Elevation of serum thrombopoietin precedes thrombocytosis in Kawasaki disease.

Kawasaki disease (KD) is an acute systemic vasculitis causing coronary arterial aneurysms and myocardial infarction in young children. Prominent thrombocytosis with increased megakaryocytes develops during the convalescent period. To clarify the mechanisms of thrombocytosis, we studied serum levels of thrombopoietin (TPO) and other thrombopoietic cytokines in 40 patients with KD (149 samples) and 106 age-matched controls using ELISA. TPO values in the controls were 1.94 +/- 0.69 fmol/ml (mean +/- SD) with a 95% reference interval of 0.85 to 3.27 fmol/ml. In the first week of KD, platelet counts were normal but TPO values increased (approximately 15.5 fmol/ml). TPO levels peaked on day 6 +/- 2 at 5.94 +/- 2.64 fmol/ml and then fell gradually. When platelet counts peaked in the second to third weeks, TPO levels were still high or comparable with the controls. TPO levels in KD patients with normal platelet counts were significantly higher than control levels. Interleukin (IL)-6 levels in the first week rose, but neither IL-11 nor leukemia inhibitory factor was detectable. These results suggest that TPO contributes to thrombocytosis in KD in conjunction with IL-6 and TPO production may be enhanced during the acute phase.

Short-term hemodynamic effect of a new oral PGI2 analogue, beraprost, in primary and secondary pulmonary hypertension.

In 4 patients with primary pulmonary hypertension, there was a -24% +/- 20% decrease in pulmonary vascular resistance, a significant increase of cardiac index by +27 +/- 14% in all 4 patients; a -15 +/- 12% decrease in pulmonary artery pressure in 3 patients; and in 3 patients with 12% secondary pulmonary hypertension, there was a -24 +/- 14% decrease in pulmonary vascular resistance. Beraprost appears to be effective as a new pulmonary vasodilative agent.

Breast conserving surgery with nipple resection.

Breast conserving surgery with nipple resection was carried out on 4 patients with early breast cancer because location of each tumor was very close to nipple. These consisted of 3 patients with state I invasive ductal carcinoma and 1 patient with stage II invasive ductal carcinoma. Cancer cells were not recognized histopathologically in the resection margins of each case and all cases underwent a curative resection with axillary dissection (up to level III). The rested areola in each case was made to be round-shaped by skin suture and the edge of the wound located in the center of areola looked like a small nipple. The cosmetic result of this operation were excellent in all patients. This operation may be effective both for these patients with early breast cancer locating under the nipple or areola and for those whose tumor was very close to nipple.

Subcutaneous mastectomy with axillary dissection for early breast cancer.

From 1983 to 1990, subcutaneous mastectomy with axillary dissection was carried out for 46 patients with early breast cancer including three bilateral breast cancer patients (four breasts). Cancer cells were recognized histopathologically in the resection margins of small mammary gland resting under the nipple in four cases, and the remaining 42 cases underwent a curative resection. Multicentric lesions were found out histopathologically by continuous sections in five cases (six breasts). There was no difference in the prognosis using the case-control comparison method between 34 patients with ipsilateral invasive carcinoma who underwent a subcutaneous mastectomy in this study group and 34 patients who underwent a radical or modified radical mastectomy in the control group. Cosmetic results of the subcutaneous mastectomy were evaluated in 37 patients, and 9 were excellent, 17 were good, 9 were not so good and 2 were poor. Subcutaneous mastectomy with axillary dissection was an effective operation for early breast cancer including multicentric lesions and some non-invasive ductal carcinomas from the prognostic and cosmetic standpoints.

Age-dependent characteristics of screen-detected patients with breast cancer.

A consecutive series of 128 breast cancer patients detected by breast screening were enrolled in this study to analyze their age-dependent characteristics. They were classified into three groups; 40 years or less (young): 26 patients, 41-55 years (middle-aged): 67 patients and 56 years or over (old): 35 patients. The percentage of patients who had noticed breast abnormality by self-examination at the time of the breast screening increased from the young patients to the old without statistical significance. Nonpalpable breast cancer was more frequently (p < 0.05) observed in the young patients or the middle-aged rather than the old patients. The incidence of noninvasive carcinoma decreased from the young patients to the old without statistical significance. Decreased survival was seen in older patients rather than younger patients, without statistical significance. As a result, prognostic features were more favorable in patients aged 40 years or less than the other. Women aged 35-40 years should be recommended to attend breast screening.

[Serum levels and in vitro production of IL-5 in children with bronchial asthma].

IL-5 play important roles in inflammatory responses in bronchial asthma, but little is known about serum levels and in vitro production of IL-5 in childhood bronchial asthma. We further examined serum IL-5 levels in children with bronchial asthma and the controls. IL-5 in serum was detected in all of asthmatic and disease-free individuals. Its values during asthma exacerbation were significantly higher than during remission of asthma. Serum IL-5 values did not significantly differ among groups divided by asthma severity. We studied IL-5 production by peripheral blood mononuclear cells cultured with or without Dermatophagoides farinae (Df) in children with mite allergy. IL-5 concentrations in culture supernatant from after stimulation with Df were significantly higher than those from asthmatic patients without stimulation and from the control subjects. In contrast, IL-5 levels in culture media from the controls were not significantly different between with and without stimulation with Df. Our results suggest that IL-5 may play roles in the pathogenesis of bronchial asthma.

[Current status and future prospect of prostacyclin therapy for pulmonary hypertension--intravenous, subcutaneous, inhaled and oral PGI2 derivatives].

Prostacyclin (PGI2) is a potent and a promising vasodilative agent in the treatment of pulmonary hypertension (PH). Epoprostenol (Flolan), an intravenous PGI2, has been used for PPH, and exerts dramatic effects such as reducing pulmonary vascular resistance and increasing cardiac output leading to an improvement of exercise tolerance. However, continuous i.v. infusion accompanies infection, thrombosis, occlusion, battery problems and variable side effects of PGI2 itself. Uniprost, administered subcutaneously, has a rather long half-life. It also needs an ambulatory infusion pump system. Beraprost, an oral PGI2 analogue, is also effective in mild PH patients. It can be absorbed easily and administered tid, or qid fashion. Inhaled iloprost may be an alternative option, but both iloprost and beraprost require frequent administrations because of their short half-life.

[The existence of thyroglobulin in metastatic lymph nodes of thyroid carcinoma and significance of measurement of blood Tg level after surgery].

On the basis of a biochemical study of thyroid papillary and follicular carcinoma tissue (original focus, its periphery and cervical lymph node metastasis), we endeavoured to determine whether or not there was any Tg in the metastatic lymph node, and if there was, to extract and refine it, and also to determine the biochemical properties of Tg. We also investigated the relationship between the increase of blood Tg and the status of lymph node metastasis after surgery for thyroid carcinoma. There was found to be a noticeable decrease in Tg content per unit weight of the metastatic lymph node, and the iodine content in most cases had dropped almost to zero. This means that although Tg is biosynthesized in the metastatic lymph node, there is, in most cases, less than one atom of iodine per molecule of Tg, and we could find very little evidence of the formation of the thyroid hormone. As far as avidity for the antibody is concerned, that in cancer tissue Tg was much lower than that in healthy tissue Tg, and this was even more noticeable in metastatic node Tg than in primary focus Tg. In the sugar chain structure of the metastatic node, there was a lack of uniformity not seen in healthy tissue. In the lymph node metastatic focus, the production of structural Tg was noted. We also recognized the possibility that the increase of blood Tg level following surgery originates from the metastatic lymph nodes and other sites of recurrence.

[Effects of long-term treatment with prostacyclin on plasma adrenomedullin in patients with primary pulmonary hypertension].

OBJECTIVES: This study investigated whether plasma levels of adrenomedullin, a potent vasodilating endogenous neurohumoral mediator, are useful for assessing the severity of primary pulmonary hypertension. METHODS: Seventeen pediatric patients with primary pulmonary hypertension (eight girls, nine boys, mean age 12 +/- 4 years) were enrolled in this study. Thirteen patients in New York Heart Association (NYHA) classes III and IV had been treated with long-term continuous intravenous prostacyclin (PGI2) infusion therapy, and four patients in classes I and II had received beraprost sodium, an oral PGI2 analogue. Blood samples were taken from all patients at the first visit. Plasma levels of atrial and brain natriuretic peptide (ANP, BNP) and endothelin-1, and mature-type adrenomedullin were measured. The relationships were investigated between neurohumoral mediator levels and NYHA class, pulmonary hemodynamics, and exercise capacity assessed by 6-minute walk test. The changes in neurohumoral mediator levels at 1 month, 3 months, and 6 to 12 months were also evaluated in 11 survivors with long-term PGI2 treatment. RESULTS: All neurohumoral mediator levels were positively correlated with severity of NYHA class. Patients in class IV demonstrated significantly elevated neurohumoral mediator levels, except endothelin-1, in comparison with patients in classes I-III. Neurohumoral mediator levels had a significant negative correlation with exercise capacity. Stepwise regression analysis revealed that the BNP to ANP ratio (BNP/ANP) was the most powerful independent factor for total pulmonary resistance (r = 0.85, p = 0.0071) and cardiac index (r = 0.84, p = 0.009). Adrenomedullin was significantly correlated with BNP (r = 0.53, p = 0.03), endothelin-1 (r = 0.66, p = 0.006), and BNP/ANP (r = 0.73, p = 0.0009). ANP and BNP decreased from 196 +/- 213 and 494 +/- 361 pg/ml at baseline to 74 +/- 47 and 153 +/- 133 pg/ml at 1 month, respectively. There was an apparent re-increase in both ANP (187 +/- 194 pg/ml) and BNP (466 +/- 621 pg/ml) at 3 months, regardless of improvement in NYHA class and exercise capacity after long-term PGI2 treatment. In contrast, adrenomedullin decreased from 3.0 +/- 2.2 (baseline) to 1.7 +/- 0.7 fmol/ml at 1 month and 1.6 +/- 0.5 fmol/ml at 3 months. Adrenomedullin was slightly increased at 6-12 months (2.1 +/- 0.9 fmol/ml) without statistical significance. There was a significant relationship between the changes in adrenomedullin at 3 months compared to values at initiation of PGI2 therapy and the changes in mean pulmonary arterial pressure (r = 0.97, p = 0.0041). CONCLUSIONS: Plasma levels of neurohumoral mediators are useful for assessing the severity of primary pulmonary hypertension. In particular, adrenomedullin was valuable for evaluating both cardiac performance and pulmonary hemodynamics after long-term treatment with PGI2 in patients with primary pulmonary hypertension.

[Characterization of thyroglobulin in a patient with functioning and non-functioning benign thyroid tumors].

The chemical and immunological properties of thyroglobulin (Tg) in tissue obtained from a patient co-existed with two types of thyroid tumors, i.e., functioning and non-functioning, and were compared with the properties of Tg that was isolated from adjacent peripheral tissue. In the present observations, the Tg content was markedly increased in the non-functioning thyroid tumor. On the other hand, the Tg content in the functioning tumor was at the normal level. The iodine content of Tg was significantly lower in the non-functioning tumor than in peripheral tissues. Affinity with Lectins differed among Tg preparations, suggesting that the carbohydrate chain in the Tg was different in each nodule in a single individual.

Fibromatosis of the breast: a case report.

Fibromatosis of the female breast is rare. We dealt with a recurrent case of fibromatosis four months after a wide excision of the tumor. It was difficult to differentiate the tumor from carcinoma and only a pathological examination could lead to the final diagnosis. Ultrasonographic findings are so characteristic that we would like to emphasize the usefulness of ultrasonography not only in distinguishing between recurrence and operative scar but also in defining the diagnosis as fibromatosis of the breast.

[Enzymatic iodination of thyroglobulins obtained from patients with thyroid disease].

Iodination of the isolated thyroglobulin (Tg) by peroxidase was compared with various Tg preparations obtained from patients with thyroid diseases. For the purpose, the iodination process was observed in the incubation medium containing Tg, iodide, H2O2-generating system, and thyroid peroxidase (TPO) or lactoperoxidase (LPO). During the incubation, iodination of Tg preparations increased gradually and reached a plateau after 90 min., and 5 min. incubation with 3mIU or 14mIU of TPO, respectively. The degree of iodination level at the plateau region was different in each Tg preparation, depending on the iodine content of the original starting (native) preparation before incubation. The iodination level of cancer Tg with a very low iodine content (less than 0.1%) was low compared with the normal Tg level (obtained from normal thyroid tissue which contained about 0.4% iodine). The above findings suggest the possible existence of some structural differences of Tg in terms of the susceptibility to the iodination between the preparations of normal and diseased Tgs. As far as the immunological aspect concerned, there was no significant difference in the affinity (avidity) of Tg with polyclonal anti-Tg antibody between the native Tg and the enzymatically iodinated one. These results suggest that the changes of iodine and thyroid hormone contents of Tg by in vitro iodination, has no significant effect on the immunological property of Tg molecule.

Oral prostaglandin E1 derivative (OP-1206) in an infant with double outlet right ventricle and pulmonary stenosis. Effect on ductus-dependent pulmonary circulation.

A small-for-gestational-age infant with cyanosis due to double outlet right ventricle with severe pulmonary stenosis and patent ductus arteriosus was treated with oral prostaglandin E1 derivative (OP-1206). The constricting ductus arteriosus dilated and the ductus-dependent pulmonary blood flow increased. The recommended dosage was 1.5-2.0 micrograms/kg/day which was lower than that of intravenous PGE1 or of oral PGE2. The administration interval was 6 hours, which was longer than that of oral PGE2. The patient was treated as an out-patient because continuous intravenous infusion was not necessary. Treatment was continued for 2 months without complication, at which time a Blalock-Taussig shunt operation was performed. Orally administered PGE1 derivative (OP-1206) was found to be equally effective to intravenous infusion of PGE1 for both short and long-term management of cyanotic heart disease in which the pulmonary blood flow is mostly dependent on the patency of the ductus arteriosus. Oral PGE1 derivative (OP-1206) may be a possible substitute for intravenous PGE1 infusion therapy.

Carbamazepine-induced thrombocytopenia defined by a challenge test.

Carbamazepine (CBZ), a widely used anticonvulsant, occasionally causes serious hematologic disorders. A 12-year-old boy was admitted because of a diffuse petechial rash and profound thrombocytopenia (10 x 10(9) platelets/l), after having been treated for epilepsy with CBZ for 12 days. Seven days following withdrawal of CBZ and initiation of prednisolone therapy, the platelet count recovered. In a subsequent challenge test with CBZ, platelet counts again decreased, and the levels of platelet-associated IgG and serum interleukin-6 increased. No antibodies against platelet glycoprotein IIb/IIIa or Ib were detected in plasma. We believe that this is the first reported occasion when CBZ-induced thrombocytopenia has been defined by a rechallenge test.

1 alpha-hydroxyvitamin D3, hypercalcemia, and growth suppression of 7,12-dimethylbenz[a]anthracene-induced rat mammary tumors.

1 alpha-hydroxyvitamin D3 [1 alpha(OH)D3] was administered to female Sprague-Dawley rats with 7,12-dimethylbenz[a]anthracene (DMBA)-induced mammary tumors. 1 alpha(OH)D3 suppressed the growth of the rat mammary tumors dose-dependently, and in the high dose groups treated with 0.5-1.0 micrograms/kg of 1 alpha(OH)D3, significant inhibition of tumor growth was observed. But daily oral administration of 1 alpha(OH)D3 for four consecutive weeks caused side effects such as hypercalcemia and weight loss. We compared 0.5 microgram/kg of 1 alpha(OH)D3 three times weekly with the same dose six times weekly to discover whether or not the side effects can be reduced by treatment schedule. Both groups showed a significant oncostatic effect, compared with the control group, while the side effects were relieved in the three times weekly group. Regarding estrogen receptors (ER) in the tumors, there was no significant difference among the groups. These results suggested that the antitumor effect of 1 alpha(OH)D3 on DMBA-induced mammary tumors was not related to ER status. Combined use of 1 alpha(OH)D3 with 5-fluorouracil (5-FU) or medroxyprogesterone acetate (MPA) was also examined. No significant augmentation of the antitumor effect was seen in the two combinations, although the combined therapy with MPA showed a significant inhibition of weight loss in the rats.

Gallium-67 myocardial imaging for the detection of myocarditis in the acute phase of Kawasaki disease (mucocutaneous lymph node syndrome): the usefulness of single photon emission computed tomography.

Myocardial imaging with gallium-67 citrate was used to detect myocarditis in 46 consecutive infants and children (31 boys and 15 girls, mean age 21 months) with Kawasaki disease. In all of them planar imaging (group A) was performed at 6 hours and at 48 or 72 hours after the intravenous administration of a mean (SD) dose of gallium-67 citrate (0.07 (0.02) mCi/kg). Thirty four patients (24 boys and 10 girls, mean age 21 months) also had single photon emission computed tomography imaging (group B) soon after planar imaging. The patients had been ill for from 5 days to 16 days (mean (SD) 10.5 (2.4) days in group A and 10.6 (3.0) days in group B). The colour images obtained at 48 or 72 hours were positive in 41% of group A and in 64% of group B. Among the patients with clinically suspected myocarditis, 63% in group A and 80% in group B had positive myocardial images. Single photon emission computed tomography imaging permitted the identification of tracer in the myocardium, the pericardium only, or in the heart chambers. Myocardial imaging with gallium-67 citrate, especially when used with single photon emission computed tomography imaging, is useful for the detection of myocarditis in the acute phase of Kawasaki disease.

[Eleven cases of spindle cell carcinoma of the breast, with special reference to cystic changes in the tumor].

The clinicopathological features of 11 cases of a spindle cell carcinoma handled by our department have been investigated and are presented, with two cases that demonstrated cystic changes. Out of a total of 1,524 breast carcinomas that were treated, 11 (0.72%) were spindle cell carcinomas. The size of the tumor was generally larger than in other more common types of breast carcinomas, but the degree of a lymph node metastasis was low and the prognosis was better. As for the ER status, 4 out of 5 cases were negative. As cystic changes in the tumor were found in 5 of the 11 cases, it would seem that spindle cell carcinomas of the breast tend to show cystic changes in their tumors.

Prolonged suppressed thyroid-stimulating hormone levels in hyperthyroidism in a neonate born to a mother with Graves' disease.

We report here a case of neonatal hyperthyroidism born to a mother, whose pregnancy was complicated by poorly controlled Graves' disease. The patient demonstrated exophthalmos and marked goiter at birth, indicating the existence of thyrotoxicosis in utero. The mother's Graves' disease was well controlled in the third trimester, resulting in a slightly lower level of free thyroxine (FT4) in the umbilical cord blood serum; however, thyroid-stimulating hormone (TSH) was undetectable. Thyroid-stimulating hormone remained undetectable for 2 months, while FT4 levels varied in the course. This case suggests that severe and prolonged thyrotoxicosis in utero, due to poor control of pregnancy with Graves' disease, might induce unresponsiveness of the hypothalamo-pituitary system in the newborn.