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Biomedical subjects

H Nakashima

Publications and source records attributed to H Nakashima.

At least 163 records · Page 9Linked to original sources
PubMed1998

Pharmacophore identification of a chemokine receptor (CXCR4) antagonist, T22 ([Tyr(5,12),Lys7]-polyphemusin II), which specifically blocks T cell-line-tropic HIV-1 infection.

We have previously found that T22 ([Tyr(5,12), Lys7]-polyphemusin II) has strong anti-human immunodeficiency virus (HIV) activity, and that T22 inhibits T cell-line-tropic HIV-1 infection mediated by CXCR4/fusin. T22 is an 18-residue peptide amide, which takes an antiparallel beta-sheet structure that is maintained by two disulfide bridges. Structure-activity relationship (SAR) studies on T22 have disclosed the contributions of each region of T22 to activity or cytotoxicity, and have provided the following useful information to develop new CXCR4 antagonists: The number of Arg residues in the N-terminal and C-terminal regions of T22 is closely related to anti-HIV activity. Addition of a variety of functional groups at the N-terminal end results in increases in activity. Disulfide rings, especially the major disulfide loop, are indispensable for anti-HIV activity and maintenance of the beta-sheet structure. Trp3 can be replaced by other aromatic residues (Tyr, Phe and L-2-naphthylalanine). Between two repeats of Tyr-Arg-Lys, which are a characteristic structure in T22, Tyr-Arg-Lys in the N-terminal portion is more closely associated with anti-HIV activity and maintenance of the beta-sheet structure. A positive charge in the side chain at the (i + 1) position of the beta-turn region is necessary for strong activity. Through these studies, we have found several compounds having higher selectivity indexes (50% cytotoxic concentration/50% effective concentration) than that of T22.

Amino Acid Sequence↗
PubMed1998

Genome-wide mapping of unselected transcripts from extraembryonic tissue of 7.5-day mouse embryos reveals enrichment in the t-complex and under-representation on the X chromosome.

Mammalian embryos can only survive if they attach to the uterus (implantation) and establish proper maternal-fetal interactions. To understand this complex implantation pathway, we have initiated genomic analysis with a systematic study of the cohort of genes expressed in extraembryonic cells that are derived from the conceptus and play a major role in this process. A total of 2103 cDNAs from the extraembryonic portion of 7.5-day post-conception mouse embryos yielded 3186 expressed sequence tags, approximately 40% of which were novel to the sequence databases. Furthermore, when 155 of the cDNA clones with no homology to previously detected genes were genetically mapped, apparent clustering of these expressed genes was detected in subregions of chromosomes 2, 7, 9 and 17, with 6.5% of the observed genes localized in the t-complex region of chromosome 17, which represents only approximately 1.5% of the mouse genome. In contrast, X-linked genes were under-represented. Semi-quantitative RT-PCR analyses of the mapped genes demonstrated that one third of the genes were expressed solely in extraembryonic tissue and an additional one third of the genes were expressed predominantly in the extraembryonic tissues. The over-representation of extraembryonic-expressed genes in dosage-sensitive autosomal imprinted regions and under-representation on the dosage-compensated X chromosome may reflect a need for tight quantitative control of expression during development.

Animals↗
PubMed1998

A lipoteichoic acid fraction of Enterococcus hirae activates cultured human monocytic cells via a CD14-independent pathway to promote cytokine production, and the activity is inhibited by serum components.

To elucidate the cellular activation mechanisms of lipoteichoic acid (LTA) compared with those of lipopolysaccharide (LPS), a quantitatively major LTA fraction, QM-1M, was prepared from hot phenol-water extracts of Enterococcus hirae (ATCC 9790) by hydrophobic octyl-Sepharose chromatography and by ion-exchange membrane (QMA-Mem Sep 1010) chromatography as a 60% 1-propanol- and 1 M NaCl-eluted fraction. Unlike the reference Escherichia coli LPS, QM-1M did not demonstrate any ability to induce cytokines in a human whole blood culture system in this study, whereas QM-1M induced a few cytokines such as interleukin (IL)-8 and tumor necrosis factor-alpha in human monocytic THP-1 cell and human peripheral mononuclear cell (PBMC) cultures in the absence of serum. Fetal calf and human sera decreased the above cytokine induction by QM-1M in THP-1 and PBMC cultures, whereas sera increased activities of the reference LPS. IL-8 induction in the absence of serum in response to QM-1M was demonstrated to proceed through a CD14-independent pathway unlike the reference LPS.

Cell Line↗
PubMed1998

Analysis of the granulocyte colony-stimulating factor receptor gene structure using PCR-SSCP in myeloid leukemia and myelodysplastic syndrome.

The membrane-proximal cytoplasmic region of the granulocyte colony-stimulating factor receptor (G-CSFR) is known to be essential for the proliferation signal, with a more distal region being required for the differentiation signal. Such a separation of functional domains raises the possibility that mutations occurring at these regions may contribute to cell proliferation in the absence of differentiation, this being the most important characteristic in acute leukemia cells. Therefore, we analysed the structural abnormalities at the transmembrane and cytoplasmic region of G-CSFR in a significant number of patients with various myeloid malignancies. When we examined the genomic DNA of G-CSFR obtained from 41 patients with acute myelogenous leukemia (AML), 18 with chronic myelogenous leukemia (CML), 7 with myelodysplastic syndrome (MDS), 2 with chronic myelomonocytic leukemia and 1 with chronic neutrophilic leukemia, we found a polymorphism in 3 patients, but no significant pathogenic mutations in any patients. The screening for this polymorphism in 100 hematologically normal controls revealed that it may be useful as a linkage marker for population and family studies, because the heterozygosity index is at a high level (0.055). While there have been several reports discussing the leukemogenic potential of mutations in the cytokine/hematopoietin receptor superfamily, genetic alterations in the transmembrane and cytoplasmic region of G-CSFR do not seem to play a pathogenic role in leukemia.

Humans↗
PubMed1998

Cross sectional observation of the effects of carbon disulphide on arteriosclerosis in rayon manufacturing workers.

OBJECTIVE: A prospective cohort study was designed to clarify the relations between occupational exposure to carbon disulphide (CS2) and its effects on arteriosclerosis in workers in 11 Japanese rayon manufacturing factories. This report is a cross sectional baseline observation in the first study year. METHODS: Study subjects were 432 male rayon workers (mean (range) age 35.5 (19.1-47.8); duration of exposure 13.4 (0.3-29.0)) and 402 male referent workers (age 35.8 (18.9-49.8)). Exposure to CS2 was assessed by determining the concentration of 2-thiothiazolidine-4-carboxylic acid (TTCA) in urine. Mean (SD) TTCA was 3.42 (2.73) mg/g creatinine (Cr) (n = 422). About a quarter of the urine samples were > 5 mg/g Cr, a biological exposure index recommended by the American Conference of Governmental Industrial Hygienists. Health effects on arteriosclerosis were evaluated by measuring blood pressure, serum lipids, pulse wave velocity of the aorta, stiffness and blood flow of the carotid artery, and blood coagulation and fibrinolysis indices, and by use of brain magnetic resonance imaging, electrocardiogram (at rest and after exercise), ophthalmograph, and Rose's questionnaire. Information on potential confounding factors was collected by self administered questionnaire. RESULTS: Prevalence of microaneurysm of the retinal artery was significantly higher in workers exposed to CS2 (8.1%) than in referent workers (3.4%), and increased with age. Other examinations did not show any differences between the two groups even after allowance for confounding factors. CONCLUSIONS: Significant effects of CS2 on arteriosclerosis were not found in current rayon manufacturing workers, with the exception of induction of microaneurysm of the retinal artery.

Adult↗
PubMed1998

Role of IL-10 in the crossregulation of prostaglandins and cytokines in monocytes.

In the present study we have focused mainly on the role of IL (interleukin)-10 in the crossregulation of prostaglandins and cytokines in human monocytes. We first determined the effects of tumor necrosis factor-alpha (TNF-alpha) and IL-10 on monocyte prostaglandin E2 (PGE2) production. Unstimulated monocytes constitutively produced a small but significant amount of PGE2 in the culture supernatants. Both TNF-alpha and lipopolysaccharide (LPS) caused a remarkable increase in monocyte PGE2 production. On the other hand, IL-10 alone was without effect on constitutive PGE2 production but drastically inhibited LPS-induced PGE2 production in monocytes. Moreover, this inhibitory effect of IL-10 was not simply attributable to its inhibition of TNF-alpha production in LPS-stimulated monocytes. Next, we determined the effect of PGE2 on TNF-alpha mRNA expression in monocytes. Treatment of monocytes with or without PGE2 showed no detectable TNF-alpha mRNA. Activation of monocytes by LPS resulted in a remarkable accumulation of TNF-alpha mRNA and PGE2 efficiently inhibited this expression. Finally, we determined the effect of PGE2 on IL-10 mRNA expression in monocytes. Similar to TNF-alpha mRNA, unstimulated monocytes showed no detectable IL-10 mRNA. Interestingly, PGE2 alone drastically induced IL-10 mRNA. Besides, activation of monocytes by LPS resulted in a remarkable accumulation of IL-10 mRNA, and PGE2 further enhanced this expression. These results indicate that TNF-alpha and PGE2 are key molecules for the induction of IL-10 in monocytes, and that IL-10, in turn, plays a crucial role in terminating the inflammatory cascade via downregulation of production of proinflammatory molecules including TNF-alpha and PGE2.

Cells, Cultured↗
PubMed1998

Spermidine determines the sensitivity to the calmodulin antagonist, chlorpromazine, for the circadian conidiation rhythm but not for the mycelial growth in Neurospora crassa.

The gene that suppresses the phenotype of the cpz-2 mutation, which results in changing the sensitivity to chlorpromazine in relation to mycelial growth and circadian rhythms, was cloned in Neurospora crassa. This gene is not the cpz-2 gene itself but rather is identical to the spe-3 gene that encodes spermidine synthase in Neurospora. The intracellular content of spermidine was lowered in the cpz-2 strain compared to that of the wild-type strain. By integration of the spe-3 gene or by the addition of spermidine into culture medium, the temperature sensitivity of mycelial growth was lost and the conidiation rhythm became sensitive to chlorpromazine in the cpz-2 strain, as was observed in the wild-type strain, but the hypersensitivity of mycelial growth on chlorpromazine in the cpz-2 strain was not affected. Therefore, it appears that spermidine determines only the sensitivity of the conidiation rhythm to chlorpromazine.

Amino Acid Sequence↗
PubMed1998

3-(5-Dimethylamino-1-naphthalenesulphonyl)-2-(3-pyridyl)thiazolidine (YHI-1) selectively inhibits human immunodeficiency virus type 1.

3-(5-Dimethylamino-1-naphthalenesulphonyl)-2-(3-pyridyl)thiazolidi ne (YHI-1), a synthetic analogue of D-cysteinolic acid isolated from sardines (Sardinops melanostictus), was found to be a specific inhibitor of human immunodeficiency virus type 1 (HIV-1) replication in various cell cultures. YHI-1 inhibited HIV-1IIIB replication with a 50% effective concentration (EC50) of 3.35, 10.23 and 4.61 microM in MT-4 cells, peripheral blood mononuclear cells and MAGI-CCR5 cells, respectively. However, no antiviral activity was observed with non-nucleoside reverse transcriptase inhibitor (NNRTI)-resistant HIV-1 strains, such as nevirapine-resistant HIV-1HE/NEV and MKC-442-resistant HIV-1IIIB-R, or with HIV-2ROD or SIVMAC. YHI-1 failed to inhibit reverse transcriptase (RT) activity in vitro with different template-primer systems. Time-of-addition experiments, the failure to inhibit NNRTI-resistant strains and the failure to show in vitro activity against RT suggest that a metabolite of YHI-1 inside the cell acts like an NNRTI. Thus, YHI-1 seems to belong to a new class of HIV-1 inhibitor and is a good candidate for further development.

Animals↗
PubMed1998

Q wave and non-Q wave myocarditis with special reference to clinical significance.

This study was designed to evaluate the differences in clinical findings between patients with and without Q waves in acute myocarditis. Among a total of 24 patients, eleven patients had Q waves and thirteen did not. Echocardiographic findings, in-hospital complications and follow-up results were compared between the two groups. In the acute stage, the Q wave group showed significantly higher creatine kinase (CK) values and a more impaired left ventricular ejection fraction than the non-Q wave group (40 +/- 11% vs 57 +/- 10%, p < 0.001). Transient left ventricular hypertrophy was also prominent in the Q wave group. The incidence of cardiogenic shock (55%) and conduction disturbances (64%) were higher in the Q wave group than in the non-Q wave group (0% and 15%, respectively). In-hospital mortality rate was 27% in the Q wave group and 8% in the non-Q wave group, respectively. Since rapid improvement occurred in survivors with Q waves, long-term prognosis was favorable for the two groups. In conclusion, Q waves might indicate a more severe course in early illness.

Adrenal Cortex Hormones↗
PubMed1998

[The effects of high-dose steroid therapy on sudden deafness].

The effect of high-dose steroid therapy on sudden deafness were investigated in 19 cases. A daily intravenous administration dose of hydrocortisone sodium succinate was tapered from 800 mg to 200 mg as follows; 800 mg 800 mg, 600 mg, 600 mg, 400 mg, 400 mg, 300 mg, and 200 mg. Another 19 cases, the control group, were treated with intravenous application of prednisolone, tapered from 50 mg to 10 mg in 10-mg steps and each dose applied for 3 days. There were no significant differences in the effect on hearing between the two groups as measured by three different analyses: criteria proposed by the Committee on Sudden Deafness of the Japan Health Ministry; magnitudes of improvement of mean thresholds at five frequencies from 250 Hz to 4 kHz in affected side; and the ratio of the magnitudes of improvement of mean thresholds in affected side to magnitudes of difference between the initial mean thresholds in affected side and those in contralateral side. These findings suggest that high-dose steroid therapy for sudden deafness is not so effective as it is for idiopathic facial palsy. This may be due to the difference in the mechanisms of development between the two conditions. No critical side effects were observed in our study, which would argue for the safety of our method of high-dose steroid therapy for routine clinical use. It might be advisable to conduct additional clinical studies to determine the effect of high-dose steroid therapy for sudden deafness, because our study was conducted on a small number of patients and was not double-blind or randomized.

Adolescent↗
PubMed1998

Immunohistological identification of epithelioid cell granulomas in Crohn's disease and its diagnostic values especially in the differentiation from ulcerative colitis.

We produced a monoclonal antibody against epithelioid cell granulomas (ECGs) by immunizing mice with a crude tissue extract of lymph nodes with sarcoidosis. The established antibody (ECM antibody) strongly reacted with epithelioid cells and Langhans' type giant cells of ECGs not only in cases of sarcoidosis, but also in cases of other granulomatous diseases such as tuberculosis and Crohn's disease. In this study, we used the ECM antibody to improve the histopathological diagnosis of Crohn's disease, in which the demonstration of ECGs is critical for diagnosis, but morphological identification of ECGs by hematoxyline and eosin (HE) staining is frequently difficult. When we examined the tissues removed at operation from 11 patients with Crohn's disease, we observed a total of 29 lesions of morphologically recognizable ECGs, all of which were immuonohistologically positive for the ECM antibody (granuloma pattern). In addition the ECM antibody revealed 43 nests of tiny inflammatory lesions (nested pattern) that could not be morphologically recognized as ECGs by HE staining only. Both the granuloma and nested patterns of ECM immunoreactivity were present in all cases of Crohn's disease we examined, but were absent in all 15 cases of ulcerative colitis that were used as controls. Thus, we concluded that the newly established ECM antibody is useful for detecting morphologically equivocal granulomatous Crohn's disease lesions, and should be helpful for the histopathological differentiation of this disease from other types of chronic inflammatory bowel diseases, such as ulcerative colitis.

Adult↗
PubMed1998

[Development of an anticancer drug in Japan based on a new clinical trial system].

According to the revision of Pharmaceutical Affairs Law in 1996, the GCP has been enacted into the law. Next year the new GCP was established based on the ICH-GCP and it has been active since April, 1997. Though the new GCP makes it possible for the regulatory authorities (Japan, the United States and European Union) to accept clinical trial data mutually, the circumstances of clinical trial in Japan have been required big changes. But considerable investigators/institutions in Japan which carry out clinical trials seem to have not still adapted their usual clinical trial system to a new one yet. At the first time, in this article are described the process of both the revision of Japanese pharmaceutical law and the establishment of the new Japanese GCP. The second, the characteristics of the new Japanese GCP especially about the roles and responsibilities of investigators are discussed. Furthermore approaches of the US FDA for new anticancer drugs development are also described.

Antineoplastic Agents↗
PubMed1998

[Interstitial cystitis in case of primary Sjögren's syndrome].

A 53-year-old woman who had xerostomia for ten years was admitted to our hospital because of refractory lower abdominal pain and pollakisuria of five years duration. Although she had undergone surgical treatments including cholecystectomy, ovarian cystectomy and groin hemiorrhaphy, she still suffered from abdominal symptoms. A diagnosis of interstitial cystitis was confirmed by hydraulic distention during a cystoscopic examination and by histopathological examination of the bladder. Her symptoms disappeared soon after the cystoscopic procedure, which also had a therapeutic effect of interstitial cystitis. Laboratory findings revealed hypergammaglobulinemia, a high titer of rheumatoid factor, positive anti-nuclear antibody, and positive anti-SS-A/Ro antibody. She was diagnosed as having primary Sjögren's syndrome based on the results of a gum test (8.5 ml/ 10 min), sialography (Stage II), and a positive minor salivary gland biopsy. Starting one month after the hydraulic distention, her abdominal symptoms gradually reappeared along with elevation of her serum IgG level. These features were markedly improved with 30 mg/day of oral prednisolone, which was then successfully tapered. These results suggested that interstitial cystitis in this case was caused by immunological abnormalities associated with Sjögren's syndrome.

Cystitis, Interstitial↗
PubMed1998

[Pneumatosis cystoides intestinalis associated with intravenous pulse cyclophosphamide treatment for systemic lupus erythematosus].

Pneumatosis cystoides intestinalis (PCI) is an uncommon disease manifestation characterized by the presence of air in the bowel wall. PCI is sometimes observed in patients with progressive systemic sclerosis or mixed connective tissue disease but extremely rare in patients with systemic lupus erythematosus (SLE). We here report a patient with SLE who developed PCI after the treatment with intravenous cyclophosphamide (IVCY). This is the first case that association between IVCY and PCI was suggested. A 51-year-old woman with a 24-year history of SLE was admitted to our hospital because of skin ulcers in the lower legs. She had been receiving prednisolone orally. Laboratory findings on the present admission showed a elevated titer of anti-double stranded DNA antibody and positive LE test. She was successfully treated with three pulses of methylprednisolone followed by two IVCY together with vasodilators for her disease activity of SLE including skin manifestation. Just after the second IVCY, abdominal distention was gradually developed without any other abdominal symptoms, including abdominal pain. Abdominal radiography and computed tomography revealed pneumoperitoneum and multiple intramural air collections which involved the ascending colon primarily. Gastrointestinal series, however, showed no evidence of intestinal perforation. The diagnosis of PCI was made radiologically. After she was treated with a combined therapy with intravenous hyperalimentation and breathing with high concentration of oxygen for three weeks, PCI and pneumoperitoneum disappeared. It would be necessary that IVCY is carefully administrated, especially for the patients under the risk of PCI, such as collagen diseases.

Cyclophosphamide↗
PubMed1998

Improvement of systemic lupus erythematosus activity by the association of delayed onset Cushing's syndrome.

We describe a 43-year-old woman with systemic lupus erythematosus (SLE) who had complete resolution of all SLE symptoms as a result of hypercortisolemia induced by a glucocorticoid-producing adenoma of the left adrenal gland. After an adrenalectomy, she developed an SLE exacerbation, characterized by photosensitivity, polyarthralgia, and hemolytic anemia, which required intensive steroid therapy. This is the first report of a patient with SLE entering apparent remission due to excessive adrenal secretion of glucocorticoids.

Adult↗
PubMed1997

Effect of the chimeric soluble granulocyte colony-stimulating factor receptor on the proliferation of leukemic blast cells from patients with acute myeloblastic leukemia.

The biological roles of the soluble granulocyte colony-stimulating factor (G-CSF) receptor, which arises as a result of alternative RNA splicing, are as yet unknown. In this study, we examined the in vitro effect of a chimeric protein composed of the extracellular region of a murine G-CSF receptor and the human IgG1 Fc region because a human natural soluble G-CSF receptor was not available. First, we found that this chimeric soluble G-CSF receptor could inhibit the biological activity of G-CSF on normal bone marrow colony formation. Because G-CSF also plays an important role in the proliferation of leukemic blast cells, we next examined the effect of the soluble G-CSF receptor on leukemic blast colony formation in 10 acute myeloblastic leukemia cases. Although G-CSF stimulated the proliferation of leukemic progenitor cells to form leukemic blast colonies, the chimeric soluble G-CSF receptor completely inhibited this stimulatory effect. Furthermore, the chimeric soluble G-CSF receptor also inhibited spontaneous leukemic blast colony formation in two cases. Because a high concentration of G-CSF was observed in the supernatants of leukemic blast cells from these two cases, it seems likely that the soluble G-CSF receptor cut off the autocrine growth mechanism of leukemic blast cells mediated by G-CSF. These findings suggest the possibility that the soluble G-CSF receptor could be used in a clinical application for acute myeloblastic leukemia patients in the future.

Animals↗
PubMed1997

Differences in dinucleotide frequencies of human, yeast, and Escherichia coli genes.

Nucleotide sequences coding proteins in human, yeast and Escherichia coli genes were analyzed in terms of dinucleotide occurrences. Every gene is plotted as a point in the dinucleotide space, which is spanned by 16 axes corresponding to the 16 components of the dinucleotide. The metric unit in the space is defined using the log-odds ratio of dinucleotide occurrences in a gene. The distribution of points showed that genes from the same organism are clustered in the space. The clusters of human and E. coli are completely separated, and the yeast cluster sits between, implying that individual genes are classified into the three sources from their location. In fact, they could be identified with accuracy of 90%, using the DNA data alone. Even genes encoding homologous proteins belonging to the same protein superfamily were discriminated by the DNA data, and were correctly identified into their sources with the same accuracy as above. DNA sequences of non-coding regions, including human introns, as well as human genes of GC-rich and GC-poor types, were also analyzed in the same manner. The most significant finding is that human genomic DNA sequences, including genes and introns together, exhibit the largest deviation of dinucleotide occurrence from the random expectation. Possible origins for this phenomenon are discussed.

Dinucleotide Repeats↗