Bone marrow scintigraphy and MRI in a patient with osteopetrosis.
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Biomedical subjects
Publications and source records attributed to S Ono.
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Xenograft acceptance, growth and spontaneous metastasis of ectopically transplanted human germinal tumors were compared among scid mice, athymic nude mice and F2 hybrids constructed from scid and nude mice, in relation to the impairments of T and B cell functions in these mice. In scid mice which are deficient in T and B cell functions, human yolk sac tumor (YST-2) that originated from the ovary grew to enormous sizes in 100% of the animals after both subcutaneous and intraperitoneal transplantation, while only half (59.1% and 51.9%) of the subcutaneous and none of the intraperitoneal transplants were accepted in usual athymic nude mice (BALB/c-nu/nu and CD1-nu/nu). The YST-2 grew rapidly in scid mice, developing 3 to 10 times larger tumors compared to nude-streaker (AKR/J-nustr/nustr) and usual nude mice, respectively. Furthermore, ectopically transplanted tumors spontaneously metastasized to distant organs (mostly to the lung) in scid mice (but less frequently in leaky scid mice), while metastases have never been found in nude mice. Although a xenograft of human classic (typical or pure) seminoma of the testis has never been established in nude mice, it grows slowly in one-third (36.4%) of scid mice and very rapidly in all of scid-nustr (scid/scid; nustr/nustr) double mutant mice. Spontaneous metastases of xenografted seminomas were also observed in distant organs (lymph node, lung, liver, spleen, and kidney). The metastastic distribution of the two human germinal tumors in scid and scid-nustr mice mimics that found in human. These results (xenograft acceptance, growth of transplanted tumors and degree of metastatic spread) were compatible with the level of T and B cell impairments indicated by FACS analysis, as well as mitogen responses, serum IgG and morphological features of the thymus.
High-resolution chromosome analysis showed the karyotype 46,XX,del(1)(p13.3 p22.3) in a female infant with an extreme tetralogy of Fallot and multiple congenital anomalies. The patient showed characteristic features: upper and lower eyelids connected to each other by a string-like epithelium, low hairline, epicanthal folds, saddle nose with a broad, flat root, micrognathia, short neck, high-arched palate, prominent xiphisternum, wide-spaced nipples, bilateral pes equinovarus, fifth toes that overlapped the fourth toes bilaterally, a deep fissure between the first and second toes bilaterally, and abnormal flexions of fingers and toes. Growth and psychomotor retardation were also noted. Cardiac catheterization revealed an extreme tetralogy of Fallot complicated by a patent ductus arteriosus. Ventricular tachycardia and ventricular premature beats developed during the neonatal period and did not respond well to anti-arrhythmic drugs. She died of the anoxia caused by closure of the patent ductus arteriosus when she was 7 months old.
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Lung platelet-activating factor (PAF) levels increased in some rats at 1-3 wk after subcutaneous injection of monocrotaline (MCT). We tested the effect of specific PAF antagonists, WEB 2086 and WEB 2170, on MCT-induced lung injury and subsequent pulmonary hypertension and right ventricular hypertrophy. Treatment with either agent decreased MCT-induced pulmonary hypertension and right ventricular hypertrophy at 3 wk after injection. Treatment with WEB 2170 reduced MCT-induced pulmonary vascular leak at 1 wk after injection, and WEB 2086-treatment exclusively during the early leak phase also decreased MCT-induced right ventricular hypertrophy at 3 wk. Treatment with WEB 2170 between the 3rd and 4th wk after MCT injection inhibited the progression of right ventricular hypertrophy at 4 wk. These results suggest that PAF contributes to the early pulmonary vascular leak, and this leak phase is important for the development of pulmonary hypertension and right ventricular hypertrophy in MCT-treated rats. Furthermore, it appears that PAF action contributes to the maintenance of a chronic inflammatory process that involves the synthesis of other lipid mediators (prostaglandins and leukotrienes) and leads to pulmonary hypertension. We conclude that PAF has a role in the MCT-induced inflammatory lung injury and pulmonary hypertension.
Generalized resistance to thyroid hormones (GRTH) commonly results from mutations in the T3-binding domain of the c-erbA beta thyroid hormone receptor gene. We have reported on a novel deletion mutation in c-erbA beta in a kindred, S, with GRTH. One patient from this kindred was the product of a consanguineous union from two affected members and was homozygous for the beta-receptor defect. This patient at 3.5 weeks of age had unprecedented elevations of TSH, free T4, and free T3 (TSH, 389 mU/L; free T4, 330.8 pmol/L; free T3, 82,719 fmol/L). He displayed a complex mixture of tissue-specific hyperthyroidism and hypothyroidism. He had delayed growth (height age, 1 3/12 yr at chronological age 2 9/12 yr) and skeletal maturation (bone age, 4 months), and developmental delay (developmental age, 8 months), but he was quite tachycardic. The homozygous patient of kindred S is markedly different from a recently reported patient with no c-erbA beta-receptor. This difference indicates that a dominant negative form of c-erbA beta in man can inhibit at least some thyroid hormone action mediated by the c-erbA alpha-receptors.
Different point mutations have been identified in the T3-binding domain of the c-erbA beta thyroid hormone receptor gene that are associated with variant phenotypes of generalized thyroid hormone resistance (GTHR). In most cases of GTHR, heterozygotes are affected; a single mutant allele results in the inhibition of the function of normal thyroid hormone receptors. We report here a novel genetic abnormality, a 3-basepair (bp) deletion in the T3-binding domain of the beta-receptor in a kindred, S, with GTHR. One patient, S1, was the product of a consanguineous union of two heterozygotes and was homozygous for this defect. Heterozygotes from kindred S harbored a CAC deletion at nucleotides 1295-1297, which resulted in the deduced loss of amino acid residue threonine at codon 332, and they displayed elevated free T4 levels and inappropriately normal TSH levels characteristic of other kindreds with GTHR. However, patient S1, who had two mutant alleles, had markedly elevated TSH and free T4 levels and displayed profound abnormalities in brain development and linear growth. A fibroblast c-erbA beta cDNA extending from codon 175 to stop codon 457 was cloned from patient S1, sequenced, and used to create a full-length mutant cDNA. The kindred S mutant receptor was synthesized in vitro and did not bind T3. This mutant receptor did bind with similar avidity as the wild-type human beta-receptor to thyroid hormone response elements of the human TSH beta (-12 to 43 bp) and rat GH (-188 to -160 bp) genes. Kindred S showed the effect in man of heterozygous and homozygous expression of a dominant negative form of c-erbA beta.
A series of 2-[4-(thiazol-2-yl)phenyl]propionic acids substituted at various positions were prepared by the reaction of diethyl 2-methyl-2-(4-thiocarbamoylphenyl)malonates with alpha-bromoaldehyde diethyl acetals or alpha-haloketones followed by hydrolysis of esters. The inhibition of prostaglandin H synthetase (cyclooxygenase) was assayed by use of an enzyme preparation from guinea pig polymorphonuclear leukocytes. Examination of the structure-activity relationship of these compounds indicated that the substitution pattern with halogens at position 3 (R1) of the benzene ring and a methyl group in position 4 (R2) and/or 5 (R3) of the thiazole ring were favorable for inhibitory activity. The compounds bearing bulky alkyl or polar functional groups at the R2 position were weak inhibitors. The potent inhibitors of cyclooxygenase were tested for their ability to reduce carrageenin-induced inflammation of rat paws. These derivatives had strong anti-inflammatory activity based on their strong inhibition of cyclooxygenase, with some exceptions, including those with a thiomethyl group at R1.
123I-Metaiodobenzylguanidine (123I-MIBG) uptake in the stunned myocardium was investigated in open chest dogs. 123I-MIBG is a tracer taken up in presynaptic adrenergic vesicles and reflects the function of the myocardial sympathetic nervous system. This study revealed that in the stunned myocardium without infarct, 123I-MIBG uptake was normal up to 40 minutes of ischemia and that exogenous noradrenaline improved deteriorated regional wall motion with increased uptake of 123I-MIBG. However, uptake of 123I-MIBG per flow decreased with infarct in ischemic areas, and it showed a linear relation with regional wall motion. Thus, in the absence of infarction 123I-MIBG is a tracer to differentiate stunning from more severe ischemia with persistent wall motion abnormality. Normal uptake and storage of 123I-MIBG in the stunned condition suggests that catecholamine release or second effector mechanism may relate to the mechanism.
Catecholamine and serotonin injected i.p. to new-born mice caused gliomas, ependymomas and choroid plexus papilloma together with multiple APUDomas within 48 hours after injection. We consider that an error in neural crest DNA may be caused through an adenylate-cyclic AMP system and Ca++ during replication and/or transcription. Multiple brain tumors caused by catecholamine and serotonin give the presumptive evidence that stem cells of neuroglia may be of neural crest origin.
A femoral, diaphyseal tumor was found in a 17-year old male, and the diagnosis of periosteal osteosarcoma was made, based on the typical radiological and pathological findings. Microscopic observation on a resected specimen revealed that the tumor was covered with the intact periosteal fibrous layer and did not extend beyond the periosteum. The adjacent cortex was free of tumor. These findings indicated that the tumor originated from the periosteal cambium layer, which lies between the periosteal fibrous layer and the cortex. For transmission electron microscopic examination, the tissue was obtained at open biopsy. Ultrastructurally, no specific cell of periosteal osteosarcoma was found. Although most types of osteosarcoma cells were identified in the tumor (osteoblast-like, chondroblast-like, fibroblast-like, primitive mesenchymal-like, osteoclast-like and so on), the ultrastructural characteristics were of wide variety and of low malignancy.
A 41-year-old man with PPP since in 1982 was admitted in May, 1987, because of the progressive asymmetric sensory disturbance in the hands and feet over 4 months, accompanied by an exacerbation of PPP. On admission, eruptions of PPP were observed in the palms and soles. Asymmetric and mildly decreased sensations of touch and pain were present in the distal part of the four extremities as well as in his trunk, accompanied by paresthesia and dysesthesia. Mild to moderate weakness was noted in the hand muscles, and slight muscular atrophy was present in the right lower leg. A work-up for collagen vascular disease was within normal limits. T lymphocyte subset showed a decreased ratio of OKT 4/OKT 8. Left sural nerve biopsy showed axonal degeneration and moderate decrease of myelinated fibers, and the vasculitis was not found. The neurological signs and symptoms as well as the skin eruptions improved with methylprednisolone 40 mg/day. A causal relationship between the multiple mononeuropathy and PPP of our patient was indicated by the almost simultaneous onset of the neuropathy and the exacerbation of PPP as well as the improvement of these two conditions with corticosteroid therapy. Such combination of multiple mononeuropathy and PPP has not so far been reported.
To evaluate clinical value of a new fatty acid imaging tracer, 123I-beta-methyl iodophenyl pentadecanoic acid (BMIPP), 27 patients with myocardial infarction (MI) underwent BMIPP imaging at rest. The results were compared with those of thallium-201 imaging and contrast ventriculography. Of 100 hypoperfused segments on thallium-201 imaging, 34 segments (34%) showed lower BMIPP uptake than thallium-201, and remaining 66 segments showed similar distribution of those tracers. This discrepancy was more often observed in a patients with acute or subacute stages of MI (less than 4 weeks from onset) than those with chronic stage of MI (greater than 4 weeks) (75% vs. 47%; p less than 0.005). In addition, in the patients with chronic stage of MI, the regional wall motion abnormality was less severe in those showing discrepant BMIPP uptake than those showing concordant distribution (the wall motion score: 1.33 +/- 0.62 vs. 0.63 +/- 0.99; p less than 0.05). Furthermore, redistribution on stress thallium-201 imaging was more often observed in than those showing concordant distribution (12%) than those showing concordant distribution (12%) (p less than 0.005). These preliminary study indicates that discrepant distribution of BMIPP and thallium-201 may be often observed, particularly in recent MI and those showing less wall motion abnormality and redistribution on stress thallium-201 imaging. Thus, the combined study of BMIPP and thallium-201 has a potential for assessing tissue viability in patients with MI.
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To evaluate clinical value of 99mTc-hexakis 2-methoxy-2-isobutyl isonitrile (MIBI) imaging for assessing coronary artery disease (CAD), 99mTc-MIBI SPECT imaging at post-exercise and at rest was compared with 201Tl SPECT imaging at post-exercise and 3 hours redistribution in 27 patients suspected with CAD. The sensitivities for detecting CAD patients were 94% (17/18) by both studies. The specificities were 71% (5/7) by 99mTc-MIBI and 57% (4/7) by 201Tl (p = NS). The sensitivities for detecting stenosed coronary arteries (greater than or equal to 75% stenosis) were also similar between 99mTc-MIBI (78%) and 201Tl (74%) (p = NS). The similar specificity values were obtained by 99mTc-MIBI (84%) and by 201Tl (82%) (p = NS). The patterns of abnormality (normal, ischemia and scar) were similar between 99mTc-MIBI and 201Tl images in 22 of the 25 cases (88%) and 117 of the 125 segments (94%). However, these patterns were occasionally different particularly in patients who received PTCA or CABG. Thus, 99mTc-MIBI SPECT imaging seems to be as accurate as 201Tl SPECT imaging for the detecting and evaluating CAD.
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Atherosclerosis involving the thoracic aorta frequently occurs in patients with familial hypercholesterolemia (FH). In this study, we employed two-dimensional (2-D) transesophageal echocardiography (TEE: 5 MHz) to assess atherosclerotic lesions of the thoracic aorta in 9 patients with FH (47.8 +/- 10.3 yrs) and 11 age-matched normal control subjects. Biplane TEE probe (i.e., transverse or sagittal scan transducer) was used to permit direct imaging of the distal half of the ascending aorta. The atherosclerotic lesions were classified based on the severity of the aortic wall sclerosis as intimal thickening (I.), atheromatous plaque, (II.) and calcification (III.). In all of the patients with FH, atherosclerotic lesions of grade I. or greater were observed particularly in the aortic arch and descending aorta, while, lesions more severe than grade I. in the thoracic aorta were not observed in any of the control subjects. In 6 FH patients (67%), atherosclerotic lesions more severe than grade II. were frequently observed, which were more frequent in the aortic arch and descending aorta than in the ascending aorta.