Yukie Ochiai

Genetic loci controlling susceptibility to γ-ray-induced thymic lymphoma

BALB/c is a susceptible strain for the development of γ-ray induced mouse thymic lymphoma whereas MSM shows resistance. Association analysis of 220 backcross mice between the two strains using 67 markers was carried out to identify loci involved in the control of susceptibility. The genotype of mice with lymphoma showed excess heterozygosity relative to MSM homozygosity at D2Mit15 and D4Mit12 and was skewed toward MSM-derived alleles at D5Mit5. The P values in Mantel-Cox test were 0.0048 (D2Mit15), 0.0034 (D4Mit12) and 0.0048 (D5Mit5), suggesting association at the three loci in the susceptibility. Cooperative effect on lymphomagenesis was also observed among the three loci. To obtain independent evidence for linkage at D4Mit12, we made partially congenic mice in which a D4Mit12 region in BALB/c was replaced by MSM-derived homolog. Examination for the lymphoma susceptibility in 78 progeny of the congenic mice confirmed the effect of the locus near D4Mit12 (P=0.0037). The result, together with the linkage analysis, shows that the locus near D4Mit12 is regarded as a confirmed linkage but the other two loci as marginally suggestive.

Therapeutic Role of Pericardiocentesis for Acute Necrotizing Eosinophilic Myocarditis With Cardiac Tamponade

We describe a patient with acute necrotizing eosinophilic myocarditis who recovered rapidly after pericardial drainage and without corticosteroid therapy. The 25-year- old man was referred to our hospital with suspected acute myocardial infarction on the basis of severe epigastralgia, abnormal Q waves and ST elevation on electrocardiography, and an increase in cardiac enzymes. Echocardiography disclosed pericardial effusion that compressed the right ventricle, left ventricular dysfunction in conjunction with posterolateral hypokinesis, and a thickened ventricular wall but no mural thrombus. The eosinophil count in the peripheral blood was slightly increased. Coronary angiography showed normal arteries and thus prompted an endomyocardial biopsy. The patient was transferred to the intensive care unit with a clinical diagnosis of myocarditis associated with cardiac tamponade. Emergency pericardiocentesis relieved symptoms immediately. The cells in the pericardial effusion were mainly eosinophils; interleukin 5 and interleukin 13 levels were predominantly elevated, and the effusion was drained for 5 days. The biopsy specimen revealed necrotizing eosinophilic myocarditis. Left ventricular function recovered within a week without corticosteroid therapy. No relapse was observed as of 8 months after diagnosis.

The D4Mit12 locus on mouse chromosome 4 provides susceptibility to both γ-ray-induced and N-methyl-N-nitrosourea-induced thymic lymphomas

Low‐penetrance genes control different susceptibilities to γ‐ray‐induced thymic lymphomas in mouse strains. Our previous genetic analyses with backcross mice between BALB/c and MSM strains and congenic lines localized one such gene near the D4Mit12 locus on chromosome 4. N‐Methyl‐N‐nitrosourea (MNU) is a guanine base‐alkylating agent and differs from γ‐radiation in its mechanism of mutagenic action. Accordingly, in this study, we examined whether or not the locus also provides susceptibility to MNU‐induced thymic lymphomas using 84 offsprings derived from congenic mice for D4Mit12. Association analysis provided a suggestive linkage at D4Mit12 (P=0.0075) and the linkage was sustained by the peak of likelihood ratio statistical values being at the same position as that for the γ‐ray‐induced lymphomas. The results strongly suggest that the BALB/c allele near D4Mit12 is associated with susceptibility to lymphomas induced by two carcinogenic agents having different mechanisms of mutagenic action.

Mapping of genetic modifiers of thymic lymphoma development in p53-knockout mice.

The strain dependency of the spectrum and latency of tumors has been reported in p53-deficient (KO) mice, suggesting the presence of modifiers for the outcome of the p53 deficiency. The modifiers provide clues to the oncogenic pathway in cells lacking p53, the most frequently mutated gene in a wide variety of human cancers. To search the modifiers, we induced 160 lymphomas and 69 skin tumors by γ-irradiation of p53(KO/+) backcross mice between BALB/c and MSM strains and performed genome scan. BALB/c-derived alleles at three loci on chromosome 19, Mp53D1 (modifier of p53-deficiency) at D19Mit5, Mp53D2 at D19Mit90 and Mp53D3 at D19Mit123, extended the latency of thymic lymphoma development (P values in Mantel–Cox test were 0.0007, 0.0007 and 0.0003, respectively). Mp53D3 also increased the latency of skin tumors (P value, 0.0008). The linkage of Mp53D2 was confirmed by the experiment using 94 p53-KO mice consomic for chromosome 19, providing a significant linkage. However, the linkage was not confirmed for Mp53D1 or Mp53D3, suggesting epistasis of genes involved in the tumorigenesis.

Clinical evaluation of serum amlodipine level in patients with angina pectoris

Serum amlodipine levels were determined in 18 patients with vasospastic angina. Patients were divided into two groups: Group A (n = 9) received amlodipine 5 mg by single daily administration, and Group B (n = 9) received 10 mg given by single daily administration for the first 3 days, then 5 mg from the 4th day on. The serum amlodipine concentration in Group A took 7 days to reach a steady state of around 8 ng/ml. The level in Group B was 8.9 ng/ml at 3 days. From these results, the optimal dosage of amlodipine in the treatment of angina pectoris is 10 mg for the initial 3 days followed by 5 mg thereafter.

Genetic analysis of radiation-induced thymic lymphoma

Abstract Mouse thymic lymphomas are one of the classic models of radiation-induced malignancies. However, little genetic study has been performed, although the mouse systems offer a number of useful features for genetic and physical mapping. We have carried out large-scale mapping toward the isolation of the genes involved in lymphoma development. Two different types of genes are chosen as targets for positional cloning. One is the tumor suppressor gene and the other is the susceptibility or resistance-giving gene, which predispose to the lymphoma development. One susceptibility locus was localized near D4Mit12 on chromosome 12 by an association study for backcross and congenic mice, and three loci, probably harboring a tumor suppressor gene, were localized by allelic loss mapping on physical maps that were covered by BAC clones. The maps are invaluable to facilitate the identification of candidate tumor suppressor genes. Also, success in identification of Ikaros as a tumor suppressor gene is described.

Recurrence of ventricular fibrillation in a patient with non-type 1 Brugada electrocardiographic morphology

A healthy 25-year-old man suffered from loss of consciousness due to ventricular fibrillation (VF). Emergency services required multiple cardioversion to restore sinus rhythm. Repeated electrocardiographic (ECG) recordings after admission showed non-type 1 Brugada ST-segment elevation in V1 and V2. Intravenous pilsicainide infusion augmented the ST-segment elevation but its morphology did not represent type-1 ECG. Intravenous administration of isoproterenol normalized the ST-segment elevation, and programmed electrical stimulation induced VF. Spontaneous VF recurred 1 year after introduction of implantable cardioverter defibrillator. Non-type 1 ST-segment elevation, to which pharmacological responses are similar to Brugada syndrome, may be used as a hallmark of ventricular tachyarrhythmia.