Takahiro Ishiwata

Ulinastatin, a Urinary Trypsin Inhibitor, for the Initial Treatment of Patients With Kawasaki Disease A Retrospective Study

Background— Markedly activated neutrophils or higher plasma levels of neutrophil elastase are involved in the poor response to intravenous immunoglobulin (IVIG) and the formation of coronary artery lesions (CAL) in patients with acute Kawasaki disease. We hypothesized that ulinastatin (UTI), by both direct and indirect suppression of neutrophils, would reduce the occurrence of CAL. Methods and Results— We retrospectively analyzed the clinical records of patients with Kawasaki disease between 1998 and 2009. Three hundred sixty-nine patients were treated with a combination of UTI, aspirin, and IVIG as an initial treatment (UTI group), and 1178 were treated with a conventional initial treatment, and IVIG with aspirin (control group). The baseline characteristics did not demonstrate notable differences between the two groups. The occurrence of CAL was significantly lower in the UTI group than in the control group (3% versus 7%; crude odds ratio [OR], 0.46; 95% confidence interval [CI], 0.25–0.86; P=0.01). The OR adjusted for sex, Gunma score (the predictive score for IVIG unresponsiveness), and dosage of initial IVIG (1 or 2 g/kg) was 0.32 (95% CI, 0.17–0.60; P<0.001). In addition, most CAL occurred in patients requiring additional rescue treatment and the proportion of those patients was significantly lower in the UTI group than in the control group (13% versus 22%; crude OR, 0.52; 95% CI, 0.38–0.73; P<0.001). The adjusted OR was 0.30 (95% CI, 0.20–0.44; P<0.001). Conclusions— UTI was associated with fewer patients requiring additional rescue treatment and reduction of CAL in this retrospective study.

Outcomes of childhood pulmonary arterial hypertension in BMPR2 and ALK1 mutation carriers

Mutations in the bone morphogenetic protein receptor type 2 (BMPR2) gene and the activin receptor-like kinase 1 (ALK1) gene have been reported in heritable pulmonary arterial hypertension (HPAH) and idiopathic pulmonary arterial hypertension (IPAH). However, the relation between clinical characteristics and each gene mutation in IPAH and HPAH is still unclear, especially in childhood. The aim of this study was to determine, in a retrospective study, the influence and clinical outcomes of gene mutations in childhood IPAH and HPAH. Fifty-four patients with IPAH or HPAH whose onset of disease was at <16 years of age were included. Functional characteristics, hemodynamic parameters, and clinical outcomes were compared in BMPR2 and ALK1 mutation carriers and noncarriers. Overall 5-year survival for all patients was 76%. Eighteen BMPR2 mutation carriers and 7 ALK1 mutation carriers were detected in the 54 patients with childhood IPAH or HPAH. Five-year survival was lower in BMPR2 mutation carriers than mutation noncarriers (55% vs 90%, hazard ratio 12.54, p = 0.0003). ALK1 mutation carriers also had a tendency to have worse outcome than mutation noncarriers (5-year survival rate 64%, hazard ratio 5.14, p = 0.1205). In conclusion, patients with childhood IPAH or HPAH with BMPR2 mutation have the poorest clinical outcomes. ALK1 mutation carriers tended to have worse outcomes than mutation noncarriers. It is important to consider aggressive treatment for BMPR2 or ALK1 mutation carriers.

A non‐obese boy with Prader‐Willi syndrome shows cardiopulmonary impairment due to severe kyphoscoliosis

Prader-Willi syndrome (PWS, OMIM #176270) is a genetic disorder characterized by hypotonia, obesity, characteristic facial appearance, hypogonadism, short stature, and behavioral abnormalities. It results from deletion or disruption of one or more genes on the proximal long arm of the paternally derived chromosome 15, or from maternal uniparental disomy 15. Musculoskeletal abnormalities are common in these individuals. Scoliosis is very common in PWS being variously reported in 62–86% of patients [Holm and Laurnen, 1981; Laurance et al., 1981]. Here, we describe a non-obese boy with PWS who also presented with cardiopulmonary impairment due to severe kyphoscoliosis. This secondary manifestation was described by Guilleminault et al. [1981]. The male patient was born to healthy and nonconsanguineous parents at 41 weeks of gestation, with a birth weight of 2,430 g ( 1.9 SD) and length of 47.0 cm ( 1.4 SD). Other family members were healthy. He showed hypotonia with poor suck in infancy. He held his head at age 9 months, sat at 1 year, and walked at 41⁄2years. He had a normal male karyotype (46,XY) and therewasno SNRPN signal on FISH. Kyphoscoliosis that was recognized at 1 year of age had progressively deteriorated (Fig. 1A,B). He had received growth hormone (GH) therapy (0.175 mg/kg/week) from age 10 years. He had a restrictive deficit on spirometry at age 1011=12 years: the median forced expiratory volume in 1 sec (FEV1) and forced vital capacity (FVC) were 1.03 L and 1.15 L, respectively. Although he had no respiratory symptoms, he underwent combined anterior fusion with posterior corrective fusion surgery using spinal instrumentation for kyphoscoliosis at age 11 years. However, the instrumentation had to be removed due to deep postoperative infection, which did not resolve until age 116=12 years. His weight management had been controlled well without any obesity from birth. At age 1510=12 years, he was admitted because of a 1-month history of shortness of breath and edema of the legs. On admission, he measured 133.0 cm and weighed 41.2 kg. Under normal conditions, his weight was 33.0 kg and his calculated body mass index (BMI) was 18.7 kg/m. He had a characteristic facial appearance, narrow hands with a straight ulnar border, and chilblain scars on the legs. Physical examination revealed tachypnea, tachycardia, cyanosis, a systolic heart murmur and gallop rhythm, distended abdomen, and edema of the whole body, especially of the legs. Neurological examination showed normal deep tendon reflexes and mild hypotonia. Laboratory tests showed respiratory acidosis, hypercapnia, and heart failure: pH, 7.285; pCO2, 70.6 mmHg in room air; hANP, 557 pg/ml; and BNP, 862 pg/ml. Echocardiogram showed the interventricular septum curved toward the left

dup(8p)/del(8q) recombinant chromosome in a girl with hepatic focal nodular hyperplasia†

A 15‐year‐old girl had exertion dyspnea, focal nodular hyperplasia of the liver, portal vein hypoplasia, portopulmonary hypertension, mental retardation, and minor facial abnormalities. Cytogenetic analysis demonstrated an abnormal chromosome 8 with 8p22‐pter duplication and 8q24.3‐qter deletion, with the duplicated 8p segment attached to band 8q24.3. Her mother had a pericentric inversion of chromosome 8, inv(8)(p22q24.3). Therefore, the girls abnormal chromosome 8 was a recombinant of maternal inversion chromosome: 46,XX,rec(8)dup(8p)inv(8)(p22q24.3)mat. Further characterization of the recombinant chromosome, using array CGH and regional FISH analyses, defined 15 Mb distal 8p duplication and 0.5 Mb 8q deletion. Possible correlation of the recombinant chromosome and hepatic focal nodular hyperplasia in the patient is discussed.

Contribution of Sarcoplasmic Reticulum Ca 2+ Release and Ca 2+ Transporters on Sarcolemmal Channels to Ca 2+ Transient in Fetal Mouse Heart

Sarcoplasmic reticulum (SR) Ca2+ release has been shown not to be the predominant mechanism responsible for excitation-contraction (E-C) coupling in fetal myocytes. However, most of the studies have been conducted either on primary cultures or acutely isolated cells, in which an apparent reduction of ryanodine receptor density have been reported. We aimed to elucidate the contribution of SR Ca2+ release and Ca2+ transporters on sarcolemmal channels to Ca2+ transients in fetal mouse whole hearts. On embryonic day 13.5, ryanodine significantly reduced the amplitude of the Ca2+ transient to 27.2 ± 4.4% of the control, and both nickel and SEA0400 significantly prolonged the time to peak from 84 ± 2 ms to 140 ± 5 ms and 129 ± 6 ms, respectively, whereas nifedipine did not alter it. Therefore, at early fetal stages, SR Ca2+ release should be an important component of E-C coupling, and T-type Ca2+ channel and reverse mode sodium-calcium exchanger (NCX)-mediated SR Ca2+ release could be the predominant contributors. Using embryonic mouse cultured cardiomyocytes, we showed that both nifedipine and nickel inhibited the ability of NCX to extrude Ca2+ from the cytosol. From these results, we propose a novel idea concerning E-C coupling in immature heart.

Ulinastatin, a Urinary Trypsin Inhibitor, for the Initial Treatment of Patients With Kawasaki Disease

Background— Markedly activated neutrophils or higher plasma levels of neutrophil elastase are involved in the poor response to intravenous immunoglobulin (IVIG) and the formation of coronary artery lesions (CAL) in patients with acute Kawasaki disease. We hypothesized that ulinastatin (UTI), by both direct and indirect suppression of neutrophils, would reduce the occurrence of CAL. Methods and Results— We retrospectively analyzed the clinical records of patients with Kawasaki disease between 1998 and 2009. Three hundred sixty-nine patients were treated with a combination of UTI, aspirin, and IVIG as an initial treatment (UTI group), and 1178 were treated with a conventional initial treatment, and IVIG with aspirin (control group). The baseline characteristics did not demonstrate notable differences between the two groups. The occurrence of CAL was significantly lower in the UTI group than in the control group (3% versus 7%; crude odds ratio [OR], 0.46; 95% confidence interval [CI], 0.25–0.86; P=0.01). The OR adjusted for sex, Gunma score (the predictive score for IVIG unresponsiveness), and dosage of initial IVIG (1 or 2 g/kg) was 0.32 (95% CI, 0.17–0.60; P<0.001). In addition, most CAL occurred in patients requiring additional rescue treatment and the proportion of those patients was significantly lower in the UTI group than in the control group (13% versus 22%; crude OR, 0.52; 95% CI, 0.38–0.73; P<0.001). The adjusted OR was 0.30 (95% CI, 0.20–0.44; P<0.001). Conclusions— UTI was associated with fewer patients requiring additional rescue treatment and reduction of CAL in this retrospective study.

Ulinastatin, a Urinary Trypsin Inhibitor, for the Initial Treatment of Patients With Kawasaki DiseaseClinical Perspective

Background— Markedly activated neutrophils or higher plasma levels of neutrophil elastase are involved in the poor response to intravenous immunoglobulin (IVIG) and the formation of coronary artery lesions (CAL) in patients with acute Kawasaki disease. We hypothesized that ulinastatin (UTI), by both direct and indirect suppression of neutrophils, would reduce the occurrence of CAL. Methods and Results— We retrospectively analyzed the clinical records of patients with Kawasaki disease between 1998 and 2009. Three hundred sixty-nine patients were treated with a combination of UTI, aspirin, and IVIG as an initial treatment (UTI group), and 1178 were treated with a conventional initial treatment, and IVIG with aspirin (control group). The baseline characteristics did not demonstrate notable differences between the two groups. The occurrence of CAL was significantly lower in the UTI group than in the control group (3% versus 7%; crude odds ratio [OR], 0.46; 95% confidence interval [CI], 0.25–0.86; P=0.01). The OR adjusted for sex, Gunma score (the predictive score for IVIG unresponsiveness), and dosage of initial IVIG (1 or 2 g/kg) was 0.32 (95% CI, 0.17–0.60; P<0.001). In addition, most CAL occurred in patients requiring additional rescue treatment and the proportion of those patients was significantly lower in the UTI group than in the control group (13% versus 22%; crude OR, 0.52; 95% CI, 0.38–0.73; P<0.001). The adjusted OR was 0.30 (95% CI, 0.20–0.44; P<0.001). Conclusions— UTI was associated with fewer patients requiring additional rescue treatment and reduction of CAL in this retrospective study.

Ulinastatin, a Urinary Trypsin Inhibitor, for the Initial Treatment of Patients With Kawasaki DiseaseClinical Perspective: A Retrospective Study

Background— Markedly activated neutrophils or higher plasma levels of neutrophil elastase are involved in the poor response to intravenous immunoglobulin (IVIG) and the formation of coronary artery lesions (CAL) in patients with acute Kawasaki disease. We hypothesized that ulinastatin (UTI), by both direct and indirect suppression of neutrophils, would reduce the occurrence of CAL. Methods and Results— We retrospectively analyzed the clinical records of patients with Kawasaki disease between 1998 and 2009. Three hundred sixty-nine patients were treated with a combination of UTI, aspirin, and IVIG as an initial treatment (UTI group), and 1178 were treated with a conventional initial treatment, and IVIG with aspirin (control group). The baseline characteristics did not demonstrate notable differences between the two groups. The occurrence of CAL was significantly lower in the UTI group than in the control group (3% versus 7%; crude odds ratio [OR], 0.46; 95% confidence interval [CI], 0.25–0.86; P=0.01). The OR adjusted for sex, Gunma score (the predictive score for IVIG unresponsiveness), and dosage of initial IVIG (1 or 2 g/kg) was 0.32 (95% CI, 0.17–0.60; P<0.001). In addition, most CAL occurred in patients requiring additional rescue treatment and the proportion of those patients was significantly lower in the UTI group than in the control group (13% versus 22%; crude OR, 0.52; 95% CI, 0.38–0.73; P<0.001). The adjusted OR was 0.30 (95% CI, 0.20–0.44; P<0.001). Conclusions— UTI was associated with fewer patients requiring additional rescue treatment and reduction of CAL in this retrospective study.