Altered glycoprotein sugar-chain structures as possible diagnostic and prognostic markers in malignant tumors.
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Alkaline Phosphatase↗
Biomedical subjects
M Yano
Publications and source records attributed to M Yano.
Molecular analysis of insulin receptor gene in Werner's syndrome.
Werner's syndrome is characterized by premature aging and frequent impaired glucose tolerance or overt diabetes. Insulin resistance may play an important role and may be caused by a post-receptor defect or dysfunctional insulin receptor. The present study was undertaken to investigate the insulin receptor gene mutation in Werner's syndrome. The genomic DNAs were obtained from four patients with Werner's syndrome. Exons 2-22 of the insulin receptor gene except exon 1 were amplified from genomic DNA by the polymerase chain reaction and screened for nucleotide variation by examining for single-stranded conformational polymorphisms. There were no nucleotide variations in exons 2, 4-->7, 9 and 12-->22. Variants were thus found in exons 3, 8, 10 and 11 and each were sequenced. The variant in exon 8 was due to a silent polymorphism (GAT-->GAC/T, Asp519) and other variants in exons 3, 10 and 11 were caused by nucleotide substitutions in introns. These results suggest that the patients with Werner's syndrome express normal insulin receptors and that the primary genetic lesion for insulin resistance is not in the insulin receptor gene. Insulin resistance in Werner's syndrome is thus likely by a post-receptor defect.
Adult↗
Cholangiocytes express the aquaporin CHIP and transport water via a channel-mediated mechanism.
Cholangiocytes line the intrahepatic bile ducts and regulate salt and water secretion during bile formation, but the mechanism(s) regulating ductal water movement remains obscure. A water-selective channel, the aquaporin CHIP, was recently described in several epithelia, so we tested the hypothesis that osmotic water movement by cholangiocytes is mediated by CHIP. Isolated rodent cholangiocytes showed a rapid increase in volume in the presence of hypotonic extracellular buffers; the ratio of osmotic to diffusional permeability coefficients was > 10. The osmotically induced increase in cholangiocyte volume was inversely proportional to buffer osmolality, independent of temperature, and reversibly blocked by HgCl2. Also, the luminal area of isolated, enclosed bile duct units increased after exposure to hypotonic buffer and was reversibly inhibited by HgCl2. RNase protection assays, anti-CHIP immunoblots, and immunocytochemistry confirmed that CHIP transcript and protein were present in isolated cholangiocytes but not in hepatocytes. These results demonstrate that (i) isolated cholangiocytes and intact, polarized bile duct units manifest rapid, mercury-sensitive increases in cell size and luminal area, respectively, in response to osmotic gradients and (ii) isolated cholangiocytes express aquaporin CHIP at both the mRNA and the protein level. The data implicate aquaporin water channels in the transcellular movement of water across cholangiocytes lining intrahepatic bile ducts and provide a plausible molecular explanation for ductal water secretion.
Animals↗
Insulin response after treatment depends on fasting plasma glucose level in NIDDM.
We investigated the relationship between the improvement in insulin secretion and glycemic control in non-insulin-dependent diabetes mellitus (NIDDM). Fifty-two patients were classified into three groups according to their pretreatment fasting plasma glucose (FPG) level: Group A, FPG < 7.8 mM, n = 20; Group B, 7.8 mM < or = FPG < 11.1 mM, n = 17; and Group C, 11.1 mM < or = FPG, n = 15. A 75-g oral glucose tolerance test (OGTT) and a glucagon loading test were performed to evaluate insulin secretion before and after treatment. Plasma glucose levels during a 75-g OGTT were decreased significantly after treatment in all groups (P < 0.01). In Group A, there was no significant change in insulin secretion before and after treatment (1466 +/- 213 pM to 1565 +/- 191 pM, P = 0.35). In contrast, in Groups B and C, insulin secretion was poor and suppressed initially, but increased significantly when good glycemic control was obtained after treatment (respectively, 587 +/- 70 pM to 863 +/- 79 pM, P < 0.01, and 621 +/- 94 pM to 1236 +/- 232 pM, P < 0.01). The degree of improvement in insulin secretion in 75-g OGTT correlated positively with the degree of improvement in FPG level after treatment (r = 0.5, P < 0.001). However, the C-peptide response to glucagon did not change before and after treatment. In conclusion, impaired insulin secretion recovered by the good glycemic control in NIDDM with FPG levels above 7.8 mM. Therefore, strict glycemic control (FPG below 7.8 mM) seems important for maintaining good insulin secretion.
Adult↗
Roles of endogenous nitric oxide in cerebellar cortical development in slice cultures.
Using the slice culture system for 9-day-old rat cerebellum, roles of nitric oxide (NO) in the cerebellar cortical development were examined. Granule cell migration was inhibited by N-nitro-L-arginine (L-NNA) and by haemoglobin (Hb), but not by N-nitro-D-arginine (D-NNA), added to the culture medium, showing that NO-mediated transmission is involved in some process for granule cell migration. Furthermore, immunohistochemical analysis revealed that the cessation of granule cell proliferation and the differentiation of Bergmann glia were inhibited in the presence of L-NNA and Hb. These results suggest that endogenous NO can be a signal for the differentiation of granule cells and Bergmann glia in cerebellar cortical development.
Animals↗
Risk of hepatocellular carcinoma in patients with cirrhosis in Japan. Analysis of infectious hepatitis viruses.
BACKGROUND: The development of hepatocellular carcinoma (HCC) is associated closely with cirrhosis. In the present study, the cumulative risk of HCC in patients with cirrhosis was investigated. METHODS: A total of 401 patients were registered from April 1977 and followed for a mean of 4.4 years. Of 401 patients, 255 (64%) were tested for hepatitis B surface antigen (HBsAg) and antibody (anti-) to the hepatitis C virus (HCV); 87 (34%) patients were positive for HBsAg but were negative for anti-HCV (hepatitis B virus [HBV] group), 126 (49%) were negative for HBsAg but were positive for anti-HCV (HCV group), 10 (4%) were positive for both and 32 (13%) were negative for both (non-B non-C group). RESULTS: By the end of March 1993, HCC was diagnosed in 127 (31.6%) patients. The cumulative risk of HCC in the HCV group was slightly higher than that in HBV group (P = 0.3, 5-year risk: 36.9 versus 21.2%). In contrast, the rate was significantly lower in the non-B non-C group than in the HBV or HCV groups (P < 0.05 and P < 0.01, respectively, 5 year risk: 12.4%). CONCLUSIONS: These results suggest that not only HBV infection but also HCV infection increase the risk for HCC in patients with cirrhosis.
Adult↗
Chemical depolarization-induced SR calcium release in triads isolated from rabbit skeletal muscle.
Excitation-Ca2+ release coupling properties in the heavy microsomal fraction of the rabbit skeletal muscle enriched in triads were investigated by following the same type of approach used for the studies of excitation-contraction coupling in the skinned fiber system. Incubation of the triads with Mg-ATP in a solution containing 150 mM K+, 15.0-37.2 mM Na+, 150-180 mM gluconate-, and 150-200 microM Ca2+ (priming solution) led to (a) the generation of a T-tubule membrane potential making the cytoplasmic side negative, as assessed by potential-dependent uptake of the potential probe [14C]SCN- by triads, and (b) active transport of Ca2+ into the SR moiety. One volume of the primed (viz., polarized and Ca(2+)-loaded) triads was mixed with nine volumes of depolarization solution according to Cl(-)-replacement [Donaldson, S.K.B. (1985) J. Gen. Physiol 86, 501-525; Stephenson, E. W. (1985) J. Gen. Physiol. 86, 813-832] and Na(4)-replacement [Lamb, G.D., & Stephenson, D.G. (1990) J. Physiol. 423, 495-517] protocols used for the induction of contraction in skinned fiber system. The ionic replacement procedure by either protocol produced a rapid release of Ca2+ from SR as determined by stopped-flow fluorometry using fluo-3 as a Ca2+ probe in the presence of BAPTA-calcium buffer. Both the rate constant and the magnitude of Ca2+ release increased with the degree of ionic replacement. The ionic replacement-dependent changes in the release kinetics showed a striking similarity to the voltage-dependent changes of the Ca2+ transient in the intact fiber system.(ABSTRACT TRUNCATED AT 250 WORDS)
Animals↗
Neomycin: a novel potent blocker of communication between T-tubule and sarcoplasmic reticulum.
Ca2+ release from the sarcoplasmic reticulum (SR) was induced in isolated triads by direct stimulation of the SR moiety by polylysine, or stimulation via chemical depolarization of the transverse tubule (T-tubule) moiety. Polylysine-induced release was blocked by neomycin with an IC50 (the concentration for half-maximal inhibition) of 0.3 microM. However, the IC50 for neomycin block of depolarization-induced Ca2+ release sharply decreased in a voltage-dependent fashion, and it was 5.3 nM at a maximal extent of T-tubule depolarization. These results suggest that the high affinity binding of neomycin to the triad leads to the specific blocking of the signal transmission from T-tubule to SR.
Animals↗
Antihypertensive effects of BQ-123, a selective endothelin ETA receptor antagonist, in spontaneously hypertensive rats treated with DOCA-salt.
We determined the antihypertensive effects of BQ-123 (cyclo(D-Trp-D-Asp-L-Pro-D-Val-L-Leu-), sodium salt), a selective endothelin ETA receptor antagonist, in spontaneously hypertensive rats treated with deoxycorticosterone acetate-salt (DOCA-salt SHR). BQ-123 (1-30 mg/kg/h) decreased blood pressure in DOCA-salt SHR in a dose-dependent manner, although plasma immunoreactive endothelin-1 did not significantly increase and the maximal contractile response to endothelin-1 in the aorta significantly decreased as compared with values observed in age-matched SHR. These results suggest that endogenous endothelin-1 is involved in the maintenance of hypertension in DOCA-salt SHR, and that circulating endothelin-1 is not sufficient to reflect the physiological role of endothelin-1.
Amino Acid Sequence↗
Cardiovascular effects of intrathecally administered endothelins and big endothelin-1 in conscious rats: receptor characterization and mechanism of action.
In conscious rats, the intrathecal (i.t.) injection of endothelin-1 (ET-1; 65-650 pmol) and endothelin-3 (ET-3; 162-650 pmol) produced dose-dependent increases of mean arterial blood pressure (MAP) accompanied by either a tachycardia or a bradycardia. A number of animals died by a sudden respiratory arrest. ET-3 was less toxic and less potent than ET-1 on MAP and heart rate (HR) while BQ-3020, a selective ETB agonist, had no toxic effect and exhibited only a weak pressor effect on blood pressure. The prior i.t. injection of 65 nmol BQ-123, a selective ETA receptor antagonist, blocked both the cardiovascular and toxic effects of ET-1 but failed to modify the cardiovascular effect evoked by i.t. substance P (6.5 nmol) or to cause intrinsic cardiovascular and toxic effects. While the pressor response to ET-1 was significantly inhibited after i.v. injection of phentolamine, the bradycardia was blocked by pentolinium. The cardiovascular response to ET-1 was, however, unaffected in rats either sympathectomized with 6-hydroxydopamine or pretreated with capsaicin. Furthermore, big ET-1 (100 pmol) caused toxic effects and delayed cardiovascular changes which were prevented by the prior i.t. administration of either BQ-123 (65 nmol) or 100 nmol phosphoramidon, an endothelin-converting enzyme (ECE) inhibitor. These results suggest: (1) that the cardiovascular and toxic effects of i.t. endothelins are mediated by ETA receptors in the rat spinal cord; (2) that the pressor response and bradycardia are likely due to the activation of the sympatho-adrenal nervous system and to a vagal reflex mechanism, respectively; and (3) that a phosphoramidon-sensitive ECE converts big ET-1 to ET-1 in the rat spinal cord.
Amino Acid Sequence↗
Sudden hearing loss associated with interferon.
With the increasing long-term use of interferon, several new adverse effects have been recognised. We have prospectively assessed auditory function in 49 patients receiving interferon, after we saw a case of sudden sensorineural hearing loss during interferon therapy. Auditory disability (tinnitus, hearing loss, or both) occurred in 22 patients (45%) during treatment with audiometry-documented sensorineural hearing loss in 18 (37%). The auditory disability often developed in the late stage of treatment and resolved in all patients within 7-14 days after discontinuation of interferon.
Adult↗
Observation of the highly organized development of granule cells in rat cerebellar organotypic cultures.
Cerebellar slices of 9-day-old rats were cultured for a week at the interface between air and a culture medium containing horse serum and hormone cocktail, and the development of granule cells was characterized morphologically. The typical layered structure of the cerebellar cortex was well preserved during the cultivation. Many granule cells in the external granular layer (EGL) proliferated actively within the early culture period. They were migrating downward at 3 days in vitro (DIV) and almost completed the migration to the internal granular layer (IGL) after 6 DIV. In the middle and upper molecular layer (ML), parallel fibers were elongated horizontally, which is the orientation 90 degrees rotated compared to that in vivo. They formed synapses with Purkinje cell dendrites. Regional differences in synapse density and maturity existed which might reflect a gradient in progressive synapse formation comparable to that in vivo. Thus, a serial process of highly organized development of granule cells was realized for the first time in vitro, although some spatial or temporal modifications existed. Such a culture system could be a useful experimental model for the study of cellular and molecular mechanisms of spatiotemporally organized neuronal development.
Animals↗
Clearance of circulating endothelin-1 by ETB receptors in rats.
Exogenous endothelin (ET) is rapidly cleared from the circulation. We investigated which ET receptor subtypes (ETA and ETB) participate in ET-1 clearance. Following an intravenous (i.v.) bolus dose of [125I]ET-1 in anesthetized rats, radioactivity was rapidly cleared from the circulation and trapped by the lungs, kidneys and liver. Tissue distribution of the radioactivity was significantly inhibited in the lungs and kidneys, but not in the liver by infusion of the ETB antagonist BQ-788 (0.1 mg/kg/min i.v.), and the ET-1 clearance rate was reduced, while the ETA antagonist BQ-123 had no such effect. Furthermore, in isolated perfused rat lungs, about 80% of bolus-injected [125I]ET-1 was retained by the lungs after one passage. The retention of ET-1 was significantly inhibited by infusion of 1 microM BQ-788, but not BQ-123. These results suggest that ETB receptors play an important role in the clearance of ET-1.
Analysis of Variance↗
[Hepatitis C antibody and HCV-RNA].
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Biomarkers↗
Evolution of the hepatitis B virus gene during chronic infection in seven patients.
We analyzed the evolution of the precore/core gene of hepatitis B virus (HBV) over a period of 6 to 11 years in seven patients with chronic HBV infection, who exhibited a variety of clinical features. Sequence analysis revealed the following results: (1) HBeAg to anti-HBe seroconversion was correlated roughly with the occurrence of precore-defective mutants, and several years appeared to be required for complete replacement of wild types by mutants; (2) core gene mutations preceded precore-defective mutations and tended to increase with time, although not cumulatively. They occurred not only during serum alanine aminotransferase (ALT) elevations but also after ALT returned to normal; (3) ALT fluctuations appeared to subside with complete replacement of the wild type by the mutant type and/or substantial accumulation of core gene mutations; (4) unexpectedly, the anti-HBe-positive "healthy" carrier was found to harbor the wild type precore gene, as did the HBeAg-positive "healthy" carrier; however, the core gene of the former evolved at a rapid rate; and (5) a partial deletion was recognized in the core gene at the onset of fatal hepatic failure in one patient. Thus, the precore/core mutation was closely related with the clinical features in the patients.
Adolescent↗
Tumor-derived components were responsible for suppression of ornithine decarboxylase activity in the rat wounded skin.
To elucidate the principal cause of delayed wound healing in a tumor-bearing host, the effect of Yoshida sarcoma-derived components on dermal wound healing was investigated in rats with the aid of ornithine decarboxylase (ODC) activity and in vivo bromodeoxyuridine (BrdU) labeling index. The ODC activity in the wounded skin decreased 3 and 7 days after intraperitoneal inoculation of Yoshida sarcoma cells (378.0 +/- 37.3 on Day 3, 280.0 +/- 140.0 on Day 7 vs. 809.3 +/- 109.5 pmol/mg protein/hour on Day 0). When administered 24 hours before and immediately after wounding, the crude nuclear component of the tumor cells significantly decreased the ODC activity in the wounded skin as compared with the control (185.9 +/- 159.8 vs. 534.0 +/- 59.1), but the non-nuclear component was not effective. When nuclear extracts of Yoshida sarcoma cells were intraperitoneally administered immediately after wounding, the 0.15 M or 0.35 M NaCl extract significantly suppressed ODC activity in the wounded skin (233.5 +/- 14.5 and 352.3 +/- 63.2 pmol/mg protein/hour, respectively) in comparison to the control (445.9 +/- 73.6). The BrdU labeling index of epidermal basal cells adjacent to the edge of the wound decreased up to 52% of the control by injection of the 0.15 M extract. It seems that tumor-derived nuclear components may be responsible for delayed wound healing which is commonly observed in cancer cachexia.
Animals↗
The heterogeneity of whole islet cell cytoplasmic antibodies evidenced by absorption test with glutamic acid decarboxylase.
A recent report identified two islet cell cytoplasmic antibody subclasses using an immunohistochemical method. The islet cell cytoplasmic antibody subclass which reacts with only Beta-cells was termed 'Beta-cell islet cell cytoplasmic antibodies' and another islet cell cytoplasmic antibody subclass which reacts with Beta and non-Beta cells was called 'whole islet cell cytoplasmic antibodies'. The whole islet cell cytoplasmic antibody reactivity with pancreatic islets has been shown not to be abolished by pre-incubation with rat brain homogenate. In this study, we examined the inhibitory effect of purified glutamic acid decarboxylase to islet cell cytoplasmic antibody reactivity among whole islet cell cytoplasmic antibodies and assessed the heterogeneity of islet cell cytoplasmic antibodies. Auto-antibodies to 64,000 Mr islet cell protein (64 K antibodies) were also determined by conventional method. Sera from 17 Type 1 (insulin-dependent) diabetic patients containing whole islet cell cytoplasmic antibodies with more than 20 Juvenile Diabetes Foundation units were used. In 11 (78.6%) of 14 sera positive for 64 K antibodies, the reactivity of islet cell cytoplasmic antibodies was markedly blocked by pre-incubation with purified glutamic acid decarboxylase. In contrast, none of the 64 K antibody-negative sera were blocked. All of the patients showed similar clinical characteristics regardless of the inhibitory effect of glutamic acid decarboxylase on islet cell cytoplasmic antibodies, except for islet cell cytoplasmic antibody titer and glutamic acid decarboxylase antibody titer. The mean log 2 islet cell cytoplasmic antibody titer was 2.4 +/- 0.6 (mean +/- SD) JDF unit in the 'markedly blocked' group and 1.6 +/- 0.3 (mean +/- SD) in the 'never blocked' group. The islet cell cytoplasmic antibody titer was significantly higher (P < 0.05) in the former, and the mean glutamic acid decarboxylase antibody titer was 624 +/- 127.0 (mean +/- SE) units in the 'markedly blocked' group and 127 +/- 55.5 (mean +/- SE) in the 'never blocked' group. The glutamic acid decarboxylase antibody titer was also significantly higher (P < 0.05) in the former. We demonstrated here that some whole islet cell cytoplasmic antibodies are absorbed by purified glutamic acid decarboxylase, suggesting heterogeneity of islet cell cytoplasmic antibodies among the 64 K glutamic acid decarboxylase antibody positive group.
Absorption↗
Evaluation of islet-specific autoantibodies in Japanese patients with insulin-dependent diabetes mellitus: a comparison between autoantibodies to glutamic acid decarboxylase, autoantibodies to 64 kDa islet cell protein and islet cell antibodies.
Autoantibodies to glutamic acid decarboxylase (GAD), autoantibodies to 64 kDa islet cell protein and islet cell antibodies (ICA) were measured in 79 Japanese patients with insulin-dependent diabetes mellitus (IDDM). The overall prevalences of GAD antibodies, 64K antibodies, and ICA in these patients were 69.6% (55/79), 48.1% (38/79), and 46.8% (37/79), respectively. However, in a subset of these patients with recent onset IDDM (< 1 year) the prevalences of GAD antibodies, 64K antibodies, and ICA were 78.8% (26/33), 66.7% (22/33), and 78.8% (26/33), respectively. Furthermore, the prevalences of GAD antibodies, 64K antibodies, and ICA were significantly decreased in patients with long standing diabetes at 60.9% (28/46), 34.8% (16/46), and 23.9% (11/46), respectively. However, when these patients were divided into two groups by the presence or absence of organ-specific autoimmune disease (OSAD), the mean levels of GAD antibodies and ICA in the patients who gave a positive result were significantly higher in patients with OSAD (397 units and 98 JDF units, respectively) than in patients without OSAD (74 units and 39 JDF units, respectively). These results demonstrate that it is important to evaluate the prevalences and levels of islet-specific autoantibodies when considering disease duration and co-existence of autoimmune disease in patients with IDDM.
Adolescent↗