[Function of Raf/MAP kinase cascade in the regulation of cellular proliferation and differentiation].
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Biomedical subjects
Publications and source records attributed to Y Nishida.
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A 45-year-old woman with multiple pulmonary leiomyomatous hamartoma was reported. Multiple round shadows were observed in the chest X-ray film of mass examination. Retrospectively chest X-ray films revealed an increase in size and number of pulmonary nodules in three years. Metastatic pulmonary tumors were suspected. Primary site was unclear. Calcified myoma uteri was recognized. The pathological diagnosis under diagnostic thoracotomy was multiple leiomyomatous hamartoma. After ten months of medical castration using superactive analogue of LHRH (buserelin) by intranasal spray, chest X-ray film showed a slight decrease in size of nodular shadows in the right middle lung field.
To clarify the role of apolipoprotein E (apo E) in the formation of amyloid deposits, we examined specimens from 11 patients with renal amyloidosis who underwent renal biopsy by an immunohistochemical method using a monoclonal antibody (murine IgG1). Apo E was distributed in the amyloid deposits of all patients in a pattern similar to that obtained with Congo red staining. Strong positive staining for apo E was found on the amyloid deposits in the glomeruli. These results suggest that apo E is a common constituent of amyloid fibrils and that it may be a useful marker for immunohistochemical studies of systemic amyloidosis including renal amyloidosis.
The horizontal extraocular muscle volume of 11 normal adults and 3 ophthalmoplegic patients was measured with magnetic resonance imaging (MRI), using a 1.5 Tesla superconductive system which can provide T1 weighted images of 3 mm gapless slices of the orbit with the spin echo technique. The MRI film was projected and magnified on Kent paper with an overhead projector; muscle shapes were traced and cut from the paper. Muscle volume was defined as the total weight of the Kent paper shapes representing the muscles from all MRI slices. The average volumes of the medial and lateral rectus muscles (MRM, LRM) of the 11 subjects were 690 +/- 87 mm3 and 734 +/- 77 mm3. In two patients with peripheral nerve palsy, the small muscle volume was classified as atrophic; in the one patient with orbital myositis, the large muscle volume was classified as hypertrophic. This measurement technique is useful for evaluation of the extraocular muscles, especially in ophthalmoplegia.
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A rare case of a patient with non-insulin-dependent diabetes mellitus (NIDDM) with small cell lung cancer, initially diagnosed as pyogenic vertebral osteomyelitis, was reported. A 40-year-old male patient was diagnosed with NIDDM about 3 years earlier, but he did not receive any treatment. Then, a two-month history of high fever, persistent cough and back pain developed. Chest X-ray film showed a lung infiltrate with a small cavity in the upper portion of the left lung. Computed tomography and magnetic resonance imaging of the chest revealed a tumor mass shadow with osteoclasia along the bodies of the 6th and 7th thoracic vertebral bone. Staphylococcus aureus infection was confirmed by arterial blood culture. Administration of antibiotics resulted in the disappearance of the left lung infiltrate and a slight reduction of the tumor mass in the thoracic vertebral bone, suggesting pyogenic vertebral osteomyelitis as an unusual complication of NIDDM. However, as the tumor mass still remained, needle biopsy for the mass lesion was performed, resulting in the diagnosis of metastasis of small cell carcinoma from the left lung. Gene aberration in this lung disease has been reported recently, and its correlation with NIDDM which may also be induced by genetic abnormality is an interesting question that remains to be resolved.
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To determine the difference in reactivity of factor VIII (FVIII) inhibitor to FVIII/von Willebrand Factor (vWF) complex and FVIII free of vWF, an autoantibody to FVIII light chain was tested. A patient (1-3) suffered from autoimmune hemolytic anemia with autoantibody to FVIII. Epitope specificity of the patient's IgG (I-3 IgG) was shown to be the C2 domain of FVIII light chain (2170-2332) by Western blotting using recombinant FVIII deletions expressed in Escherichia coli. The inhibitory effect on FVIII procoagulant activity (VIII:C) of I-3 IgG was tested against a conventional FVIII concentrate; Haemate P, a monoclonal antibody-purified FVIII concentrate; Hemofil M, and a recombinant FVIII (rFVIII); Kogenate. I-3 IgG showed only 1.3 BU/mgIgG for Haemate P, in contrast to 20 BU/mgIgG for both Hemofil M and Kogenate. The ratio of VIII:C/vWF:Ag in Haemate P and Hemofil M was 1/3.43 and 1/0.01, respectively, while Kogenate did not contain vWF. The inhibitory effect of the I-3 IgG was then compared with Kogenate and its complex with vWF. The inhibitory effect was decreased against the rFVIII by forming a complex with vWF from 22 BU/mgIgG to 0.5 BU/mgIgG. Fab from the I-3 IgG had the same effect. In addition, vWF showed a protective effect on FVIII inactivation by the I-3 IgG in a dose dependent manner. Fifty-nine percent of residual VIII:C was retained in the presence of 8 U/ml of vWF after 1 hr incubation with I-3 IgG. These results suggested that vWF could compete with the I-3 IgG for binding to FVIII.
We report a Japanese family with chronic progressive external ophthalmoplegia (CPEO) with autosomal dominant inheritance, and review 54 reported CPEO patients in seven families (including the present family) with autosomal dominant inheritance and mtDNA deletions in the skeletal muscle. Mean age at onset in the CPEO was 26 years, which is older than that in published solitary cases. In addition to blepharoptosis and external opthalmoplegia, proximal muscle atrophy and weakness were found in 62%, hearing loss in 25%, and ataxia in 17% of the patients. Retinal degeneration was not found, and cardiac involvement was very rare. mtDNA deletions in the muscle were multiple and large scale, and all such deletions were located in the non-D-loop region. Autosomal dominant CPEO has unique clinical features which differ from those of solitary CPEO, and is associated with multiple large-scale mtDNA deletions. Thus, autosomal dominant CPEO can be considered a clinical and genetic entity of mitochondrial diseases.
Activities of nine lysosomal enzymes and pH-dependent isozyme patterns of alpha-mannosidase were examined in the skeletal muscle of patients with neuromuscular diseases, and the ratios of these enzyme activities in leukocytes to those in myocytes (L/M ratio) were determined. The activities of enzymes with a high L/M ratio were markedly increased in the muscles of patients with Duchenne muscular dystrophy (DMD), myotonic dystrophy (MyD), or polymyositis (PM). In contrast, those which showed a low L/M ratio were increased in the muscles of amyotrophic lateral sclerosis (ALS) and disuse muscle atrophy (DUA). The isozyme pattern of alpha-mannosidase in DMD muscle resembled that in leukocytes, while those in ALS and DUA muscle resembled that in normal muscle. These results may suggest that the increased activity of lysosomal enzymes in the muscles of patients with DMD, MyD, or PM is due primarily to infiltrating leukocytes, while that in patients with ALS or DUA is due to intramyofiber lysosomes.
Our purpose was to determine the correlation between cathepsin L mRNA levels and serum cathepsin L levels of patients with ovarian cancer. Moreover, we compared serum cathepsin L levels with cancer antigen 125 (CA125) and cancer antigen 72-4 (CA72-4) levels. Using an ELISA assay, serum samples of 30 patients with gynecological tumors were analyzed for cathepsin L, CA125, and CA72-4. We also examined whether cathepsin L gene expression was enhanced in ovarian cancer samples, by quantitative Northern blot analysis with a human cathepsin L complementary DNA (cDNA) probe. Significantly increased serum levels of cathepsin L in patients with ovarian cancer (P < 0.05) were observed. We also measured serum levels of CA125 and CA72-4 in the same patients. Compared with CA125 and CA72-4, cathepsin L showed a lower false-positive rate (27.2%) in gynecological diseases, and no correlation was observed between cathepsin L and CA125 or CA72-4 values. Moreover, ovarian cancer samples were found to express higher levels of cathepsin L mRNA than those of uterine cancer, benign ovarian tumor, and normal ovary samples. Our data demonstrated that serum cathepsin L may be useful in the early detection of ovarian cancer. Furthermore, the combination assay consisting of cathepsin L, CA125, and CA72-4 may be a more useful method than those currently in use for the detection of ovarian cancer.
Two monoclonal antibodies, SC1 and SC2, were raised in vitro against antigens from the stereocilia of guinea-pig hair cells. They both labelled stereociliary antigens that were not detected in any other cell within the cochlear duct or the vestibular epithelial. SC1 cross-reacted with the tectorial membrane in the cochlea and labelled both cochlear and vestibular hair cells from both the mouse and the rat. In the mouse the SC1 antigen was labelled from embryonic days 16-18, coincident with the development of the stereociliary bundles. SC1 cross-reacted with neuromuscular junctions from striated muscle and with basal keratinocytes in skin. SC2 did not cross-react cleanly with hair cells from the mouse or the rat but it cross-reacted with proximal tubules of the guinea-pig kidney. Both antibodies can be used as cellular markers within the guinea-pig cochlea and SC1 should be particularly useful for studies of hair cell differentiation in the mouse.
OBJECTIVE: To measure the umbilical plasma concentration of endothelin (ET)-1 in the presence of labor, fetal heart rate (FHR) abnormalities, and fetal hypoxia. METHODS: Umbilical and maternal plasma concentrations of ET-1 were measured in 100 pregnant women at full-term deliveries (60 with vaginal delivery without induction and 40 with elective cesarean delivery without labor). We assessed the FHR pattern, measured umbilical blood gases and plasma concentration of vasopressin, and investigated the relationships between the umbilical vein-artery ET-1 concentration difference and these variables. RESULTS: The concentration of ET-1 in the umbilical vein was higher than in the umbilical artery and the maternal vein in all cases. The umbilical vein-artery ET-1 concentration difference (mean +/- standard error of the mean) was significantly greater in the vaginal delivery group (4.5 +/- 2.0 pmol/L) than in those delivered by elective cesarean (1.7 +/- 1.5 pmol/L) (P < .05). The umbilical vein-artery ET-1 concentration difference was significantly greater when more than three episodes of severe variable decelerations occurred during the 30-minute period before delivery (7.0 +/- 2.0 pmol/L) than in the absence of any decelerations (1.6 +/- 1.5 pmol/L) (P < .05). The umbilical vein-artery ET-1 concentration difference correlated positively with the umbilical arterial concentration of vasopressin (r = 0.45, P < .05) and negatively with the umbilical arterial oxygen pressure (r = -0.47, P < .05). CONCLUSION: In cases of vaginal delivery with FHR abnormalities and with fetal hypoxia, the fetoplacental concentration of ET-1 was increased.
The expression of connexin 32 (Cx32), a major liver gap junction protein, after partial hepatectomy (PH) and during development and progression of hepatocarcinogenesis was studied in the rat. Cx32 was quantitatively analyzed by counting immunohistochemically demonstrated protein spots on the membranes of hepatocytes. Livers were sequentially examined after PH to assess the correlation with cell proliferation. For the analysis of different stages in carcinogenesis, Cx32 was assayed in N-ethyl-N-hydroxyethylnitrosamine-induced enzyme altered foci (EAF), hyperplastic nodules (HN), hepatocellular carcinomas (HCC), pulmonary metastatic HCC and transplanted HCC in relation to their degree of altered enzyme expression. Cx32 showed: (i) a rapid decrease after PH to its lowest levels during and 12 h after the S phase of cell proliferation when 5-bromo-2'-deoxyuridine (BrdU) labeling indices were examined; (ii) a progressive decrease from early preneoplasia EAF to HN and HCC, values for pulmonary metastatic and transplanted HCC being 0; (iii) clearly inverse correlations with increased BrdU index and degree of altered enzyme expression in HN, indicating that these, with the lowest Cx32 count, are closest to HCC. Therefore, the observed decrease appears linked to cell proliferation and progression of hepatocarcinogenesis, providing a reflection of cellular independence and growth advantage.
1. We measured systolic arterial pressure (SAP) and tissue noradrenaline concentrations (tNA) of 16 organs (heart, kidney, aorta, brain stem, pancreas, spleen, stomach, jejunum, ileum, colon, lung, muscle, cerebrum, liver, bone, salivary gland) in Dahl salt-resistant (DSR) and -sensitive rats (DSS) fed 0.4 (0.4%) or 8% salt diet (8%) from 5 weeks old until the age of 5, 7, 9 and 11 weeks. 2. SAP increased in DSS with the 8% salt diet. An increased rate of SAP of DSS with the 0.4% salt diet was larger than DSR with the 0.4% diet. In DSR with 0.4%, tNA tended to increase from 5 weeks old except in the bone, which may have been the result of ageing. In DSS with 0.4%, tNA did not increase from 5 weeks old. DSS showed salt-sensitivity even to 0.4%. 3. tNA of the heart and kidney of both DSS and DSR with 8% were lower than 0.4%. These organs are high-salt-sensitive organs. tNA of the aorta, spleen, stomach, jejunum, ileum, and colon of DSS with 8% were lower than 0.4%, but not DSR. These organs are medium salt-sensitive organs. tNA of the pancreas of DSS with 8% was lower than 0.4% which was not different from DSR with 0.4 and 8%. The pancreas is a low salt-sensitive organ. tNA of the lung, muscle, cerebrum, liver, bone and salivary gland did not show any differences between 0.4 and 8% in DSS as well as DSR. These organs are not salt-sensitive organs. 4. There were large organ differences in tNA among organs studied. There were large organ differences in decrease rate of tNA in response to a high-salt diet. The organ function and the period of salt diet influence tNA.
To test the hypothesis that angiotensin II (ANG II) modulates arterial baroreflex function via a central alpha 1-adrenoceptor mechanism, we examined the effects of intravertebral infusion of ANG II on baroreflex function curves before and after intravertebral administration of the alpha 1-adrenoreceptor antagonist prazosin. Rabbits were chronically instrumented with subclavian and vertebral arterial catheters, venous catheters, and aortic and vena caval occludes. Baroreflex curves were obtained by relating heart rate (HR) to mean arterial pressure during increases and decreases in arterial pressure. Intravertebral infusions of ANG II (5, 10, and 20 ng.kg-1.min-1) produced a dose-dependent shift of the midrange of the curve toward higher pressures (64 +/- 1 to 68 +/- 1, 76 +/- 1, and 85 +/- 2 mmHg, respectively). Pretreatment with prazosin (10 micrograms/kg) via the vertebral artery markedly reduced the shift in the baroreflex curve induced by the highest dose of ANG II (64 +/- 2 to 70 +/- 2 mmHg). These data suggest that ANG II resets the operating point of the HR baroreflex curve to a higher blood pressure and that this effect is mediated via a central alpha 1 mechanism. When the effects of vertebral ANG II on the baroreflex control of renal sympathetic nerve activity (RSNA) were examined, intravertebral administration of ANG II, while reducing the gain and the maximum RSNA, did not reset the RSNA baroreflex curve. These data suggest that ANG II acutely resets the HR baroreflex but not the RSNA baroreflex and that the resetting involves an alpha 1-adrenergic mechanism.
The late troponin T (TnT) peak concentration, which is known to be independent of reperfusion of the infarcted zone in acute myocardial infarction (MI), has been suggested to be correlated with clinical estimates of cardiac function and myocardial infarct size. To refine the clinical application of the late TnT peak in infarct sizing, and to examine differences in this estimation in different infarct sites, we measured the serum concentrations of TnT and myosin light chain 1 (MLC1), and compared these values with left ventricular ejection fraction (LVEF) obtained from left ventriculography, and extent score (ES) and severity score (SS) obtained from 201Tl scintigraphy in patients with anterior and inferior myocardial infarction. The late TnT peak concentration was strongly correlated with the MLC1 peak value in patients with anterior MI (r = 0.67, p < 0.05) and in those with inferior MI (r = 0.92, p < 0.0005). Furthermore, there were strong linear correlations between the late TnT peak values and all of the clinical data (LVEF; r = -0.79, p < 0.01, ES; r = 0.75, p < 0.05, SS; r = 0.75, p < 0.05, respectively) in patients with anterior MI. However, these correlations were weak in patients with inferior MI. Similar correlations were observed between MLC1 and the clinical data. Thus, TnT and MLC1 have similar kinetics in the serum at the late phase and can be used to estimate the size of anterior infarct.
In vivo efficacy of orally administered lufenuron, an insect growth regulator, in disinfesting cat fleas was evaluated, using flea-free cats and dogs which were purchased and infested every 10 days with cat fleas from a colony kept in our laboratory. Lufenuron was orally administered as a single dose of 15, 30, or 60 mg/kg to cats, and 5, 10 or 20 mg/kg to dogs. In cats, adult flea emergence was intensively prevented for 30 days by dosing of 15 mg/kg of lufenuron and 40 days by 30 or 60 mg/kg. The average egg hatch rate in 15 mg/kg group was, however, significantly higher than those in 30 mg/kg or more, suggesting necessity to dose 30 mg/kg to cats to prevent development of cat fleas effectively. In dogs, a lower dose of the drug, 10 mg/kg seemed to be sufficient for the complete prevention of flea development.