of homologous regions between vertebrate and ascidian nervous systems, however, remains to be resolved. Here we report the expression of HrPax-258 gene: an ascidian homologue of vertebrate Pax-2, Pax-5 and Pax-8 genes. Molecular phylogenetic analyses indicate that HrPax-258 is descendant from a single precursor gene that gave rise to the three vertebrate genes. The expression pattern of HrPax-258 suggests that this subfamily of Pax genes has conserved roles in regional specification of the brain. Comparison with expression of ascidian Otx (Hroth) and a Hox gene (HrHox1) by double-staining in situ hybridizations indicate that the ascidian brain region can be subdivided into three regions; the anterior region marked by Hroth probably homologous to the vertebrate forebrain and midbrain, the middle region marked by HrPax-258 probably homologous to the vertebrate anterior hindbrain (and maybe also midbrain) and the posterior region marked by Hox genes which is homologous to the vertebrate hindbrain and spinal cord. Later expression of HrPax-258 in atrial primordia implies that basal chordates such as ascidians have already acquired a sensory organ that develops from epidermal thickenings (placodes) and expresses HrPax-258; we suggest it is homologous to the vertebrate ear. Therefore, placodes are not likely to be a newly acquired feature in vertebrates, but may have already been possessed by the earliest chordates.
STUDY OBJECTIVE: The objectives of the present study were to evaluate the importance of intrapulmonary lymph nodes (IPLNs) in the differential diagnosis of small pulmonary nodules and to review the CT findings of IPLNs. DESIGN: Retrospective analysis of patient records. SETTING: Chest Disease Research Institute Hospital, Kyoto University. PATIENTS: Between January 1991 and May 1996, we examined 26 patients with pulmonary nodular shadows smaller than 1 cm in diameter that could not be diagnosed before surgery. All patients (19 men, 7 women) underwent chest CT (28 to 72 years old; mean, 52.3 years). RESULTS: The pathologic diagnoses were IPLNs in 46.2% (12/26), pulmonary hamartoma in 23.1% (6/26), lung cancer in 11.5% (3/26), pulmonary tuberculoma in 11.5% (3/26), and metastatic lung tumor in 7.7% (2/26). IPLNs were located in the lower lobe in 72%. The characteristic CT findings of IPLNs were a clear border and location close to the pleura. Two of them resembled lung cancer. The CT features in these two IPLNs and in three small lung cancers overlapped. CONCLUSIONS: In the present study, we investigated small nodular shadows <1 cm in diameter and found that IPLNs located underneath the pleura are important to consider in the differential diagnosis of lung cancer. The CT scan findings of IPLNs were not necessarily specific and sometimes resembled those of lung cancer. Because of their location, video-assisted thoracic surgery is useful in making a definite diagnosis.
The Otsuka Long-Evans Tokushima fatty (OLETF) rat is a new spontaneous non-insulin-dependent diabetes mellitus (NIDDM) model rat strain developed in Tokushima, Japan. After 18 weeks of age, decreases of 45% and 40% respectively in insulin- and phorbol ester-stimulated [3H]2-deoxyglucose (DOG) uptake were observed, compared with those in Long-Evans Tokushima (LETO) rats (control). Insulin-specific binding and 95 kDa autophosphorylation of insulin receptor in OLETF rats were not different from those in LETO rats. Insulin-induced diacylglycerol (DG) production and Mono Q column-purified protein kinase C (PKC) translocation in adipocytes of OLETF rats were decreased compared with those of LETO rats. Insulin-induced PKC beta translocation from cytosol to membrane was also decreased in adipocytes of OLETF rats. Increases of the PKC beta I, beta II, epsilon and zeta isoforms in membranes of OLETF rats were markedly smaller than those of LETO rats. Analysis of mRNA levels of PKC isoforms in adipocytes of OLETF rats showed decreases of basal level and insulin-induced delayed responses of PKC beta I, beta II, epsilon and zeta mRNA in OLETF rats. On the other hand, insulin- or phorbol ester-induced phosphatidylinositol 3-kinase (PI 3-kinase) activation was decreased in adipocytes of OLETF rats compared with those of LETO rats. These results suggest that insulin resistance in OLETF rats, a spontaneous NIDDM model rat, may be associated with deterioration of insulin-induced DG-PKC signaling and subsequent decrease in PI 3-kinase activation.
Blood-brain barrier (BBB) permeability in the demented elderly was investigated by use of the ratio of cerebrospinal fluid (CSF) albumin (Alb) to serum Alb (Q-Alb). Subjects with Alzheimer type dementia (AD), vascular dementia (VD), and controls without dementia (C) were investigated. Patients with AD were divided into mild AD (mAD) and severe AD (sAD) by the use of Hasegawa's dementia scale. The Q-Alb and the ratio of CSF alpha1-antichymotrypsin (ACT) to serum ACT (Q-ACT) were evaluated. Correlations between Q-Alb and Q-ACT were compared among the groups (mAD, sAD, VD, C). Correlations between Q-Alb and major monoaminergic neurochemicals were also analyzed. It was suggested that BBB permeability was preserved in C group, while it was impaired in the patients with VD. In AD group it appeared to be rather well preserved in mAD, while it seemed to be disturbed in a graded manner according to the progression of dementia.
Troglitazone and pioglitazone, antidiabetic thiazolidinediones, are known to improve insulin resistance. However, the effect of these drugs on platelet aggregation remains unclear. The chemical structure of troglitazone contains vitamin E. Accordingly, we studied the effect of troglitazone, pioglitazone, and vitamin E on thrombin-induced platelet aggregation, metabolism of phosphoinositide, protein phosphorylation, protein kinase C (PKC)-alpha and -beta, and phosphatidylinositol (PI) 3-kinase activation in vitro in human platelets. Maximum platelet aggregation by ADP, collagen, and thrombin decreased in the presence of 0.1-1 micromol/l troglitazone and 500 nmol/l vitamin E for 60 min compared with controls. However, pioglitazone did not inhibit ADP-, collagen-, or thrombin-induced platelet aggregation. Pretreatment with troglitazone and vitamin E, but not with pioglitazone, resulted in decreases in thrombin-induced phosphatidic acid production, hydrolysis of phosphatidylinositol 4,5-bisphosphate by phospholipase C, and 47-kDa protein phosphorylation. Thrombin-induced PKC-alpha and -beta activation in membrane fraction was suppressed by pretreatment with troglitazone and vitamin E, but not with pioglitazone. Separately, troglitazone and pioglitazone stimulated PI 3-kinase activity, but thrombin-induced PI 3-kinase activation was suppressed by pretreatment with troglitazone and pioglitazone for 60 min. These results suggest that troglitazone and vitamin E, but not pioglitazone, have a potent inhibitory effect on platelet aggregation via suppression of the thrombin-induced activation of phosphoinositide signaling in human platelets. Finally, the chemical structure of vitamin E may contribute to the inhibitory effect of troglitazone on platelet aggregation in human platelets.
A new human myeloma cell line, KMS-18, was established from a 58-year-old male with multiple myeloma associated with hyperammonemia. The original leukemic cells and established KMS-18 cells possessed several of the same chromosomal abnormalities, including add(1)(q32), add(10) (q24) and add(17)(p11). In addition, the KMS-18 cells showed novel t(4;14)(p16.3;q32.3) masked translocation which was determined by the FISH method. Moreover, we compared the ammonia production in culture medium of the KMS-18 cell line with that of non-myeloma hematological malignant cell lines and a hepatocellular carcinoma cell line. KMS-18 produced higher levels of ammonia in medium than the other cell lines examined. This new cell line may prove helpful in analyzing the role and biological mechanisms of the t(4;14)(p16.3;q32.3) translocation in myeloma and also in investigating hyperammonemia in cases with myeloma.
As compared to the conventional standard chemotherapy of solid cancer such as lung, biochemical modulation (BCM) therapy has been proven to have a good therapeutic efficiency. BCM therapy uses the low dose and low infusion rate of anti-cancer drug. To increase of the QOL of cancer patients, oral BCM therapy is needed. For this purpose, two kinds of new oral sustained-release cisplatin preparations were developed, micro-porous CDDP capsule made of ethylcellulose(EC) and CDDP-EC-stearic acid solid dispersion. After oral administrations of these preparations, serum CDDP levels were maintained over 0.2 microgram/ml for 24h. Experimental therapy using P815 tumor cells transplanted mice suggested the usefulness of CDDP solid dispersion preparation.
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Recent advances in molecular biology have broadened our knowledge of the biological characteristics of cancer. In the present paper, we review and discuss new modalities of therapy for non-small cell lung cancer (NSCLC) based on biological findings. These modalities include: 1) diagnosis of cancer based on gene abnormalities: 2) decision making on chemo-/radiotherapy based on new biological findings: 3) gene therapy: and 4) new chemotherapeutic agents. Mutation of the p53 gene, which occurs most frequently in NSCLC, is a well-documented molecular target in these modalities. The development of polymerase chain reaction technology has enabled early diagnosis of NSCLC by detection of p53 gene abnormalities in sputum. Transfer of the wild-type p53 gene using a retrovirus vector to cancer tissues with mutant p53 gene has already been tested clinically. Inhibition of tumor neovascularization has been studied extensively in attempts to develop noveal chemotherapeutic agents. Angiostatin or endostatin, an inhibitor of tumor neovascularization is in clinical use. Matrix metalloprotease inhibitions (MMPs) also inhibit neovascularization of tumors. Marimastat, an oral MMP, is expected to prevent cancer metastasis.
Laparoscopic inguinal hernia repair (LH) requires similar scar size to traditional open repair. To perform LH with minimal access, finer instruments were used. A 5-mm laparoscope was inserted from the umbilicus, and surgical instruments were inserted through 5- and 3-mm trocars to perform LH by the transabdominal preperitoneal approach. Polyester mesh was placed over the hernia orifice and the peritoneum was closed with 3-0 silk sutures. Sixteen patients underwent smaller access LH and 24 had standard LH. Although smaller access LH took longer (105.7 versus 83.9 min), significantly fewer patients required analgesia after smaller access LH than after standard LH (12.5 versus 70.8%), and the postoperative hospital stay was shorter (4.6 versus 5.6 days). In addition, a better cosmetic outcome was obtained with smaller access LH. In conclusion, access was minimized by using fine-caliber instruments and polyester mesh, making LH less invasive and improving the cosmetic outcome.
We report the case of a 66-year-old man who had a descending thoracic aneurysm, diagnosed as aortitis syndrome. He subsequently underwent an aneurysmectomy under simultaneous sensory and motor spinal cord monitoring. Spinal cord ischemia was diagnosed during prosthetic replacement of the aneurysm by changes in evoked spinal cord potentials and motor evoked potentials from the lumbar spinal cord enlargement and 2 pairs of intercostal arteries were reconstructed at the level of T9 and 10. After surgery, the patient developed paraparesis below T10, but the resulting neurological deficits were overcome with postoperative rehabilitation. Simultaneous monitoring of evoked spinal cord potentials and motor evoked potentials were useful in evaluating spinal cord ischemia during aortic aneurysm surgery and in determing whether intercostal arteries should be reconstructed.
Dentatorubral-pallidoluysian atrophy (DRPLA) is a neurodegenerative disease showing autosomal dominant inheritance, which is associated with a specific trinucleotide repeat expansion in the DRPLA gene. We performed DNA analysis of two affected and one non-affected individuals of a Japanese family with DRPLA. The proband (case 1) developed seizures at age 17, and these gradually evolved to intractable myoclonic epilepsy. His father (case 2) had manifested gait disturbance since the age of 40, which was followed by progressive dementia. DNA analysis disclosed that these patients had an expanded CAG repeat in the DRPLA gene, which confirmed the diagnosis. The brother of case 1, who was asymptomatic, expressed a desire to undergo predictive DNA testing for DRPLA. We discussed the ethical and social issues of this predictive testing, and decided to carry out the testing after obtaining informed consent from him and his wife. The test revealed no expanded allele, thus proving that he would not develop DRPLA, and relieving him of his fears. Our results suggest that predictive testing improves the psychological well-being of non-affected individuals in DRPLA families.
Several studies have previously demonstrated tissue factor (TF) expression in solid tumors. In our study, we evaluated by immunohistochemical staining TF expression in 79 cases of colorectal cancer and 17 cases of metastatic cancer of the liver from colorectal cancer, and investigated the relationship between the clinicopathological features and TF expression. TF was detected in the tumor of 57% of colorectal cancer patients, and its expression was significantly increased (p=0.01) in metastatic tumors (88%). TF expression was more commonly observed in metastatic tumors than in any Dukes' stage of primary cancer. In primary cancer, the detection of TF was more frequent in cases with lymph node metastasis (Dukes' C, 63%) or with hematogenous metastasis (Dukes' D, 82%) than in tumors without lymph node or hematogenous metastasis (Dukes' A and B, 46%, p=0.03). These results suggest that the expression of TF is related with the metastatic potential of colorectal cancer.
Little is known about mechanisms for the perception of gibberellin (GA), a phytohormone, by plants. A GA-binding protein (GBP) with receptor-like characteristics was partially purified from azuki bean (Azukia angularis) seedlings. Gibberellins that caused much elongation of azuki epicotyl sections showed strong binding affinity for the GBP, and their biosynthetic precursors and inactive metabolites had weak affinity for it. The apparent Kd value for GA4 was calculated to be 7 x 10(-10) M from Scatchard plots. The molecular weight of the GBP in the native state was estimated to be 25,000 by high-performance liquid chromatography with a gel-permeation column. The GBP may be one of the receptor candidates for GAs.
The pathogenesis of carcinosarcoma is still a subject of controversy. In the present study, molecular techniques were applied to determine the pathogenesis of uterine carcinosarcomas. The patterns of chromosome X inactivation were analyzed, targeting a portion of exon 1 of the human androgen receptor (HUMARA) in malignant epithelial and mesenchymal components. The presence of p53 and K-ras mutations were also analyzed. H&E-stained sections of paraffin-embedded, formalin-fixed tissues were microdissected to obtain both epithelial and nonepithelial lesions from 25 carcinosarcomas, and DNAs were extracted by proteinase K digestion. Following treatment with methylation-sensitive restriction endonuclease (HhaI or HpaII), PCR amplification was performed using nested primers targeted to the HUMARA locus. Mutations in the p53 gene and K-ras gene were found in eight (32%) and six (24%) tumors, respectively. The patterns of chromosome X inactivation were different between the carcinomatous and sarcomatous components of three carcinosarcomas, indicating that these three tumors represent collision tumors. By contrast, the patterns of chromosome X inactivation, K-ras sequence, and p53 sequence were identical in both carcinomatous and sarcomatous components in 21 carcinosarcomas, indicating that these 21 tumors represent combination tumors. One case produced equivocal results that precluded determination of whether it represented a collision or combination tumor. These observations show that although most carcinosarcomas are combination tumors, some develop as collision tumors. The determination of histogenesis in individual cases of carcinosarcoma using molecular markers may be worthwhile, because the result could help predict the prognosis of individual cases and help guide clinical management.