Shinji Oana

Vascular endothelial growth factor in acute Kawasaki disease

Vascular endothelial growth factor (VEGF), also known as vascular permeability factor, is an important regulator of angiogenesis and blood vessel permeability. Kawasaki disease (KD) is characterized by systemic vasculitis with increased vascular permeability, implying a possible role of VEGF in KD. To elucidate the involvement of VEGF in the pathogenesis of KD, we investigated 30 patients with acute KD, comparing the time course of plasma VEGF levels (n = 123) with clinical symptoms and laboratory findings. Compared with control values, the peak levels of plasma VEGF were significantly elevated (38+/-26 vs 244+/-248 pg/ml, p <0.001). The VEGF levels at the appearance of skin rash and/or edema of hands and feet were also elevated to 176+/-163 pg/ml (p <0.001). In 7 patients (23%), the plasma VEGF levels remained increased after the resolution of the skin rash and peripheral edema. The VEGF levels were independent of gamma globulin therapy and levels of serum albumin and C-reactive protein. We also measured the plasma levels of transforming growth factor-beta1 (TGF-beta1) and tumor necrosis factor alpha, both of which can upregulate VEGF in vitro. The plasma levels of VEGF were highly correlated with those of TGF-beta1 (n = 63, r = 0.73, p <0.001) but not with those of tumor necrosis factor alpha. These findings suggest that the production of VEGF is increased and may be upregulated by TGF-beta1 in acute KD. VEGF may be involved in the hyperpermeability of local blood vessels in acute KD.

Dramatic decrease of circulating levels of monocyte chemoattractant protein-1 in Kawasaki disease after gamma globulin treatment.

Kawasaki disease (KD) is a systemic vasculitis preferentially affecting coronary arteries. Extensive monocytes/macrophages infiltrate in the vascular lesions, implying the involvement of a chemotactic cytokine in their recruitment. We investigated the role of monocyte chemoattractant protein‐1 (MCP‐1, also termed monocyte chemotactic and activating factor) in KD. In the immunohistochemical studies using the cardiac tissues of patients with fatal KD, MCP‐1 but not interleukin (IL) ‐8 or macrophage inflammatory protein‐1α was localized at the extracellular matrix associated with mononuclear cellular infiltration. The sites of MCP‐1 expression correlated with the distribution of the acute inflammation, including early coronary vasculitis. In prospectively studied patients with KD, circulating levels of MCP‐1, IL‐8, tumor necrosis factor a (TNF‐α), and IL‐1α were elevated in 73, 77, 57, and 0% of samples before gamma globulin (GG) treatment (400 mg/kg × 5 days = total 2 g/kg), respectively, compared with respective control values. GG treatment correlated with a rapid decrease in the circulating levels of MCP‐1 (P = 0.001) but not IL‐8 (P = 0.19) or TNF‐α (P = 0.33). In the sensitive Western blotting, MCP‐1 bound to GG. Furthermore, GG inhibited the MCP‐1‐induced Ca2+ influx in a human monocytic cell line in vitro. These findings suggest a role of MCP‐1 in KD, and indicate that GG treatment may block MCP‐1 activity, thus alleviating KD vasculitis. J. Leukoc. Biol. 65: 566–572; 1999.

Alleviation of Myocardial Ischemia After Kawasaki Disease by Heparin and Exercise Therapy

Background—Heparin promotes angiogenesis. We evaluated the effects of combined treatment with heparin and exercise on myocardial ischemia in the chronic stage of Kawasaki disease. Methods and Results—This study was conducted in 7 patients (aged 6 to 19 years) who had a totally occluded coronary artery and stress-induced myocardial ischemia in the collateral-dependent areas. Twice-daily exercise using a bicycle ergometer was performed with increments of 0.5 W/kg every 3 minutes up to maximal exertion for 10 days. Heparin, which immediately increased circulating hepatocyte growth factor, was given intravenously 10 minutes before each exercise period. Newly developed myocardial infarction, ventricular tachyarrhythmia, anginal attack, or hemorrhagic complication was not observed in any patient. Dipyridamole-loading single photon emission computed tomography documented improved myocardial perfusion in the collateral-dependent areas and a significant reduction in total defect scores in all patients after the completion of 20 sessions (P =0.01). In control patients who did not receive the heparin-exercise therapy, however, stress defect scores remained unchanged (n=1) or increased (n=2) during follow-up. Computerized quantitative coronary angiography provided evidence that the heparin-exercise therapy increased the diameter of the occluded artery to which collaterals terminated (P =0.001) but not that of the reference artery with which collaterals were not connected (P =0.96). Conclusions—The findings suggest that a series of heparin and exercise treatments over 10 days may have a dramatic effect on the alleviation of myocardial ischemia in collateral-dependent regions. This may be a safe, noninvasive revascularization therapy for patients with coronary artery occlusion in the chronic stage of Kawasaki disease.

A case of persistent Enterobacter cloacae bacteremia

A 10-month-old girl was admitted to a community hospital in Chiba prefecture, Japan, because of fever and wheezing. She was found to have pulmonary hyperinflation on chest radiograph examination and the diagnosis of asthmatic bronchitis was made. The patient was hospitalized and treated with parenteral continuous aminophylline administration and β2-adrenoceptor agonist inhalation. No antibiotics or corticosteroids were administered. Response to treatment was favorable and the respiratory problem disappeared at day 10 of admission. However, on day 10, a sudden onset of high fever occured and the patient vomited three times without coughing (Fig. 1). No other symptoms, such as rhinorrhea, wheezing or diarrhea, were seen. The white blood cell (WBC) count was 18.3`109 /L and the serum C-reactive protein (CRP) concentration was 10.5 mg/dL (Table 1). Blood, cerebrospinal fluid (CSF), stool and urine cultures were examined. Examination of CSF disclosed pleocytosis and a WBC count of 284 /mm3, a protein level of 45 mg/dL and negative Gram stain. Enterobacter cloacae was isolated from a blood culture, but the CSF was sterile. Because of the patient’s possible susceptibility to bacterial meningitis, empiric therapy with ceftriaxone (100 mg/kg per day) and panipenem (100 mg/kg per day) was administered. Gentamicin (5 mg/kg per day) was also administered, according to antimicrobial susceptibility shown in Table 2. The patient’s fever subsided after day 5 of treatment and laboratory data also demonstrated an improvement (Table 1). However, because E. cloacae was still present (Fig. 1), the patient was transferred to Chiba University Hospital for further evaluation and treatment. The same chemotherapy regimen was continued. Finally, the antibiotics were changed from panipenem to ceftazidime, because the results of the blood culture of the first day in Chiba University Hospital were still positive. However, it was later found that blood culture on the second day was sterile (Fig. 1).

Plasma brain natriuretic peptides and renal hypertension.

Abstract Three children with renal hypertension are described. Two had histories of neuroblastoma treated by surgical resection and chemotherapy. They both presented later with unilateral atrophic kidney and marked hypertension. Only the child with severe cardiac failure demonstrated high plasma brain natriuretic peptide (BNP) concentrations. The remaining patient had a history of chronic nephritis treated with continuous ambulatory peritoneal dialysis. She also had chronic hypertension and severe cardiac failure. This child demonstrated high plasma BNP levels. The endogenous secretion of BNP is not triggered by hypertension alone, even though exogenous BNP has the pharmacological effect of reducing renin activity.

The program for personnel in medical institutions in Japan to combat child maltreatment

In 2014, we created a training program for personnel in medical institutions in Japan to combat child maltreatment. The aim of the present study was to document the effectiveness of this program.

Recurrence of Fever After Initial Intravenous Immunoglobulin Treatment in Children With Kawasaki Disease

The standard treatment for Kawasaki disease (KD) is high-dose intravenous immunoglobulin (IVIG). Some patients experienced recurrent fever after IVIG following defervescence. However, little is known about the frequency of such episodes and the clinical outcome for such patients. We classified 195 KD patients into 4 groups based on their fever patterns after initial IVIG treatment: group NR (no response), group EF (early recurrent fever within 72 hours after defervescence), group LF (late recurrent fever >72 hours after defervescence), and group GR (good response). We compared the clinical characteristics and laboratory data among these groups retrospectively. Nearly a third of patients had recurrent fever (group EF, n = 45; group LF, n = 11). In two-thirds of these patients, the fever had subsided spontaneously without retreatment; 2 patients in Group LF with smoldering KD symptoms had developed coronary artery lesions (CALs) even after additional IVIG. Recurrent fever and smoldering symptoms might be risk factors for CAL.

National survey of hospital child protection teams in Japan

This study aimed to investigate the penetration rate of child protection teams (CPTs) in medical institutions and associations between CPT functions and hospital services. We collected data in October of 2015 from 377 hospitals in Japan offering pediatric organ transplantation. The questionnaire included questions regarding the existence of a CPT, the number of child maltreatment cases discussed and reported per year, CPT functions including 21 items about staffing, manuals, meeting, prevention, education, and collaboration, and the services provided by the hospital. Of the 377 institutions, 122 (32.4%) answered the survey. There were significant associations between CPT functions and the number of pediatric beds (r = .27), number of pediatricians (r = .27), number of outpatients (r = .39), number of emergency outpatients (r = .28), and emergency medical care (p = .009). In a multiple regression analysis, CPT functions were significantly associated with the number of CPT members, pediatric outpatient numbers, and pediatric emergency outpatient numbers. Japan has no CPT guidelines that outline what CPTs should offer in terms of structure, staffing, functions, and systems. Hospitals with many pediatric and emergency outpatients are expected to play major roles in providing services such as specialty care, intensive care, and education. They are also expected to play a role in detecting and managing child maltreatment, and have, by their own initiative, improved their capacities to achieve these goals.

Effects of Intravenous Gammmaglobulin Therapy Combined with Dexamethasone for the Initial Treatment of Acute Kawasaki Disease

We studied effects of intravenous gammmaglobulin therapy (IVGG) combined with dexamethasone (DEX) for the initial treatment of acute Kawasaki disease(KD). Prospectively studied 33 KD patients received total of 2g/kg IVGG for consecutive 4-5days plus 0.3mg/kg DEX for consecutive 3days (group 1). Retrospectively studied 33 KD patients received standard IVGG therapy (2g/kg IVGG for consecutive 4-5days)(group 2) were compared to analyze the efficacy and safety of the new regimen. There were no differences in age, sex, body weight, duration of illness, or given doses of gammmaglobulin between those two groups. Clinical no responders to the initial treatment received additive IVGG treatment. Informed consent was obtained from childrens parents before therapy. No serious adverse effect was noted in both groups. The duration of high fever after the start of initial treatment in group1(1-12 days) was shorter than in group 2 (1-16 days)(p=0.07, by Mann-Whitney U-test). Two patients in group 1 and two patients in group 2 developed small coronary aneurysms. Although further analysis using larger numbers of patients are necessary to confirm the efficacy of this new regimen, we preriminaly demonstrated that IVGG combined with DEX in the initial treatment of acute KD was safe and may shorten the duration of fever.

CATCH22 syndrome with gastroesophageal reflux.

defects treated with prostaglandin E1 has been described.1,2 Gastric outlet obstruction usually leads to vomiting and feeding disorders, or gastroesophageal reflux (GER).1,2 Gastroesophageal reflux usually regresses after the cessation of prostaglandin E1 administration.1,2 We report an infant with CATCH22 (cardiac defects, abnormal faces, thymic hypoplasia, cleft palate and hypocalcemia with chromosome 22q11 deletion) with tetralogy of Fallot (TOF) who demonstrated severe and persistent GER.