Biomedical subjects
Publications and source records attributed to K Ichimura.
A case of a young girl manifesting sudden unilateral total loss of auditory and vestibular function following administration of a mumps vaccine is reported. This is supposed to be caused by adverse reaction of the vaccination.
The possible contribution of a non-adrenergic, non-cholinergic (NANC) vasodilator mechanism in human nasal mucosa was studied using an in vitro muscle tension measuring technique. Strips of the nasal mucosa were suspended in a Magnus tube filled with Krebs solution and aerated with 95% O2. Isometric changes in tension were detected on administration of various drugs under electric stimulation and recorded with a transducer. The relaxing reaction under electrical train pulse stimulation with pretreatment of blockers of the autonomic nerves was suppressed by nitric oxide synthase inhibitor (L-NAME) and antagonists to the receptors of sensory nerve transmitters (Spantide, hCGRP8-37). This result suggests that nitric oxide, substance P and CGRP may be mediators in the NANC inhibitory nerve system.
The first gene found to be amplified in human glioblastomas was EGFR at 7p12. More recently the MET gene at 7q31 was also reported amplified. We have studied chromosome 7 in a series of 47 glioblastomas by FISH, RFLP and microsatellite analysis. Four per cent (2/47) had 1 centromere, 26% (12/47) 2, 32% (15/47) 3, 4% (2/47) 4, and 34% (16/47) had subpopulations with variable numbers of chromosome 7 centromeres. In 25 of the 47 tumors (53%) the pattern of allelic imbalance observed at each informative locus was similar and in accord with the FISH data, indicating loss or gain of complete chromosome copies. In 32% of tumors (15/47) varying allelic imbalance was seen at different loci along the chromosome indicative of loss or gain of parts of chromosome 7 on a background of disomy, trisomy, tetrasomy, or polysomy. Amplification was studied in an extended series of 121 glioblastomas, and was seen at the 7p12 region in 47 tumors (39%). Forty-two tumors showed amplification of EGFR and 12 of these had extensive amplicons including a number of adjacent loci, always involving only 1 allele. The amplicons of 5 tumors (11%) did not include EGFR, indicating that other unidentified genes in the region are targeted for amplification. Amplification of MET was not found. The findings show that copy number changes of chromosome 7 are common and that a number of genes may be targeted for amplification at 7p12 in glioblastomas.
Twenty primary central nervous system lymphomas (PCNSL) from immunocompetent patients (nineteen B-cell lymphomas and one T-cell lymphoma) were investigated for genetic alterations and/or expression of the genes BCL2, CCND1, CDK4, CDKN1A, CDKN2A, MDM2, MYC, RB1, REL, and TP53. The gene found to be altered most frequently was CDKN2A. Eight tumors (40%) showed homozygous and two tumors (10%) hemizygous CDKN2A deletions. Furthermore, methylation analysis of six PCNSL without homozygous CDKN2A loss revealed methylation of the CpG island within exon 1 of CDKN2A in three instances. Reverse transcription PCR analysis of CDKN2A mRNA expression was performed for 11 tumors and showed either no or weak signals. Similarly, immunocytochemistry for the CDKN2A gene product (p16) remained either completely negative or showed expression restricted to single tumor cells. None of the PCNSL showed amplification of CDK4. Similarly, investigation of CCND1 revealed no amplification, rearrangement or overexpression. The retinoblastoma protein was strongly expressed in all tumors. Only one PCNSL showed a mutation of the TP53 gene, i.e., a missense mutation at codon 248 (CGG to TGG:Arg to Trp). No evidence of BCL2 gene rearrangement was found in 11 tumors investigated. The bcl-2 protein, however, was strongly expressed in most tumors. None of the 20 PCNSL demonstrated gene amplification of MDM2, MYC or REL. In summary, inactivation of CDKN2A by either homozygous deletion or DNA methylation represents an important molecular mechanism in PCNSL. Mutation of the TP53 gene and alterations of the other genes investigated appear to be of minor significance in these tumors.
A full-length cDNA clone encoding a novel Rab protein AtRab alpha of the monomeric small GTP-binding protein family has been isolated from Arabidopsis thaliana. AtRab alpha has 210 amino acids with a calculated molecular mass of 23.3 kDa. The highest homology was found to Rab1x and Rab1y from Lotus japonicus. Southern blot analysis of genomic DNA indicated that AtRab alpha was encoded by a single copy gene. Northern blot analysis showed that expression of the AtRab alpha mRNA was rich in stems and roots, but poor in leaves and flowers, which is different from the expression pattern of other Arabidopsis Rab genes.
BACKGROUND: We assessed the incidence of neural complications in submandibular surgery in relation to the type of surgery, experience of the surgeon, and other factors. METHODS: We retrospectively reviewed the records of 133 patients who underwent excision of the submandibular triangle components at the University of Tokyo Hospital during the last 19 years. RESULTS: The most frequent complication was mandibular branch paralysis. Excluding 12 patients with malignant tumors, facial weakness was present postoperatively in 29.8% (37) or 124 resections. All palsies subsequently resolved. The paralysis was more frequent when nerve identification was performed than when it was not. CONCLUSIONS: The cardinal factors in minimizing incidence of nerve damage are an understanding of the anatomy of the nerves, low and generous skin incision, awareness of orientation in the surgical planes, avoidance of the use of metal retractors, and avoidance of elaborate identification of the nerve.
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Mitogen-activated protein kinase (MAPK) cascades have essential roles in diverse intracellular signaling processes in plants, animals and yeasts. In plants, transcription of genes encoding protein kinases involved in MAPK cascades is upregulated by environmental stresses and plant hormones; in addition, MAPK-like kinase activities are transiently activated in response to environmental stresses. Consequently, MAPK cascades are now thought to have important roles in stress signal transduction pathways in higher plants.
We sometimes experience patients with persistent or progressive arytenoid edema, among which residual or recurrent cancer is often accompanied. Because it is difficult to distinguish tumour rest or recurrence from normal tissue sequelae in the early period after irradiation, it is important to know both the contributing factors for arytenoid edema, and the incidence of residual or recurrent tumours in patients with postirradiation laryngeal edema. We therefore reviewed the charts of 67 patients with early laryngeal carcinoma who had received a curative dose of irradiation in the last 5 years. Fourteen patients (20.9%) had moderate or severe laryngeal edema persisting for or developing at more than 3 months after completion of a course of definitive radiotherapy. The incidence was highest in supraglottic T2 disease, followed by glottic T2 tumour. Of the 14 patients with edema, six (42.9%) had persistent or recurrent disease. The primary disease was uncontrolled in 18 patients, 17 of whom received successful salvage surgery. In patients without residual tumours, the edema was usually moderate and resolved within a year, although four patients had chronic edema lasting more than a year after treatment. All four had supraglottic T2 lesions and received 70 Gy of X-ray. We also reviewed, for sake of comparison, the records of 38 patients treated with radiotherapy at doses of more than 40 Gy between 1975 and 1980, when endoscopic microsurgery for laryngeal cancer was introduced as a primary part of treatment. The incidence of persistent or late developed edema over the period, though not significant, was 36.8%: nearly twice that of the last 5 years. Microscopic endolaryngeal surgical procedures seem to have been a causal factor for edema in this period.
We treated ten patients with malignant glioma by intracarotid chemotherapy with cis-diamminedichloroplatinum (CDDP) and/or 3-(4-amino-2-methyl-5-pyrimidinyl)methyl-1-(2-chloroethyl)-3-nitrosourea (ACNU). Three of the patients who underwent supraophthalmic intracarotid infusion of CDDP developed a low-density area in the basal ganglia on CT scan or an enhancing lesion in the hypothalamic region on MRI, with or without neurologic symptoms. No patient had such complications with supraophthalmic infusions of ACNU, or with cervical intracarotid infusion of CDDP or selective infusion of CDDP via the anterior or middle cerebral arteries. Supraophthalmic intracarotid administration of CDDP may augment drug delivery to tumors and prevent visual complications, but is accompanied by considerable risk of parenchymal damage in the territory of the anterior choroidal artery. Possible mechanisms for such complications are discussed.
In a series of 46 glioblastomas, 16 anaplastic astrocytomas and eight astrocytomas, all tumours retaining one or both alleles of CDKN2A (48 tumours) and CDKN2B (49 tumours) were subjected to sequence analysis (entire coding region and splice acceptor and donor sites). One glioblastoma with hemizygous deletion of CDKN2A showed a missense mutation in exon 2 (codon 83) that would result in the substitution of tyrosine for histidine in the protein. None of the tumours retaining alleles of CDKN2B showed mutations of this gene. Glioblastomas with retention of both alleles of CDKN2A (14 tumours) and CDKN2B (16 tumours) expressed transcripts for these genes. In contrast, 7/13 glioblastomas with hemizygous deletions of CDKN2A and 8/11 glioblastomas with hemizygous deletions of CDKN2B showed no or weak expression. Anaplastic astrocytomas and astrocytomas showed a considerable variation in the expression of both genes, regardless of whether they retained one or two copies of the genes. The methylation status of the 5' CpG island of the CDKN2A gene was studied in all 15 tumours retaining only one allele of CDKN2A as well as in the six tumours showing no significant expression of transcript despite their retaining both CDKN2A alleles. Three tumours (one of each malignancy grade studied) were found to have partially methylated the 5' CpG island of CDKN2A. It appears that in human astrocytic gliomas point mutations of the CDKN2A and CDKN2B genes are uncommon and hypermethylation of the 5' CpG region of CDKN2A does not appear to be a major mechanism for inhibiting transcription of this gene.
With the improved survival rate of patients with retinoblastoma, the incidence of second malignancies has become substantial. We had two retinoblastoma survivors with secondary malignancies in the naso-ethmoidal complex, one a 21-year-old man with anaplastic carcinoma and the other a 16-year-old girl with malignant fibrous histiocytoma. They underwent repeated craniofacial surgery. Secondary malignancies arising at the nose and ethmoidal cells often invade the anterior skull base. The introduction of skull base surgery has provided wider surgical margins and increased the resultant likelihood of cure. Both patients have so far shown no evidence of recurrence.
The biological properties of non-melibiose-fermenting (NMF) strains of Yersinia pseudotuberculosis O3 were investigated. These strains were clearly distinguished from representative melibiose-fermenting (MF) strains of Y. pseudotuberculosis O3 by their pathogenicity in mice, sensitivity to some phages, production of catalase, restriction endonuclease analysis of virulence plasmid DNA with BamHI, detection of specific yersinia outer-membrane proteins with SDS-PAGE, antigenicity of the outer-membrane proteins and neutrophil resistance to phagocytosis. The pathogenicity of NMF strains was clearly less than that of MF strains. In addition, the resistance of NMF strains to phagocytosis and catalase activity was evidently weaker than that of MF strains. These results suggested that the difference of pathogenicity was due to the ability of catalase production. Although the relationship between the above characteristics and melibiose-fermentation was not analysed, the pathogenicity of Y. pseudotuberculosis O3 strains can probably be predicted by testing melibiose-fermentation and catalase production.
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Eicosapentaenoic acid (EPA) is composed of 20 unsaturated fatty acids and is similar to arachidonic acid. Epadel, the drug made from EPA, is reported not only to reduce levels of serum lipids, but also to have antiinflammatory and antiallergic effects. EPA may exert these effects via control of the production of prostanoids and leukotrienes. We studied the effects of EPA in patients with bronchial asthma who had hyperlipidemia. The patents were given EPA at 1800 mg/day and they recorded signs and symptoms in an asthma diary during a 2-week observation period and the 8 weeks during which they took the drug. Peak flow, leukotriene B4 concentration in urine, Leukotriene E4 concentration in urine, IgE level, total cholesterol level, and triglyceride level were measured before and after the 8 weeks of medication. Administration of EPA was associated with improvements in symptom score, therapeutic score, asthma score, and peak flow. EPA may be useful in patients with asthma complicated by hyperlipidemia.
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We have reported previously that about 15% of anaplastic astrocytomas and glioblastomas show amplification and overexpression of one or more genes from chromosomal segment 12q13-q15 (G. Reifenberger et al., Cancer Res., 54, 4299-4303, 1994). The genes most frequently amplified and overexpressed were CDK4 (with coamplification of SAS) and MDM2. Because individual malignant gliomas showed CDK4/SAS amplification but no MDM2 amplification and vice versa, the possibility remained of a common amplification target gene located between CDK4 and MDM2. We have addressed this question by performing a detailed amplicon mapping of a series of 24 primary malignant gliomas and two glioblastoma cell lines with 12q13-q15 amplification. All tumors and cell lines were analyzed at eight gene loci and six anonymous loci from 12q13-q15, including seven loci located between CDK4 and MDM2. These studies revealed two centers of amplification, one at CDK4/SAS and the other at MDM2. A number of loci located close to either MDM2 or CDK4/SAS, including the genes GADD153, GLI, RAP1B, A2MR, and IFNG, were found to be coamplified in some tumors but not overexpressed consistently. All amplicons were discontinuous between CDK4/SAS and MDM2. Our results thus exclude a common amplification target between CDK4/SAS and MDM2 and provide additional evidence that these genes represent two independent targets of selection.
A series of 195 human gliomas were studied as to the status of their CDKN2A, CDK4 and RB1 genes. Among 120 glioblastomas, 40% had no wild-type CDKN2A gene, 12% amplified the CDK4 gene, and 14% had no wild-type RBI gene. With two exceptions, each tumour had only one of these abnormalities. Thus the majority of the glioblastomas (64%) had distinct genetic aberrations which would obviously disrupt the control of transition from G1 to the S-phase of the cell cycle. A further 30% had loss of one allele of the CDKN2A and/or RBI genes. Only seven (6%) glioblastomas had no abnormalities of these genes. Anaplastic astrocytomas showed similar changes to the glioblastomas but at lower frequencies-34% showing no aberrations of the genes analysed. The astrocytomas showed solely loss of one allele of the RBI gene in 28% of tumours, with retention of one wild-type copy. In the glioblastomas with no alterations of CDKN2A, CDK4 or RB1, several other genes (CCND1, CCND2, CCND3, CDK6, E2F, CDK7, MYC and MYCN) whose products take part in cell cycle regulation were examined. No abnormalities were detected. Thus some aberration of the CDKN2A, CDK4 and RB1 genes appears to be almost obligatory in glioblastomas.