The 5th International Conference on Mechanisms of Antimutagenesis and Anticarcinogenesis.
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Animals↗
Biomedical subjects
K Negishi
Publications and source records attributed to K Negishi.
Synthesis and RNA polymerase incorporation of the degenerate ribonucleotide analogue rPTP.
The synthesis and enzymatic incorporation into RNA of the hydrogen bond degenerate nucleoside analogue 6-(beta-d-ribofuranosyl)-3, 4-dihydro-8H-pyrimido[4,5-c]-[1,2]oxazin-7-one (P) is described. The 5'-triphosphate of this analogue is readily incorporated by T3, T7 and SP6 RNA polymerases into RNA transcripts, being best incorporated in place of UTP, but also in place of CTP. When all the uridine residues in an HIV-1 TAR RNA transcript are replaced by P the transcript has similar characteristics to the wild-type TAR RNA, as demonstrated by similar melting temperatures and CD spectra. The P-substituted TAR transcript binds to the Tat peptide ADP-1 with only 4-fold lowered efficiency compared with wild-type TAR.
Base Sequence↗
Association between preinfarction angina and a lower risk of right ventricular infarction.
BACKGROUND: Right ventricular infarction occurs in conjunction with inferior myocardial infarction caused by proximal occlusion of the right coronary artery. However, right ventricular infarction occurs infrequently, and the reasons for this are uncertain. METHODS: We retrospectively assessed the association between preinfarction angina and right ventricular infarction, as well as the short-term outcome, in 113 patients with a first acute inferior myocardial infarction caused by right-coronary-artery occlusion. The association between the timing of angina during the week before infarction and the clinical outcome was also assessed. RESULTS: The absence of preinfarction angina predicted the development of right ventricular infarction (odds ratio, 6.3; 95 percent confidence interval, 2.7 to 15.1; P<0.001), complete atrioventricular block (odds ratio, 3.6; 95 percent confidence interval, 1.4 to 10.3; P=0.01), and combined hypotension and shock (odds ratio, 12.4; 95 percent confidence interval, 4.5 to 40.6; P<0.001). Angina 24 to 72 hours before infarction was most strongly associated with reductions in the rates of right ventricular infarction (adjusted odds ratio, 0.2; 95 percent confidence interval, 0 to 0.8; P=0.02) and combined hypotension and shock (adjusted odds ratio, 0.1; 95 percent confidence interval, 0 to 0.5; P=0.02). CONCLUSIONS: Preinfarction angina was an independent predictor of the absence of right ventricular infarction in patients with acute inferior myocardial infarction. The patients with preinfarction angina also had better short-term outcomes than those without preinfarction angina.
Angina Pectoris↗
Increased night:day blood pressure ratio in microalbuminuric normotensive NIDDM subjects.
OBJECTIVE: To determine the relationship of day- and night-time blood pressure (BP) with the degree of albuminuria in subjects with non-insulin-dependent diabetes (NIDDM). RESEARCH DESIGN AND METHODS: BP was determined hourly for 24 h in 27 NIDDM normotensive patients, and 10 age- and BMI-matched controls. Diabetic subjects were separated into normo- and microalbuminuric groups according to the urinary albumin excretion rate (AER < 15 and > or = 15 micrograms/min), respectively. RESULTS: Non-dippers defined by a nocturnal fall in BP of less then 10/5 mmHg represented 68.8% of the normo- and 81.8% of the microalbuminuric patients. Microalbuminuric diabetics demonstrated a significantly higher ratio of night:day BP in comparison to controls, but not to normoalbuminuric diabetics. AER was significantly correlated with BP ratio in the normoalbuminuric, but not in microalbuminuric group. CONCLUSIONS: Ambulatory 24-h BP monitoring is useful to find blunted nocturnal fall in BP even in normotensive NIDDM subjects with or without microalbuminuria. However, whether or not an increase in the night-time BP and/or the night:day ratio in NIDDM patients plays a pathogenetic role in the progression of diabetic nephropathy remains to be clarified.
Albuminuria↗
Reduced alkaline phosphatase activity in diabetic rat bone: a re-evaluation.
We found previously that human bone alkaline phosphatase (AP) was glycated by aseptic incubation with glucose, and partially broken down by reactive oxygen species. In this study, we examined whether selective in vivo glycation of AP molecules occurred in bone tissue, using experimental diabetic rats induced by streptozotocin and spontaneously diabetic rats. Additionally, the effects of hyperlipidemia on bone AP activity were examined. Serum AP activity was significantly elevated after incipient onset of diabetes, and the increased activity originated from the intestinal isozyme. High levels of intestinal AP activity were also observed in rats with hyperlipidemia induced by feeding high-fat or high-fructose chow, but the AP activity in bone tissues was maintained at a constant level. AP activity in bone was reduced after the onset of diabetes. The resulting bone AP molecule bound to an aminophenylboronic acid column, which had affinity for glycated proteins, and contained smaller molecular sizes than the native bone AP. These results suggest that elevated levels of serum AP activity originated from the intestinal isozyme accompanied with hyperlipidemia induced by diabetes. In contrast, the reduced serum levels of AP activity in diabetic rats might be dependent on inactivation of bone AP, which was glycated, followed by partial breakdown of bone AP molecules, possibly due to reactive oxygen species.
Alkaline Phosphatase↗
The eyes of deep-sea fish. II. Functional morphology of the retina.
Three different aspects of the morphological organisation of deep-sea fish retinae are reviewed: First, questions of general cell biological relevance are addressed with respect to the development and proliferation patterns of photoreceptors, and problems associated with the growth of multibank retinae, and with outer segment renewal are discussed in situations where there is no direct contact between the retinal pigment epithelium and the tips of rod outer segments. The second part deals with the neural portion of the deep-sea fish retina. Cell densities are greatly reduced, yet neurohistochemistry demonstrates that all major neurotransmitters and neuropeptides found in other vertebrate retinae are also present in deep-sea fish. Quantitatively, convergence rates in unspecialised parts of the retina are similar to those in nocturnal mammals. The differentiation of horizontal cells makes it unlikely that species with more than a single visual pigment are capable of colour vision. In the third part, the diversity of deep-sea fish retinae is highlighted. Based on the topography of ganglion cells, species are identified with areae or foveae located in various parts of the retina, giving them a greatly improved spatial resolving power in specific parts of their visual fields. The highest degree of specialisation is found in tubular eyes. This is demonstrated in a case study of the scopelarchid retina, where as many as seven regions with different degrees of differentiation can be distinguished, ranging from an area giganto cellularis, regions with grouped rods to retinal diverticulum.
Animals↗
Association of CTLA-4 gene A-G polymorphism (IDDM12 locus) with acute-onset and insulin-depleted IDDM as well as autoimmune thyroid disease (Graves' disease and Hashimoto's thyroiditis) in the Japanese population.
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Abatacept↗
A novel missense mutation in the homeodomain of the hepatocyte nuclear factor-1alpha/maturity-onset diabetes of the young 3 in a Japanese early-onset type 2 diabetic patient and time-course of glucose-stimulated insulin secretion.
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Adolescent↗
Troglitazone has a scavenging effect on reactive oxygen species.
Troglitazone (CS-045), a newly developed antidiabetic thiazolidinedione that enhances insulin sensitivity, is similar in structure to several antioxidants, including alpha-tocopherol and probucol. The in vitro antioxidant activity of troglitazone has been demonstrated in alloxan-induced hyperlipoperoxidemic and hyperlipidemic mice. In this study, we found that troglitazone had a scavenging effect on reactive oxygen produced by xanthine-xanthine oxidase and generated by stimulated neutrophils and tends to be the radical form. Our results suggest that troglitazone is an antioxidant similar to alpha-tocopherol. However, under the same conditions, pioglitazone, another thiazolidinedione drug, did not have a scavenging effect. The antioxidant action of troglitazone, which is attributable to the similarity of its molecular structure to that of alpha-tocopherol, may be of benefit in preventing diabetic vascular complications, in addition to having hypoglycemic and hypolipidemic effects.
Antioxidants↗
The mechanism of mutation induction by a hydrogen bond ambivalent, bicyclic N4-oxy-2'-deoxycytidine in Escherichia coli.
The triphosphate of the nucleoside deoxyribosyl dihydropyrimido[4,5-c][1,2]oxazin-7-one (dP) is known to be incorporated into DNA efficiently by Taq polymerase and is a useful tool for polymerase-mediated in vitro mutagenesis. It is shown here that dP is a potent mutagen in Escherichia coli and Salmonella typhimurium . In E.coli , this deoxycytidine analog induces both GC-->AT and AT-->GC transitions. No induced transversions are observed. It is highly mutagenic in wild-type E.coli, but this is much reduced in a strain lacking thymidine kinase. Mutagenesis induced by dP is efficiently inhibited by the addition of thymidine. Partially purified thymidine kinase from E.coli catalyzes phosphorylation of dP to its 5'-monophosphate. When E.coli was grown in the presence of dP, the nucleoside analog was incorporated into its DNA. The content of dP in DNA was dependent on the concentration of dP added to the medium. The incorporation characteristics of the 5'-triphosphate of dP (dPTP) were also studied using E.coli DNA polymerase I large fragment. The results confirm that this triphosphate can be incorporated opposite A and G in the template with similar efficiencies. This indicates that dP is metabolized as a thymidine analog and that the resulting triphosphate induces a high rate of mutagenesis through replicational errors.
Base Sequence↗
Density ratio of dopaminergic versus serotonergic cells correlates with cone-to-rod ratio in teleost retinas.
Dopaminergic and serotonergic cells were visualised immunohistochemically with antibodies against tyrosine hydroxylase and serotonin in retinal wholemounts of eight teleosts from different habitats and with different rod-to-cone ratios. The cell densities were calculated, and the density ratio of dopaminergic cells versus serotonergic cells was compared among these fish species. The density ratio was high (1.9-2.7) in three out of the four species of cichlid fish studied with cone densities roughly equalling rod densities, medium in roach (0.8) where rods dominate cone numbers, and low in deep-sea fish (0.2-0.4) with pure rod retinas. These observations confirm earlier findings on the species-specificity of the ratio of dopaminergic versus serotonergic cells in the retina and further demonstrate a close correlation between the rod-to-cone ratio, and the density ratio of dopaminergic versus serotonergic cells in the inner retina. The possible significance for the processing of photopic and scotopic information in the inner retina is discussed.
Animals↗
Origins of horizontal cell spectral responses in the retina of marine teleosts (Centropomus and Mugil sp).
Intracellular recording and marking of horizontal cells (HCs) were carried out in isolated retinas of marine teleosts (Centropomus and Mugil sp.) to identify the cellular origins of different spectral types of S-potential. The spectral responses recorded under mesopic conditions were classified into four types: photopic L, biphasic C(R/G), biphasic C(G/R), and scotopic L(sL). Intracellular marking with Lucifer yellow (LY) or Procion yellow (PY) revealed that in the Centropomus retina an L-type response was recorded from H1 and H2 cells, C(R/G)-type from H3 cells, and sL-type from H4 cells. However, in 20% of microelectrode penetrations from the photoreceptor surface, the sequential order of response appearances was found to be L-, sL-, and C(R/G)-types. In this species, thick dendritic processes of H3 and H4 cells are distributed at the same level as the cell body. In the Mugil retina, on the other hand, L-type response was recorded from H1 cells, C(G/R)-type from H2 cells, C(R/G)-type from H3 cells, and sL-type from H4 cells, this sequential arrangement being very regular. In both species, the cone-connected H1 cells are small and possess an axon, while the two other cone HCs as well as rod-connected H4 cells are axonless. Earlier (Negishi et al., 1988) and present findings indicate that there is a wide variety of HC morphology and functional organization in the teleost retina.
Animals↗
Evaluation of a zonal-progressive multifocal intraocular lens.
PURPOSE: To determine the clinical usefulness of a five-zone refractive multifocal intraocular lens. METHODS: After more than 1 year of follow-up, we evaluated the visual function of 22 patients (36 eyes) who had received the MPC-25NB intraocular lens for distance and near visual acuity, kinetic visual acuity, and near contrast sensitivity, and for patient satisfaction. RESULTS: Of 31 study eyes with less than 1.5 diopters of preoperative keratometric astigmatism, 28 (90.3%) achieved an uncorrected distance visual acuity of 20/40 or better; best-corrected distance visual acuity was 20/20 or better in 31 (86.1%) of 36 eyes. Near visual acuity with distance correction was 20/40 or better in 20 (60.6%) of 33 eyes. Kinetic visual acuity in these patients was comparable to that in patients with monofocal intraocular lenses. Distance visual acuity and near contrast sensitivity were below normal or within the low normal range. There was no significant difference in contrast visual acuity measured by variable contrast visual acuity charts between MPC-25NB and monofocal intraocular lens-implanted eyes (P > .05). Four (22.2%) of 18 patients did not require spectacles when the intraocular lens was implanted for emmetropia. Despite some complaints about near or night vision, all patients expressed satisfaction. CONCLUSIONS: The MPC-25NB lens provides a level of distance vision comparable to that of a monofocal intraocular lens and a useful level of near visual acuity without spectacles. However, we should carefully evaluate the indication for use of MPC-25NB in patients who require good near vision or night vision.
Adult↗
Acarbose controls postprandial hyperproinsulinemia in non-insulin dependent diabetes mellitus.
We investigated how fasting or postprandial insulin levels were altered by treatment with acarbose or sulfonylureas. Plasma glucose and serum insulin, C-peptide, and proinsulin levels were measured before as well as 1 and 2 h after breakfast in 23 patients with non-insulin-dependent diabetes mellitus and 17 patients with impaired glucose tolerance. In the diabetic patients, 12 weeks of acarbose therapy decreased the postprandial levels of glucose (1 h: -60.0%; 2 h: -67.6%), insulin (1 h: -67.5%; 2 h: -72.2%) and proinsulin (1 h: -55.2%; 2 h: -46.7%), and proinsulin (1 h: -20.9%; 2 h: -57.5%). In contrast, sulfonylurea treatment increased postprandial insulin and proinsulin levels. Since increased in the serum insulin or proinsulin levels are associated with a higher risk of cardiovascular disease, the present findings suggest that the acarbose-induced reduction of the postprandial serum insulin or proinsulin responses to food intake might be useful for preventing vascular complications in patients with diabetes.
Acarbose↗
Elschnig pearl formation along the posterior capsulotomy margin after neodymium:YAG capsulotomy.
PURPOSE: To determine the incidence of Elschnig pearl formation along the capsulotomy margin (string of pearls) after neodymium:YAG (Nd:YAG) laser posterior capsulotomy and to elucidate its clinical features, predisposing factors, effect on visual function, and association with additional capsulotomy. SETTING: Keio University Hospital, Tokyo, Japan. METHODS: The records of 418 eyes that had had Nd:YAG posterior capsulotomy after cataract surgery were retrospectively reviewed. Of those, 315 were excluded for short follow-up (fewer than 12 months) or insufficient clinical examination data. In the remaining 103 eyes, the incidence of string of pearls was calculated, and its clinical features, predisposing factors, effect on visual function, and correlation with additional capsulotomy were evaluated. RESULTS: String of pearls was identified in 49 eyes (47.6%); 37 (75.5%) developed pearls within 1 year after Nd:YAG capsulotomy. The incidence was significantly higher in patients having intraocular lens implantation and continuous curvilinear capsulorhexis (CCC) than in those without (95.9 versus 61.1% and 97.9 versus 55.6%, respectively). No significant differences were found in patient age and sex, total Nd:YAG energy, and the presence of diabetes mellitus or high myopia. String of pearls caused visual disturbances in 17 eyes (34.7%). The rate of repeat capsulotomy was higher in patients with string of pearls than in those without (36.7 and 9.3%, respectively). CONCLUSIONS: String of pearls formation was a common and significant complication after Nd:YAG posterior capsulotomy. Intraocular lens implantation and CCC may promote its formation.
Adult↗
Polynucleotide-chitosan complex, an insoluble but reactive form of polynucleotide.
DNA formed an insoluble complex on mixing with chitosan (poly-D-glucosamine) in solution. The DNA content of the complex was about 50% and the DNA remained insoluble in aqueous media of pH 2-7%; e.g., on treatment of the DNA-chitosan complex with phosphate-buffered saline at pH 7 and 37 degrees C for 26 h, the DNA released into the aqueous phase was less than 0.05%. Obviously, DNA and chitosan formed a tight complex due to ionic interactions. The DNA can be solubilized by treatment with 0.1 N NaOH. RNA and other polynucleotides formed similar insoluble complexes with chitosan. The DNA attached to chitosan can be digested with a mixture of DNase I and phosphodiesterase. Cytosine residues in the DNA (denatured DNA) can be deaminated by treatment with sodium bisulfite, forming uracil DNA-chitosan. The uracil DNA-chitosan served as a substrate for uracil DNA glycosylase. Using polynucleotide-chitosan as an adsorbent, the affinities of reagents for polynucleotides can be determined directly. With this technique it was found that carcinogenic heterocyclic amines have an affinity for RNA as well as DNA. The results with homopolyribonucleotide-chitosans as adsorbents for 4 heterocyclic amines indicated that the binding occurs in a purine nucleotide-specific manner. These results suggest that the polynucleotides in the chitosan complex are accessible to enzymes and reagents. This new derivative may be useful in chemical and biological studies of polynucleotides and substances interacting with polynucleotides.
Chitin↗
Hyperinsulinemia in relation to hypertension and other coronary risk factors in Japanese men.
In addition to obesity, abnormalities in glucose and lipid metabolism are common in hypertensives, indicating a possible link between hypertension and hyperinsulinemia. Since the frequency of obesity in Japanese is lower than that in Caucasians, the present study was designed to clarify the frequencies of hyperinsulinemia, glucose and lipid abnormalities, and obesity. We surveyed consecutively 470 men without a history of gastrectomy who visited a health clinic after excluding previously known hypertensives receiving hypotensive agents (4.2%) and diabetics (6.1%). Hypertensives with a blood pressure exceeding 150 and/or 90 mmHg (n = 62) had a significantly higher frequency of diabetes mellitus (6.5%) associated with hypercholesterolemia (24.2%) and mild obesity with a body mass index (BMI) of more than 25 (24.2%) than those of normotensives. When reanalyzed according to the presence or absence of hyperinsulinemia after 75 g oral glucose loading, hyperinsulinemic men demonstrated a higher blood pressure. The incidences of impaired glucose tolerance (67.1%), hypertriglyceridemia (64.4%), low HDL-cholesterol (53.4%), hypercholesterolemia (21.9%) and mild obesity (37.0%) were also significantly higher than those of normoinsulinemic subjects. Subjects with either hypertension and/or hyperinsulinemia had a significantly higher incidence of coexistence of these risk factors. Multiple regression analysis revealed that not only BMI, but also the plasma glucose and insulin response during the 75 g glucose loading test independently correlated with mean blood pressure. These results suggest that hypertensive and/or hyperinsulinemic subjects may be associated with excess cardiovascular risk and should be managed more carefully.
Antihypertensive Agents↗
Evidence for association between the class I subset of the insulin gene minisatellite (IDDM2 locus) and IDDM in the Japanese population.
Although the shortest (class I) minisatellite (i.e., variable number of tandem repeats [VNTR]) alleles in the 5' region of the insulin gene are positively associated with IDDM in Caucasians, the majority of Japanese are homozygous for class I alleles. Here, we determined the exact length, in number of repeat units (RUs), of class I alleles in Japanese subjects. The distribution of class I alleles in Japanese was trimodal, with peaks located at 32/33, 41, and 44 RUs. The shortest component (i.e., 1S [25-38 RUs]) alleles were significantly increased in the IDDM group compared with the control group (54 vs. 46%; P = 0.040). The 1S/1S genotype was significantly increased in the IDDM patients (34 vs. 20%; P = 0.005; relative risk 2.1). Furthermore, the transmission disequilibrium test of Japanese families with 1S/1M or 1S/1L heterozygous parents confirmed the association of 1S alleles; 17 alleles of 1S and 6 alleles of 1M (39-41 RUs) or 1L (42-44 RUs) were transmitted to affected offspring (P = 0.022). In addition, we found tight linkage of 1S with allele 9 of the tyrosine hydroxylase gene microsatellite and allele (-) of the IGF-II gene Apa I polymorphism, but neither 9 nor (-) alleles were significantly associated with IDDM. The present study suggests that a class I subset may have a role in IDDM susceptibility in Japan. It was revealed that the difference between 1S alleles and 1M or 1L alleles is almost consistently characterized by a sequence variation generated by deletion of two copies of an ACAGGGGTCC CGGGG repeat element, implying that sequence variation of class I alleles may influence disease susceptibility.
Adolescent↗