Alkylation carcinogenesis in mice with altered levels of DNA repair methyltransferase.
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Alkylating Agents↗
Biomedical subjects
M Sanada
Publications and source records attributed to M Sanada.
Familial essential thrombocythemia associated with one-base deletion in the 5'-untranslated region of the thrombopoietin gene.
Familial essential thrombocythemia (ET) is inherited in an autosomal-dominant manner. This finding implies that familial ET may arise as a consequence of a mutation(s) that activates platelet production. In 1994, the thrombopoietin (TPO) gene was isolated and cloned. The TPO-TPO receptor, encoded for by the c-mpl gene, are essential regulators of thrombopoiesis. Alterations of TPO or c-Mpl thus may constitute a pathogenic event leading to familial ET. In a case of familial ET presented in our institute, serum TPO levels were significantly elevated in affected members of the family as compared with nonaffected members. Moreover, we identified a one-base deletion in the 5'-untranslated region of the TPO gene in affected but not in nonaffected family members. In vitro experiments showed that the identified mutation increased TPO production. Based on our findings, we propose that this region of the TPO gene may play a crucial role in regulating TPO expression. Our results strongly suggest that the identified mutation leads to familial ET.
DNA Mutational Analysis↗
CD2 loss and CD8 expression by Epstein-Barr virus-associated NK leukemia cells in culture.
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Adult↗
Apolipoprotein E phenotype associations with plasma lipoproteins and bone mass in postmenopausal women.
OBJECTIVE: The aim of the study was to investigate the effects of apolipoprotein E (apo E) phenotype on plasma lipids and bone mass in postmenopausal Japanese women. METHODS: In 320 subjects aged 40-65 years (mean +/- SE, 54.0 +/- 0.6), apo E phenotype was determined by isometric electrophoresis. Phenotypic frequencies were 0.3% for E2/2 (n = 1), 8.1% for E3/2 (n = 26), 70.3% for E3/3 (n = 225), 0.6% for E4/2 (n = 2), 19.4% for E4/3 (n = 62) and 1.3% for E4/4 (n = 4). Apo E2/2 and apo E3/2 were classified as E2+ (n = 27); apo E3 homozygotes were placed in another group (E3/3; n = 225), as were apo E4/3 together with apo E4/4 subjects (group E4+; n = 66). Bone density and bone quality were assessed with a newly developed ultrasonic bone densitometer, and plasma lipids were also measured. RESULTS: Age, body mass index and years since menopause did not differ significantly between the three groups. The E4+ group had the highest levels of total cholesterol, low-density lipoprotein cholesterol and apolipoprotein B, significantly higher than in the E2+ group. Plasma lipoprotein(a) concentrations were significantly higher in the E4+ group than in the other two groups. Ultrasonic parameters of bone density and quality tended to be lower in the E4+ group than in the E2+ group. CONCLUSIONS: The apo E4 allele was associated with high plasma cholesterol levels and an unfavorable change of bone structure in postmenopausal women.
Adult↗
Enhancement of synaptic transmission by HPC-1 antibody in the cultured hippocampal neuron.
To clarify the function of HPC-1/syntaxin 1A in the mammalian central synapse, the effects of intracellularly applied antibody on the synaptic transmission were examined at the autapse of the cultured rat hippocampal neuron. Intracellularly applied antibody against HPC-1/syntaxin 1A (IgG, 0.3 mg ml(-1)) during whole-cell recording enhanced the autaptic excitatory postsynaptic current (EPSC). Pre-immune IgG (0.3 mg ml(-1)) showed no effect. The amplitude-distribution of an asynchronous EPSC was not affected by administration of this antibody, indicating that the increase in the amplitude of the evoked EPSC was attributable to an increase in transmitter release from the presynaptic terminal HPC-1/syntaxin 1A could be involved in suppressing as well as facilitating process of the exocytosis at the mammalian central synapse.
Animals↗
Characterization of HPC-1 antigen, an isoform of syntaxin-1, with the isoform-specific monoclonal antibody, 14D8.
We raised polyclonal and monoclonal antibodies against rat recombinant HPC-1/syntaxin 1A lacking a transmembrane domain. The polyclonal antibody recognized two major bands at 35 and 40 kDa from rat brain membranes. A hybridoma clone designated 14D8, however, recognized only one band at 35 kDa. A polyclonal antibody detected recombinant syntaxin 1B, as well as HPC-1/syntaxin 1A on an immunoblot, whereas 14D8 recognized recombinant HPC-1/ syntaxin 1A, but not syntaxin 1B. Therefore, 14D8 is specific for HPC-1/syntaxin 1A. Using this monoclonal antibody, we investigated the expression of HPC-1/syntaxin 1A in the rat hippocampal membranes. HPC-1/syntaxin 1A was present even in the embryonic d 19 (E19) hippocampal membranes, and it increased during the next two postnatal wk. Pyramidal cell axons were intensely stained with the 14D8 monoclonal antibody, suggesting that HPC-1/syntaxin 1A was not restricted to the presynaptic terminal. Furthermore, we investigated the phosphorylation of HPC-1/syntaxin 1A in the rat brain membranes. HPC-1/syntaxin 1A affinity-purified on a 14D8 IgG-coupled column was recognized by antiphosphoserine antibody, but not by antiphosphotyrosine and phosphothreonine antibodies.
Animals↗
[Diffuse large B-cell lymphoma mainly involving the heart and showing t(8;14) (q24;q32) with c-myc rearrangement].
A 77-year-old man was admitted because of massive pericardial effusion and cardiac tumor. Cytological examination of the effusion and histological examination of a subcutaneous tumor in the chest wall revealed diffuse large B cell lymphoma. The immunophenotype of tumor cells was CD5+ CD20+ CD22+ CD38+ HLA-DR+ CD19-. Chromosome analysis revealed complex abnormal karyotypes containing t(8;14) (q24;q32). C-myc gene rearrangement was shown by Southern blotting. Chemotherapy with pirarubicin, cyclophosphamide, vincristin, and prednisolone (THP-COP) was not effective for his lymphoma. He suffered from cardiac tamponade and died at 5 months after diagnosis. Autopsy revealed a large cardiac tumor, extensive epicardial infiltration, tiny tumors in the lung and pancreas, but no lymphadenopathy, the combination of which suggested a primary cardiac lymphoma. Immunohistochemistry for p53 protein showed nuclear staining of more than 50% of the lymphoma cells. In situ hybridization for EBER-1 was negative. Rearrangement of c-myc gene and overexpression of p53 protein are usually observed in Burkitt's lymphoma and some cases of high grade lymphomas including AIDS-associated non-Hodgkin lymphomas. In this case the association of these molecular findings and resistance to chemotherapy is suggested.
Aged↗
Mechanism of enhanced antipseudomonal activity of BO-2727, a new injectable 1-beta-methyl carbapenem.
The mechanism of the enhanced activity of BO-2727 against imipenem-resistant Pseudomonas aeruginosa was studied by using a set of four isogenic strains derived from beta-lactamase-deficient P. aeruginosa PAO4089 (blaJ blaP). Complementation of the blaJ and blaP mutations conferred greater resistance to biapenem, panipenem, and imipenem than to BO-2727 and meropenem, most notably in the outer membrane protein D2-deficient strain. The higher levels of resistance to biapenem, panipenem, and imipenem can be explained by the slow but significant hydrolysis by beta-lactamase, whereas the reduced levels of resistance to BO-2727 and meropenem would be attributable to their stability in the presence of high levels of beta-lactamase and the fact that they cause only low induction of beta-lactamase. It is also noted that the activity of BO-2727 against the beta-lactamase-deficient strain was less affected by the loss of the D2 porin than was that of meropenem, indicating that BO-2727 in comparison with meropenem can overcome an intrinsic resistance caused by the loss of D2. Moreover, comparative in vitro resistance studies have shown that BO-2727 and meropenem selected fewer resistant cells than other carbapenems. In conclusion, BO-2727 exhibited improved activity against imipenem-resistant P. aeruginosa, probably because of its ability to overcome loss of the D2 porin and beta-lactamase hydrolysis.
Anti-Bacterial Agents↗
[Epstein-Barr virus associated natural killer cell leukemia: report of an autopsy case].
A 20-year-old female was admitted because of high fever, hepatosplenomegaly, severe hepatic dysfunction and coagulopathy. Peripheral blood showed pancytopenia and granular lymphocytes bearing the natural killer cell phenotype (CD2+CD3-CD16+CD56+CD57-TCR alpha beta-TCR gamma delta-) constituted 97% of leucocytes. Southern blot analysis of DNA obtained from peripheral blood mononuclear cells showed germ-line configuration of TCR beta, gamma and delta chain genes. EBV-DNA was detected in a single episomal form by using EBV-terminal repeat probe. Bone marrow findings were consistent with hemophagocytic syndrome and administration of VP-16 was effective transiently. After ten months she died from massive gastrointestinal bleeding. An in situ hybridization study identified EBV-RNA (EBER-1) in atypical lymphocytes infiltrating bone marrow, spleen and lymph nodes. Sections of liver showed steatosis and infiltration of T cells (CD3+ and EBER-1-negative) in the portal areas and few atypical lymphocytes in sinusoids. The patients developed an EBV-associated clonal proliferation of natural killer (NK) cells, but the clinical features were suggestive of chronic active EBV infection or virus-associated hemophagocytic syndrome (VAHS) rather than leukemia. Bone marrow transplantation for NK cell leukemia is an issue to be discussed.
Adult↗
[Effect of intravaginal administration of cisplatin (CDDP) suppositories to uterine cervical cancer--blood and tissue concentrations and the therapeutic effects].
Four patients with cervical cancer (squamous cell carcinoma: two cases of stage Ib, one of stage IIa, adenocarcinoma: one of stage Ib), were treated preoperatively by intravaginal administration of CDDP (20 mg) suppositories with pessary 7 times every other day. The uptake, distribution and antitumor effect of CDDP were investigated. Results were as follows. 1) Serum total platinum (Pt) concentration varied between individual patients. Cmax profile (0.17-0.57 micrograms/ml) of Pt was observed at 12 hours after the total dose of 140 mg administration in all patients. 2) The tissue Pt concentration showed high values in the cervix (average 55.4 micrograms/g), followed by the vagina (13.13), endometrium (3.17), uterine wall (0.64), ovary (0.57), lymph node group: parametrial (1.14), obturator (0.34), inguinal (0.28), external iliac (0.51), internal iliac (0.42) and common iliac (0.54). Para-aortic node value was too low to detect. 3) Colposcopic findings were disappearance of bleeding and reduction of tumor outgrowth. Microscopic findings were degeneration and necrosis of cancer nest from the surface to about 2 mm depth of the cervix. In conclusion, it may be necessary to improve CDDP penetration from the tumor surface for effective local chemotherapy.
Adenocarcinoma↗
Pharmacokinetics and safety of BO-2727, a new injectable 1-beta-methyl carbapenem antibiotic, and its effect on the faecal microflora in healthy male volunteers.
The safety and pharmacokinetics of BO-2727, a new injectable 1-beta-methyl carbapenem antibiotic, and its effect on the faecal microflora were evaluated in single- and multiple-dose studies involving twenty-four healthy male adult volunteers following a preliminary safety evaluation of 25, 50 and 125 mg iv doses in six volunteers. BO-2727 was administered by iv infusion over 30 min. There was a good correlation between BO-2727 concentrations assayed by HPLC and a microbiological method; the HPLC results were used in the pharmacokinetic analysis. The single-dose study indicated that plasma concentration versus time curves at doses of 250, 500 and 1000 mg were well described by a two-compartment open model. The mean (+/- S.D.) elimination half-life ranged from 1.41 +/- 0.21 h to 1.54 +/- 0.10 h, and the peak plasma concentrations (Cmax) and the area under the plasma concentration versus time curves increased linearly with the dose. The mean urinary recoveries within the first 24 h were 70.63 +/- 5.24% to 77.38 +/- 4.55% of the dose. The highest concentration of BO-2727 in saliva was 0.72 mg/L which was reached 1 h after the start of the 1000 mg infusion and accounted for approximately 1% of the Cmax. No BO-2727 was found in faecal samples collected 24 and 48 h after a single 1000 mg dose. In the multiple-dose study, BO-2727 500 mg bd was administered for 4.5 days. There were no obvious differences in plasma concentrations and urinary recoveries between the single- and multiple-dose regimens. BO-2727 did not accumulate as determined by plasma concentrations and urinary recoveries. No marked changes in the aerobic and anaerobic faecal microflora were observed during multiple-dose administration. There were no significant adverse reactions, and likewise no abnormalities in physical and laboratory examinations that were definitely related to the drug.
Adolescent↗
[Photodensitometry: microdensitometry (MD): digital image processing method (DIP)].
The principles of microdensitometry (MD) and digital image processing method (DIP), as well as the application of these methods to measure bone mineral density in clinical practice, were mentioned in the report. MD and DIP assess bone mineral content and bone mineral density by analyzing relative contrast of the metacarpus II on X-ray image. However, the parameters obtained by these methods have been reported to be closely related to lumber vertebral bone mineral density and whole-body bone mineral content as measured by dual energy X-ray absorptiometry (DXA). Being easy to use, MD and DIP are adequate for the screening of osteoporosis. Once any reduction in bone mineral content or bone mineral density is shown by MD or DIP, it is recommendable to measure bone mineral density of vertebrae and femoral neck by DXA.
Absorptiometry, Photon↗
Alteration in expression of Serratia marcescens porins associated with decreased outer membrane permeability.
The porin expression of two clinical isolates of Serratia marcescens, which overproduced cephalosporinase and had decreased outer membrane permeability, were studied in comparison with those of reference strains. Separation of the porin proteins assessed by SDS-PAGE containing urea revealed that both clinical isolates overexpressed a single porin of 44 and 43 kilodalton (kDa), respectively. In contrast, the in-vitro porin deficient mutant, which was derived from the reference strain IFO3736 as latamoxef-resistant, showed decreased outer membrane permeability, but produced low levels of all three peptidoglycan associated porins of 45, 44 and 43 kDa, and overexpressed 39 kDa OmpA protein. These observations suggested that the clinical isolates had a different mechanism of latamoxef resistance compared with the mutant and overexpressed possible narrow transport channels of 44 or 43 kDa. The 45 kDa porin may facilitate a more effective channel than the other two proteins. Heterogeneity of porin profiles between biotypes was also suggested. The two isolates were also resistant to penicillins and cephalosporins tested, but imipenem was the most active agent and inhibited the isolates at 1.56 mg/L.
Anti-Bacterial Agents↗
Synergic activity of imipenem/cilastatin combined with cefotiam against methicillin-resistant Staphylococcus aureus.
The synergic activity of imipenem/cilastatin combined with cefotiam was studied in a mouse bacteraemia model. Combinations of imipenem plus cefotiam in ratios from 1:5 to 1:160 were more effective than either imipenem alone or cefotiam alone (P < 0.05). Synergy was observed against both beta-lactamase producing and beta-lactamase non-producing MRSA. Staggered combinations of imipenem with cefotiam (each drug was administered at a different time) were studied in an in-vitro pharmacokinetic system to clarify relationships between killing kinetics and pharmacodynamics of the combinations. In the in-vitro system, cefotiam (1 g over 30 min) administered 2 h after imipenem administration (250 mg over 30 min) reduced viable cell counts to an undetectable level and maintained this for 4 h, while the simultaneous administration of imipenem and cefotiam maintained an undetectable cell count for only 2 h. Furthermore, imipenem administered after cefotiam showed no synergy. These results indicate that the timing of dosing of each antibiotic influences synergy, and administration of cefotiam 2 h after imipenem is more effective than the other regimens.
Animals↗
In vitro activity of a new carbapenem antibiotic, BO-2727, with potent antipseudomonal activity.
BO-2727, a new 1-beta-methyl-carbapenem, was active at concentrations of 6.25 micrograms/ml or less against gram-positive and gram-negative bacteria, including some imipenem- and/or meropenem-resistant (MICs, > or = 12.5 micrograms/ml) Pseudomonas aeruginosa strains, against which it proved generally fourfold more active than imipenem and meropenem. BO-2727's antipseudomonal activity and its broad spectrum merit further investigation for clinical use by itself, since it was stable in the presence of renal dehydropeptidase I.
Anti-Bacterial Agents↗
[Electrocardiographic study of sinus bradycardia associated with enterohemorrhagic Escherichia coli O157: H7 infection].
A severe outbreak of hemorrhagic colitis occurred at a kindergarten in Saitama, Japan in October, 1990. Children who were affected by enterohemorrhagic E. coli O157: H7 infection showed apparent bradycardia as well as severe bloody diarrhea, generalized convulsion, or hemolytic uremic syndrome. Cardiac involvement such as bradycardia observed in the patients of this outbreak has not been described in previous reports about EHEC infection, while bradycardia has been well known in typhoid fever due to salmonella typhosa infection. Electrocardiographic examination was performed to evaluate bardicardia, utilizing electrocardiography at rest and Holter's twenty-four hour electrocardiography. In the report, we demonstrate that the bradicardia was due to reduced frequency of sinus node. Both average heart rate and average minimum heart rate of the patients at night (74.0 +/- 5.6 BPM and 57.0 +/- 5.1 BPM, respectively) decreased significantly, as compared with controls (84.6 +/- 9.3 BPM and 66.3 +/- 8.0 BPM respectively) (p < 0.01). CVRR of the patients (0.120 +/- 0.019, respectively) increased significantly as compared with controls (0.090 +/- 0.010, respectively). These results indicate that an activated parasympathetic nervous system, that is, activation of the vagal nerve, might have induced the sinus bradycardia observed in the patients with EHEC infection.
Bradycardia↗
[Primary splenic lymphoma complicated by malignant rheumatoid arthritis and bladder cancer].
A 64-year-old man had been found to have primary splenic lymphoma (stage III) seven years after the diagnosis of rheumatoid arthritis (RA). Histological diagnosis of the lymphoma was diffuse, medium sized cell type (LSG) or intermediate lymphocytic lymphoma (ILL). Splenectomy and ten courses of CHOP regimen produced continuing remission. After tow years, he suffered from peripheral neuropathy due to vasculitis of polyarteritis nodosa (PN) type. He was treated with prednisolone (PSL) and cyclophosphamide (CPM) for malignant rheumatoid arthritis. One year later, evaluation for intermittent hematuria revealed bladder cancer and he underwent total cystectomy. He has been treated with small doses of PSL under observation. The high incidence of ILL in lymphomas developing in patients with autoimmune diseases of the thyroid and salivary glands has been reported. This case suggests an association between antecedent RA and splenic lymphoma, the influence of splenectomy and chemotherapy on occurrence of rheumatoid vasculitis, and a causal relationship between CPM and bladder cancer.
Arthritis, Rheumatoid↗
Resistance to a new catecholic cephem, BO-1341, in Pseudomonas aeruginosa PAO.
Two distinct types of mutant resistant to the catecholic cephem BO-1341 were isolated spontaneously from Pseudomonas aeruginosa PAO2146: (i) a mutant (CCB5-type) which produced beta-lactamase constitutively, and which appeared to result from a mutation in the regulatory gene (blaI at 41 min) controlling the structural gene (blaP at 25 min); (ii) a mutant (CCB7-type) with specific resistance to BO-1341. Induction of beta-lactamase production in strain CCB7 by BO-1341 was diminished markedly when compared with that in the parent strain. This was not the case for ceftazidime or cefoxitin, suggesting impaired uptake of BO-1341 as an explanation for the resistance. Electrophoretic analysis demonstrated increased production of a 55 kDa protein in the periplasmic space and a 84 kDa outer membrane protein. These data suggested that specific resistance to BO-1341 might involve quantitative alterations in the composition of the outer membrane and periplasmic proteins.
Cefoxitin↗