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Biomedical subjects

S Okubo

Publications and source records attributed to S Okubo.

At least 55 records · Page 3Linked to original sources
PubMed1997

A randomized controlled trial for chemoprevention of gastric cancer in high-risk Japanese population; study design, feasibility and protocol modification.

We have initiated a population-based, double-blind, randomized controlled trial to examine the effects of supplementation of beta-carotene and vitamin C on the incidence of gastric cancer. The subjects were participants in an annual health screening program conducted by four municipalities in Akita prefecture, one of the regions with the highest mortality from gastric cancer in Japan. We measured their serum levels of pepsinogens (PGs) I and II, and asked persons diagnosed with chronic atrophic gastritis (defined as PG I < 70 ng/ml and PG I/PG II ratio < 3.0) to take diet supplements containing 0 or 15 mg/day beta-carotene and 50 or 500 mg/day vitamin C for 5 years. During the first year of recruitment conducted in one village from June through September, 1995, 52% (635/1214) of screening participants had chronic atrophic gastritis and 73% (439/602) of eligible persons responded. However, in response to a National Cancer Institute press report released on January 18, 1996, indicating that two beta-carotene trials had shown no benefit and potential harm from the supplement, we discontinued the beta-carotene and continued with the trial using only vitamin C. Of 397 participants remaining at this point, 77% (305) consented to stay in the study. The results indicate that a randomized controlled trial for cancer prevention is feasible in the Japanese asymptomatic population.

Adult↗
PubMed1997

Temporal and spatial expression pattern of the angiotensinogen gene in mice and rats.

In situ hybridization for mouse angiotensinogen (Ao) mRNA was performed using a Stu I-Pst I 0.43-kb fragment of exon 2 as a template to synthesize RNA probes. The mouse Ao mRNA expression patterns were different from those reported for rats. Ao mRNA was expressed in the fetal liver as early as 12.5 days postcoitus, and the liver remained the predominant organ of its expression in utero. Within the developing kidney, Ao mRNA was demonstrated at 17.5 days postcoitus in the proximal straight tubules undergoing loop formation in the medulla. In the matured mouse kidney, the expression site is within the outer stripe of outer medulla, hence identified as the pars recta, not proximal convoluted tubules. Additional studies revealed that, in rats also, Ao mRNA was localized in the pars recta. This was in contrast to previously published results that showed that Ao mRNA was localized primarily in the proximal convoluted tubules in rats. Thus the pars recta appears to be an important intrarenal source of Ao for both rats and mice throughout pre- and postnatal periods, whereas the liver can be the major extrarenal source in utero in mice, but not in rats.

Aging↗
PubMed1997

Targeting deletion of angiotensin type 1B receptor gene in the mouse.

We null mutated the mouse angiotensin type 1B (AT1B) receptor gene (Agtr1b) by gene targeting. To identify the specific cell types carrying high Agtr1b gene transcriptional activities, the AT1B coding exon was replaced with a reporter gene, lacZ. In 6- to 8-wk-old Agtr1b -/- mice, high AT1B transcriptional activity was observed in adrenal zona glomerulosa cells and the testis, including mature and immature spermatic cells, whereas low activity was detected homogeneously in anterior pituitary cells and choroidal plexus vessel walls. A similar pattern was observed in Agtr1b +/- mice with less intensity. Microscopically, the anterior pituitary, heart, adrenal, zona glomerulosa, kidney, and the testis of Agtr1b -/- mice were intact and were indistinguishable from those of Agtr1b +/+ mice. Systemic blood pressure was comparable in Agtr1b -/- and Agtr1b +/+ mice. Moreover, plasma aldosterone level was comparable between the two mouse groups. No compensatory enhancement of AT1A mRNA was found in the kidney and adrenal gland of Agtr1b -/- mice. The observed absence of the abnormal phenotypes in Agtr1b -/- mice, which have been described for homozygous angiotensinogen null mutant mice, indicates that 1) AT1A receptors can take over the role of AT1B receptors in Agtr1b -/- mice or 2) functionally significant non-AT1, non-AT2 receptor(s) may exist for the action of angiotensin.

Aldosterone↗
PubMed1997

Role of angiotensin: insight from gene targeting studies.

We and others have recently produced, by gene targeting, several strains of mice deficient of a specific gene within the renin-angiotensin system. Detailed examination of these mutant mice not only confirmed the well-known blood pressure raising action of angiotensin II, but also revealed several important biological functions of angiotensin II that have not been well recognized, most notably the role in the ontogenesis of the kidney. Since gene targeting causes complete inactivation of the targeted gene, this approach also allows us to address the question, "is angiotensin really essential for the induction of aldosterone during ECF volume depletion?" In our studies, we obtained unequivocal evidence indicating that angiotensin is not essential, but instead, potassium becomes an effective regulator for aldosterone during extracellular fluid (ECF) volume depletion through mechanisms that are indistinguishable from those of angiotensin, that is, selective stimulation of aldosterone synthetase and proliferation of zona glomerulosa cells within the adrenal gland. In this context, angiotensin can be regarded as a modifier of K-dependent aldosterone regulation.

Angiotensin II↗
PubMed1996

Human antibodies responsible for binding inhibition and polymerization inhibition of human immunodeficiency virus type 1 reverse transcriptase.

Using a solid-phase non-radioisotopic (non-RI) reverse transcriptase (RT) assay, antibodies inhibiting human immunodeficiency virus type 1 (HIV-1) RT activity (RTI antibody) were investigated for their ability to inhibit binding of RT to a template-primer and DNA polymerization. The RTI antibody inhibited the binding of RT to the template-primer (BI antibody), and directly reacted with the RT-template-primer complex and inhibited enzymatic activity (PI antibody). The RTI antibody interfered with formation of the RT-template-primer complex suggesting that it recognized the antigenic site involved in template-primer binding of RT molecules. Since deoxynucleotide triphosphates (dNTPs) blocked inhibition of the RT activity by the PI antibody, the antigenic site recognized by the PI antibody may be closely related to the dNTP binding site. The seropositivities of the BI and PI antibodies were 84.6% and 91.2%, respectively, in HIV-1-infected individuals; healthy individuals, HTLV-I-positive individuals, autoimmune disease patients and leukemia patients were all seronegative. No significant correlation of residual RT activities was observed when BI and PI antibodies were compared (r = 0.688). It is possible that the epitopes recognized by the BI antibody differs from those recognized by the PI antibody. The assays described are able to detect BI and PI antibodies in the sera of HIV-1-infected individuals.

Animals↗
PubMed1996

Legionella pneumophila heat-shock protein-induced increase of interleukin-1 beta mRNA involves protein kinase C signalling in macrophages.

Heat-shock proteins (hsp) are chaperon molecules important in protein folding and assembly. Furthermore, they may have functions in immunoregulatory processes, like T-cell stimulation and antigen presentation, which are not yet fully understood. It has been shown that several hsp of various species and family derivations modulate functions in macrophage immunity by directly increasing cytokine production. In the present study we showed that the 60,000 MW hsp of Legionella pneumophila (Lp-hsp 60) increased cellular steady-state levels of interleukin-1 beta (IL-1 beta) mRNA measured by quantitative reverse transcription-polymerase chain reaction and Northern blotting as well as IL-1 secretion, when added to cultures of thioglycollate-elicited mouse peritoneal macrophages in vitro. The level of mRNA increased in a dose-dependent manner with a minimum effective concentration of 0.5 microgram/ml and peaked 3 hr after stimulation. Lp-hsp 60-coated latex beads also increased IL-1 beta mRNA levels in the presence of cytochalasin D, which inhibits bead uptake but permits binding, indicating that binding to the macrophage surface was sufficient for induction. Accumulation of IL-1 beta mRNA was completely blocked by pretreatment with the protein kinase C (PKC) inhibitor, H7, but not decreased by prior treatment with cycloheximide. The cell lysates of macrophages stimulated with Lp-hsp 60 showed an increased PKC activity measured by phosphorylation of PKC pseudosubstrate. The IL-1 bioactivity in culture supernatants after 24 hr of stimulation with Lp-hsp 60 was increased in a dose-dependent manner but at hsp concentrations in excess of those needed to increase mRNA. Thus, the present study demonstrates that Lp-hsp 60 rapidly increases the steady-state level of IL-1 beta mRNA, possibly through a cell surface receptor system involving a PKC-dependent signalling pathway.

1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine↗
PubMed1996

A pilot study for a randomized controlled trial to prevent gastric cancer in high-risk Japanese population: study design and feasibility evaluation.

Observational epidemiological studies suggest that some nutrients reduce the risk of gastric cancer and that individuals with atrophic gastritis are at high risk of developing gastric cancer. One possible measure for gastric cancer prevention is therefore nutritional supplementation for the high risk group. Before recommending this strategy for the general public, however, a randomized controlled trial (RCT) is necessary. To evaluate the feasibility of an RCT, the authors conducted a pilot study using recipients of a health check-up program in a general hospital in Japan. The subjects who were asked to participate in the trial had been diagnosed as having atrophic gastritis on the basis of serum pepsinogen I < 70 ng/ml and the ratio of pepsinogen I to II < 3.0. They were requested to ingest double-blinded capsules containing different levels of vitamin C and beta-carotene every day. Out of the 219 subjects (118 males, 101 females) who were eligible for the study and had the required pepsinogen measurement, 90 (41%) met the criteria for atrophic gastritis. Among them, 55 (61%) (35 males, 20 females) gave their informed consent to participate in the RCT. Fifty-four participants completed a 3-month course of supplementation, and all of them agreed to a 5-year supplementation period. The authors concluded that an RCT using double-blinded nutritional supplements and targeting apparently healthy individuals is feasible in an intervention study for cancer prevention in Japan.

Adult↗
PubMed1996

[Follow-up of HIV carriers by a laboratory method. I: Virus isolation is useful for prognostication of the onset of symptoms].

We followed 54 HIV-1 carriers (44 asymptomatic carriers and 10 AIDS patients) by virus isolation and immunological examination and evaluated their usefulness for prognostication of the onset of symptoms. From 37 carriers (27 asymptomatic carriers and 10 symptomatic), 132 HIV-1 strains were isolated; the virus isolation rate was 60% in the asymptomatic carriers (AC) but 100% in the symptomatic. In the AC, the isolation rate was 54.5% in the group showing stable in the CD4+ level but 95.5% in the group showing a decrease in the CD4+ level. With progression of the disease, the culture time required for virus isolation was shortened, and the percentage of isolates showing infectivity to the T-cell line (MT-4 cells) increased. These findings suggest that the virus in the body is changed with progression of the disease to that showing rapid replication, T-cell tropic, and high pathogenicity. Indeed, progression of the disease was observed in all carriers in whom a highly pathogenic virus was detected; some developed the disease within 1 year, some showed temporary recovery in the CD4+ level after AZT administration followed by progression to ARC, and others showed a rapid decrease in the CD4+ level. In contrast, in carriers with only slightly pathogenic virus, the CD4+ level was maintained for a long period. These results suggest that the detection of a highly pathogenic virus is one of the most reliable marker for the prognostication of the onset of the disease. The detection of HIV-1 antigen in the plasma and a decrease in the gag antibody were also associated with the progression of the disease. However, the reliability of these markers seems to be lower than that of virus isolation.

Acquired Immunodeficiency Syndrome↗
PubMed1996

[Prognosis and evaluation of drug therapy by V3 and RT gene analysis of HIV-1].

We have reported on the investigation of 54 HIV-1 patients concerning the isolation and clinical marker in the preceding paper. We have attempted the analysis of the V3 and RT genes. HIV-1 from a patient who had rapidly taken a turn for the worse had basic amino acid at position 11 (Arg) and lost an acidic amino acid at position 25 (Gln) of V3. This sequence pattern was a distinguished feature of a virus with a rapid-high, syncytium inducing (SI) and T-cell-line tropic phenotype. In contrast, patients with no or mild clinical symptoms had sequences characterized as slow-low, non-synsytium inducing (NSI) and macrophage tropic. We then investigated the appearance of resistant to AZT and ddI. It was shown that the virulent virus obtained drug resistant variants faster than the wild type by analysis of the RT gene. We consider that these data concerning virus isolation and gene analysis are useful for prognosis and strategy for clinical therapy.

Acquired Immunodeficiency Syndrome↗
PubMed1996

The effect of non-activated prothrombin complex concentrate (Proplex ST) on intraperitoneal hematoma in a hemophilia A patient with a factor VIII inhibitor.

A 28-year-old severe hemophiliac with a factor VIII inhibitor was admitted to our hospital with a massive and serious intraperitoneal hematoma. He was a high-responder patient showing maximal serum inhibitor levels as high as 255 Bethesda Units/ml (BU/ml). He was successfully treated with "bypass therapy" using a prothrombin complex concentrate (PCC).

Adult↗
PubMed1995

Gene targeting in mice reveals a requirement for angiotensin in the development and maintenance of kidney morphology and growth factor regulation.

Elevated levels of endogenous angiotensin can cause hypertensive nephrosclerosis as a result of the potent vasopressor action of the peptide. We have produced by gene targeting mice homozygous for a null mutation in the angiotensinogen gene (Atg-1-). Postnatally, Atg-1- animals show a modest delay in glomerular maturation. Although Atg-1- animals are hypotensive by 7 wk of age, they develop, by 3 wk of age, pronounced lesions in the renal cortex, similar to those of hypertensive nephrosclerosis. In addition, the papillae of homozygous mutant kidneys are reduced in size. These lesions are accompanied by local up-regulation of PDGF-B and TGF-beta1 mRNA in the cortex and down-regulation of PDGF-A mRNA in the papilla. The study demonstrates an important requirement for angiotensin in achieving and maintaining the normal morphology of the kidney. The mechanism through which angiotensin maintains the volume homeostasis in mammals includes promotion of the maturational growth of the papilla.

Aging↗
PubMed1995

[A study of urinary podocalyxin in children with IgA nephropathy].

The existence of podocalyxin (PCX) in urine sediments of 30 children with IgA nephropathy was identified by positive findings of immunofluorescence testing using a monoclonal antibody (PHM-5). Three structures (cells (podocytes), casts, granules) were stained and arbitrarily scored according to their numbers and intensity of fluorescence. The urinary scores for podocytes and casts were higher in the acute stage than in the chronic stage (p < 0.02 and p < 0.01, respectively). Protein excretion and hematuria showed a strong parallel correlation in the podocytes (p < 0.005 and p < 0.001), and in the casts (p < 0.001 and p < 0.005) in the urine sediments. The urinary scores for podocytes and casts were significantly higher in cases with extracapillary lesions (p < 0.003 and p < 0.01) and with interstitial lesions (p < 0.02 and p < 0.008) but no correlation existed with the intensity of mesangial proliferation. The urinary scores for podocytes and casts were also higher in cases with mesangiocapillary IgA deposits (p < 0.04 and p < 0.04) and C 3 deposits (p < 0.03 and p < 0.04). These findings suggest that PCX in the urine sediments indicate the degree of the glomerular epithelial cell injury and is useful for clinical evaluations.

Adolescent↗
PubMed1994

Characterization of the myosin-binding subunit of smooth muscle myosin phosphatase.

A myosin phosphatase was purified from chicken gizzard smooth muscle. The holoenzyme is a trimer and consists of 130,000-, 38,000-, and 20,000-Da subunits (in agreement with the results of Alessi et al.: Alessi, D., MacDougall, L. K., Sola, M. M., Ikebe, M., and Cohen, P. (1992) Eur. J. Biochem. 210, 1023-1035). The catalytic subunit, 38,000 Da, is the type 1 delta isoform, and its derived amino acid sequence is identical to the rat isoform. The larger subunit bound to myosin and also interacted with the catalytic subunit. cDNA clones encoding the large subunit were isolated from chicken gizzard cDNA libraries. Overlapping clones indicated the presence of two isoforms, and open reading frames of 2889 and 3012 bases were obtained. These encoded proteins of 963 and 1004 amino acids, with masses of 106,700 and 111,600 Da, respectively. The insert in the larger isoform is in the center of the molecule, at residues 512-552. The N-terminal third of the molecule is composed of eight repeat sequences, similar to the cdc10/SWI6 or ankyrin repeat. Myosin binding and binding to the catalytic subunit are properties of a 58,000-Da fragment that represents the N-terminal part of the molecule.

Amino Acid Sequence↗
PubMed1994

A regulatory subunit of smooth muscle myosin bound phosphatase.

The relationship between two putative myosin-binding subunits of smooth muscle myosin phosphatase was investigated. A monoclonal antibody (MoAb) to the 58 kD component of smooth muscle myosin-bound phosphatase (MBP) cross-reacted with a 130 kD protein in extracts of fresh chicken gizzards. The MoAb in combination with protein A immunoprecipitated from gizzard extracts a complex of the 130 kD protein plus the 38 kD catalytic subunit of the type 1 delta protein phosphatase. It is proposed that the 130 kD component is a native subunit of MBP and that the 58 kD protein is its proteolytic degradation product. The distribution of the 130 kD component in chicken tissues was screened using the MoAb. An immunoreactive band of appropriate mass was detected in all tissues except liver and skeletal muscle. Higher concentrations of the 130 kD component were evident in the smooth muscle samples.

Animals↗
PubMed1994

Effects of heart rate on phasic coronary blood flow pattern and flow reserve in patients with normal coronary arteries: a study with an intravascular Doppler catheter and spectral analysis.

To assess the effects of pacing-induced tachycardia on phasic coronary blood flow pattern and flow reserve of left anterior descending artery, we examined 16 patients with chest pain and angiographically normal coronary arteries by using an intravascular Doppler catheter with spectral analysis of the velocity signal. The heart rate was increased from a mean of 68 +/- 11 beats/min during sinus rhythm to 100 beats/min and again to 120 beats/min. Cross-sectional area of the epicardial artery and resting systolic and diastolic coronary blood flows increased progressively, resulting in an elevation of total coronary flow from 142 +/- 54 ml/min during sinus rhythm to 190 +/- 66 ml/min at 100 beats/min (p < 0.05) and to 219 +/- 69 ml/min at 120 beats/min (p < 0.01). During maximal hyperemia with intracoronary injection of 10 to 12 mg of papaverine, there was an increase in the systolic coronary blood flow with a decrease in the diastolic flow, resulting in no significant change in the total flow. These alterations led to progressive reductions in coronary flow reserve from 3.9 +/- 0.7 during sinus rhythm to 2.9 +/- 0.9 at 100 beats/min (p < 0.01) and to 2.3 +/- 0.3 at 120 beats/min (p < 0.001). Thus careful consideration should be given to the effects of heart rate when phasic coronary blood flow pattern and flow reserve are assessed.

Adult↗
PubMed1994

[Effect of catechin on the ultrastructure of Trichophyton mentagrophytes].

The effects of (-) epigallocatechin gallate (EGCg) on the morphology of hyphae and conidia of Trichophyton mentagrophytes were examined using scanning and transmission electron microscopy. EGCg inhibited the germination of conidia and subsequent hyphal growth. After being treated with EGCg for 3 days, conidia showed morphological changes such as deformation, swelling, wrinkles, exfoliation of the surface layer and accumulation of granular, amorphous materials on the conidia and short hyphae surfaces. These morphological changes became apparent day by day. After 5 days, most of the ungerminating conidia were broken down. The hyphal cell walls were also exfoliated and the cytoplasm in most of the cells disappeared completely. Inner organellas were variable in size and shape. Many high electron dense particles, greatly enlarged vacuoles appeared in the cytoplasm. The degradation of cells occurred. These observations indicates that EGCg causes lysis of the conidia and hyphae. These findings suggest that EGCg may be used as an antidermatophytic agent against T. mentagrophytes infection.

Catechin↗