Coronary risks after high-dose gamma-globulin in children with Kawasaki disease.

OBJECTIVES: The goals of the present study were to develop a predictive coronary risk scoring system after intravenous gamma-globulin (IVGG) therapy of any dose for the different preparations currently used in the treatment of children with Kawasaki disease and to determine the predictive value of the system. The previously reported scoring systems were based on treatment with high-dose IVGG therapy at limited doses and were determined using investigative methods. METHODS: Four hundred and fifty-one patients were randomized into one of three groups and received either i.v. polyethylene glycol-treated human immunoglobulin at a dose of either 200 (n = 147) or 400 mg/kg per day (n = 152) or freeze-dried sulfonated human immunoglobulin at 200 mg/kg per day (n = 152) for 5 consecutive days. We documented 31 cases of coronary abnormalities (CA). Univariate and multivariate logistic regression was performed using 49 clinical variables and the resulting predictive model was validated. RESULTS: The duration of fever (odds (I day)/odds (- 5 days)= 0.158; 95% confidence interval (CI) 0.0385-0.648), hemoglobin (odds (Q1 = 10.3)/odds (Q3 = 11.6) = 3.97; 95% CI 1.92-8.20), IgG (odds (Q1 = 1,900)/odds (Q3=2,658)=2.72, 95% CI 1.18-6.25) and IgA (odds (Q1 =72)/odds (Q3= 160) = 0.415; 95% CI 0.253-0.680) levels after completion of gamma-globulin infusion were independent predictors. The model is quasi-cross validated and has acceptable sensitivity and selectivity. The estimated risk and observed occurrence of CA coincide. CONCLUSIONS: Determinants of the risk of CA after IVGG therapy are a longer duration of fever, a lower IgG level, a higher IgA level and a lower hemoglobin level after IVGG infusion. This model is applicable for IVGG doses from 1 to 2 g/kg and for at least two different gamma-globulin preparations.

Coronary risk factors in school children in relation to their family history of coronary heart disease and hyperlipidemia.

A school-based study was implemented to assess the family history of coronary heart disease (CHD) and hyperlipidemia (HL) in relation to serum lipoprotein and apolipoprotein levels. One hundred and twenty-five elementary school students (aged 9-10 years) and 297 junior high school students (aged 12-13 years) participated. Family history was evaluated by the following scoring method: positive family history in a parent, 2 points; in a grandparent, 1 point; and onset of CHD before age 60, 1 additional point. Family history of HL was positive in 8.2% of elementary school students, and 4.2% in junior high school students. Family history of CHD was positive in 11.5% of elementary students, and 11.0% in junior students. Family history score (FHS) for HL was related to serum total cholesterol (TC), low density lipoprotein cholesterol (LDLC), high density lipoprotein cholesterol, apolipoprotein A-I, apolipoprotein B (apoB) and lipoprotein (a) in elementary students, and to TC, LDLC, triglyceride and apoB in junior students. There was no relationship between FHS for CHD and serum lipoprotein or apolipoprotein levels in any student. The children with a positive FH of HL already demonstrated an atherogenic lipid profile while those with FH of CHD did not, which was probably because lipid profiles in children are more genetically mediated by a FH of HL than of CHD.

A nationwide surveillance study of rheumatic diseases among Japanese children.

To estimate the number of children with rheumatic diseases, a questionnaire was distributed to the pediatrics department of 1,290 hospitals in Japan in June 1994. From this survey, 1,606 cases with juvenile rheumatoid arthritis (JRA), 906 cases with systemic lupus erythematosus (SLE), 320 cases with dermatomyositis/polymyositis (DM/PM), 28 cases with scleroderma (PSS), 70 cases with Sjögren's syndrome (Sjs), 93 cases with mixed connective tissue disease (MCTD), 25 cases with aortitis syndrome, 20 cases with polyarteritis (PN) and 51 cases with Behçet disease were reported. The crude annual incidence rates per 100,000 among the childhood population were estimated as JRA, 0.83; SLE, 0.47; DM/PM, 0.16; PSS, 0.01; Sjs, 0.04; MCTD, 0.05; aortitis syndrome, 0.01; PN, 0.01; and Behçet disease, 0.03. The present study reveals that there are more children with rheumatic diseases than are estimated from the reported cases in the literature and the number of children who are receiving Assistance Medical Costs Insurance covered by the Japanese government.

Clinical analysis of 570 cases with juvenile rheumatoid arthritis: results of a nationwide retrospective survey in Japan.

The purpose of the present study was to investigate the incidence of juvenile rheumatoid arthritis (JRA) among Japanese children and to evaluate the clinical features of this disease. A questionnaire was sent to the department of pediatrics of 1290 hospitals in Japan, in 1994, asking for the number of rheumatic patients during the past 10 years. Subsequently, a second questionnaire was sent asking for the type of onset, clinical features, treatment, and other details. The results of 570 cases were obtained. Of these, 310 cases (54%) were the systemic onset type, 140 cases were the polyarticular onset type (25%), and 120 cases (21%) were the pauciarticular onset type. Hence, in the present series of children, the proportion of the pauciarticular type was less than the other two types of JRA. In the laboratory findings of the systemic onset type, hyperferritinemia and thrombocytosis were noted, in addition to leukocytosis, positive C- reactive protein (CRP) and accentuated erythrocyte sedimentation rate (ESR). The rheumatoid factor was positive in 50% of patients with the polyarticular onset type. Chronic uveitis was recognized in 13 cases (10.8%) of the pauciarticular onset type. In four girls, uveitis started before the onset of arthritis. Non-steroidal anti-inflammatory drugs were used in almost one-third of cases, and methotrexate (MTX) was used in 12.8% of cases. The quality of life of children with JRA was disturbed in almost 20% of cases. Therefore, for the early and definitive diagnosis of the systemic type of JRA, diagnostic procedures including thrombocyte counts and serum ferritin level, should be performed. In order to obtain good results and to avoid side effects, a protocol for the use of disease modifying anti-rheumatic drugs and immunosuppressants, especially for the use of MTX, must be established.

Autologous bone marrow transplantation in children with advanced neuroblastoma.

BACKGROUND: Encouraging results have been reported with high dose chemotherapy and total body radiation followed by bone marrow autotransplantation in children with advanced neuroblastoma; however, relapse remains a significant problem. METHODS: The authors treated 22 children with advanced neuroblastoma with high dose chemotherapy, surgery, intraoperative radiation, and a bone marrow autotransplant (treated in vitro to remove tumor cells) followed by 13-cis-retinoic acid. RESULTS: The 3-year relapse rate was 25% (95% confidence interval [CI], 6-44%). The 3-year disease free survival rate was 72% (95% CI, 52-92%). Toxicities included hemolytic uremic syndrome, herpes infection, and hepatic venoocclusive disease. CONCLUSION: These data suggest that this treatment strategy offers an increased rate of 3-year disease free survival. The nonrandomized nature of this study and its use of multiple modalities precludes the analysis of the specific contribution of each treatment component and comparison with conventional therapy.

A multicenter, randomized, controlled trial of intravenous gamma globulin therapy in children with acute Kawasaki disease.

We studied the effect of intravenous, polyethyleneglycol-treated, human immunoglobulin, administered at 200 mg/kg per day (group A: n = 147; male 86, female 61; age < 1 year, 50) or 400 mg/kg per day (group B: n = 152; male 87, female 65; age < 1 year, 52) for five consecutive days and compared it with freeze-dried, sulfonated human immunoglobulin [group C: n = 152; male 87, female 65; age < 1 year, 51), administered at 200 mg/kg per day for five consecutive days, on the prevention of coronary artery abnormalities in Kawasaki disease. Echocardiograms were interpreted blindly and independently. Proportions of 87.1%, 95.4%, and 82.3% in groups A, B, and C, respectively, had no coronary artery abnormalities. The confidence limits of difference between the proportions of groups A and C, groups B and C, and groups B and A were -4.4% and 10.4%, 7.8% and 15.9%, and 4.0% and 10.8%, respectively. Duration of fever and serum immunoglobulin G (IgG) levels were correlated with the prevalence of coronary artery abnormalities. We concluded that intravenous, polyethyleneglycol-treated, human immunoglobulin and freeze-dried, sulfonated human immunoglobulin had clinically equivalent effects on coronary artery abnormalities, and that five daily doses of 400 mg/kg of intravenous, polyethyleneglycol-treated, human immunoglobulin is more effective than that of 200 mg/kg gamma globulin.

Chronic, infantile, neurological, cutaneous and articular syndrome in Japan; two case reports.

We report two Japanese children with chronic, infantile, neurological, cutaneous and articular syndrome. Although the shoulder joint lesion has been rare in the literature of Europe and America, our first case showed overgrowth of the epiphysis in the bilateral shoulder joints. The second case exhibited severe growth retardation caused by early closure of the physis. The influence of GH is irrelevant in this syndrome. The existence of this syndrome in the Orient should be recognized.

[Effective dose of flecainide for arrhythmia in children].

Nine children with arrhythmia (1 automatic atrial tachycardia, 1 premature ventricular construction, and 7 ventricular tachycardia) who started oral treatment using flecainide were studied. All but 2 cases (1 post operative ventricular septal defect, 1 post operative tetralogy of Fallot) had ostensibly normal heart on physical examination, chest X ray and echocardiogram. To raise serum level above 200ng/ml, flecainide dose over 80mg/m2 or 3mg/kg was needed. There was negative correlation between dose (y: mg/kg) and age (x: year) (y = 5.2-0.16x, r = 0.88) in this group. No serious side effect indicating the need to discontinue further medication was detected. In electrocardiogram, PR, QRS and QT interval was not changed before or after the medication. Premature ventricular contraction disappeared in 2 of 8 cases (25%), decreased in number in 3 (38%), did not change in 1 (13%) and increased in number in 2 (25%). However ventricular tachycardia rate decreased or disappeared in all of the 5 cases whose ventricular tachycardia was detected in Holter electrocardiogram. Flecainide seems more effective for sustained ventricular tachycardia than for nonsustained ventricular tachycardia.

Auditory event-related potentials and reaction time in children: evaluation of cognitive development.

The authors studied age-related correlations of auditory event-related potentials (ERPs) using the conventional 'oddball' paradigm and reaction time in 175 normal subjects, aged between four and 21 years. From four years, the latencies of N100, N200 and P300 in ERP progressively shortened until about 16 to 17 years, after which they reached adult level, but with a slight tendency to prolongation towards 20 years; there was no trend for amplitude changes. The reaction time was more rapid than that of P300 latency. These findings indicate that the cognitive function of children improves rapidly until 16 to 17 years. A reduced difference between P300 latency and reaction time with age implies additional progress in motor skill. Combining P300 latency and reaction-time studies may provide more detailed information for the evaluation of the development of cognitive function and motor skill.

Findings on magnetic resonance imaging of the spine and femur in a case of McCune-Albright syndrome.

Polyostotic fibrous dysplasia, a major osseous change in McCune-Albright syndrome, is seen in the cranium, facial bones, bones of the extremities, and ribs, but rarely in the spine. Spinal X-rays revealed no abnormalities in an 8-year-old girl with this syndrome, but 99mTc-methylene diphosphonate bone scintigraphy disclosed high-density areas in the thoracic and lumbar vertebrae. Multiple well-circumscribed areas of low signal intensity were seen on T1-weighted magnetic resonance imaging (MRI) of the spine. Although MRI spine scans in this disease have never been reported, our findings in this case proved interesting for evaluating osseous lesions. MRI made it possible to differentiate between fibrous lesions (low signal intensity on T1- and T2-weighted MRI) and cartilaginous lesions (low signal intensity on T1-weighted MRI and high signal intensity on T2-weighted MRI).

[The study of mismatch negativity].

We studied age related correlations of mismatch negativity (MMN) auditory event-related potentials (ERPs) using odd ball paradigm in 121 normal subjects (from 6 months to 43 years) and 33 mentally retarded subjects (from 2 to 18 years). The subject was instructed to read a book in order to ignore the stimulus during the experiment, or no specific task was imposed on young child. The MMN wave form was clearly obtained in normal 6 month old subjects. As the age advanced from 6-months, the latencies of MMN progressively shortened till about 7 years, when the latency reached adult level. One-third of mentally retarded patients had prolonged MMN than that normal age-matched subjects. Reliable recording of P300 requires subject's cooperation and attentiveness, which are difficult to achieve in young children or mentally retarded patients. MMN may be utilized in children to evaluate the development of the cognitive function.

Trace elements and mineral requirements for very low birth weight infants in rickets of prematurity.

To establish mineral and trace element requirements for very low birth it is important to prevent bone mineral disorder. Those infants fed mother's milk only are thought to be at higher risk of this disorder. Both calcium and phosphorus supplementation were thought to be needed to prevent it. Copper and zinc are important as cofactors of major enzymes involved in the synthesis of collagen. These trace elements especially zinc may not be enough for very low birth weight infants fed mother's milk. At present however the relationship between these trace elements and minerals, and bone metabolic disease in preterm infants is not completely clear.

[Clinical evaluation of effects of KRN8601 (rhG-CSF) on neutropenia].

Clinical effects of KRN8601 (recombinant human granulocyte colony-stimulating factor:rhG-CSF) were studied in 26 patients with chronic neutropenia including 4 Kostmann's disease, 1 Shwachman's syndrome, 1 Lonsdale's syndrome, 1 glycogen storage disease Ib-associated, 6 chronic benign, 5 chronic hypoplastic, 2 cyclic, 4 autoimmune and 2 miscellaneous neutropenia. The patients were given rhG-CSF intravenously at doses of 20-540 micrograms/m2 or subcutaneously at doses 20-400 micrograms/m2, over the periods of 2-32 weeks. Increases in neutrophil counts occurred after rhG-CSF administration in 23 of the 26 patients. Patients with Kostmann's disease, Shwachman's syndrome and chronic hypoplastic neutropenia responded poorly compared to patients with other types of neutropenia. There were no serious side effects which caused interruption of the study. These results indicated a beneficial effect of KRN8601 in various types of chronic neutropenia.

Precocious puberty caused by an hCG-producing tumor of the septum pellucidum.

A 6 year 9 month old boy with rapidly progressing precocious puberty was immunohistochemically and histologically diagnosed as having an hCG-producing mixed tumor consisting of choriocarcinoma and teratoma in the septum pellucidum. His serum hCG was elevated, but the serum LH was low as determined by LH immunoradiometric assay (IRMA). He did not exhibit a characteristic endocrinological pattern, e.g., high basal levels of LH and failure to respond with high LH levels to the LH-RH stimulation test using the conventional LH RIA method.

Host responses and neuroendocrinological changes in pyrexia in childhood.

Host responses and neuroendocrinological changes during pyrexia in childhood were studied. Serum IL-1 beta could not be detected in most subjects either during pyrexia or in afebrile periods. IL-1 beta was detected in two cases, increasing during pyrexia and decreasing during the afebrile period. Plasma ACTH increased during pyrexia, but this was not statistically significant. Serum cortisol during pyrexia increased to around twice the normal value, and many subjects showed a high level of arginine vasopressin. The subjects, who did not develop dehydration, showed a decrease in serum osmolality and serum sodium during the pyrexia period. Serum Fe and Zn decreased, but serum Cu increased during both periods. It could not be confirmed that IL-1 activates the hypothalamic-pituitary-adrenal axis during pyrexia. It is concluded that AVP is important in the control of fever and the maintenance of homeostasis of body fluid during pyrexia.

[Treatment of aplastic anemia with KRN8601 (rhG-CSF)].

Thirty-nine patients with severe or moderate aplastic anemia received treatment with recombinant human granulocyte colony-stimulating factor (rhG-CSF). The first group of eight patients received rhG-CSF in doses of 100 to 400 micrograms/m2/d by a daily 30-minute intravenous infusion for one or two weeks. Doses up to 400 micrograms/m2/d were well tolerated and resulted in increases of neutrophil counts in 5 out of 8 patients. We gave rhG-CSF (400 micrograms/m2/d) to the second group of 26 patients by a daily 30-minute intravenous infusion for two weeks. The treatment resulted in an increase of neutrophil counts in 15 out of 26 patients (3.1 to 29.5 fold). Further, higher doses (800 or 1,200 micrograms/m2/d) were administered in 5 patients who did not respond to the dose of 400 micrograms/m2/d. The treatment increased the neutrophil counts in 3 out of 5 patients. The third group of five patients received rhG-CSF subcutaneously in doses of 20 to 400 micrograms/m2/d. An increase of neutrophil counts was noted in all five patients. Differential counts of bone marrow aspirate revealed an increase of myeloid: erythroid ratios. However, the responses were transient and neutrophil counts returned to basal levels within 1 approximately 2 weeks after discontinuing treatment. No severe toxicity due to rhG-CSF was observed. These results suggest that rhG-CSF is effective on stimulating granulopoiesis in patients with aplastic anemia. This treatment will be particularly useful for the patient with aplastic anemia suffering from bacterial or fungal infections.