Publishing type：Research paper (scientific journal)  

INTRODUCTION: There is no information on the factors that influence the time required to induce resolution of diabetic ketoacidosis (DKA). New methods are currently available for bedside measurement of serum 3-hydroxybutyrate (3HB). The aim of this study was to determine the relationship between serum 3HB and the time to DKA resolution. METHODS: We reviewed the medical records of patients with type 1 diabetes (T1D) and a history of DKA who were admitted to the Department of Pediatrics, Osaka City University Hospital, between November 2008 and October 2018. DKA resolution was defined as 3HB below 1.0 mmol/L as measured by a bedside ketone meter. RESULTS: Data of 52 T1D-DKA episodes were analyzed (median age, 8.0 years; 20 male patients; 32 female patients; new T1D diagnosis, n = 13; established diagnosis, n = 39). In all cases, correction of serum 3HB was an important aspect of T1D management. The median time to DKA resolution (defined as the time from the start of insulin infusion until the fall of 3HB level to below 1.0 mmol/L) was 11 and 10 h in new and established T1D cases, respectively. 3HB on admission and the required insulin infusion dose per body weight, but not blood pH level on admission, correlated with time to DKA resolution. There was no relationship between blood pH level and 3HB on admission. CONCLUSIONS: Our results showed that DKA resolution could be achieved within 10-11 h when DKA treatment is guided by bedside 3HB monitoring without any severe complications. Blood 3HB level is a potentially suitable marker for the severity and resolution of DKA.

DOI： 10.1007/s13300-021-01167-y

PubMed

Publishing type：Research paper (scientific journal)   International / domestic magazine：International journal  

INTRODUCTION: There is no information on the factors that influence the time required to induce resolution of diabetic ketoacidosis (DKA). New methods are currently available for bedside measurement of serum 3-hydroxybutyrate (3HB). The aim of this study was to determine the relationship between serum 3HB and the time to DKA resolution. METHODS: We reviewed the medical records of patients with type 1 diabetes (T1D) and a history of DKA who were admitted to the Department of Pediatrics, Osaka City University Hospital, between November 2008 and October 2018. DKA resolution was defined as 3HB below 1.0 mmol/L as measured by a bedside ketone meter. RESULTS: Data of 52 T1D-DKA episodes were analyzed (median age, 8.0 years; 20 male patients; 32 female patients; new T1D diagnosis, n = 13; established diagnosis, n = 39). In all cases, correction of serum 3HB was an important aspect of T1D management. The median time to DKA resolution (defined as the time from the start of insulin infusion until the fall of 3HB level to below 1.0 mmol/L) was 11 and 10 h in new and established T1D cases, respectively. 3HB on admission and the required insulin infusion dose per body weight, but not blood pH level on admission, correlated with time to DKA resolution. There was no relationship between blood pH level and 3HB on admission. CONCLUSIONS: Our results showed that DKA resolution could be achieved within 10-11 h when DKA treatment is guided by bedside 3HB monitoring without any severe complications. Blood 3HB level is a potentially suitable marker for the severity and resolution of DKA.

DOI： 10.1007/s13300-021-01167-y

PubMed

Publishing type：Research paper (scientific journal)   International / domestic magazine：International journal  

We investigated the decline of activities of daily living with symptomatic progression in patients with mucopolysaccharidosis type II (MPS II) and investigated the associated factors. Clinical data were retrospectively collected from the medical records of 28 patients with MPS II who visited our hospital between October 2007 and August 2019. Activities of daily living were assessed over time using a 5-point scale (from stage 1, indicating independent, to stage 5, indicating total assistance + medical care); the relationships of the interval years from stage 2 (mild symptoms) to stage 4 (total assistance) with therapeutic intervention, anti-drug antibodies (ADA), urinary glycosaminoglycans (uGAG), and genotypes were analyzed. Eight are attenuated types, and 20 are severe types. Further, 20 underwent enzyme replacement therapy (ERT) alone, 5 underwent hematopoietic stem cell transplantation (HSCT) alone, and 3 underwent both therapy. The mean interval years (standard deviation) from stage 2 to 4 was 3.5 (0.7) and 7.3 (3.3) in patients who started undergoing ERT (n = 6) and HSCT (n = 3) at stage 2, respectively, whereas it was 3.1 (1.5) in patients who received no treatment until they reached stage 4 (n = 8). The study findings revealed the process of changes in the activities of daily living over a long duration in patients with MPS II undergoing different treatments. In severe type, the activity deteriorated regardless of the stage at which ERT was initiated. The activity declined slower in patients who received HSCT at an early stage.

DOI： 10.1016/j.ymgmr.2021.100816

PubMed

Publishing type：Research paper (scientific journal)  

Mucopolysaccharidosis type II (MPS II; Hunter syndrome) is an X-linked recessive lysosomal storage disease caused by a mutation in the IDS gene and characterized by systemic accumulations of glycosaminoglycans. Its somatic symptoms can be relieved by enzyme replacement therapy (ERT) with idursulfase, but because the enzyme cannot cross the blood-brain-barrier (BBB), it does not address the progressive neurodegeneration and subsequent central nervous system (CNS) manifestations seen in patients with neuropathic MPS-II. However, pabinafusp alfa, a human iduronate-2-sulfatase (IDS) fused with a BBB-crossing anti-transferrin receptor antibody, has been shown to be efficacious against both the somatic and CNS symptoms of MPS II. We report two cases of MPS-II in Japanese siblings sharing the same G140V mutation in the IDS gene, who showed markedly contrasting developmental trajectories following enzyme replacement therapy (ERT). Sibling 1 was diagnosed at 2 years of age, started undergoing conventional ERT shortly afterward, and scored a developmental quotient (DQ) of 53 on the Kyoto Scale of Psychological Development (KSPD) at 4 years of age. Sibling 2 was diagnosed prenatally and received conventional ERT from the age of 1 month through 1 year and 11 months, when he switched to pabinafusp alpha. He attained a DQ of 104 at age 3 years and 11 months, along with significant declines in heparan sulfate concentrations in the cerebrospinal fluid. This marked difference in neurocognitive development highlights the importance of early initiation of ERT with a BBB-penetrating enzyme in patients with neuropathic MPS-II.

DOI： 10.1002/jmd2.12239

PubMed

Publishing type：Research paper (scientific journal)  

INTRODUCTION: Recently, many seriously ill children requiring medical equipment are being recommended to transition from hospital to home care in Japan. Since 2011, our recovery center has provided a support program for the transfer process from hospital to home for ill children and their families. The purpose of this study was to evaluate the factors related to high care burden after completing the discharge-support program. METHODS: A questionnaire-based cross-sectional study was conducted on all primary caregivers whose children received the program in our center and moved from hospital to home (30 children and 29 families) from May 2011 to May 2018. Fifteen children came from the neonatal intensive care unit. The questionnaire consisted of three parts: characteristics of children and families and life after the program; the Zarit Burden Interview (ZBI); and the Positive and Negative Affect Schedule (PANAS). RESULTS: Twenty-three primary caregivers responded (79% response rate). All children received tracheostomy and 71% received home mechanical ventilation. Primary caregivers were all mothers. High ZBI score was not related to the severity and type of medical equipment. There were relationships between high ZBI score and following factors: 'unimproved relationship between patients and family members without primary caregivers' and 'additional medical equipment after discharge'. The result of PANAS showed that positive attitude was not different between those with high and low ZBI scores. CONCLUSION: It is crucial to reach out to family members without a primary caregiver. Additional medical care/equipment after the program is related to the care burden of primary caregivers.

DOI： 10.1016/j.braindev.2021.06.003

PubMed

International / domestic magazine：International journal  

Mucopolysaccharidosis type II (MPS II; Hunter syndrome) is an X-linked recessive lysosomal storage disease caused by a mutation in the IDS gene and characterized by systemic accumulations of glycosaminoglycans. Its somatic symptoms can be relieved by enzyme replacement therapy (ERT) with idursulfase, but because the enzyme cannot cross the blood-brain-barrier (BBB), it does not address the progressive neurodegeneration and subsequent central nervous system (CNS) manifestations seen in patients with neuropathic MPS-II. However, pabinafusp alfa, a human iduronate-2-sulfatase (IDS) fused with a BBB-crossing anti-transferrin receptor antibody, has been shown to be efficacious against both the somatic and CNS symptoms of MPS II. We report two cases of MPS-II in Japanese siblings sharing the same G140V mutation in the IDS gene, who showed markedly contrasting developmental trajectories following enzyme replacement therapy (ERT). Sibling 1 was diagnosed at 2 years of age, started undergoing conventional ERT shortly afterward, and scored a developmental quotient (DQ) of 53 on the Kyoto Scale of Psychological Development (KSPD) at 4 years of age. Sibling 2 was diagnosed prenatally and received conventional ERT from the age of 1 month through 1 year and 11 months, when he switched to pabinafusp alpha. He attained a DQ of 104 at age 3 years and 11 months, along with significant declines in heparan sulfate concentrations in the cerebrospinal fluid. This marked difference in neurocognitive development highlights the importance of early initiation of ERT with a BBB-penetrating enzyme in patients with neuropathic MPS-II.

DOI： 10.1002/jmd2.12239

PubMed

Publishing type：Research paper (scientific journal)   International / domestic magazine：International journal  

INTRODUCTION: Recently, many seriously ill children requiring medical equipment are being recommended to transition from hospital to home care in Japan. Since 2011, our recovery center has provided a support program for the transfer process from hospital to home for ill children and their families. The purpose of this study was to evaluate the factors related to high care burden after completing the discharge-support program. METHODS: A questionnaire-based cross-sectional study was conducted on all primary caregivers whose children received the program in our center and moved from hospital to home (30 children and 29 families) from May 2011 to May 2018. Fifteen children came from the neonatal intensive care unit. The questionnaire consisted of three parts: characteristics of children and families and life after the program; the Zarit Burden Interview (ZBI); and the Positive and Negative Affect Schedule (PANAS). RESULTS: Twenty-three primary caregivers responded (79% response rate). All children received tracheostomy and 71% received home mechanical ventilation. Primary caregivers were all mothers. High ZBI score was not related to the severity and type of medical equipment. There were relationships between high ZBI score and following factors: 'unimproved relationship between patients and family members without primary caregivers' and 'additional medical equipment after discharge'. The result of PANAS showed that positive attitude was not different between those with high and low ZBI scores. CONCLUSION: It is crucial to reach out to family members without a primary caregiver. Additional medical care/equipment after the program is related to the care burden of primary caregivers.

DOI： 10.1016/j.braindev.2021.06.003

PubMed

Publishing type：Research paper (scientific journal)  

Spinal muscular atrophy (SMA) is a genetic neuromuscular disorder that causes degeneration of anterior horn cells in the human spinal cord and subsequent loss of motor neurons. The severe form of SMA is among the genetic diseases with the highest infant mortality. Although SMA has been considered incurable, newly developed drugs-nusinersen and onasemnogene abeparvovec-improve the life prognoses and motor functions of affected infants. To maximize the efficacy of these drugs, treatments should be started at the pre-symptomatic stage of SMA. Thus, newborn screening for SMA is now strongly recommended. Herein, we provide some data based on our experience of SMA diagnosis by genetic testing in Japan. A total of 515 patients suspected of having SMA or another lower motor neuron disease were tested. Among these patients, 228 were diagnosed as having SMA with survival motor neuron 1 (SMN1) deletion. We analyzed the distribution of clinical subtypes and ages at genetic testing in the SMN1-deleted patients, and estimated the SMA incidence based on data from Osaka and Hyogo prefectures, Japan. Our data showed that confirmed diagnosis by genetic testing was notably delayed, and the estimated incidence was 1 in 30,000-40,000 live births, which seemed notably lower than in other countries. These findings suggest that many diagnosis-delayed or undiagnosed cases may be present in Japan. To prevent this, newborn screening programs for SMA (SMA-NBS) need to be implemented in all Japanese prefectures. In this article, we also introduce our pilot study for SMA-NBS in Osaka Prefecture.

DOI： 10.3390/ijns7030045

PubMed

Publishing type：Research paper (scientific journal)   International / domestic magazine：International journal  

Spinal muscular atrophy (SMA) is a genetic neuromuscular disorder that causes degeneration of anterior horn cells in the human spinal cord and subsequent loss of motor neurons. The severe form of SMA is among the genetic diseases with the highest infant mortality. Although SMA has been considered incurable, newly developed drugs-nusinersen and onasemnogene abeparvovec-improve the life prognoses and motor functions of affected infants. To maximize the efficacy of these drugs, treatments should be started at the pre-symptomatic stage of SMA. Thus, newborn screening for SMA is now strongly recommended. Herein, we provide some data based on our experience of SMA diagnosis by genetic testing in Japan. A total of 515 patients suspected of having SMA or another lower motor neuron disease were tested. Among these patients, 228 were diagnosed as having SMA with survival motor neuron 1 (SMN1) deletion. We analyzed the distribution of clinical subtypes and ages at genetic testing in the SMN1-deleted patients, and estimated the SMA incidence based on data from Osaka and Hyogo prefectures, Japan. Our data showed that confirmed diagnosis by genetic testing was notably delayed, and the estimated incidence was 1 in 30,000-40,000 live births, which seemed notably lower than in other countries. These findings suggest that many diagnosis-delayed or undiagnosed cases may be present in Japan. To prevent this, newborn screening programs for SMA (SMA-NBS) need to be implemented in all Japanese prefectures. In this article, we also introduce our pilot study for SMA-NBS in Osaka Prefecture.

DOI： 10.3390/ijns7030045

PubMed

症例は生後9ヵ月の女児。周産期に異常所見を認めず、1ヵ月健診まで体重増加は良好であった。3ヵ月健診時に体重増加不良を、6ヵ月時には頻脈、発疹を指摘されるも心雑音なく、食物アレルギーの疑いで小麦、牛乳の除去食を行っていた。9ヵ月時に体重増加不良が改善せず、胸部聴診異常を認め、精査目的に当院へ紹介となった。胸部CT検査にて左胸腔内に腸管の逸脱像を認め、横隔膜ヘルニアと診断した。待機的に胸腔鏡下横隔膜ヘルニア修復術が施行され、術後経過は問題なく、術後5日目に退院となった。手術後3年になるが、再発はなく体重増加も順調となり、問題なく経過している。先天性横隔膜ヘルニアは生後早期に発症する早発型と、生後30日以降に発症する遅発性先天性横隔膜ヘルニア(以下本症)に分類される。本症は先天性横隔膜ヘルニアの5%程度と稀であるのに加え、呼吸器症状や循環不全などの症状を呈さない症例が多く、診断には時間を要することが多いとされる。また、一般的に予後は良好であるが、急激に悪化し死に至った報告もあり、注意を要する疾患である。自験例では乳幼児健診での胸部聴診という一般的な身体診察の異常が診断の契機となった。症状が続く場合にはフォローをとぎらせず、慎重に身体所見を確認し、必要に応じて精査を行うことの重要性が再確認された。稀な疾患ではあるが鑑別すべき疾患の一つであると再認識されたため、文献的考察を加え報告する。(著者抄録)

Publishing type：Research paper (scientific journal)  

DOI： 10.1016/j.omtm.2021.02.018

PubMed

Publishing type：Research paper (scientific journal)   International / domestic magazine：International journal  

This open-label, phase 1/2 study (JMACCT CTR JMA-IIA00350) evaluated the efficacy and safety of intracerebroventricular idursulfase beta in patients with mucopolysaccharidosis II (MPS II). Herein, we report the 100-week results. Six patients with severe MPS II aged 23-65 months were enrolled. Idursulfase beta (increasing from 1 to 30 mg between weeks 0 and 24, followed by a 30-mg final dose) was administered intracerebroventricularly once every 4 weeks using an implanted cerebrospinal fluid (CSF) reservoir; intravenous administration of idursulfase was also continued throughout the study. Efficacy endpoints included developmental age by the Kyoto Scale of Psychological Development 2001 and heparan sulfate (HS) concentration in CSF (primary outcome). In all six patients, HS concentrations decreased (40%-80%) from baseline to week 100. For overall developmental age, the difference in change from baseline to week 100 in each patient compared with patients treated by intravenous idursulfase administration (n = 13) was +8.0, +14.5, +4.5, +3.7, +8.2, and -8.3 months (mean, +5.1 months). Idursulfase beta was well tolerated. The most common adverse events were pyrexia, upper respiratory tract infection, and vomiting. The results suggest that intracerebroventricular idursulfase beta is well tolerated and can be effective at preventing and stabilizing developmental decline in patients with neuronopathic MPS II.

DOI： 10.1016/j.omtm.2021.02.018

PubMed

Publishing type：Research paper (scientific journal)  

Publishing type：Research paper (scientific journal)  

キャップ依存性エンドヌクレアーゼであるbaloxavir marboxil(以下、baloxavir)とノイラミニダーゼ阻害薬の臨床効果を比較した報告は少ない。本研究では、2019〜2020年のインフルエンザ流行期における各種抗インフルエンザ薬投与後のインフルエンザ罹患患者の臨床経過を調査した。インフルエンザの迅速診断キットで陽性の診断を受けた患者に対して質問紙調査が送付され、有効回答の得られたインフルエンザ罹患患者252例(男性120例、女性132例、平均21.8歳)を解析対象とした。baloxavirは10歳未満の患者97例のうち3例(3.1%)に、10歳以上の患者155例のうち19例(12.3%)に投与された。抗インフルエンザ薬が投与された患者の発熱期間の中央値は2〜2.5日であり、oseltamivir(94例)、laninamivir(101例)、zanamivir(32例)またはbaloxavir(22例)の抗インフルエンザ薬の違いによる有意な差はなかった。249例中10例(4.0%)で2相性の発熱エピソードが生じたが、2相性の発熱エピソードの発症頻度と抗インフルエンザ薬の選択に有意な差はなかった。各有害事象の発生頻度にも4群間で差はなかった。以上の結果より、baloxavirの投与と早期発熱の緩和および2相性の発熱エピソードの発症頻度には有意な関連性がないことが示された。

Publishing type：Research paper (scientific journal)  

Publishing type：Research paper (scientific journal)   International / domestic magazine：International journal  

AIM: Patients who undergo the Fontan procedure for complex congenital heart disease are prone to liver cirrhosis. Liver stiffness (LS) reflects liver fibrosis stage in patients with chronic viral hepatitis; however, its accuracy in predicting liver fibrosis stage in Fontan patients is controversial. We aimed to clarify the correlation between LS and liver fibrosis stage in Fontan patients. METHODS: Fifty-eight Fontan patients were prospectively measured for LS with transient elastography. We undertook liver biopsy, cardiac catheterization, and laboratory tests in 22 of these patients (median age, 14.7 years; range, 9.9-32.1 years) with LS > 11.0 kPa (median, 19.2 kPa; range, 12.2-39.8 kPa); these elevated LS values suggest liver cirrhosis. RESULTS: Histologically, all patients showed mild-to-severe portal and sinusoidal fibrosis but no cirrhosis. Statistically, LS did not predict histological liver fibrosis scores (p = 0.175). Liver stiffness was not correlated with central venous pressure (p = 0.456) or with the hepatic venous pressure gradient (HVPG; p = 0.062), although the p value for HVPG was only slightly above the threshold for significance. CONCLUSIONS: Fontan patients are prone to developing both portal and sinusoidal fibrosis. Liver stiffness could be influenced by HVPG, and using the conventional cut-off values for LS overestimates and overtreats liver fibrosis in these patients.

DOI： 10.1111/hepr.13627

PubMed

フォンタン手術を受けた患者における肝硬度(LS)と肝線維化ステージとの相関を調べた。フォンタン手術を受けた患者58名に対し、transient elastographyを用いてLSを前向きに測定した。58名うち、LSが11.0kPa以上(中央値19.2kPa、範囲12.2〜39.8kPa)の22名(男性12名、女性10名、年齢9.9〜32.1歳)を対象に、肝生検、心カテーテル検査、臨床検査を行った。その結果、組織学的には、LSが11.0kPa以上であった22名全てが軽度から重度の門脈および類洞の線維化を示したが、肝硬変はなかった。統計的には、LSは組織学的な肝線維化スコアを予測しなかった。LSは中心静脈圧(p=0.456)や肝静脈圧較差(HVPG、p=0.062)とは相関しなかったが、HVPGのp値は有意性の閾値を僅かに上回った。これらの結果から、フォンタン手術を受けた患者は、門脈および類洞の線維化の両方を発症しやすいことが示された。LCはHVPGの影響を受ける可能性があり、従来のLSのカットオフ値を使用すると、これらの患者の肝線維化を過大評価し、治療し過ぎてしまう可能性があることが示唆された。

Publishing type：Research paper (scientific journal)   International / domestic magazine：International journal  

Phenylketonuria (PKU) and hyperphenylalaninemia (HPA), both identified in newborn screening, are attributable to variants in PAH. Reportedly, the p.R53H(c.158G>A) variant is common in patients with HPA in East Asia. Here, we aimed to define the association between p.R53H and HPA phenotype, and study the long-term outcome of patients with HPA carrying p.R53H. We retrospectively reviewed the genotype in 370 patients detected by newborn screening, and identified the phenotype in 280 (117, HPA; 163, PKU). p.R413P(c.1238G>C) was the most frequently found (n = 117, 31.6%) variant, followed by p.R53H (n = 89, 24.1%). The odds ratio for heterozygous p.R53H to cause HPA was 48.3 (95% CI 19.410-120.004). Furthermore, we assessed the non-linear association between the phenylalanine (Phe) value and elapsed time using the follow-up data of the blood Phe levels of 73 patients with HPA carrying p.R53H. The predicted levels peaked at 161.9 μmol (95% CI 152.088-172.343) at 50-60 months of age and did not exceed 360 μmol/L during the 210-month long observation period. The findings suggest that patients with HPA, carrying p.R53H, do not need frequent Phe monitoring as against those with PKU. Our study provides convincing evidence to determine clinical management of patients detected through newborn screening in Japan.

DOI： 10.3390/ijns7010017

PubMed

Publishing type：Research paper (scientific journal)  

DOI： 10.1111/hepr.13627

PubMed

Publishing type：Research paper (scientific journal)  

Phenylketonuria (PKU) and hyperphenylalaninemia (HPA), both identified in newborn screening, are attributable to variants in PAH. Reportedly, the p.R53H(c.158G>A) variant is common in patients with HPA in East Asia. Here, we aimed to define the association between p.R53H and HPA phenotype, and study the long-term outcome of patients with HPA carrying p.R53H. We retrospectively reviewed the genotype in 370 patients detected by newborn screening, and identified the phenotype in 280 (117, HPA; 163, PKU). p.R413P(c.1238G>C) was the most frequently found (n = 117, 31.6%) variant, followed by p.R53H (n = 89, 24.1%). The odds ratio for heterozygous p.R53H to cause HPA was 48.3 (95% CI 19.410-120.004). Furthermore, we assessed the non-linear association between the phenylalanine (Phe) value and elapsed time using the follow-up data of the blood Phe levels of 73 patients with HPA carrying p.R53H. The predicted levels peaked at 161.9 μmol (95% CI 152.088-172.343) at 50-60 months of age and did not exceed 360 μmol/L during the 210-month long observation period. The findings suggest that patients with HPA, carrying p.R53H, do not need frequent Phe monitoring as against those with PKU. Our study provides convincing evidence to determine clinical management of patients detected through newborn screening in Japan.

DOI： 10.3390/ijns7010017

PubMed

症例は11歳5ヵ月女児。9歳頃から成長率が低下していたが近医や学校をはじめ誰からも指摘されていなかった。11歳3ヵ月時より頭痛が出現、11歳4ヵ月時に右眼視力低下を自覚し、眼科で右眼水平下半盲を認めた。頭部MRIでトルコ鞍上部に3cm大の腫瘍性病変を認め、PRL高値のためプロラクチノーマの疑いで当院を紹介された。受診時に右眼視力が著しく低下しており緊急に経鼻内視鏡下腫瘍摘出術が施行され、組織診断によりプロラクチノーマと診断された。術後、PRL高値が残存したためドパミン作動薬による追加治療を開始した。術後にTSH・GH・LH・FSH分泌の回復は得られなかった。経過中に尿崩症の合併はなく、視機能障害は完全に回復した。早期に腫瘍の圧迫を解除すれば視機能は回復する可能性が高い。成長率低下や視機能低下を認めた場合は頭蓋内病変の迅速な精査を考慮すべきと考える。(著者抄録)

はじめに:新生児マススクリーニング(NBS)は発症前に発見して治療を開始し発症を予防することが目的である。高フェニルアラニン血症にはフェニルアラニン水酸化酵素欠損症と補酵素のテトラヒドロビオプテリン(BH4)欠損症があるが、BH4欠損症はフェニルケトン尿症(PKU)と異なり神経症状の発現が早く重篤なため、診断が付き次第すぐに治療を始める必要がある。最近10年間のNBSで発見された高フェニルアラニン血症の病型分類とその分布を、さらにBH4欠損症については1977年以前の症例についても診断時の血中フェニルアラニン(Phe)値を調査しカットオフ値について検討した。方法:最近10年間のNBSで精密検査の対象となった216人の病型分布を調査し、BH4欠損症では1977年以後に生まれた34人とそれ以前に出生していた11人について診断時の血中Phe値について調査した。結果:NBS時の血中Phe値が明らかであったBH4欠損症は日本人32人と中国人2人で、血中Phe値の最小値はそれぞれ360μmol/L(6.0mg/dL)と204μmol/L(3.4mg/dL)であった。またNBS前に出生したBH4欠損症の血中Phe値の最小値は175μmol/L(2.9mg/dL)であった。考察:BH4欠損症をできるだけ見逃さないようにするためにはNBSのカットオフ値はこれまで通り120μmol/L(2mg/dL)が勧められる。(著者抄録)

Publishing type：Research paper (scientific journal)  

OBJECTIVE: Patients who undergo Fontan surgery for complex cardiac anomalies are prone to developing liver and gastrointestinal complications. In particular, gastroesophageal varices (GEVs) can occur, but their prevalence is unknown. We aimed to elucidate the occurrence of GEVs and the predicting parameters of GEVs in these patients. MATERIALS AND METHODS: Twenty-seven patients (median age, 14.8 years; median time since surgery, 12.9 years) who had undergone the Fontan surgery and were examined by abdominal dynamic computed tomography (CT) for the routine follow-up were included in the study. Radiological findings including GEVs and extraintestinal complications were retrospectively evaluated by experienced radiologists in a blinded manner. Relationships between blood-biochemical and demographic parameters and the presence of GEVs were statistically analyzed. RESULTS: Dynamic CT revealed gastric varices (n = 3, 11.1%), esophageal varices (n = 1, 3.7%), and gastrorenal shunts (n = 5, 18.5%). All patients with gastric varices had gastrorenal shunts. All gastric varices were endoscopically confirmed as being isolated and enlarged, with indications for preventive interventional therapy. A platelet count lower than 119 × 109 /L was identified as a predictor of GEV (area under the receiver operating curve, 0.946; sensitivity, 100%; and specificity, 87%). CONCLUSIONS: GEVs are important complications that should not be ignored in patients who have undergone a Fontan procedure. Platelet counts lower than 119 × 109 /L may help to prompt patient screening by using abdominal dynamic CT to identify GEVs and their draining collateral veins in these patients.

DOI： 10.1371/journal.pone.0257441

PubMed

Publishing type：Research paper (scientific journal)   International / domestic magazine：International journal  

OBJECTIVE: Patients who undergo Fontan surgery for complex cardiac anomalies are prone to developing liver and gastrointestinal complications. In particular, gastroesophageal varices (GEVs) can occur, but their prevalence is unknown. We aimed to elucidate the occurrence of GEVs and the predicting parameters of GEVs in these patients. MATERIALS AND METHODS: Twenty-seven patients (median age, 14.8 years; median time since surgery, 12.9 years) who had undergone the Fontan surgery and were examined by abdominal dynamic computed tomography (CT) for the routine follow-up were included in the study. Radiological findings including GEVs and extraintestinal complications were retrospectively evaluated by experienced radiologists in a blinded manner. Relationships between blood-biochemical and demographic parameters and the presence of GEVs were statistically analyzed. RESULTS: Dynamic CT revealed gastric varices (n = 3, 11.1%), esophageal varices (n = 1, 3.7%), and gastrorenal shunts (n = 5, 18.5%). All patients with gastric varices had gastrorenal shunts. All gastric varices were endoscopically confirmed as being isolated and enlarged, with indications for preventive interventional therapy. A platelet count lower than 119 × 109 /L was identified as a predictor of GEV (area under the receiver operating curve, 0.946; sensitivity, 100%; and specificity, 87%). CONCLUSIONS: GEVs are important complications that should not be ignored in patients who have undergone a Fontan procedure. Platelet counts lower than 119 × 109 /L may help to prompt patient screening by using abdominal dynamic CT to identify GEVs and their draining collateral veins in these patients.

DOI： 10.1371/journal.pone.0257441

PubMed

Publishing type：Research paper (scientific journal)  

DOI： 10.1038/s41598-020-78930-x

PubMed

Publishing type：Research paper (scientific journal)   International / domestic magazine：International journal  

Ischemic brain injury provokes complex, time-dependent downstream pathways that ultimately lead to cell death. We aimed to demonstrate the levels of a wide range of metabolites in brain lysates and their on-tissue distribution following neonatal stroke and cell therapies. Postnatal day 12 mice underwent middle cerebral artery occlusion (MCAO) and were administered 1 × 105 cells after 48 h. Metabolomic analysis of the injured hemisphere demonstrated that a variety of amino acids were significantly increased and that tricarboxylic acid cycle intermediates and some related amino acids, such as glutamate, were decreased. With the exception of the changes in citric acid, neither mesenchymal stem/stromal cells nor CD34+ cells ameliorated these changes. On-tissue visualization with matrix-assisted laser desorption/ionization-mass spectrometry (MALDI-MS) imaging revealed that the signal intensity of glutamate was significantly decreased in the infarct area, consistent with the metabolomic analysis, while its intensity was significantly increased in the peri-infarct area after MCAO. Although cell therapies did not ameliorate the changes in metabolites in the infarct area, mesenchymal stem cells ameliorated the increased levels of glutamate and carnitine in the peri-infarct area. MALDI-MS imaging showed the location-specific effect of cell therapies even in this subacute setting after MCAO. These methodologies may be useful for further investigation of possible treatments for ischemic brain injury.

DOI： 10.1038/s41598-020-78930-x

PubMed

Publishing type：Research paper (scientific journal)  

我々は極低出生体重児SGAの1歳半時点の神経学的予後をAGAと比較検討した。当院NICUに2010年から2016年の間に入院した極低出生体重児76例(AGA26例、SGA50例)を対象とし、診療録を後方視的に検討した。修正1歳半時点の新版K式発達検査における発達指数(DQ)を全領域、姿勢・運動、認知・適応、言語・社会の各々で検討したところ、姿勢・運動のみSGA群が有意に低い結果となった(100.7 vs 90.5;p=0.037)。またAGA群は全例、全項目でDQ70以上であったが、SGA群は全項目においてDQ70未満を呈する症例を認めた。DQ85未満の割合は全領域、姿勢・運動においてSGA群の方が高い傾向にあった。また、多変量解析を行いDQ85未満に寄与する周産期因子について検討した結果、SGAが神経学的予後に影響を及ぼすことが示唆された。特に、在胎週数が30週未満のSGA群では出生体重-2.5SDを境界に発達に強く影響のある可能性が示唆された。(著者抄録)

我々は極低出生体重児SGAの1歳半時点の神経学的予後をAGAと比較検討した。当院NICUに2010年から2016年の間に入院した極低出生体重児76例(AGA26例、SGA50例)を対象とし、診療録を後方視的に検討した。修正1歳半時点の新版K式発達検査における発達指数(DQ)を全領域、姿勢・運動、認知・適応、言語・社会の各々で検討したところ、姿勢・運動のみSGA群が有意に低い結果となった(100.7 vs 90.5;p=0.037)。またAGA群は全例、全項目でDQ70以上であったが、SGA群は全項目においてDQ70未満を呈する症例を認めた。DQ85未満の割合は全領域、姿勢・運動においてSGA群の方が高い傾向にあった。また、多変量解析を行いDQ85未満に寄与する周産期因子について検討した結果、SGAが神経学的予後に影響を及ぼすことが示唆された。特に、在胎週数が30週未満のSGA群では出生体重-2.5SDを境界に発達に強く影響のある可能性が示唆された。(著者抄録)

Publishing type：Research paper (scientific journal)  

DOI： 10.1016/j.orcp.2020.08.005

PubMed

Publishing type：Research paper (scientific journal)  

DOI： 10.1016/j.ymgme.2020.07.007

PubMed

<p>Background: The relevance between sublingual immunotherapy (SLIT) with Japanese cedar pollen extract and pollen-food allergy syndrome (PFAS) to tomato has not been reported.</p><p>Patient: A 12-year-old boy with Japanese cedar pollinosis, asthma, and PFAS to apple, kiwi, and avocado. He was able to eat tomato without symptoms. After 1 month of SLIT with Japanese cedar pollen extract, he experienced throat itching and dyspnea immediately after eating two small tomatoes. Serum-specific IgE antibody levels to Japanese cedar pollen and tomato increased, and prick-to-prick test (PPT) with tomato changed from negative to positive after 5 months of SLIT. Oral food challenge (OFC) of tomato was positive immediately after taking one small tomato with throat itching. By contrast, he was able to eat cooked and processed tomatoes without symptoms. Therefore, we considered he developed PFAS to tomato and instructed him not to eat fresh tomatoes.</p><p>Conclusion: The first case report of PFAS to tomato during SLIT for Japanese cedar pollen allergy. Patients receiving SLIT with any pollen should be paid attention when taking cross-reactive foods.</p>

DOI： 10.3388/jspaci.34.334

CiNii Article

Publishing type：Research paper (scientific journal)  

【背景】スギ花粉舌下免疫療法(SLIT)導入後にトマトの花粉-食物アレルギー症候群(PFAS)を発症した報告はこれまで認めない。【症例】12歳男児。スギ花粉症と気管支喘息、リンゴ、キウイ、アボカドのPFASあり。トマトは無症状で摂取可能であった。スギ花粉症に対しSLIT開始1ヵ月後、ミニトマトを2個摂取した直後に咽頭そう痒感と呼吸苦を認めた。SLIT開始前と比べ5ヵ月後のスギ、トマト特異的IgE抗体価は共に上昇を認め、トマトのprick-to-prick testは陰性から陽性に変化した。SLIT開始5ヵ月後の食物経口負荷試験はミニトマト1個摂取直後に咽頭そう痒感を認めた。なおトマトの加熱加工品は症状なく摂取可能であった。以上からトマトのPFASを発症したと考え、生のトマトは除去するよう指導した。【結語】スギSLITによりトマトに対する感作が増強され、トマトのPFASを発症した可能性が考えられる。SLITを行う上で、対象となる花粉と交差反応性のある食物を摂取する際は注意が必要かもしれない。(著者抄録)

【背景】スギ花粉舌下免疫療法(SLIT)導入後にトマトの花粉-食物アレルギー症候群(PFAS)を発症した報告はこれまで認めない。【症例】12歳男児。スギ花粉症と気管支喘息、リンゴ、キウイ、アボカドのPFASあり。トマトは無症状で摂取可能であった。スギ花粉症に対しSLIT開始1ヵ月後、ミニトマトを2個摂取した直後に咽頭そう痒感と呼吸苦を認めた。SLIT開始前と比べ5ヵ月後のスギ、トマト特異的IgE抗体価は共に上昇を認め、トマトのprick-to-prick testは陰性から陽性に変化した。SLIT開始5ヵ月後の食物経口負荷試験はミニトマト1個摂取直後に咽頭そう痒感を認めた。なおトマトの加熱加工品は症状なく摂取可能であった。以上からトマトのPFASを発症したと考え、生のトマトは除去するよう指導した。【結語】スギSLITによりトマトに対する感作が増強され、トマトのPFASを発症した可能性が考えられる。SLITを行う上で、対象となる花粉と交差反応性のある食物を摂取する際は注意が必要かもしれない。(著者抄録)

Publishing type：Research paper (scientific journal)  

Small for gestational age(SGA)の成因は様々で半数程度が原因不明とされてきた。しかし近年の遺伝学的検査の進歩により、原因不明のSGAの原因が同定できることがある。今回、SGA性低身長症として成長ホルモン治療中に、サブテロメアfluorescence in situ hybridization(FISH)法において5番染色体短腕欠失と19番染色体長腕重複が判明した症例を経験した。5p-症候群としては典型症状に乏しく、17歳4ヵ月と年長で診断された。アレイcomparative genomic hybridization(CGH)解析で5pの欠失領域は狭く、さらに19q重複を合併していたことから、本症例の臨床像は説明されると考えられた。SGAという多彩な病態を含む状態に対し遺伝学的診断をつけることで、養育者に正しい知識や予後予測の情報提供ができる利点がある。(著者抄録)

Publishing type：Research paper (scientific journal)  

14歳10ヵ月の女子。母方叔父が潰瘍性大腸炎、母方いとこがCrohn病。両足関節の腫脹と両下腿の結節性紅斑が出現し、腹痛や下痢、体重増加不良はなかった。血液検査では白血球数10,400/μL、CRP5.12mg/dLと炎症所見がみられ、抗dsDNA抗体等の自己抗体は陰性を示し、ベーチェット病の鑑別目的に実施したHLA検査においてB*35、B*39が陽性であった。経過中、肛門周囲膿瘍がみられ、家族歴も含め炎症性腸疾患を疑い内視鏡検査を施行した。胃には竹の節状所見、小腸から大腸にはびらんを散在性に認めた。大腸の生検組織には非乾酪性類上皮細胞肉芽腫を認めCrohn病と診断した。関節症状は非ステロイド性消炎鎮痛薬により軽減が得られたが、弛張熱が持続するため経口5-ASA製剤・ステロイド製剤を併用し、アザチオプリンとインフリキシマブにより寛解導入した。HLA-B*35は1型末梢性関節炎を合併するCrohn病に、B*39は日本人におけるHLA-B*27陰性脊椎関節炎に陽性率が高いとされる。HLA所見と本症例の病態との関連について考察を加えた。(著者抄録)

Small for gestational age(SGA)の成因は様々で半数程度が原因不明とされてきた。しかし近年の遺伝学的検査の進歩により、原因不明のSGAの原因が同定できることがある。今回、SGA性低身長症として成長ホルモン治療中に、サブテロメアfluorescence in situ hybridization(FISH)法において5番染色体短腕欠失と19番染色体長腕重複が判明した症例を経験した。5p-症候群としては典型症状に乏しく、17歳4ヵ月と年長で診断された。アレイcomparative genomic hybridization(CGH)解析で5pの欠失領域は狭く、さらに19q重複を合併していたことから、本症例の臨床像は説明されると考えられた。SGAという多彩な病態を含む状態に対し遺伝学的診断をつけることで、養育者に正しい知識や予後予測の情報提供ができる利点がある。(著者抄録)

14歳10ヵ月の女子。母方叔父が潰瘍性大腸炎、母方いとこがCrohn病。両足関節の腫脹と両下腿の結節性紅斑が出現し、腹痛や下痢、体重増加不良はなかった。血液検査では白血球数10,400/μL、CRP5.12mg/dLと炎症所見がみられ、抗dsDNA抗体等の自己抗体は陰性を示し、ベーチェット病の鑑別目的に実施したHLA検査においてB*35、B*39が陽性であった。経過中、肛門周囲膿瘍がみられ、家族歴も含め炎症性腸疾患を疑い内視鏡検査を施行した。胃には竹の節状所見、小腸から大腸にはびらんを散在性に認めた。大腸の生検組織には非乾酪性類上皮細胞肉芽腫を認めCrohn病と診断した。関節症状は非ステロイド性消炎鎮痛薬により軽減が得られたが、弛張熱が持続するため経口5-ASA製剤・ステロイド製剤を併用し、アザチオプリンとインフリキシマブにより寛解導入した。HLA-B*35は1型末梢性関節炎を合併するCrohn病に、B*39は日本人におけるHLA-B*27陰性脊椎関節炎に陽性率が高いとされる。HLA所見と本症例の病態との関連について考察を加えた。(著者抄録)

Publishing type：Research paper (scientific journal)  

DOI： 10.1038/s41598-020-61311-9

PubMed

Publishing type：Research paper (scientific journal)   International / domestic magazine：International journal  

Neonatal hypoxic-ischaemic encephalopathy (HIE) is a serious condition; many survivors develop neurological impairments, including cerebral palsy and intellectual disability. Preclinical studies show that the systemic administration of umbilical cord blood cells (UCBCs) is beneficial for neonatal HIE. We conducted a single-arm clinical study to examine the feasibility and safety of intravenous infusion of autologous UCBCs for newborns with HIE. When a neonate was born with severe asphyxia, the UCB was collected, volume-reduced, and divided into three doses. The processed UCB was infused at 12-24, 36-48, and 60-72 hours after the birth. The designed enrolment was six newborns. All six newborns received UCBC therapy strictly adhering to the study protocol together with therapeutic hypothermia. The physiological parameters and peripheral blood parameters did not change much between pre- and postinfusion. There were no serious adverse events that might be related to cell therapy. At 30 days of age, the six infants survived without circulatory or respiratory support. At 18 months of age, neurofunctional development was normal without any impairment in four infants and delayed with cerebral palsy in two infants. This pilot study shows that autologous UCBC therapy is feasible and safe.

DOI： 10.1038/s41598-020-61311-9

PubMed

Publishing type：Research paper (scientific journal)  

DOI： 10.1007/s10157-019-01810-w

PubMed

Publishing type：Research paper (scientific journal)  

Publishing type：Research paper (scientific journal)  

Publishing type：Research paper (scientific journal)  

症例は13歳女児。体重減少と血便を契機に小腸・大腸型Crohn病と診断された。メサラジン内服、成分栄養剤による栄養療法、ステロイド坐薬による治療を開始し、症状の改善が得られた。しかし、治療開始12日目から下血・腹痛がみられ、血液所見は白血球数21,200/μL、CRP 5.7mg/dLと炎症反応の上昇を示したため、Crohn病の急性増悪、細菌性腸炎あるいはメサラジン不耐症を疑い、メサラジンの投薬中止ならびにステロイド静注と抗菌薬内服を開始し、症状と血液検査所見の速やかな改善が得られた。便中に有意な病原微生物や毒素は検出されず、メサラジン不耐症は疑われたものの、メサラジンが寛解導入・維持療法のキードラッグであるため、治療開始24日目にメサラジンの投薬を再開したところ、12時間後に発熱および白血球数の上昇(48,500/μL)を認め、メサラジンの内服を再度中止した。また、メサラジン製剤に対する薬剤誘発性リンパ球刺激試験(DLST)が陽性であることも判明し、メサラジン不耐症と診断した。以後、メサラジンは使用せず、寛解導入ならびに維持療法を行っている。メサラジン投薬中、比較的早期に血便や腹痛、発熱がみられ症状が急性である場合には、メサラジン不耐症を積極的に疑い薬剤中止および薬剤誘発性リンパ球刺激試験による精査を行う必要があると考えられた。(著者抄録)

Publishing type：Research paper (scientific journal)  

DOI： 10.1016/j.ymgme.2019.11.310

Publishing type：Research paper (scientific journal)   International / domestic magazine：Domestic journal  

BACKGROUND: Fabry disease is a progressive X-linked lysosomal disorder. In this subgroup analysis of the global phase III ATTRACT study, the efficacy and safety of oral migalastat, a pharmacologic chaperone, were investigated in Japanese patients with Fabry disease. METHODS: Patients were randomly assigned to receive migalastat (150 mg every other day) or to continue biweekly enzyme replacement therapy infusions (ERT; agalsidase alfa 0.2 mg/kg or agalsidase beta 1.0 mg/kg) for 18 months followed by a 12-month open-label extension during which all patients received migalastat. End points included glomerular filtration rate (estimated and measured), left ventricular mass index (LVMi), composite clinical outcomes, leukocyte alpha-galactosidase A activity, plasma globotriaosylsphingosine (lyso-Gb3), and safety. RESULTS: Data from 7 Japanese patients (migalastat, 5; ERT, 2), mean age 55 years, with high disease burden, were analyzed. All patients in the migalastat group completed the open-label comparison and extension periods. At 18 months, efficacy in the Japanese patient population was similar to that in the overall ATTRACT population. Migalastat treatment increased leukocyte alpha-galactosidase A activity, stabilized renal function, and decreased LVMi. Plasma lyso-Gb3 levels remained low and stable. Additionally, the long-term extension study showed that efficacy of migalastat was maintained for up to 48 months. Migalastat was safe and well tolerated in the Japanese patients, as in the overall ATTRACT population. CONCLUSION: Migalastat can be used to treat Japanese patients with Fabry disease with GLA mutations amenable to migalastat according to the dosage and administration approved in other countries. TRIAL REGISTRATION NUMBERS: ClinicalTrials.gov, NCT01218659 and NCT02194985.

DOI： 10.1007/s10157-019-01810-w

PubMed

ATTRACT研究のサブグループ解析として、日本人Fabry病患者を対象に経口ミガラスタット(M)の有効性と安全性を調査した。患者を、M投与群(150mg隔日投与)またはこれまでの酵素補充療法(ERT)を継続する群(アガルシダーゼアルファ0.2mg/kgまたはアガルシダーゼベータ1.0mg/kg隔週投与)に無作為に割り付けて18ヵ月間治療した後、全例に12ヵ月間に亘りM(150mg隔日)を投与した。糸球体濾過量、左室重量係数(LVMi)、白血球アルファ-ガラクトシダーゼA活性、血漿グロボトリアオシルスフィンゴシン(lyso-Gb3)と安全性を評価した。7例のうち5例(男性3例、女性2例、平均51.8±4.8歳)をM群、2例をERT継続群とした。M群の5例全例が30ヵ月の研究期間を完了した。日本人集団の18ヵ月時点の有効性はATTRACT集団全体と同様であった。Mによって白血球アルファ-ガラクトシダーゼA活性が増加し、腎機能が安定化し、LVMiが減少した。血漿lyso-Gb3値は低く安定した状態を継続した。Mの有効性は48ヵ月間継続した。Mは日本人患者では安全で忍容性が良好であった。

症例は13歳女児。体重減少と血便を契機に小腸・大腸型Crohn病と診断された。メサラジン内服、成分栄養剤による栄養療法、ステロイド坐薬による治療を開始し、症状の改善が得られた。しかし、治療開始12日目から下血・腹痛がみられ、血液所見は白血球数21,200/μL、CRP 5.7mg/dLと炎症反応の上昇を示したため、Crohn病の急性増悪、細菌性腸炎あるいはメサラジン不耐症を疑い、メサラジンの投薬中止ならびにステロイド静注と抗菌薬内服を開始し、症状と血液検査所見の速やかな改善が得られた。便中に有意な病原微生物や毒素は検出されず、メサラジン不耐症は疑われたものの、メサラジンが寛解導入・維持療法のキードラッグであるため、治療開始24日目にメサラジンの投薬を再開したところ、12時間後に発熱および白血球数の上昇(48,500/μL)を認め、メサラジンの内服を再度中止した。また、メサラジン製剤に対する薬剤誘発性リンパ球刺激試験(DLST)が陽性であることも判明し、メサラジン不耐症と診断した。以後、メサラジンは使用せず、寛解導入ならびに維持療法を行っている。メサラジン投薬中、比較的早期に血便や腹痛、発熱がみられ症状が急性である場合には、メサラジン不耐症を積極的に疑い薬剤中止および薬剤誘発性リンパ球刺激試験による精査を行う必要があると考えられた。(著者抄録)

症例は13歳女児。体重減少と血便を契機に小腸・大腸型Crohn病と診断された。メサラジン内服、成分栄養剤による栄養療法、ステロイド坐薬による治療を開始し、症状の改善が得られた。しかし、治療開始12日目から下血・腹痛がみられ、血液所見は白血球数21,200/μL、CRP 5.7mg/dLと炎症反応の上昇を示したため、Crohn病の急性増悪、細菌性腸炎あるいはメサラジン不耐症を疑い、メサラジンの投薬中止ならびにステロイド静注と抗菌薬内服を開始し、症状と血液検査所見の速やかな改善が得られた。便中に有意な病原微生物や毒素は検出されず、メサラジン不耐症は疑われたものの、メサラジンが寛解導入・維持療法のキードラッグであるため、治療開始24日目にメサラジンの投薬を再開したところ、12時間後に発熱および白血球数の上昇(48,500/μL)を認め、メサラジンの内服を再度中止した。また、メサラジン製剤に対する薬剤誘発性リンパ球刺激試験(DLST)が陽性であることも判明し、メサラジン不耐症と診断した。以後、メサラジンは使用せず、寛解導入ならびに維持療法を行っている。メサラジン投薬中、比較的早期に血便や腹痛、発熱がみられ症状が急性である場合には、メサラジン不耐症を積極的に疑い薬剤中止および薬剤誘発性リンパ球刺激試験による精査を行う必要があると考えられた。(著者抄録)

Publishing type：Research paper (scientific journal)  

DOI： 10.1016/j.ymgme.2019.11.310

Publishing type：Research paper (scientific journal)  

DOI： 10.1002/jgf2.286

PubMed

Publishing type：Research paper (scientific journal)  

慢性便秘症による大きな硬い便塊を伴う梗塞栓に対して、従来の経口・経直腸薬物療法が奏効しない場合、コンセンサスの得られた便塊除去療法はない。今回我々は、ガストログラフィン注腸による便塊除去(disimpaction)を施行した2例を経験したので報告する。症例は8歳3ヵ月および6歳1ヵ月の女児。当院受診までの便秘による病悩期間はそれぞれ1年4ヵ月と1年であった。基礎疾患を示唆する徴候(red flags)はなく、2例とも漏便があり、腹部触診で便塊を触知し、便塞栓(fecal impaction)があると判断した。生活指導と経口下剤薬やグリセリン浣腸液による治療効果が得られず、積極的な便塊除去が必要と判断し、鎮静下でガストログラフィンの注腸を行った。処置後、1例は24時間以内に便塊の除去が確認され、もう1例は24時間後に再度ガストログラフィンの注腸を施行し、48時間以内に便塊の除去を認めた。2例とも同注腸による合併症はなかった。便塊除去後は2例とも生活指導と経口薬物治療によって、排便コントロールが得られている。大きな硬い便塊を伴う便塞栓に対して従来の経口・経直腸薬物療法による効果が得られない例では、ガストログラフィン注腸療法は治療の選択肢として考えられる。(著者抄録)

Publishing type：Research paper (scientific journal)   International / domestic magazine：Domestic journal  

Background: After the A/H1N1 influenza pandemic in 2009, two new drugs against influenza, namely laninamivir and peramivir, were released in 2010 in Japan. We investigated prescription trends of four neuraminidase inhibitors (NAIs), which are laninamivir, peramivir, oseltamivir, and zanamivir, and assessed clinical data related to influenza for 8 years. Methods: Patients living in Osaka Prefecture and diagnosed with influenza responded to a postcard questionnaire that collected data regarding their demographic characteristics, symptoms including fever, prescribed drugs, and influenza type. Results: Laninamivir was most prescribed to patients aged ≥ 10 years, and oseltamivir was most prescribed to patients aged < 10 years. All four NAIs had similar effects on influenza. Patients with type A influenza experienced fever alleviation earlier than those with type B influenza. Older patients tended to have lower fever. Most seasons had similar results. Conclusions: Our descriptive epidemiologic study revealed the status of patients with influenza and their medication use.

DOI： 10.1002/jgf2.286

PubMed

慢性便秘症による大きな硬い便塊を伴う梗塞栓に対して、従来の経口・経直腸薬物療法が奏効しない場合、コンセンサスの得られた便塊除去療法はない。今回我々は、ガストログラフィン注腸による便塊除去(disimpaction)を施行した2例を経験したので報告する。症例は8歳3ヵ月および6歳1ヵ月の女児。当院受診までの便秘による病悩期間はそれぞれ1年4ヵ月と1年であった。基礎疾患を示唆する徴候(red flags)はなく、2例とも漏便があり、腹部触診で便塊を触知し、便塞栓(fecal impaction)があると判断した。生活指導と経口下剤薬やグリセリン浣腸液による治療効果が得られず、積極的な便塊除去が必要と判断し、鎮静下でガストログラフィンの注腸を行った。処置後、1例は24時間以内に便塊の除去が確認され、もう1例は24時間後に再度ガストログラフィンの注腸を施行し、48時間以内に便塊の除去を認めた。2例とも同注腸による合併症はなかった。便塊除去後は2例とも生活指導と経口薬物治療によって、排便コントロールが得られている。大きな硬い便塊を伴う便塞栓に対して従来の経口・経直腸薬物療法による効果が得られない例では、ガストログラフィン注腸療法は治療の選択肢として考えられる。(著者抄録)

慢性便秘症による大きな硬い便塊を伴う梗塞栓に対して、従来の経口・経直腸薬物療法が奏効しない場合、コンセンサスの得られた便塊除去療法はない。今回我々は、ガストログラフィン注腸による便塊除去(disimpaction)を施行した2例を経験したので報告する。症例は8歳3ヵ月および6歳1ヵ月の女児。当院受診までの便秘による病悩期間はそれぞれ1年4ヵ月と1年であった。基礎疾患を示唆する徴候(red flags)はなく、2例とも漏便があり、腹部触診で便塊を触知し、便塞栓(fecal impaction)があると判断した。生活指導と経口下剤薬やグリセリン浣腸液による治療効果が得られず、積極的な便塊除去が必要と判断し、鎮静下でガストログラフィンの注腸を行った。処置後、1例は24時間以内に便塊の除去が確認され、もう1例は24時間後に再度ガストログラフィンの注腸を施行し、48時間以内に便塊の除去を認めた。2例とも同注腸による合併症はなかった。便塊除去後は2例とも生活指導と経口薬物治療によって、排便コントロールが得られている。大きな硬い便塊を伴う便塞栓に対して従来の経口・経直腸薬物療法による効果が得られない例では、ガストログラフィン注腸療法は治療の選択肢として考えられる。(著者抄録)

ノイラミニダーゼ阻害剤(NAI)であるラニナミビル、ペラミビル、オセルタミビル、ザナミビルの処方傾向を8年にわたって調べ、インフルエンザに関連する臨床データを評価した。インフルエンザと診断された患者に対しアンケート調査を依頼し、人口統計学的特徴、発熱などの症状、処方薬、インフルエンザの種類に関するデータを収集した。その結果、ラニナミビルは10歳以上の患者に最も処方され、オセルタミビルは10歳未満の患者に最も処方されていた。4種類のNAIはいずれもインフルエンザに対して同様の効果を示した。A型インフルエンザの患者はB型インフルエンザの患者よりも早く熱が下がった。高齢患者は発熱時の体温が低い傾向があった。ほとんどの季節で同様の結果となった。

Publishing type：Research paper (scientific journal)  

DOI： 10.1016/j.orcp.2020.08.005

PubMed

Publishing type：Research paper (scientific journal)  

<p>Background: The relevance between sublingual immunotherapy (SLIT) with Japanese cedar pollen extract and pollen-food allergy syndrome (PFAS) to tomato has not been reported.</p><p>Patient: A 12-year-old boy with Japanese cedar pollinosis, asthma, and PFAS to apple, kiwi, and avocado. He was able to eat tomato without symptoms. After 1 month of SLIT with Japanese cedar pollen extract, he experienced throat itching and dyspnea immediately after eating two small tomatoes. Serum-specific IgE antibody levels to Japanese cedar pollen and tomato increased, and prick-to-prick test (PPT) with tomato changed from negative to positive after 5 months of SLIT. Oral food challenge (OFC) of tomato was positive immediately after taking one small tomato with throat itching. By contrast, he was able to eat cooked and processed tomatoes without symptoms. Therefore, we considered he developed PFAS to tomato and instructed him not to eat fresh tomatoes.</p><p>Conclusion: The first case report of PFAS to tomato during SLIT for Japanese cedar pollen allergy. Patients receiving SLIT with any pollen should be paid attention when taking cross-reactive foods.</p>

DOI： 10.3388/jspaci.34.334

CiNii Article

Publishing type：Research paper (scientific journal)  

DOI： 10.1016/j.ymgme.2020.07.007

PubMed

Publishing type：Research paper (scientific journal)  

DOI： 10.3390/ijms20235829

PubMed

Publishing type：Research paper (scientific journal)  

軽症高フェニルアラニン血症(HPA)は通常無症状であり、ガスリー法からタンデムマス法への移行後、新生児マススクリーニングでの発見頻度上昇が推測される。テトラヒドロビオプテリン(BH4)欠損症を除外してフェニルアラニン水酸化酵素(PAH)欠損症と診断したのちは、治療を要するレベルのフェニルアラニン高値を呈することがないか、慎重に経過観察を行う必要がある。今回、感染症罹患を契機に血中フェニルアラニン値が14.6mg/dLまで上昇したHPA症例を経験した。BH4・1週間投与試験を行った。実施時のPhe値が低く判断は難しかったが、1歳5ヵ月時よりBH4療法を導入した。遺伝子診断ではフェニルケトン尿症古典型症例で報告のあるPAH遺伝子変異を片アレルに同定した。3歳5ヵ月時の発達検査に異常は認めていない。一過性の血中フェニルアラニン上昇であっても中枢神経系の発達への悪影響は否定できず、治療導入をためらうべきではないと考える。(著者抄録)

Publishing type：Research paper (scientific journal)  

軽症高フェニルアラニン血症(HPA)は通常無症状であり、ガスリー法からタンデムマス法への移行後、新生児マススクリーニングでの発見頻度上昇が推測される。テトラヒドロビオプテリン(BH4)欠損症を除外してフェニルアラニン水酸化酵素(PAH)欠損症と診断したのちは、治療を要するレベルのフェニルアラニン高値を呈することがないか、慎重に経過観察を行う必要がある。今回、感染症罹患を契機に血中フェニルアラニン値が14.6mg/dLまで上昇したHPA症例を経験した。BH4・1週間投与試験を行った。実施時のPhe値が低く判断は難しかったが、1歳5ヵ月時よりBH4療法を導入した。遺伝子診断ではフェニルケトン尿症古典型症例で報告のあるPAH遺伝子変異を片アレルに同定した。3歳5ヵ月時の発達検査に異常は認めていない。一過性の血中フェニルアラニン上昇であっても中枢神経系の発達への悪影響は否定できず、治療導入をためらうべきではないと考える。(著者抄録)

軽症高フェニルアラニン血症(HPA)は通常無症状であり、ガスリー法からタンデムマス法への移行後、新生児マススクリーニングでの発見頻度上昇が推測される。テトラヒドロビオプテリン(BH4)欠損症を除外してフェニルアラニン水酸化酵素(PAH)欠損症と診断したのちは、治療を要するレベルのフェニルアラニン高値を呈することがないか、慎重に経過観察を行う必要がある。今回、感染症罹患を契機に血中フェニルアラニン値が14.6mg/dLまで上昇したHPA症例を経験した。BH4・1週間投与試験を行った。実施時のPhe値が低く判断は難しかったが、1歳5ヵ月時よりBH4療法を導入した。遺伝子診断ではフェニルケトン尿症古典型症例で報告のあるPAH遺伝子変異を片アレルに同定した。3歳5ヵ月時の発達検査に異常は認めていない。一過性の血中フェニルアラニン上昇であっても中枢神経系の発達への悪影響は否定できず、治療導入をためらうべきではないと考える。(著者抄録)

Publishing type：Research paper (scientific journal)   International / domestic magazine：International journal  

Mucopolysaccharidosis type II (MPS II) is a rare lysosomal storage disease (LSD) involving a genetic error in iduronic acid-2-sulfatase (IDS) metabolism that leads to accumulation of glycosaminoglycans within intracellular lysosomes. The primary treatment for MPS II, enzyme replacement therapy, is not effective for central nervous system (CNS) symptoms, such as intellectual disability, because the drugs do not cross the blood-brain barrier. Recently, autophagy has been associated with LSDs. In this study, we examined the morphologic relationship between neuronal damage and autophagy in IDS knockout mice using antibodies against subunit c of mitochondrial adenosine triphosphate (ATP) synthetase and p62. Immunohistological changes suggesting autophagy, such as vacuolation, were observed in neurons, microglia, and pericytes throughout the CNS, and the numbers increased over postnatal development. Oral administration of chloroquine, which inhibits autophagy, did not suppress damage to microglia and pericytes, but greatly reduced neuronal vacuolation and eliminated neuronal cells with abnormal inclusions. Thus, decreasing autophagy appears to prevent neuronal degeneration. These results suggest that an autophagy modulator could be used in addition to conventional enzyme replacement therapy to preserve the CNS in patients with MPS II.

DOI： 10.3390/ijms20235829

PubMed

Publishing type：Research paper (scientific journal)  

DOI： 10.1016/j.jri.2019.102614

PubMed

Publishing type：Research paper (scientific journal)  

症例は13歳3ヵ月の女児。10歳1ヵ月時から乳汁漏出が出現したが、本人と家族が病的と考えず、受診に至らなかった。11歳時に月経発来し周期は正常だった。乳汁漏出は持続し、乳汁量が増加したため13歳3ヵ月で初診となった。血中プロラクチン高値、頭部造影MRIで下垂体に径6mmの腫瘤を認め、プロラクチノーマと診断した。ほかの下垂体ホルモン分泌に異常を認めなかった。カベルゴリンで加療開始し、プロラクチン値は正常化、画像上も腫瘍は消失した。一般に、女性ではプロラクチノーマは無月経が診断契機となることが多い。しかし本症例のように乳汁漏出症のみが持続し、月経異常が目立たないプロラクチノーマがあることにも注意が必要である。(著者抄録)

Publishing type：Research paper (scientific journal)   International / domestic magazine：International journal  

Toll-like receptors (TLRs) are important components of the innate immune system, but how neonatal TLR-mediated immune responses differ from those of adults is unknown. We aimed to clarify the TLR-mediated expression profiles of cell surface antigens related to antigen presentation in neonates. CD14-positive monocytes were isolated from human cord blood and adult peripheral blood and then stimulated with lipopolysaccharide (LPS; TLR4 agonist) or zymosan (TLR2/6 agonist) or left unstimulated. Expression levels of the surface antigens major histocompatibility (MHC)-class II, CD80, CD86, CD11b, CD11c, CD14, and CD16 were then evaluated by flow cytometry. Cord blood CD14+CD16high monocytes (CBM) showed significantly lower basal levels of MHC-class II, CD80, and CD11b than adult blood CD14+CD16intermediate monocytes (ABM) (P < 0.01, P < 0.001, P < 0.001, respectively). LPS stimulation enhanced expression of MHC class II, CD80, and CD11b significantly more in CBM than in ABM (P < 0.001, P < 0.01, P < 0.01, respectively), resulting in levels that did not differ between CBM and ABM. Zymosan stimulation also enhanced expression of MHC class II, CD86, CD11b, and CD11c significantly more in CBM than in ABM (P < 0.001, P < 0.01, P < 0.001, P < 0.01, respectively), resulting in levels of CD86 and CD11c that did not differ in CBM and ABM. However, MHC class II, CD80, and CD11b remained significantly higher in ABM than in CBM (P < 0.05, P < 0.01, P < 0.05, respectively). These data indicate that CBM and ABM have distinct phenotypes and responses to stimulation.

DOI： 10.1016/j.jri.2019.102614

PubMed

症例は13歳3ヵ月の女児。10歳1ヵ月時から乳汁漏出が出現したが、本人と家族が病的と考えず、受診に至らなかった。11歳時に月経発来し周期は正常だった。乳汁漏出は持続し、乳汁量が増加したため13歳3ヵ月で初診となった。血中プロラクチン高値、頭部造影MRIで下垂体に径6mmの腫瘤を認め、プロラクチノーマと診断した。ほかの下垂体ホルモン分泌に異常を認めなかった。カベルゴリンで加療開始し、プロラクチン値は正常化、画像上も腫瘍は消失した。一般に、女性ではプロラクチノーマは無月経が診断契機となることが多い。しかし本症例のように乳汁漏出症のみが持続し、月経異常が目立たないプロラクチノーマがあることにも注意が必要である。(著者抄録)

症例は13歳3ヵ月の女児。10歳1ヵ月時から乳汁漏出が出現したが、本人と家族が病的と考えず、受診に至らなかった。11歳時に月経発来し周期は正常だった。乳汁漏出は持続し、乳汁量が増加したため13歳3ヵ月で初診となった。血中プロラクチン高値、頭部造影MRIで下垂体に径6mmの腫瘤を認め、プロラクチノーマと診断した。ほかの下垂体ホルモン分泌に異常を認めなかった。カベルゴリンで加療開始し、プロラクチン値は正常化、画像上も腫瘍は消失した。一般に、女性ではプロラクチノーマは無月経が診断契機となることが多い。しかし本症例のように乳汁漏出症のみが持続し、月経異常が目立たないプロラクチノーマがあることにも注意が必要である。(著者抄録)

Publishing type：Research paper (scientific journal)  

DOI： 10.1038/s41439-019-0079-1

PubMed

Publishing type：Research paper (scientific journal)  

Publishing type：Research paper (scientific journal)  

神経合併症を中心に、当院小児科の神経線維腫症1型(NF1)患者の疾患の臨床的特徴と、その遺伝子型を調べた。81名(男児39名、女児42名、年齢中央値10.3歳)の電子カルテからデータを抽出し、家族歴とNF1の特徴的な身体的所見を調べ、症状と脳・脊椎のMRIのデータを解析した。中等度から重篤な神経合併症のある6名の患者のNF1遺伝子解析を行った。45名を明確なNF1患者に、24名をNF1疑い患者に分類した。56名に神経合併症を認め、12名は視神経膠腫、毛様細胞性星細胞腫、神経鞘腫または叢状神経線維腫であった。遺伝子分析を行った6名の患者では、NF1の病原性変異が見つかり、1名では変異は確定できなかった。新しい変異が3家族の4名の患者で見つかった。NF1患者ではMRIと遺伝子分析を行うべきであり、中等度から重症の神経合併症については特にその必要があると考えられた。

日本人の1型糖尿病患者におけるインスリン(I)投与量の年齢による変更について検討した。Iポンプを使用している45歳以下の1型糖尿病患者35名を対象に、体重あたりの1日の総I量、1日の総I量当たりの1日基礎I量、1時間ごとの基礎I率、炭水化物/I比(CIR)、および補正率を求めた。また、300ルール(CIR=300/1日の総I量)または1800ルール(補正率=1800/1日の総I量)により算出した数値を用いて、CIRや補正率も比較した。就学前、青年期前、青年期、成人に分けて比較した。その結果、I量の設定には年齢特異的な傾向があり、最も顕著な例として、就学前の児童では300ルールで算出されたCIRより低くし、1800ルールで算出された補正率より高くする必要があることが分かった。以上より、日本人1型糖尿病患者へのIの投与量設定において、既存のルールは就学前児童の一部には適用できないこと、I量の設定は個人ごとの血糖値に合わせて個別に設定することが重要であると考えられた。

Publishing type：Research paper (scientific journal)  

Publishing type：Research paper (scientific journal)  

Publishing type：Research paper (scientific journal)  

家族性血球貪食症候群(familial hemophagocytic lymphohistiocytosis:FHL)は、無治療では生存期間中央値はわずか2ヵ月であり、唯一の根治療法として造血幹細胞移植が必要なことから、早期の診断を要する。しかし、稀な原発性免疫不全症であり、特に新生児期には診断に苦慮することも多い。今回我々が経験した症例は、胎児期に胎児水腫と腹水を指摘されていた。日齢1の腹部MRIで肝への鉄沈着を示唆する所見を認め、骨髄生検や胎盤病理で貪食像の確認が困難であったため、新生児ヘモクロマトーシス(neonatal hemochromatosis:NH)との鑑別に難渋したが、肝生検の結果、鉄沈着はごくわずかで、貪食像を認めたことから血球貪食症候群(hemophagocytic lymphohistiocytosis:HLH)が疑われた。後日の血小板染色や遺伝子検査でFHL3と診断した。本症例の経験から、FHLを含めたHLHとNHとの鑑別に肝生検が有用な可能性が示唆された。(著者抄録)

Publishing type：Research paper (scientific journal)  

家族性血球貪食症候群(familial hemophagocytic lymphohistiocytosis:FHL)は、無治療では生存期間中央値はわずか2ヵ月であり、唯一の根治療法として造血幹細胞移植が必要なことから、早期の診断を要する。しかし、稀な原発性免疫不全症であり、特に新生児期には診断に苦慮することも多い。今回我々が経験した症例は、胎児期に胎児水腫と腹水を指摘されていた。日齢1の腹部MRIで肝への鉄沈着を示唆する所見を認め、骨髄生検や胎盤病理で貪食像の確認が困難であったため、新生児ヘモクロマトーシス(neonatal hemochromatosis:NH)との鑑別に難渋したが、肝生検の結果、鉄沈着はごくわずかで、貪食像を認めたことから血球貪食症候群(hemophagocytic lymphohistiocytosis:HLH)が疑われた。後日の血小板染色や遺伝子検査でFHL3と診断した。本症例の経験から、FHLを含めたHLHとNHとの鑑別に肝生検が有用な可能性が示唆された。(著者抄録)

CiNii Article

家族性血球貪食症候群(familial hemophagocytic lymphohistiocytosis:FHL)は、無治療では生存期間中央値はわずか2ヵ月であり、唯一の根治療法として造血幹細胞移植が必要なことから、早期の診断を要する。しかし、稀な原発性免疫不全症であり、特に新生児期には診断に苦慮することも多い。今回我々が経験した症例は、胎児期に胎児水腫と腹水を指摘されていた。日齢1の腹部MRIで肝への鉄沈着を示唆する所見を認め、骨髄生検や胎盤病理で貪食像の確認が困難であったため、新生児ヘモクロマトーシス(neonatal hemochromatosis:NH)との鑑別に難渋したが、肝生検の結果、鉄沈着はごくわずかで、貪食像を認めたことから血球貪食症候群(hemophagocytic lymphohistiocytosis:HLH)が疑われた。後日の血小板染色や遺伝子検査でFHL3と診断した。本症例の経験から、FHLを含めたHLHとNHとの鑑別に肝生検が有用な可能性が示唆された。(著者抄録)

CiNii Article

家族性血球貪食症候群(familial hemophagocytic lymphohistiocytosis:FHL)は、無治療では生存期間中央値はわずか2ヵ月であり、唯一の根治療法として造血幹細胞移植が必要なことから、早期の診断を要する。しかし、稀な原発性免疫不全症であり、特に新生児期には診断に苦慮することも多い。今回我々が経験した症例は、胎児期に胎児水腫と腹水を指摘されていた。日齢1の腹部MRIで肝への鉄沈着を示唆する所見を認め、骨髄生検や胎盤病理で貪食像の確認が困難であったため、新生児ヘモクロマトーシス(neonatal hemochromatosis:NH)との鑑別に難渋したが、肝生検の結果、鉄沈着はごくわずかで、貪食像を認めたことから血球貪食症候群(hemophagocytic lymphohistiocytosis:HLH)が疑われた。後日の血小板染色や遺伝子検査でFHL3と診断した。本症例の経験から、FHLを含めたHLHとNHとの鑑別に肝生検が有用な可能性が示唆された。(著者抄録)

Publishing type：Research paper (scientific journal)  

DOI： 10.1016/j.ymgme.2018.12.120

Publishing type：Research paper (scientific journal)  

DOI： 10.1016/j.ymgme.2018.12.120

Publishing type：Research paper (scientific journal)  

<p><i>Background:</i> Pteridines are metabolites of tetrahydrobiopterin, which serves as co-enzyme of nitric oxide synthase. We sought to investigate the usefulness of pteridines as biomarkers for childhood asthma control.</p><p><i>Methods:</i> We conducted a single-center prospective cohort study involving 168 asthmatic children aged 4-17 years who visited the periodical asthma checkup program. Serum neopterin and biopterin levels were measured as pteridines at each visit along with measurement of FeNO, respiratory function tests, nasal eosinophil test, blood eosinophil count, and IgE level. We calculated coefficients for relation between pteridines and asthma control, which was assessed by questionnaires (JPAC: Japanese Pediatric Asthma Control Program).</p><p><i>Results:</i> A total of 168 participants aged 10.3 ± 3.39 years (mean ± SD) with asthma were recruited. The participants in this study contained 58 patients (34.5%) of complete-controlled based on JPAC, 132 patients (76.0%) of well-controlled group based on GINA. FeNO and serum neopterin level did not correlate with following period's JPAC scores. In contrast, serum biopterin level significantly correlated with following period's JPAC total score (Coefficients 0.398; 95% CI 0.164 to 0.632; <i>p</i> value 0.001) and frequency of wheezing during exercise (Coefficients 0.272; 95% CI 0.217 to 0.328; <i>p</i> value < 0.001).</p><p><i>Conclusions:</i> We found serum biopterin effected the following period's control status of asthmatic children, thus monitoring biopterin level will be a useful for management of asthma to adjust treatment.</p>

DOI： 10.1016/j.alit.2018.08.012

PubMed

CiNii Article

喘息児における、テトラヒドロビオプテリンの代謝物であるプテリジン類と喘息管理状態の関連性を単一施設前向きコホート研究により検討した。喘息児168例(男児96例、年齢4〜17歳)を対象に、プテリジン類として血清中のネオプテリンとビオプテリンを測定するとともに、呼気一酸化窒素濃度(FeNO)、呼吸機能、鼻好酸球、血中好酸球数、免疫グロブリンE値を測定した。またJapanese Pediatric Asthma Control Program(JPAC)質問票で評価した喘息管理とプテリジンとの関連を推定した。喘息管理状況は、JPACで「完全管理」に分類された症例は58例、Global Initiative for Asthma分類で「管理良好」とされた症例は132例であった。FeNOとネオプテリン値は経過観察期間のJPACスコアとは相関しなかったが、血清ビオプテリン値は経過観察期間のJPAC総スコアおよび運動中の喘鳴頻度とは有意な相関関係があった。血清ビオプテリンは、喘息児の経過観察期間の管理状態に影響しており、ビオプテリン値のモニタリングが喘息管理に有用であることが示唆された。

Publishing type：Research paper (scientific journal)   International / domestic magazine：International journal  

BACKGROUND: Pteridines are metabolites of tetrahydrobiopterin, which serves as co-enzyme of nitric oxide synthase. We sought to investigate the usefulness of pteridines as biomarkers for childhood asthma control. METHODS: We conducted a single-center prospective cohort study involving 168 asthmatic children aged 4-17 years who visited the periodical asthma checkup program. Serum neopterin and biopterin levels were measured as pteridines at each visit along with measurement of FeNO, respiratory function tests, nasal eosinophil test, blood eosinophil count, and IgE level. We calculated coefficients for relation between pteridines and asthma control, which was assessed by questionnaires (JPAC: Japanese Pediatric Asthma Control Program). RESULTS: A total of 168 participants aged 10.3 ± 3.39 years (mean ± SD) with asthma were recruited. The participants in this study contained 58 patients (34.5%) of complete-controlled based on JPAC, 132 patients (76.0%) of well-controlled group based on GINA. FeNO and serum neopterin level did not correlate with following period's JPAC scores. In contrast, serum biopterin level significantly correlated with following period's JPAC total score (Coefficients 0.398; 95% CI 0.164 to 0.632; p value 0.001) and frequency of wheezing during exercise (Coefficients 0.272; 95% CI 0.217 to 0.328; p value < 0.001). CONCLUSIONS: We found serum biopterin effected the following period's control status of asthmatic children, thus monitoring biopterin level will be a useful for management of asthma to adjust treatment.

DOI： 10.1016/j.alit.2018.08.012

PubMed

CiNii Article

DOI： 10.1016/j.alit.2018.08.012

PubMed

Publishing type：Research paper (scientific journal)   International / domestic magazine：International journal  

BACKGROUND: Pteridines are metabolites of tetrahydrobiopterin, which serves as co-enzyme of nitric oxide synthase. We sought to investigate the usefulness of pteridines as biomarkers for childhood asthma control. METHODS: We conducted a single-center prospective cohort study involving 168 asthmatic children aged 4-17 years who visited the periodical asthma checkup program. Serum neopterin and biopterin levels were measured as pteridines at each visit along with measurement of FeNO, respiratory function tests, nasal eosinophil test, blood eosinophil count, and IgE level. We calculated coefficients for relation between pteridines and asthma control, which was assessed by questionnaires (JPAC: Japanese Pediatric Asthma Control Program). RESULTS: A total of 168 participants aged 10.3 ± 3.39 years (mean ± SD) with asthma were recruited. The participants in this study contained 58 patients (34.5%) of complete-controlled based on JPAC, 132 patients (76.0%) of well-controlled group based on GINA. FeNO and serum neopterin level did not correlate with following period's JPAC scores. In contrast, serum biopterin level significantly correlated with following period's JPAC total score (Coefficients 0.398; 95% CI 0.164 to 0.632; p value 0.001) and frequency of wheezing during exercise (Coefficients 0.272; 95% CI 0.217 to 0.328; p value < 0.001). CONCLUSIONS: We found serum biopterin effected the following period's control status of asthmatic children, thus monitoring biopterin level will be a useful for management of asthma to adjust treatment.

DOI： 10.1016/j.alit.2018.08.012

PubMed

DOI： 10.1016/j.alit.2018.08.012

Publishing type：Research paper (scientific journal)  

2歳8ヵ月男児。中等度の発育遅延と難聴、停留精巣などの臨床的特徴に関連する遺伝子欠失と、1q23.3q24.1領域に、最小の微小欠失が検出されたため報告した。症例は出生直後に先天性難聴と停留精巣が認められ、4ヵ月時には体重増加不良と発育遅延を呈し、10ヵ月時には寝返りや介助なしで座位を保持することができなかった。また、軽度の両眼接近症、耳介低位、テント状の上唇、小顎、体軸性筋緊張低下を示し、19ヵ月時に撮像された脳MRI像では、12ヵ月時にはみられなかった右内包膝部にT2強調画像で高信号が描出された。2歳8ヵ月時に成長異常と中等度の発育遅延が認められたため、マイクロアレイ染色体検査を施行したところ、arr[GRCh37]1q23.3q24.1(164816055_165696996)×1のde novo微小欠失が同定された。さらに、重複欠損患者と共通する臨床的特徴に絞り、欠失範囲の責任領域について、遺伝情報データベースOMIMを用いて検索した結果からは、欠失領域が7遺伝子含まれ、LMX1A、RXRG、ALDH9A1が、本例の精神発達遅延の発症要因であることが示された。なお、本例に同定された微小欠失は、既報例に比べ最小の欠失サイズ881kbであり、1q24近接領域での中間部微小欠失は極めて稀である。

2歳8ヵ月男児。中等度の発育遅延と難聴、停留精巣などの臨床的特徴に関連する遺伝子欠失と、1q23.3q24.1領域に、最小の微小欠失が検出されたため報告した。症例は出生直後に先天性難聴と停留精巣が認められ、4ヵ月時には体重増加不良と発育遅延を呈し、10ヵ月時には寝返りや介助なしで座位を保持することができなかった。また、軽度の両眼接近症、耳介低位、テント状の上唇、小顎、体軸性筋緊張低下を示し、19ヵ月時に撮像された脳MRI像では、12ヵ月時にはみられなかった右内包膝部にT2強調画像で高信号が描出された。2歳8ヵ月時に成長異常と中等度の発育遅延が認められたため、マイクロアレイ染色体検査を施行したところ、arr[GRCh37]1q23.3q24.1(164816055_165696996)×1のde novo微小欠失が同定された。さらに、重複欠損患者と共通する臨床的特徴に絞り、欠失範囲の責任領域について、遺伝情報データベースOMIMを用いて検索した結果からは、欠失領域が7遺伝子含まれ、LMX1A、RXRG、ALDH9A1が、本例の精神発達遅延の発症要因であることが示された。なお、本例に同定された微小欠失は、既報例に比べ最小の欠失サイズ881kbであり、1q24近接領域での中間部微小欠失は極めて稀である。

<p><i>Background:</i> Pteridines are metabolites of tetrahydrobiopterin, which serves as co-enzyme of nitric oxide synthase. We sought to investigate the usefulness of pteridines as biomarkers for childhood asthma control.</p><p><i>Methods:</i> We conducted a single-center prospective cohort study involving 168 asthmatic children aged 4-17 years who visited the periodical asthma checkup program. Serum neopterin and biopterin levels were measured as pteridines at each visit along with measurement of FeNO, respiratory function tests, nasal eosinophil test, blood eosinophil count, and IgE level. We calculated coefficients for relation between pteridines and asthma control, which was assessed by questionnaires (JPAC: Japanese Pediatric Asthma Control Program).</p><p><i>Results:</i> A total of 168 participants aged 10.3 ± 3.39 years (mean ± SD) with asthma were recruited. The participants in this study contained 58 patients (34.5%) of complete-controlled based on JPAC, 132 patients (76.0%) of well-controlled group based on GINA. FeNO and serum neopterin level did not correlate with following period's JPAC scores. In contrast, serum biopterin level significantly correlated with following period's JPAC total score (Coefficients 0.398; 95% CI 0.164 to 0.632; <i>p</i> value 0.001) and frequency of wheezing during exercise (Coefficients 0.272; 95% CI 0.217 to 0.328; <i>p</i> value < 0.001).</p><p><i>Conclusions:</i> We found serum biopterin effected the following period's control status of asthmatic children, thus monitoring biopterin level will be a useful for management of asthma to adjust treatment.</p>

DOI： 10.1016/j.alit.2018.08.012

CiNii Article

Publishing type：Research paper (scientific journal)   International / domestic magazine：International journal  

Interstitial deletions of 1q23.3q24.1 are rare. Here, chromosomal microarray testing identified a de novo microdeletion of arr[GRCh37]1q23.3q24.1(164816055_165696996) × 1 in a patient with moderate developmental delay, hearing loss, cryptorchidism, and other distinctive features. The clinical features were common to those previously reported in patients with overlapping deletions. The patient's deletion size was 881 kb-the smallest yet reported. This therefore narrowed down the deletion responsible for the common clinical features. The deleted region included seven genes; deletion of LMX1A, RXRG, and ALDH9A1 may have caused our patient's neurodevelopmental delay.

DOI： 10.1038/s41439-019-0079-1

PubMed

A 5-year-old boy was referred to our hospital from public health service due to progressive short stature noticed at their three-years-old check-up. Perinatal history was unremarkable. At two years of age, he received chondrectomy of the left fourth digit. Based on his father's height (162 cm) and his mother's height (147 cm), his target height was estimated as 163cm (-1.4SD). On examination at our hospital, height was 100.5cm (-2.2SD) and obesity was 8.3%. No characteristic facial feature nor cardiac murmur was recognized, no joint stiffness nor pain was detected, and laboratory tests showed normal thyroid function and normal IGF-1 levels (94ng/mL). Left hand-wrist radiograph for bone age revealed multiple osteochondromas. Additional osteochondromas were found in the scapula and distal radial bone thorough physical examination. Family interviewing revealed that his mother's uncle and grandmother also had similar osteochondromas. We diagnosed him as hereditary multiple osteochondromas (HMO) by detecting a c.992C>A (p.A331D) mutation in exon2 of EXT1. Since patients with HMO will be referred to pediatricians due to short stature as a chief complain, pediatric physicians need to be aware of this disease as a differential diagnosis for short stature. A detailed family history and physical inspection are essential for early diagnosis of this disease, and if diagnosed, genetic counseling is also important for the family.

CiNii Article

Publishing type：Research paper (scientific journal)  

Publishing type：Research paper (scientific journal)  

5歳7ヵ月男児が3歳児健診で低身長を指摘され、改善しないため当科受診した。周産期・発達歴に異常なし。既往歴として2歳時に左4指の軟骨切除術を受けていた。父の身長162cm、母の身長147cm、目標身長163cm(-1.4SD)であった。初診時、身長100.5cm(-2.2SD)、肥満度8.3%、特異顔貌や心雑音なく、関節可動域制限、疼痛部位なし。血液検査で甲状腺機能正常、IGF-1 94ng/mLであった。骨年齢計測目的で撮影した左手単純レントゲンにて軟骨腫が多発していた。全身を観察すると、肩甲骨や橈骨遠位に外表から突出を触知した。家族歴で母、母方叔父、母方祖母に同様に軟骨腫があり、本人と母についてEXT1遺伝子のExon 2にc.992C>A(p.A331D)変異を同定したため、遺伝性多発性骨軟骨腫と考えた。遺伝性多発性骨軟骨腫の小児例では、低身長を主訴として小児科医師が初診対応することもあるため、成長障害の鑑別疾患の一つとして念頭に置くとともに、詳細な家族歴聴取と全身診察が重要である。(著者抄録)

7歳時に急性骨髄性白血病(AML)を発症したfamilial platelet disorder with propensity to develop acute myeloid leukemia(FPD/AML)の男児を対象に、白血病発症機序について検討した。患児の末梢血および骨髄を用いて、寛解期と再発期に精密G-Band染色体検査、Micro-array based comparative genomic hybridization、蛍光in situハイブリダイゼーション(FISH)を行い、再発期にRNAシークエンスとリアルタイムPCRを行った。その結果、21番染色体に先天的な複雑構造異常が認められた。FISHでRUNX1の分離と、白血病再発時には分離したRUNX1の増幅を認めた。リアルタイムPCRでは、RUNX1領域のエクソン3とエクソン4の間に分離部があり、その5'側領域は数倍に増幅していることが確認された。RNAシークエンスでは、既知の融合遺伝子や突然変異は認めなかった。FPD/AMLでは、RUNX1のハプロ不全によって先天性血小板減少が引き起こされ、変異RUNX1遺伝子の増幅が白血病の発症を促進する可能性があることが示唆された。

5歳7ヵ月男児が3歳児健診で低身長を指摘され、改善しないため当科受診した。周産期・発達歴に異常なし。既往歴として2歳時に左4指の軟骨切除術を受けていた。父の身長162cm、母の身長147cm、目標身長163cm(-1.4SD)であった。初診時、身長100.5cm(-2.2SD)、肥満度8.3%、特異顔貌や心雑音なく、関節可動域制限、疼痛部位なし。血液検査で甲状腺機能正常、IGF-1 94ng/mLであった。骨年齢計測目的で撮影した左手単純レントゲンにて軟骨腫が多発していた。全身を観察すると、肩甲骨や橈骨遠位に外表から突出を触知した。家族歴で母、母方叔父、母方祖母に同様に軟骨腫があり、本人と母についてEXT1遺伝子のExon 2にc.992C>A(p.A331D)変異を同定したため、遺伝性多発性骨軟骨腫と考えた。遺伝性多発性骨軟骨腫の小児例では、低身長を主訴として小児科医師が初診対応することもあるため、成長障害の鑑別疾患の一つとして念頭に置くとともに、詳細な家族歴聴取と全身診察が重要である。(著者抄録)

Publishing type：Research paper (scientific journal)  

Publishing type：Research paper (scientific journal)   International / domestic magazine：International journal  

INTRODUCTION: Menkes disease (MD) is an X-linked recessive disorder caused by dysfunction of a copper-transporting protein, leading to severe neurodegeneration in early childhood. We investigated whether a lipophilic copper chelator, disulfiram, could enhance copper absorption from the intestine and transport copper across the blood-brain barrier in MD model mice. METHODS: Wild type and MD model mice were pretreated with disulfiram for 30 min before oral administration of 64CuCl2. Each organ was sequentially analyzed for radioactivity with γ counting. Copper uptake into the brain parenchyma was assessed by ex vivo autoradiography. RESULTS: In wild type mice, orally administered copper was initially detected in the intestine within 2 h, reaching a maximum level in the liver (19.6 ± 3.8 percentage injected dose per gram [%ID/g]) at 6 h. In MD model mice, the copper reached the maximum level in the liver (5.3 ± 1.5 %ID/g) at 4 h, which was lower than that of wild type mice (19.0 ± 7.4 %ID/g) (P < 0.05). Pretreatment of disulfiram in MD model mice increased the copper level in the brain (0.59 ± 0.28 %ID/g) at 24 h compared with MD model mice without disulfiram (0.07 ± 0.05 %ID/g) (P < 0.05). Ex vivo autoradiography revealed that high levels of copper uptake was observed in the cerebral cortex upon disulfiram pretreatment. CONCLUSION: Our data demonstrated that disulfiram enhanced the delivery of orally administered copper into the central nervous system in MD model mice. The administration of disulfiram will enable patients to avoid unpleasant subcutaneous copper injection in the future.

DOI： 10.1007/s10545-018-0239-3

PubMed

Publishing type：Research paper (scientific journal)  

症例1は18歳男性で、Wilson病であった。腹部CTで肝硬変および胃腎短絡路を排血路とする胃静脈瘤(GV)があり、内視鏡では連珠状のGVを認めた。胃腎短絡路を介しバルーン下逆行性静脈的塞栓術(BRTO)によりGVと排血路を塞栓し、術後GVの消失が得られた。症例2は18歳男性で、4歳時に両大血管右室起始症に対しFontan手術を施行していた。肝生検で門脈域と類洞周囲に広範囲な線維化を呈し、腹部CTと内視鏡で症例1と同様のGVを認めた。胃腎短絡路のバルーン閉塞試験で術後門脈圧亢進の増悪が懸念され、BRTOによりGVのみ塞栓した。症例3は19歳女性で、2歳時に肺動脈閉塞症に対しFontan手術施行があった。肝生検で症例2と同様の線維化を呈し、腹部CTおよび内視鏡で症例1と同様のGVを認めた。胃腎短絡路を介しBRTOによりGVと排血路を塞栓し、術後高アンモニア血症とGVの消失が得られた。症例2と3はBRTO後食道静脈瘤の増悪を認めた。

症例1は18歳男性で、Wilson病であった。腹部CTで肝硬変および胃腎短絡路を排血路とする胃静脈瘤(GV)があり、内視鏡では連珠状のGVを認めた。胃腎短絡路を介しバルーン下逆行性静脈的塞栓術(BRTO)によりGVと排血路を塞栓し、術後GVの消失が得られた。症例2は18歳男性で、4歳時に両大血管右室起始症に対しFontan手術を施行していた。肝生検で門脈域と類洞周囲に広範囲な線維化を呈し、腹部CTと内視鏡で症例1と同様のGVを認めた。胃腎短絡路のバルーン閉塞試験で術後門脈圧亢進の増悪が懸念され、BRTOによりGVのみ塞栓した。症例3は19歳女性で、2歳時に肺動脈閉塞症に対しFontan手術施行があった。肝生検で症例2と同様の線維化を呈し、腹部CTおよび内視鏡で症例1と同様のGVを認めた。胃腎短絡路を介しBRTOによりGVと排血路を塞栓し、術後高アンモニア血症とGVの消失が得られた。症例2と3はBRTO後食道静脈瘤の増悪を認めた。

Publishing type：Research paper (scientific journal)  

症例1は18歳男性で、Wilson病であった。腹部CTで肝硬変および胃腎短絡路を排血路とする胃静脈瘤(GV)があり、内視鏡では連珠状のGVを認めた。胃腎短絡路を介しバルーン下逆行性静脈的塞栓術(BRTO)によりGVと排血路を塞栓し、術後GVの消失が得られた。症例2は18歳男性で、4歳時に両大血管右室起始症に対しFontan手術を施行していた。肝生検で門脈域と類洞周囲に広範囲な線維化を呈し、腹部CTと内視鏡で症例1と同様のGVを認めた。胃腎短絡路のバルーン閉塞試験で術後門脈圧亢進の増悪が懸念され、BRTOによりGVのみ塞栓した。症例3は19歳女性で、2歳時に肺動脈閉塞症に対しFontan手術施行があった。肝生検で症例2と同様の線維化を呈し、腹部CTおよび内視鏡で症例1と同様のGVを認めた。胃腎短絡路を介しBRTOによりGVと排血路を塞栓し、術後高アンモニア血症とGVの消失が得られた。症例2と3はBRTO後食道静脈瘤の増悪を認めた。

Publishing type：Research paper (scientific journal)  

DOI： 10.1007/s10545-018-0239-3

PubMed

Publishing type：Research paper (scientific journal)  

DOI： 10.20632/vso.92.4_185

CiNii Article

DOI： 10.18888/rp.0000000399

CiNii Article

Publishing type：Research paper (scientific journal)  

1歳7ヵ月女児。主訴は発達遅滞であった。生後10ヵ月以降次第に発達遅滞を認め、生後16ヵ月で独歩不可能であった。脊椎側面単純X線では高度の後彎を認め、椎体は高さが減じ卵円形〜くちばし状のものまで認めた。頭部MRIのT2強調像では大脳皮質下白質から深部白質に淡い高信号を認め、両側の視床と淡蒼球に低信号を認め、小脳は萎縮していた。髄鞘形成遅延を呈する先天性代謝疾患が疑われ、遺伝子診断の結果、GLB1遺伝子のM1C変異とR49Gが確認され、GM1ガングリオシドーシスと診断した。その後MRIによる経過観察では大脳白質病変が徐々に目立ち、大脳や脳梁の萎縮を認めるようになり、視床と淡蒼球のT2強調像低信号化が明瞭化し、橋被蓋の萎縮も目立つようになった。

Publishing type：Research paper (scientific journal)  

1歳7ヵ月女児。主訴は発達遅滞であった。生後10ヵ月以降次第に発達遅滞を認め、生後16ヵ月で独歩不可能であった。脊椎側面単純X線では高度の後彎を認め、椎体は高さが減じ卵円形〜くちばし状のものまで認めた。頭部MRIのT2強調像では大脳皮質下白質から深部白質に淡い高信号を認め、両側の視床と淡蒼球に低信号を認め、小脳は萎縮していた。髄鞘形成遅延を呈する先天性代謝疾患が疑われ、遺伝子診断の結果、GLB1遺伝子のM1C変異とR49Gが確認され、GM1ガングリオシドーシスと診断した。その後MRIによる経過観察では大脳白質病変が徐々に目立ち、大脳や脳梁の萎縮を認めるようになり、視床と淡蒼球のT2強調像低信号化が明瞭化し、橋被蓋の萎縮も目立つようになった。

1歳7ヵ月女児。主訴は発達遅滞であった。生後10ヵ月以降次第に発達遅滞を認め、生後16ヵ月で独歩不可能であった。脊椎側面単純X線では高度の後彎を認め、椎体は高さが減じ卵円形〜くちばし状のものまで認めた。頭部MRIのT2強調像では大脳皮質下白質から深部白質に淡い高信号を認め、両側の視床と淡蒼球に低信号を認め、小脳は萎縮していた。髄鞘形成遅延を呈する先天性代謝疾患が疑われ、遺伝子診断の結果、GLB1遺伝子のM1C変異とR49Gが確認され、GM1ガングリオシドーシスと診断した。その後MRIによる経過観察では大脳白質病変が徐々に目立ち、大脳や脳梁の萎縮を認めるようになり、視床と淡蒼球のT2強調像低信号化が明瞭化し、橋被蓋の萎縮も目立つようになった。

Publishing type：Research paper (scientific journal)  

DOI： 10.3389/fneur.2018.00133

PubMed

Publishing type：Research paper (scientific journal)  

DOI： 10.1016/j.ymgme.2017.12.289

Publishing type：Research paper (scientific journal)  

DOI： 10.1016/j.ymgme.2017.12.289

Publishing type：Research paper (scientific journal)  

CD34 surface antigen has been extensively used as a marker for hematopoietic stem cells in adult bone marrow. Cord blood contains high number of hematopoietic and non-hematopoietic stem/progenitor cells. This chapter focuses on recent progresses in stem cell biology on cord blood cells. During embryonic development, expression of CD34 is tightly regulated in a spatial and temporal manner. Subpopulations of CD34+ cells in cord blood have been characterized by their functional potency. CD133 positivity and aldehyde dehydrogenase activity are well overlapped to show higher regenerative potentials in CD34+ cells. Proportion of CD34+ cells tends to be higher in cord blood from preterm baby. The higher number of circulating CD34+ cells in neonate has been found to be linked to the lower risk of prematurity-related complications. Further mechanistic studies will be required to reveal the role of circulating CD34+ cells in neonate.

DOI： 10.1007/978-981-10-1412-3_8

Publishing type：Part of collection (book)  

CD34 surface antigen has been extensively used as a marker for hematopoietic stem cells in adult bone marrow. Cord blood contains high number of hematopoietic and non-hematopoietic stem/progenitor cells. This chapter focuses on recent progresses in stem cell biology on cord blood cells. During embryonic development, expression of CD34 is tightly regulated in a spatial and temporal manner. Subpopulations of CD34+ cells in cord blood have been characterized by their functional potency. CD133 positivity and aldehyde dehydrogenase activity are well overlapped to show higher regenerative potentials in CD34+ cells. Proportion of CD34+ cells tends to be higher in cord blood from preterm baby. The higher number of circulating CD34+ cells in neonate has been found to be linked to the lower risk of prematurity-related complications. Further mechanistic studies will be required to reveal the role of circulating CD34+ cells in neonate.

DOI： 10.1007/978-981-10-1412-3_8

Publishing type：Research paper (scientific journal)  

DOI： 10.1038/pr.2017.260

PubMed

Publishing type：Research paper (scientific journal)  

Neonatal ischemic brain injury causes permanent motor-deficit cerebral palsy. Hypoxic-ischemic encephalopathy (HIE) is a very serious condition that can result in death and disability. In 1997, we reported that irreversible neuronal cell damage is induced by the elevation of intracellular Ca ion concentration that has occurred in sequence after excess accumulation of the excitatory neurotransmitter glutamate during ischemia. We also reported that hypothermia was effective in treating ischemic brain damage in rats by suppressing energy loss and raising intracellular Ca ion concentration. Following the 2010 revised International Liaison Committee on Resuscitation guideline, our group developed the Guideline for the treatment of Hypothermia in Japan, and we started online case registry in January 2012. However, therapeutic hypothermia must be initiated within the first 6 h after birth. By contrast, cell therapy may have a much longer therapeutic time window because it might reduce apoptosis/oxidative stress and enhance the regenerative process. In 2014, we administered autologous umbilical cord blood stem cell (UCBC) therapy for neonatal HIE, for the first time in Japan. We enrolled five full-term newborns with moderate-to-severe HIE. Our autologous UCBC therapy is leading to new protocols for the prevention of ischemic brain damage.

DOI： 10.1038/pr.2017.260

PubMed

Publishing type：Research paper (scientific journal)   Kind of work：Single Work  

DOI： 10.20632/vso.92.4_185

CiNii Article

Publishing type：Research paper (scientific journal)  

Neonatal brain injury induced by stroke causes significant disability, including cerebral palsy, and there is no effective therapy for stroke. Recently, mesenchymal stem cells (MSCs) have emerged as a promising tool for stem cell-based therapies. In this study, we examined the safety and efficacy of intravenously administered human umbilical cord-derived MSCs (UC-MSCs) in neonatal stroke mice. Pups underwent permanent middle cerebral artery occlusion at postnatal day 12 (P12), and low-dose (1 × 104) or high-dose (1 × 105) UC-MSCs were administered intravenously 48 h after the insult (P14). To evaluate the effect of the UC-MSC treatment, neurological behavior and cerebral blood flow were measured, and neuroanatomical analysis was performed at P28. To investigate the mechanisms of intravenously injected UC-MSCs, systemic blood flowmetry, in vivo imaging and human brain-derived neurotrophic factor (BDNF) measurements were performed. Functional disability was significantly improved in the high-dose UC-MSC group when compared with the vehicle group, but cerebral blood flow and cerebral hemispheric volume were not restored by UC-MSC therapy. The level of exogenous human BDNF was elevated only in the cerebrospinal fluid of one pup 24 h after UC-MSC injection, and in vivo imaging revealed that most UC-MSCs were trapped in the lungs and disappeared in a week without migration toward the brain or other organs. We found that systemic blood flow was stable over the 10 min after cell administration and that there were no differences in mortality among the groups. Immunohistopathological assessment showed that the percent area of Iba1-positive staining in the peri-infarct cortex was significantly reduced with the high-dose UC-MSC treatment compared with the vehicle treatment. These results suggest that intravenous administration of UC-MSCs is safe for a mouse model of neonatal stroke and improves dysfunction after middle cerebral artery occlusion by modulating the microglial reaction in the peri-infarct cortex.

DOI： 10.3389/fneur.2018.00133

PubMed

Publishing type：Research paper (scientific journal)  

Publishing type：Research paper (scientific journal)  

Publishing type：Research paper (scientific journal)  

Publishing type：Research paper (scientific journal)  

Publishing type：Research paper (scientific journal)  

DOI： 10.1016/j.bbmt.2017.06.020

PubMed

Publishing type：Research paper (scientific journal)  

There is limited information regarding the long-term outcomes of hematopoietic stem cell transplantation (HSCT) for mucopolysaccharidosis II (MPS II). In this study, clinical, biochemical, and radiologic findings were assessed in patients who underwent HSCT and/or enzyme replacement therapy (ERT). Demographic data for 146 HSCT patients were collected from 27 new cases and 119 published cases and were compared with 51 ERT and 15 untreated cases. Glycosaminoglycan (GAG) levels were analyzed by liquid chromatography tandem mass spectrometry in blood samples from HSCT, ERT, and untreated patients as well as age-matched controls. Long-term magnetic resonance imaging (MRI) findings were investigated in 13 treated patients (6 ERT and 7 HSCT). Mean age at HSCT was 5.5 years (range, 2 to 21.4 years) in new patients and 5.5 years (range, 10 months to 19.8 years) in published cases. None of the 27 new patients died as a direct result of the HSCT procedure. Graft-versus-host disease occurred in 8 (9%) out of 85 published cases, and 9 (8%) patients died from transplantation-associated complications. Most HSCT patients showed greater improvement in somatic features, joint movements, and activity of daily living than the ERT patients. GAG levels in blood were significantly reduced by ERT and levels were even lower after HSCT. HSCT patients showed either improvement or no progression of abnormal findings in brain MRI while abnormal findings became more extensive after ERT. HSCT seems to be more effective than ERT for MPS II in a wide range of disease manifestations and could be considered as a treatment option for this condition. (C) 2017 American Society for Blood and Marrow Transplantation.

DOI： 10.1016/j.bbmt.2017.06.020

PubMed

Publishing type：Research paper (scientific journal)  

Publishing type：Research paper (scientific journal)  

発達障害患者における遺伝的病因の同定を試みた。患者とその家族から血液検体を採取して、DNAを抽出して次世代シーケンシングを行った。X染色体不活性化(XCI)パターンを判定した。知的障害、自閉症スペクトラム症(ASD)、小頭症の5歳男児(症例1)において新規カルシウム/カルモジュリン依存性タンパク質キナーゼ遺伝子(CASK)変異、c.1424G>T(p.Ser475Ile)を検出した。脳MRIでは構造的異常は示されなかった。同定した変異は症例1の健康な母親と妹の3歳女児(症例2)で共有されていた。症例2では知的障害を認めなかったが、症例1と同様にASD症状を示した。XCIパターンを母親と症例2で解析したところ、母親はほとんど完全に歪んだXCIパターンを示したが、症例2は逆説的なXCIパターンを示した。新規CASK変異を知的障害またはASDの2同胞で同定し、CASK変異とASDの関係性が示唆された。

Publishing type：Research paper (scientific journal)  

Publishing type：Research paper (scientific journal)  

DOI： 10.5582/irdr.2017.01031

PubMed

CiNii Article

発達障害患者における遺伝的病因の同定を試みた。患者とその家族から血液検体を採取して、DNAを抽出して次世代シーケンシングを行った。X染色体不活性化(XCI)パターンを判定した。知的障害、自閉症スペクトラム症(ASD)、小頭症の5歳男児(症例1)において新規カルシウム/カルモジュリン依存性タンパク質キナーゼ遺伝子(CASK)変異、c.1424G>T(p.Ser475Ile)を検出した。脳MRIでは構造的異常は示されなかった。同定した変異は症例1の健康な母親と妹の3歳女児(症例2)で共有されていた。症例2では知的障害を認めなかったが、症例1と同様にASD症状を示した。XCIパターンを母親と症例2で解析したところ、母親はほとんど完全に歪んだXCIパターンを示したが、症例2は逆説的なXCIパターンを示した。新規CASK変異を知的障害またはASDの2同胞で同定し、CASK変異とASDの関係性が示唆された。

Publishing type：Research paper (scientific journal)  

Publishing type：Research paper (scientific journal)  

DOI： 10.5582/irdr.2017.01031

PubMed

DOI： 10.1507/endocrj.EJ16-0370

PubMed

Publishing type：Research paper (scientific journal)  

16歳以上のターナー症候群(TS)女性63名の臨床プロファイルを遡及的に調べた。35名は当院小児科の内分泌科医が継続して追跡し、20名は婦人科医がプライマリーケア医として引き継いだ。小児科での健診から脱落したのは8名で、そのうち7名はエストロゲン補充療法を施行されていた。小児科で継続して追跡した33名の合併症と管理について検討したところ、肥満と肝機能不全が高頻度で認められた。33名のうち19名は、心血管系合併症について成人を診る心臓専門医での診察を受けた。婦人科医が引き継いだ20名の分析では、主に2人の婦人科医が転科を受け入れ、継続的にTSの臨床的ケアをするようになった。当院婦人科医により追跡された7名は生涯にわたる合併症を適切に管理されていた。日本では小児科からの引き継ぎに関して明確な枠組みがないため、TS女性の管理を成功させるには他の専門家、特に婦人科医との調整が不可欠であると考えられた。

16歳以上のターナー症候群(TS)女性63名の臨床プロファイルを遡及的に調べた。35名は当院小児科の内分泌科医が継続して追跡し、20名は婦人科医がプライマリーケア医として引き継いだ。小児科での健診から脱落したのは8名で、そのうち7名はエストロゲン補充療法を施行されていた。小児科で継続して追跡した33名の合併症と管理について検討したところ、肥満と肝機能不全が高頻度で認められた。33名のうち19名は、心血管系合併症について成人を診る心臓専門医での診察を受けた。婦人科医が引き継いだ20名の分析では、主に2人の婦人科医が転科を受け入れ、継続的にTSの臨床的ケアをするようになった。当院婦人科医により追跡された7名は生涯にわたる合併症を適切に管理されていた。日本では小児科からの引き継ぎに関して明確な枠組みがないため、TS女性の管理を成功させるには他の専門家、特に婦人科医との調整が不可欠であると考えられた。

Publishing type：Research paper (scientific journal)  

DOI： 10.1136/jmedgenet-2016-104178

PubMed

Publishing type：Research paper (scientific journal)  

Background Fabry disease is an X-linked lysosomal storage disorder caused by GLA mutations, resulting in alpha-galactosidase (alpha-Gal) deficiency and accumulation of lysosomal substrates. Migalastat, an oral pharmacological chaperone being developed as an alternative to intravenous enzyme replacement therapy (ERT), stabilises specific mutant (amenable) forms of alpha-Gal to facilitate normal lysosomal trafficking.
Methods The main objective of the 18-month, randomised, active-controlled ATTRACT study was to assess the effects of migalastat on renal function in patients with Fabry disease previously treated with ERT. Effects on heart, disease substrate, patient-reported outcomes (PROs) and safety were also assessed.
Results Fifty-seven adults (56% female) receiving ERT (88% had multiorgan disease) were randomised (1.5: 1), based on a preliminary cell-based assay of responsiveness to migalastat, to receive 18 months open-label migalastat or remain on ERT. Four patients had non-amenable mutant forms of alpha-Gal based on the validated cell-based assay conducted after treatment initiation and were excluded from primary efficacy analyses only. Migalastat and ERT had similar effects on renal function. Left ventricular mass index decreased significantly with migalastat treatment (-6.6 g/m(2) (-11.0 to -2.2)); there was no significant change with ERT. Predefined renal, cardiac or cerebrovascular events occurred in 29% and 44% of patients in the migalastat and ERT groups, respectively. Plasma globotriaosylsphingosine remained low and stable following the switch from ERT to migalastat. PROs were comparable between groups. Migalastat was generally safe and well tolerated.
Conclusions Migalastat offers promise as a first-in-class oral monotherapy alternative treatment to intravenous ERT for patients with Fabry disease and amenable mutations.

DOI： 10.1136/jmedgenet-2016-104178

PubMed

Publishing type：Research paper (scientific journal)  

DOI： 10.1111/ncn3.12108

Publishing type：Research paper (scientific journal)  

2008年1月〜2015年6月までの期間内に、診断未確定であったミオパシー当院患者42例(男性21例、女性21例、年齢6〜78歳、平均年齢35.9±21.1歳)を対象に、遅発性Pompe病のスクリーニングを行った。スクリーニングでは、42例中41例には乾燥血液濾紙(DBS)検査により、Acid alpha-glucosidase(以下AAG)酵素活性測定を行い、次に、培養皮膚線維芽細胞を用いてAAG活性を測定し、1例に関しては筋生検組織からAAG活性測定を行い、最終的には遺伝子解析で確定診断した。その結果、DBS検査で、4例にAAG活性低下を認め、偽欠損症アレル(c.546G>Tのホモ接合体)が認められた。一方、筋生検でAAG活性低下を認めた症例は、遺伝子解析をもとに遅発性Pompe病と診断された。以上の結果から、42例中1例のみ(55歳男性)が、遅発性Pompe病と診断された。

Publishing type：Research paper (scientific journal)  

DOI： 10.1002/stem.2570

PubMed

Publishing type：Research paper (scientific journal)  

Recent advances in DNA sequencing technologies are revealing how human genetic variations associate with differential health risks, disease susceptibilities, and drug responses. Such information is now expected to help evaluate individual health risks, design personalized health plans and treat patients with precision. It is still challenging, however, to understand how such genetic variations cause the phenotypic alterations in pathobiologies and treatment response. Human induced pluripotent stem cell (iPSC) technologies are emerging as a promising strategy to fill the knowledge gaps between genetic association studies and underlying molecular mechanisms. Breakthroughs in genome editing technologies and continuous improvement in iPSC differentiation techniques are particularly making this research direction more realistic and practical. Pioneering studies have shown that iPSCs derived from a variety of monogenic diseases can faithfully recapitulate disease phenotypes in vitro when differentiated into disease-relevant cell types. It has been shown possible to partially recapitulate disease phenotypes, even with late onset and polygenic diseases. More recently, iPSCs have been shown to validate effects of disease and treatment-related single nucleotide polymorphisms identified through genome wide association analysis. In this review, we will discuss how iPSC research will further contribute to human health in the coming era of precision medicine.

DOI： 10.1002/stem.2570

PubMed

Publishing type：Research paper (scientific journal)  

BackgroundPompe disease is caused by a deficiency of acid alpha-glucosidase. Its prevalence varies depending on ethnicity, and is less prevalent in Japan as compared with other countries. Because of the wide spectrum of clinical features in late-onset cases, some patients might be misdiagnosed with another myopathy, thus the actual prevalence in Japan might not be accurately reported.AimTo clarify the actual prevalence of late-onset Pompe disease, we investigated acid alpha-glucosidase activity in patients with undiagnosed myopathies.MethodsOf 42 patients with undiagnosed myopathies, 41 underwent assessment of acid alpha-glucosidase enzyme activity using dried blood spot analysis. As a second step, reassessment of acid alpha-glucosidase activity was carried out using cultured skin fibroblasts. We also determined acid alpha-glucosidase activity in biopsied muscle tissue obtained from the one other patient, who had previously undergone a muscle biopsy. Finally, gene analysis was carried out to confirm diagnosis.ResultsFour patients showed reduced acid alpha-glucosidase activity in dried blood spot findings, of whom one possessed a pseudo-deficiency allele. Furthermore, one patient who showed reduced acid alpha-glucosidase activity in a biopsied muscle specimen was diagnosed with late-onset Pompe disease based on gene analysis.ConclusionsOf the present 42 patients, only one patient was diagnosed with late-onset Pompe disease. The prevalence of Pompe disease in Japan does not seem to be as high as in other countries, though a certain number of patients might exist among those with undiagnosed myopathies. A larger and more systematic survey is necessary to elucidate the actual prevalence of late-onset Pompe disease in Japan.

DOI： 10.1111/ncn3.12108

2008年1月〜2015年6月までの期間内に、診断未確定であったミオパシー当院患者42例(男性21例、女性21例、年齢6〜78歳、平均年齢35.9±21.1歳)を対象に、遅発性Pompe病のスクリーニングを行った。スクリーニングでは、42例中41例には乾燥血液濾紙(DBS)検査により、Acid alpha-glucosidase(以下AAG)酵素活性測定を行い、次に、培養皮膚線維芽細胞を用いてAAG活性を測定し、1例に関しては筋生検組織からAAG活性測定を行い、最終的には遺伝子解析で確定診断した。その結果、DBS検査で、4例にAAG活性低下を認め、偽欠損症アレル(c.546G>Tのホモ接合体)が認められた。一方、筋生検でAAG活性低下を認めた症例は、遺伝子解析をもとに遅発性Pompe病と診断された。以上の結果から、42例中1例のみ(55歳男性)が、遅発性Pompe病と診断された。

Publishing type：Research paper (scientific journal)  

BackgroundPompe disease is caused by a deficiency of acid alpha-glucosidase. Its prevalence varies depending on ethnicity, and is less prevalent in Japan as compared with other countries. Because of the wide spectrum of clinical features in late-onset cases, some patients might be misdiagnosed with another myopathy, thus the actual prevalence in Japan might not be accurately reported.AimTo clarify the actual prevalence of late-onset Pompe disease, we investigated acid alpha-glucosidase activity in patients with undiagnosed myopathies.MethodsOf 42 patients with undiagnosed myopathies, 41 underwent assessment of acid alpha-glucosidase enzyme activity using dried blood spot analysis. As a second step, reassessment of acid alpha-glucosidase activity was carried out using cultured skin fibroblasts. We also determined acid alpha-glucosidase activity in biopsied muscle tissue obtained from the one other patient, who had previously undergone a muscle biopsy. Finally, gene analysis was carried out to confirm diagnosis.ResultsFour patients showed reduced acid alpha-glucosidase activity in dried blood spot findings, of whom one possessed a pseudo-deficiency allele. Furthermore, one patient who showed reduced acid alpha-glucosidase activity in a biopsied muscle specimen was diagnosed with late-onset Pompe disease based on gene analysis.ConclusionsOf the present 42 patients, only one patient was diagnosed with late-onset Pompe disease. The prevalence of Pompe disease in Japan does not seem to be as high as in other countries, though a certain number of patients might exist among those with undiagnosed myopathies. A larger and more systematic survey is necessary to elucidate the actual prevalence of late-onset Pompe disease in Japan.

DOI： 10.1111/ncn3.12108

Publishing type：Research paper (scientific journal)  

Publishing type：Research paper (scientific journal)  

DOI： 10.1507/endocrj.EJ16-0370

Publishing type：Research paper (scientific journal)  

The calcium/calmodulin-dependent serine protein kinase gene (CASK) mutations are associated with various neurological disorders
a syndrome of intellectual disability (ID) and microcephaly with pontine and cerebellar hypoplasia (MICPCH), FG syndrome, X-linked ID with/without nystagmus, epileptic encephalopathy, and autistic spectrum disorder (ASD). Next generation sequencing was performed to elucidate genetic causes in siblings exhibiting developmental disorders, and a novel CASK mutation, c.1424G &gt
T (p.Ser475Ile), was detected in a male patient with ID, ASD, and microcephaly. Radiological examination of his brain showed no structural abnormality. The identified mutation was shared with the healthy mother and a younger sister exhibiting ASD. Although the mother showed a skewed X-chromosome inactivation (XCI) pattern, the sister showed a paradoxical XCI pattern. This would explain why this sister possessed a normal intellectual level, but showed the same ASD symptoms as the affected brother. A novel CASK mutation was identified in two siblings with ID and/or ASD, suggesting a relationship between the CASK mutation and ASD. Recently performed large molecular cohorts for patients with developmental disorders suggest that CASK is one of the genes related to developmental disorders. For better understanding of genotype-phenotype correlation in ASD cases with CASK mutations, more information should be accumulated.

DOI： 10.5582/irdr.2017.01031

Publishing type：Research paper (scientific journal)  

Turner syndrome results from the entire or partial loss of the second X chromosome, and is associated with a number of medical problems. Affected women require long-term medical follow-up. This study investigated the status of medical follow-up focusing on the transition for young adult women with Turner syndrome (TS). The clinical profiles of 63 women with TS over the age of 16 were retrospectively examined. Thirty-three women are continuously followed by pediatric endocrinologists at our pediatric division. Twenty women were transferred to gynecologists as primary care physicians. Eight young adult women dropped out of the regular health check-up from our pediatric division even though 7 women were undergoing estrogen replacement therapy. We further reviewed the complications and management of the 33 women who were continuously followed at our pediatric division. A high incidence of obesity and liver dysfunction were observed in this age group (23.5 +/- 8.7). Nineteen out of 33 women consulted a cardiologist in the adult care division for cardiovascular complications. In the analysis of 20 women who were transferred to gynecologists, mainly two gynecologists accepted the transfer and have become accustomed to clinical care for TS. Seven women who were followed by the gynecologist in our facility were adequately managed for lifelong complications. Since there is no clear framework for transition in Japan, coordination with other specialists, especially gynecologists, is essential for the successful management of adult women with TS. Patient education and provision of information are required for establishing self-advocacy, which will prevent drop-out.

DOI： 10.1507/endocrj.EJ16-0370

Turner syndrome results from the entire or partial loss of the second X chromosome, and is associated with a number of medical problems. Affected women require long-term medical follow-up. This study investigated the status of medical follow-up focusing on the transition for young adult women with Turner syndrome (TS). The clinical profiles of 63 women with TS over the age of 16 were retrospectively examined. Thirty-three women are continuously followed by pediatric endocrinologists at our pediatric division. Twenty women were transferred to gynecologists as primary care physicians. Eight young adult women dropped out of the regular health check-up from our pediatric division even though 7 women were undergoing estrogen replacement therapy. We further reviewed the complications and management of the 33 women who were continuously followed at our pediatric division. A high incidence of obesity and liver dysfunction were observed in this age group (23.5±8.7). Nineteen out of 33 women consulted a cardiologist in the adult care division for cardiovascular complications. In the analysis of 20 women who were transferred to gynecologists, mainly two gynecologists accepted the transfer and have become accustomed to clinical care for TS. Seven women who were followed by the gynecologist in our facility were adequately managed for lifelong complications. Since there is no clear framework for transition in Japan, coordination with other specialists, especially gynecologists, is essential for the successful management of adult women with TS. Patient education and provision of information are required for establishing self-advocacy, which will prevent drop-out.

DOI： 10.1507/endocrj.ej16-0370

PubMed

CiNii Article

Publishing type：Research paper (scientific journal)  

Turner syndrome results from the entire or partial loss of the second X chromosome, and is associated with a number of medical problems. Affected women require long-term medical follow-up. This study investigated the status of medical follow-up focusing on the transition for young adult women with Turner syndrome (TS). The clinical profiles of 63 women with TS over the age of 16 were retrospectively examined. Thirty-three women are continuously followed by pediatric endocrinologists at our pediatric division. Twenty women were transferred to gynecologists as primary care physicians. Eight young adult women dropped out of the regular health check-up from our pediatric division even though 7 women were undergoing estrogen replacement therapy. We further reviewed the complications and management of the 33 women who were continuously followed at our pediatric division. A high incidence of obesity and liver dysfunction were observed in this age group (23.5 +/- 8.7). Nineteen out of 33 women consulted a cardiologist in the adult care division for cardiovascular complications. In the analysis of 20 women who were transferred to gynecologists, mainly two gynecologists accepted the transfer and have become accustomed to clinical care for TS. Seven women who were followed by the gynecologist in our facility were adequately managed for lifelong complications. Since there is no clear framework for transition in Japan, coordination with other specialists, especially gynecologists, is essential for the successful management of adult women with TS. Patient education and provision of information are required for establishing self-advocacy, which will prevent drop-out.

DOI： 10.1507/endocrj.EJ16-0370

Publishing type：Research paper (scientific journal)  

Turner syndrome results from the entire or partial loss of the second X chromosome, and is associated with a number of medical problems. Affected women require long-term medical follow-up. This study investigated the status of medical follow-up focusing on the transition for young adult women with Turner syndrome (TS). The clinical profiles of 63 women with TS over the age of 16 were retrospectively examined. Thirty-three women are continuously followed by pediatric endocrinologists at our pediatric division. Twenty women were transferred to gynecologists as primary care physicians. Eight young adult women dropped out of the regular health check-up from our pediatric division even though 7 women were undergoing estrogen replacement therapy. We further reviewed the complications and management of the 33 women who were continuously followed at our pediatric division. A high incidence of obesity and liver dysfunction were observed in this age group (23.5 +/- 8.7). Nineteen out of 33 women consulted a cardiologist in the adult care division for cardiovascular complications. In the analysis of 20 women who were transferred to gynecologists, mainly two gynecologists accepted the transfer and have become accustomed to clinical care for TS. Seven women who were followed by the gynecologist in our facility were adequately managed for lifelong complications. Since there is no clear framework for transition in Japan, coordination with other specialists, especially gynecologists, is essential for the successful management of adult women with TS. Patient education and provision of information are required for establishing self-advocacy, which will prevent drop-out.

DOI： 10.1507/endocrj.EJ16-0370

Publishing type：Research paper (scientific journal)  

The calcium/calmodulin-dependent serine protein kinase gene (CASK) mutations are associated with various neurological disorders
a syndrome of intellectual disability (ID) and microcephaly with pontine and cerebellar hypoplasia (MICPCH), FG syndrome, X-linked ID with/without nystagmus, epileptic encephalopathy, and autistic spectrum disorder (ASD). Next generation sequencing was performed to elucidate genetic causes in siblings exhibiting developmental disorders, and a novel CASK mutation, c.1424G &gt
T (p.Ser475Ile), was detected in a male patient with ID, ASD, and microcephaly. Radiological examination of his brain showed no structural abnormality. The identified mutation was shared with the healthy mother and a younger sister exhibiting ASD. Although the mother showed a skewed X-chromosome inactivation (XCI) pattern, the sister showed a paradoxical XCI pattern. This would explain why this sister possessed a normal intellectual level, but showed the same ASD symptoms as the affected brother. A novel CASK mutation was identified in two siblings with ID and/or ASD, suggesting a relationship between the CASK mutation and ASD. Recently performed large molecular cohorts for patients with developmental disorders suggest that CASK is one of the genes related to developmental disorders. For better understanding of genotype-phenotype correlation in ASD cases with CASK mutations, more information should be accumulated.

DOI： 10.5582/irdr.2017.01031

PubMed

CiNii Article

<p>The calcium/calmodulin-dependent serine protein kinase gene (<i>CASK</i>) mutations are associated with various neurological disorders; a syndrome of intellectual disability (ID) and microcephaly with pontine and cerebellar hypoplasia (MICPCH), FG syndrome, X-linked ID with/without nystagmus, epileptic encephalopathy, and autistic spectrum disorder (ASD). Next generation sequencing was performed to elucidate genetic causes in siblings exhibiting developmental disorders, and a novel <i>CASK</i> mutation, c.1424G>T (p.Ser475Ile), was detected in a male patient with ID, ASD, and microcephaly. Radiological examination of his brain showed no structural abnormality. The identified mutation was shared with the healthy mother and a younger sister exhibiting ASD. Although the mother showed a skewed X-chromosome inactivation (XCI) pattern, the sister showed a paradoxical XCI pattern. This would explain why this sister possessed a normal intellectual level, but showed the same ASD symptoms as the affected brother. A novel <i>CASK</i> mutation was identified in two siblings with ID and/or ASD, suggesting a relationship between the <i>CASK</i> mutation and ASD. Recently performed large molecular cohorts for patients with developmental disorders suggest that <i>CASK</i> is one of the genes related to developmental disorders. For better understanding of genotype-phenotype correlation in ASD cases with <i>CASK</i> mutations, more information should be accumulated.</p>

DOI： 10.5582/irdr.2017.01031

CiNii Article

Publishing type：Research paper (scientific journal)  

DOI： 10.1089/thy.2016.0005

PubMed

Publishing type：Research paper (scientific journal)  

Publishing type：Research paper (scientific journal)  

PubMed

Publishing type：Research paper (scientific journal)   International / domestic magazine：Domestic journal  

Background: Mitochondrial myopathy, Encephalopathy, Lactic Acidosis, Stroke-like episodes/Leigh overlap syndrome (MELAS) is caused by defects in the mitochondrial respiratory chain. It is still largely unknown how these mitochondrial respiratory chain defects affect cellular metabolisms and lead to variable clinical phenotypes. Here, we analyzed metabolic signatures in a cellular model of MELAS/ Leigh overlap syndrome using untargeted gas chromatography coupled to mass spectrometry (GC-MS). . Methods: We obtained fibroblasts from a MELAS/Leigh overlap syndrome patient carrying the heteroplasmic m.10191T>C mutation, and generated induced pluripotent stem cells (iPSCs) from these fibroblast. Isogenic iPSC clones carrying two different loads of the heteroplasmic mutation (ND3hig-iPSC, ND3"*w- iPSC-) were subjected to metabolome analysis. Metabolite profiles, which were identified by GC-MS, were analyzed by principal component analysis (PCA). Results: We were able to identify about 40 metabolites in control fibroblasts and iPSCs. Upon comparative metabolome analysis between fibroblasts and iPSCs, lactic acid and proline were distinct between the two groups. When we compared patient fibroblasts and control fibroblasts, no significant distinct metabolites were found. On the other hand, patient specific iPSC with high mutational load (ND3high_ iPSC) showed a distinct metabolite profile compared with ND3"-iPSC and control-iPSCs. Metabolites that contributed to this distinction were pyruvate, malic acid, palmitic acid, stearic acid, and lactic acid. This metabolomic signature was only seen in the undifferentiated state of iPSCs and was lost upon differentiation Conclusions: These findings suggest that patient specific iPSC technology is useful to elucidate unique pathogenic metabolic pathways ,6mitochondrial chain diseases.

PubMed

Publishing type：Research paper (scientific journal)   International / domestic magazine：Domestic journal  

Background: Mitochondrial myopathy, Encephalopathy, Lactic Acidosis, Stroke-like episodes/Leigh overlap syndrome (MELAS) is caused by defects in the mitochondrial respiratory chain. It is still largely unknown how these mitochondrial respiratory chain defects affect cellular metabolisms and lead to variable clinical phenotypes. Here, we analyzed metabolic signatures in a cellular model of MELAS/ Leigh overlap syndrome using untargeted gas chromatography coupled to mass spectrometry (GC-MS). . Methods: We obtained fibroblasts from a MELAS/Leigh overlap syndrome patient carrying the heteroplasmic m.10191T>C mutation, and generated induced pluripotent stem cells (iPSCs) from these fibroblast. Isogenic iPSC clones carrying two different loads of the heteroplasmic mutation (ND3hig-iPSC, ND3"*w- iPSC-) were subjected to metabolome analysis. Metabolite profiles, which were identified by GC-MS, were analyzed by principal component analysis (PCA). Results: We were able to identify about 40 metabolites in control fibroblasts and iPSCs. Upon comparative metabolome analysis between fibroblasts and iPSCs, lactic acid and proline were distinct between the two groups. When we compared patient fibroblasts and control fibroblasts, no significant distinct metabolites were found. On the other hand, patient specific iPSC with high mutational load (ND3high_ iPSC) showed a distinct metabolite profile compared with ND3"-iPSC and control-iPSCs. Metabolites that contributed to this distinction were pyruvate, malic acid, palmitic acid, stearic acid, and lactic acid. This metabolomic signature was only seen in the undifferentiated state of iPSCs and was lost upon differentiation Conclusions: These findings suggest that patient specific iPSC technology is useful to elucidate unique pathogenic metabolic pathways ,6mitochondrial chain diseases.

PubMed

PubMed

Publishing type：Research paper (scientific journal)  

Background: Hemizygous mutations in the immunoglobulin superfamily member 1 (IGSF1) gene have been demonstrated to cause congenital central hypothyroidism in males. This study reports a family with a novel mutation in the IGSF1 gene located on the long arm of the X chromosome. Patient findings: A two-month-old boy was diagnosed with central hypothyroidism because of prolonged jaundice. A thyrotropin-releasing hormone (TRH) stimulation test indicated dysfunction in both the hypothalamus and the pituitary gland, and prompted the IGSF1 gene to be analyzed. The patient had a novel nonsense variant, c.2713C>T (p.Q905X), in exon 14 of the IGSF1 gene. Studies of the family revealed that the patient's sister and mother were heterozygous carriers of the IGSF1 mutation. The patient's maternal uncle carried the same mutation as the proband but had no overt symptoms. The mother and uncle started levothyroxine supplementation because of subclinical hypothyroidism. Summary: A novel mutation (c.2713C>T, p.Q905X) of the IGSF1 gene was identified that causes congenital central hypothyroidism in a Japanese family. The findings further expand the clinical heterogeneity of this entity.

DOI： 10.1089/thy.2016.0005

PubMed

Publishing type：Research paper (scientific journal)  

DOI： 10.1111/ped.13009

PubMed

Publishing type：Research paper (scientific journal)  

Publishing type：Research paper (scientific journal)  

ヒト胎児肺線維芽細胞と肺胞上皮細胞を、慢性肺疾患を有する超低出生体重児より採取した気管吸引液(TAF)に曝露させ、ヒドロコルチゾン(HDC)、デキサメタゾン(DEX)、ベタメタゾン(BET)、エリスロポエチン(EPO)、スピロノラクトン(SPL)の影響を調べた。妊娠23〜28週で出生し、NICUに入室した未熟児22例からTAF検体を採取した。ヒト胎児肺線維芽細胞株と肺胞上皮細胞株をTAFの有無でHDC、DEX、BET、SPL、EPOの異なる濃度で処理した。TAFへの曝露によって線維芽細胞と肺胞上皮細胞に濃度依存的増殖がもたらされた。TAFに曝露させた線維芽細胞はDEX 100μmol/LとEPO 300mIU/mLで最も有意に抑制され、HDC 0.4μmol/Lで最も有意に促進された。肺胞上皮細胞は、TAF存在下で、HDC 4μmol/L、DEX 10μmol/L、BET 0.2μmol/L、EPO 300mIU/mLによって促進された。グルココルチコイドのみの処理は、線維芽細胞の増殖に有意な影響を及ぼさなかった。

Publishing type：Research paper (scientific journal)  

ヒト胎児肺線維芽細胞と肺胞上皮細胞を、慢性肺疾患を有する超低出生体重児より採取した気管吸引液(TAF)に曝露させ、ヒドロコルチゾン(HDC)、デキサメタゾン(DEX)、ベタメタゾン(BET)、エリスロポエチン(EPO)、スピロノラクトン(SPL)の影響を調べた。妊娠23〜28週で出生し、NICUに入室した未熟児22例からTAF検体を採取した。ヒト胎児肺線維芽細胞株と肺胞上皮細胞株をTAFの有無でHDC、DEX、BET、SPL、EPOの異なる濃度で処理した。TAFへの曝露によって線維芽細胞と肺胞上皮細胞に濃度依存的増殖がもたらされた。TAFに曝露させた線維芽細胞はDEX 100μmol/LとEPO 300mIU/mLで最も有意に抑制され、HDC 0.4μmol/Lで最も有意に促進された。肺胞上皮細胞は、TAF存在下で、HDC 4μmol/L、DEX 10μmol/L、BET 0.2μmol/L、EPO 300mIU/mLによって促進された。グルココルチコイドのみの処理は、線維芽細胞の増殖に有意な影響を及ぼさなかった。

Publishing type：Research paper (scientific journal)  

BackgroundWe investigated the effects of glucocorticoids, erythropoietin (EPO) and spironolactone (SPL) n human fetal lung fibroblasts and human alveolar epithelial cells exposed to tracheal aspirate fluid (TAF) from extremely premature infants with chronic lung disease (CLD), characterized by fibrosis and changes in the alveolar epithelium.MethodsFibroblasts and epithelial cells (FHs 738Lu and A549, respectively) were treated with different concentrations of hydrocortisone (HDC), dexamethasone (DEX), betamethasone (BET), SPL, and EPO in the absence or presence of TAF from infants with CLD (gestational age, 25.3 0.8 weeks; birthweight, 658 77 g; postnatal age, 0-28 days) and assayed for proliferation.ResultsExposure to TAF resulted in a concentration-dependent proliferation of fibroblasts and epithelial cells. Proliferation of TAF-exposed fibroblasts was suppressed most significantly by 100 mol/L DEX (21%, P = 0.046) and 300 mIU/mL EPO (18%, P = 0.02) and promoted most significantly by 0.4 mol/L HDC (10%, P = 0.04). Epithelial proliferation was promoted by 4 mol/L HDC (15%, P = 0.04), 10 mol/L DEX (53%, P < 0.01), 0.2 mol/L BET (56%, P < 0.01), and 300 mIU/mL EPO (35%, P < 0.01) in the presence of TAF. Treatment with glucocorticoids alone did not significantly affect fibroblast proliferation.ConclusionsGlucocorticoids and EPO reduced fibroproliferation while promoting epithelial cell growth in vitro within certain dose ranges. Appropriate doses of glucocorticoids and EPO may be useful in the prevention and resolution of CLD in extremely premature infants.

DOI： 10.1111/ped.13009

DOI： 10.1111/ped.13009

PubMed

Publishing type：Research paper (scientific journal)  

BackgroundWe investigated the effects of glucocorticoids, erythropoietin (EPO) and spironolactone (SPL) n human fetal lung fibroblasts and human alveolar epithelial cells exposed to tracheal aspirate fluid (TAF) from extremely premature infants with chronic lung disease (CLD), characterized by fibrosis and changes in the alveolar epithelium.MethodsFibroblasts and epithelial cells (FHs 738Lu and A549, respectively) were treated with different concentrations of hydrocortisone (HDC), dexamethasone (DEX), betamethasone (BET), SPL, and EPO in the absence or presence of TAF from infants with CLD (gestational age, 25.3 0.8 weeks; birthweight, 658 77 g; postnatal age, 0-28 days) and assayed for proliferation.ResultsExposure to TAF resulted in a concentration-dependent proliferation of fibroblasts and epithelial cells. Proliferation of TAF-exposed fibroblasts was suppressed most significantly by 100 mol/L DEX (21%, P = 0.046) and 300 mIU/mL EPO (18%, P = 0.02) and promoted most significantly by 0.4 mol/L HDC (10%, P = 0.04). Epithelial proliferation was promoted by 4 mol/L HDC (15%, P = 0.04), 10 mol/L DEX (53%, P < 0.01), 0.2 mol/L BET (56%, P < 0.01), and 300 mIU/mL EPO (35%, P < 0.01) in the presence of TAF. Treatment with glucocorticoids alone did not significantly affect fibroblast proliferation.ConclusionsGlucocorticoids and EPO reduced fibroproliferation while promoting epithelial cell growth in vitro within certain dose ranges. Appropriate doses of glucocorticoids and EPO may be useful in the prevention and resolution of CLD in extremely premature infants.

DOI： 10.1111/ped.13009

PubMed

Publishing type：Research paper (scientific journal)  

Publishing type：Research paper (scientific journal)  

Publishing type：Research paper (scientific journal)  

膵炎を繰り返した糖原病Ia型の男児例を経験した。1歳時に肝腫大を指摘され、遺伝子解析により糖原病Ia型と診断を受け、治療ミルクとコーンスターチを用いた食事療法が行われたがコントロールは悪く、高トリグリセライド(TG)血症(600〜1,600mg/dL)、高尿酸血症、低身長、肝腫大が認められた。10歳7ヵ月時と12歳7ヵ月時に膵炎を発症し、絶食・輸液・抗菌薬投与・蛋白分解酵素阻害剤による治療を受けた。膵・胆管合流異常や胆石、外傷はなく、高TG血症が繰り返す膵炎の原因と考えられた。1980年以降、急性膵炎を発症した糖原病I型の症例は自験例を含め国内外で8例報告されており、重症例や反復例が多く、全例で高TG血症が認められている。高TG血症を呈する頻度の高い糖原病Ia型患者では膵炎は重要な合併症の1つであり、食事・薬物療法により高TG血症をコントロールするとともに、高TG血症が学童期まで持続した場合には、膵炎の合併・重症化に十分な注意を払い腹痛の診療に当たる必要があると考えられる。(著者抄録)

Publishing type：Research paper (scientific journal)  

膵炎を繰り返した糖原病Ia型の男児例を経験した。1歳時に肝腫大を指摘され、遺伝子解析により糖原病Ia型と診断を受け、治療ミルクとコーンスターチを用いた食事療法が行われたがコントロールは悪く、高トリグリセライド(TG)血症(600〜1,600mg/dL)、高尿酸血症、低身長、肝腫大が認められた。10歳7ヵ月時と12歳7ヵ月時に膵炎を発症し、絶食・輸液・抗菌薬投与・蛋白分解酵素阻害剤による治療を受けた。膵・胆管合流異常や胆石、外傷はなく、高TG血症が繰り返す膵炎の原因と考えられた。1980年以降、急性膵炎を発症した糖原病I型の症例は自験例を含め国内外で8例報告されており、重症例や反復例が多く、全例で高TG血症が認められている。高TG血症を呈する頻度の高い糖原病Ia型患者では膵炎は重要な合併症の1つであり、食事・薬物療法により高TG血症をコントロールするとともに、高TG血症が学童期まで持続した場合には、膵炎の合併・重症化に十分な注意を払い腹痛の診療に当たる必

CiNii Article

膵炎を繰り返した糖原病Ia型の男児例を経験した。1歳時に肝腫大を指摘され、遺伝子解析により糖原病Ia型と診断を受け、治療ミルクとコーンスターチを用いた食事療法が行われたがコントロールは悪く、高トリグリセライド(TG)血症(600〜1,600mg/dL)、高尿酸血症、低身長、肝腫大が認められた。10歳7ヵ月時と12歳7ヵ月時に膵炎を発症し、絶食・輸液・抗菌薬投与・蛋白分解酵素阻害剤による治療を受けた。膵・胆管合流異常や胆石、外傷はなく、高TG血症が繰り返す膵炎の原因と考えられた。1980年以降、急性膵炎を発症した糖原病I型の症例は自験例を含め国内外で8例報告されており、重症例や反復例が多く、全例で高TG血症が認められている。高TG血症を呈する頻度の高い糖原病Ia型患者では膵炎は重要な合併症の1つであり、食事・薬物療法により高TG血症をコントロールするとともに、高TG血症が学童期まで持続した場合には、膵炎の合併・重症化に十分な注意を払い腹痛の診療に当たる必要があると考えられる。(著者抄録)

Publishing type：Research paper (scientific journal)  

Turner女性(TS女性)86例(6〜48歳:中央値21歳)を対象に、診断時年齢別の臨床像について解析した。内訳は3歳以下24例、4〜6歳18例、7〜12歳28例、13歳以上16例であった。その結果、診断契機はTS徴候、低身長、二次性徴遅延の順に推移を認め、年長診断例ではGH治療適応であるにも関わらずGH治療歴がない低身長例を認めた。中学卒業後の診断例8例の半数以上が産婦人科へトランジションしていた。3歳以下で診断された症例は、新生児科・小児科医によって出生直後にTS徴候を指摘された例があったが、低身長が進行してから診断されている例が多かった。また、医療情勢や社会背景により治療法が変遷しており、TS徴候や身長SDスコア低下は早期診断に重要であることが分かった。

Publishing type：Research paper (scientific journal)  

DOI： 10.1177/1087057115624637

PubMed

Publishing type：Research paper (scientific journal)  

Transport of ADP and ATP across mitochondria is one of the primary points of regulation to maintain cellular energy homeostasis. This process is mainly mediated by adenine nucleotide translocase (ANT) located on the mitochondrial inner membrane. There are four human ANT isoforms, each having a unique tissue-specific expression pattern and biological function, highlighting their potential as drug targets for diverse clinical indications, including male contraception and cancer. In this study, we present a novel yeast-based high-throughput screening (HTS) strategy to identify compounds inhibiting the function of ANT. Yeast strains generated by deletion of endogenous proteins with ANT activity followed by insertion of individual human ANT isoforms are sensitive to cell-permeable ANT inhibitors, which reduce proliferation. Screening hits identified in the yeast proliferation assay were characterized in ADP/ATP exchange assays employing recombinant ANT isoforms expressed in isolated yeast mitochondria and Lactococcus lactis as well as by oxygen consumption rate in mammalian cells. Using this approach, closantel and CD437 were identified as broad-spectrum ANT inhibitors, whereas leelamine was found to be a modulator of ANT function. This yeast knock-out/knock-in screening strategy is applicable to a broad range of essential molecular targets that are required for yeast survival.

DOI： 10.1177/1087057115624637

PubMed

DOI： 10.18888/j00639.2016153583

Publishing type：Research paper (scientific journal)  

DOI： 10.1371/journal.pone.0137239

PubMed

Publishing type：Research paper (scientific journal)  

DOI： 10.1186/s13039-015-0162-3

PubMed

Publishing type：Research paper (scientific journal)  

DOI： 10.1016/j.ymgme.2014.12.254

Publishing type：Research paper (scientific journal)  

DOI： 10.1016/j.ymgme.2014.12.101

Publishing type：Research paper (scientific journal)  

DOI： 10.1016/j.ymgme.2014.12.254

Publishing type：Research paper (scientific journal)  

DOI： 10.1016/j.ymgme.2014.12.101

Publishing type：Research paper (scientific journal)  

DOI： 10.1038/labinvest.2014.104

PubMed

Publishing type：Research paper (scientific journal)  

Approximately 3 years ago, we assessed how patient induced pluripotent stem cell (iPSC) research could potentially impact human pathobiology studies in the future. Since then, the field has grown considerably with numerous technical developments, and the idea of modeling diseases 'in a dish' is becoming increasingly popular in biomedical research. Likely, it is even acceptable to include patient iPSCs as one of the standard research tools for disease mechanism studies, just like knockout mice. However, as the field matures, we acknowledge there remain many practical limitations and obstacles for their genuine application to understand diseases, and accept that it has not been as straightforward to model disorders as initially proposed. A major practical challenge has been efficient direction of iPSC differentiation into desired lineages and preparation of the large numbers of specific cell types required for study. Another even larger obstacle is the limited value of in vitro outcomes, which often do not closely represent disease conditions. To overcome the latter issue, many new approaches are underway, including three-dimensional organoid cultures from iPSCs, xeno-transplantation of human cells to animal models and in vitro interaction of multiple cell types derived from isogenic iPSCs. Here we summarize the areas where patient iPSC studies have provided truly valuable information beyond existing skepticism, discuss the desired technologies to overcome current limitations and include practical guidance for how to utilize the resources. Undoubtedly, these human patient cells are an asset for experimental pathology studies. The future rests on how wisely we use them.

DOI： 10.1038/labinvest.2014.104

PubMed

Publishing type：Research paper (scientific journal)  

Background & AimsThe utility of transient elastography (FibroScan) is well studied in adults but not in children. We sought to assess the feasibility of performing FibroScans and the characteristics of FibroScan-based liver profiles in Japanese obese and non-obese children.MethodsFibroScan examinations were performed in pediatric patients (age, 1-18 yr) who visited Osaka City University Hospital. Liver steatosis measured by controlled attenuation parameter (CAP), and hepatic fibrosis evaluated as the liver stiffness measurement (LSM), were compared among obese subjects (BMI percentile >= 90%), non-obese healthy controls, and non-obese patients with liver disease.ResultsAmong 214 children examined, FibroScans were performed successfully in 201 children (93.9%; median, 11.5 yr; range, 1.3-17.6 yr; 115 male). CAP values (mean +/- SD) were higher in the obese group (n = 52, 285 +/- 60 dB/m) compared with the liver disease (n = 40, 202 +/- 62, P<0.001) and the control (n = 107, 179 +/- 41, P<0.001) group. LSM values were significantly higher in the obese group (5.5 +/- 2.3 kPa) than in the control (3.9 +/- 0.9, P<0.001), but there were no significant differences in LSM between the liver disease group (5.4 +/- 4.2) and either the obese or control group. LSM was highly correlated with CAP in the obese group (rho = 0.511) but not in the control (rho = 0.129) or liver disease (rho = 0.170) groups.ConclusionsChildhood obesity carries a high risk of hepatic steatosis associated with increased liver stiffness. FibroScan methodology provides simultaneous determination of CAP and LSM, is feasible in children of any age, and is a non-invasive and effective screening method for hepatic steatosis and liver fibrosis in Japanese obese children.

DOI： 10.1371/journal.pone.0137239

PubMed

Publishing type：Research paper (scientific journal)  

Ring chromosome 6 is a rare chromosome abnormality that arises typically de novo. The phenotypes can be highly variable, ranging from almost normal to severe malformations and neurological defects. We report a case of a 3-year-old girl with mosaic ring chromosome 6 who presented with being small for gestational age and intellectual disability, and whose brain MRI later revealed periventricular heterotopia and white matter abnormalities. Mosaicism was identified in peripheral blood cells examined by standard G-bands, mos 46,XX,r(6)(p25q27)[67]/45,XX,-6[25]/46,XX,dic r(6:6)(p25q27:p25q27)[6]/47,XX, r(6)(p25q27) x 2[2]. Using array-comparative genomic hybridization, we identified terminal deletion of 6q27 (1.5 Mb) and no deletion on 6p. To our knowledge, this is the first report of periventricular heterotopia and white matter abnormalities manifested in a patient with ring chromosome 6. These central nervous system malformations are further discussed in relation to molecular genetics.

DOI： 10.1186/s13039-015-0162-3

PubMed

Publishing type：Research paper (scientific journal)  

症例1は12歳女児で、全身筋痛で発症し、ミオグロビン尿・CK値上昇に輸液と安静で軽快し、横紋筋融解症の鑑別精査で当院転院後、極長鎖脂肪酸アシルCoA脱水素酵素(VLCAD)欠損症と診断し、脂肪食制限、MCTミルク内服を指導したが、年数回筋痛を伴う横紋筋融解発作が起こり、ブドウ糖点滴加療を要した。症例2は新生児マススクリーニング陽性(NBS)男児で、新生児期よりMCTミルク使用と哺乳間隔の指導を行った。1歳7ヵ月時に全身強直間代発作が群発し、レベチラセタム投与で痙攣再発はなくなり、諸検査値からもVLCADDとの関連性は不明である。症例3はNBS男児で、新生児期よりMCTミルク、脂肪摂取制限を行い、発熱時にブドウ糖点滴加療を行った。現在4歳で低血糖症状や代謝不全は認めていない。症例4はNBS女児で、乳児期よりMCTミルク、脂肪摂取制限を行った。生後6ヵ月時に急性胃腸炎に罹患した際にCK値が上昇したが、現在4歳で低血糖や代謝不全は認めていない。

症例1は12歳女児で、全身筋痛で発症し、ミオグロビン尿・CK値上昇に輸液と安静で軽快し、横紋筋融解症の鑑別精査で当院転院後、極長鎖脂肪酸アシルCoA脱水素酵素(VLCAD)欠損症と診断し、脂肪食制限、MCTミルク内服を指導したが、年数回筋痛を伴う横紋筋融解発作が起こり、ブドウ糖点滴加療を要した。症例2は新生児マススクリーニング陽性(NBS)男児で、新生児期よりMCTミルク使用と哺乳間隔の指導を行った。1歳7ヵ月時に全身強直間代発作が群発し、レベチラセタム投与で痙攣再発はなくなり、諸検査値からもVLCADDとの関連性は不明である。症例3はNBS男児で、新生児期よりMCTミルク、脂肪摂取制限を行い、発熱時にブドウ糖点滴加療を行った。現在4歳で低血糖症状や代謝不全は認めていない。症例4はNBS女児で、乳児期よりMCTミルク、脂肪摂取制限を行った。生後6ヵ月時に急性胃腸炎に罹患した際にCK値が上昇したが、現在4歳で低血糖や代謝不全は認めていない。

Publishing type：Research paper (scientific journal)  

症例1は12歳女児で、全身筋痛で発症し、ミオグロビン尿・CK値上昇に輸液と安静で軽快し、横紋筋融解症の鑑別精査で当院転院後、極長鎖脂肪酸アシルCoA脱水素酵素(VLCAD)欠損症と診断し、脂肪食制限、MCTミルク内服を指導したが、年数回筋痛を伴う横紋筋融解発作が起こり、ブドウ糖点滴加療を要した。症例2は新生児マススクリーニング陽性(NBS)男児で、新生児期よりMCTミルク使用と哺乳間隔の指導を行った。1歳7ヵ月時に全身強直間代発作が群発し、レベチラセタム投与で痙攣再発はなくなり、諸検査値からもVLCADDとの関連性は不明である。症例3はNBS男児で、新生児期よりMCTミルク、脂肪摂取制限を行い、発熱時にブドウ糖点滴加療を行った。現在4歳で低血糖症状や代謝不全は認めていない。症例4はNBS女児で、乳児期よりMCTミルク、脂肪摂取制限を行った。生後6ヵ月時に急性胃腸炎に罹患した際にCK値が上昇したが、現在4歳で低血糖や代謝不全は認めていない。

Publishing type：Research paper (scientific journal)  

DOI： 10.1186/2193-1801-3-527

PubMed

Publishing type：Research paper (scientific journal)  

DOI： 10.2967/jnumed.113.131797

PubMed

Publishing type：Research paper (scientific journal)  

Menkes disease (MD), an X-linked recessive disorder of copper metabolism caused by mutations in the copper-transporting ATP7A gene, results in growth failure and severe neurodegeneration in early childhood. Subcutaneous copper-histidine injection is the standard treatment for MD, but it has limited clinical efficacy. Furthermore, long-term copper injection causes excess copper accumulation in the kidneys, resulting in renal dysfunction. To attempt to resolve this issue, we used PET imaging with Cu-64 to investigate the effects of disulfiram on copper biodistribution in living mice serving as an animal model for MD (MD model mice). Methods: Macular mice were used as MD model mice, and C3H/He mice were used as wild-type mice. Mice were pretreated with 2 types of chelators (disulfiram, a lipophilic chelator, and D-penicillamine, a hydrophilic chelator) 30 min before (CuCl2)-Cu-64 injection. After 64CuCl2 injection, emission scans covering the whole body were performed for 4 h. After the PET scans, the brain and kidneys were analyzed for radioactivity with. counting and autoradiography. Results: After copper injection alone, marked accumulation of radioactivity (Cu-64) in the liver was demonstrated in wild-type mice, whereas in MD model mice, copper was preferentially accumulated in the kidneys (25.56 +/- 3.01 percentage injected dose per gram [% ID/g]) and was detected to a lesser extent in the liver (13.83 +/- 0.26 % ID/g) and brain (0.96 +/- 0.08 % ID/g). Copper injection with disulfiram reduced excess copper accumulation in the kidneys (14.54 +/- 2.68 % ID/g) and increased copper transport into the liver (29.42 +/- 0.98 % ID/g) and brain (5.12 +/- 0.95 % ID/g) of MD model mice. Copper injection with D-penicillamine enhanced urinary copper excretion and reduced copper accumulation in most organs in both mouse groups. Autoradiography demonstrated that disulfiram pretreatment induced copper transport into the brain parenchyma and reduced copper accumulation in the renal medulla. Conclusion: PET studies with Cu-64 revealed that disulfiram had significant effects on the copper biodistribution of MD. Disulfiram increased copper transport into the brain and reduced copper uptake in the kidneys of MD model mice. The application of Cu-64 PET for the treatment of MD and other copperrelated disorders may be useful in clinical settings.

DOI： 10.2967/jnumed.113.131797

PubMed

Publishing type：Research paper (scientific journal)  

DOI： 10.1016/j.ymgme.2013.12.110

Publishing type：Research paper (scientific journal)  

DOI： 10.1016/j.ymgme.2013.12.253

Publishing type：Research paper (scientific journal)  

DOI： 10.1089/hgtb.2013.011

PubMed

Publishing type：Research paper (scientific journal)  

Induced pluripotent stem (iPS) cells have great potential for personalized regenerative medicine. Although several different methods for generating iPS cells have been reported, improvement of safety and efficiency is imperative. In this study, we tested the feasibility of using a triple tyrosine mutant AAV2 (Y444 + 500 + 730F) vector, designated AAV2.3m, to generate iPS cells. We developed a polycistronic rAAV2.3m vector expressing three reprogramming factors, Klf4, Oct4, and Sox2, and then used this vector to infect mouse adipose-derived mesenchymal stem cells (AT-MSCs) to induce the generation of iPS cells. We demonstrated that (1) the triple tyrosine mutant AAV2 vector is able to reprogram mouse adult adipose tissue-derived stem cells into the pluripotent state. Those rAAV2.3m-derived iPS (rAAV2.3m-iPS) cells express endogenous pluripotency-associated genes including Oct4, Sox2, and SSEA-1, and form teratomas containing multiple tissues in vivo; (2) c-myc, an oncogene, is dispensable in rAAV2.3m-mediated cellular reprogramming; and (3) transgene expression is undetectable after reprogramming, whereas vector DNA is detectable, indicating that transgenes are silenced. These results indicated the rAAV vector may have some advantages in generating iPS cells.

DOI： 10.1089/hgtb.2013.011

PubMed

Publishing type：Research paper (scientific journal)  

DOI： 10.1016/j.ymgme.2013.12.110

Publishing type：Research paper (scientific journal)  

DOI： 10.1016/j.ymgme.2013.12.253

Publishing type：Research paper (scientific journal)  

Glucocorticoids (GCs) are frequently used for treating and preventing chronic lung disease and circulatory dysfunction in premature infants. However, there is growing concern about the detrimental effects of systemic GC administration on neurodevelopment. The first choice of GCs to minimize the adverse effects on the developing brain is still under debate. We investigated the effect of commonly used GCs such as dexamethasone (DEX), betamethasone (BET) and hydrocortisone (HDC) on the proliferation of human-induced pluripotent stem cell (iPSC)-derived neuronal progenitor cells (NPCs). In this study, NPCs were treated with various concentrations of GCs and subjected to cell proliferation assays. Furthermore, we quantified the number of microtubule-associated protein 2 (MAP2) positive neurons in NPCs by immunostaining. All GCs promoted NPC proliferation in a dose-dependent manner. We also confirmed that MAP2-positive neurons in NPCs increased upon GC treatment. However, differential effects of GCs on MAP2 positive neurons were observed when we treated NPCs with H2O2. The total numbers of NPCs increased upon any GC treatment even under oxidative conditions but the numbers of MAP2 positive neurons increased only by HDC treatment. GCs promoted human iPSCs-derived NPC proliferation and the differential effects of GCs became apparent under oxidative stress. Our results may support HDC as the preferred choice over DEX and BET to prevent adverse effects on the developing human brain.

DOI： 10.1186/2193-1801-3-527

PubMed

Publishing type：Research paper (scientific journal)  

DOI： 10.1007/s12031-012-9930-2

PubMed

Publishing type：Research paper (scientific journal)  

We report a case of Menkes disease with occipital horns. Occipital horns are wedge-shaped calcifications at the sites of attachment of the trapezius muscle and sternocleidomastoid muscle to the occipital bone. Although occipital horns are a characteristic radiographic finding in occipital horn syndrome, there are only few reports of Menkes disease with occipital horns. It is supposed that mild Menkes disease may exhibit occipital horns.

Publishing type：Research paper (scientific journal)  

We report a case of Menkes disease with occipital horns. Occipital horns are wedge-shaped calcifications at the sites of attachment of the trapezius muscle and sternocleidomastoid muscle to the occipital bone. Although occipital horns are a characteristic radiographic finding in occipital horn syndrome, there are only few reports of Menkes disease with occipital horns. It is supposed that mild Menkes disease may exhibit occipital horns.

Publishing type：Research paper (scientific journal)  

Spinocerebellar ataxia type 2 (SCA2) is caused by triple nucleotide repeat (CAG) expansion in the coding region of the ATAXN2 gene on chromosome 12, which produces an elongated, toxic polyglutamine tract, leading to Purkinje cell loss. There is currently no effective therapy. One of the main obstacles that hampers therapeutic development is lack of an ideal disease model. In this study, we have generated and characterized SCA2-induced pluripotent stem (iPS) cell lines as an in vitro cell model. Dermal fibroblasts (FBs) were harvested from primary cultures of skin explants obtained from a SCA2 subject and a healthy subject. For reprogramming, hOct4, hSox2, hKlf4, and hc-Myc were transduced to passage-3 FBs by retroviral infection. Both SCA2 iPS and control iPS cells were successfully generated and showed typical stem cell growth patterns with normal karyotype. All iPS cell lines expressed stem cell markers and differentiated in vitro into cells from three embryonic germ layers. Upon in vitro neural differentiation, SCA2 iPS cells showed abnormality in neural rosette formation but successfully differentiated into neural stem cells (NSCs) and subsequent neural cells. SCA2 and normal FBs showed a comparable level of ataxin-2 expression; whereas SCA2 NSCs showed less ataxin-2 expression than normal NSCs and SCA2 FBs. Within the neural lineage, neurons had the most abundant expression of ataxin-2. Time-lapsed neural growth assay indicated terminally differentiated SCA2 neural cells were short-lived compared with control neural cells. The expanded CAG repeats of SCA2 were stable throughout reprogramming and neural differentiation. In conclusion, we have established the first disease-specific human SCA2 iPS cell line. These mutant iPS cells have the potential for neural differentiation. These differentiated neural cells harboring mutations are invaluable for the study of SCA2 pathogenesis and therapeutic drug development.

DOI： 10.1007/s12031-012-9930-2

PubMed

Publishing type：Research paper (scientific journal)  

DOI： 10.1016/j.jmgm.2013.08.016

PubMed

Publishing type：Research paper (scientific journal)  

The protein adenine nucleotide translocase (ANT) is localized in the mitochondrial inner membrane and plays an essential role in transporting ADP into the mitochondrial matrix and ATP out from the matrix for cell utilization. In mammals there are four paralogous ANT genes, of which ANT4 is exclusively expressed in meiotic germ cells. Since ANT4 has been shown essential for spermatogenesis and male fertility in mice, inhibition of ANT4 appears to be a reasonable target for male contraceptive development. Further, in contrast to ANTI, ANT2 and ANT3 that are highly homologous to each other, ANT4 has a distinguishable amino acid sequence, which serves as a basis to develop a selective ANT4 inhibitor. In this study, we aimed to identify candidate compounds that can selectively inhibit ANT4 activity over the other ANTs. We used a structure-based method in which ANT4 was modeled then utilized as the basis for selection of compounds that interact with sites unique to ANT4. A large chemical library (&gt;100,000 small molecules) was screened by molecular docking and effects of these compounds on ADP/ATP exchange through ANT4 were examined using yeast mitochondria expressing human ANT4. Through this, we identified one particular candidate compound, [2,2'-methanediylbis(4-nitrophenol)], which inhibits ANT4 activity with a lower IC50 than the other ANTs (5.8 mu M, 4.1 mu M, 5.1 mu M and 1.4 mu M for ANTI, 2,3 and 4, respectively). This newly identified active lead compound and its chemical structure are expected to provide new opportunities to optimize selective ANT4 inhibitors for contraceptive purposes. (C) 2013 Elsevier Inc. All rights reserved.

DOI： 10.1016/j.jmgm.2013.08.016

PubMed

Publishing type：Research paper (scientific journal)  

DOI： 10.4161/epi.25522

PubMed

Publishing type：Research paper (scientific journal)  

DOI： 10.1152/ajpendo.00136.2013

PubMed

Publishing type：Research paper (scientific journal)  

In somatic cells, a collection of signaling pathways activated by amino acid limitation have been identified and referred to as the amino acid response (AAR). Despite the importance of possible detrimental effects of nutrient limitation during in vitro culture, the AAR has not been investigated in embryonic stem cells (ESC). AAR activation caused the expected increase in transcription factors that mediate specific AAR pathways, as well as the induction of asparagine synthetase, a terminal AAR target gene. Neither AAR activation nor stable knockdown of activating transcription factor (Atf) 4, a transcriptional mediator of the AAR, adversely affected ESC self-renewal or pluripotency. Low-level induction of the AAR over a 12-day period of embryoid body differentiation did alter lineage specification such that the primitive endodermal, visceral endodermal, and endodermal lineages were favored, whereas mesodermal and certain ectodermal lineages were suppressed. Knockdown of Atf4 further enhanced the AAR-induced increase in endodermal formation, suggesting that this phenomenon is mediated by an Atf4-independent mechanism. Collectively, the results indicate that, during differentiation of mouse embryoid bodies in culture, the availability of nutrients, such as amino acids, can influence the formation of specific cell lineages.

DOI： 10.1152/ajpendo.00136.2013

PubMed

Publishing type：Research paper (scientific journal)  

The E2f6 transcriptional repressor is an E2F-family member essential for the silencing of a group of meiosis-specific genes in somatic tissues. Although E2f6 has been shown to associate with both polycomb repressive complexes (PRC) and the methyltransferase Dnmt3b, the cross-talk between these repressive machineries during E2f6-mediated gene silencing has not been clearly demonstrated yet. In particular, it remains largely undetermined when and how E2f6 establishes repression of meiotic genes during embryonic development. We demonstrate here that the inactivation of a group of E2f6 targeted genes, including Stag3 and Smc1β, first occurs at the transition from mouse embryonic stem cells (ESC s) to epiblast stem cells (EpiSC s), which represent pre-and post-implantation stages, respectively. This process was accompanied by de novo methylation of their promoters. Of interest, despite a clear difference in DNA methylation status, E2f6 was similarly bound to the proximal promoter regions both in ESC s and EpiSC s. Neither E2f6 nor Dnmt3b overexpression in ESC s decreased meiotic gene expression or increased DNA methylation, indicating that additional factors are required for E2f6-mediated repression during the transition. When the SET domain of Ezh2, a core subunit of the PRC2 complex, was deleted, however, repression of Stag3 and Smc1β during embryoid body differentiation was largely impaired, indicating that the event required the enzymatic activity of Ezh2. In addition, repression of Stag3 and Smc1β occurred in the absence of Dnmt3b. The data presented here suggest a primary role of PRC2 in E2f6-mediated gene silencing of the meiotic genes. © 2013 Landes Bioscience.

DOI： 10.4161/epi.25522

PubMed

Publishing type：Research paper (scientific journal)  

DOI： 10.1089/cell.2012.0058

PubMed

Publishing type：Research paper (scientific journal)  

Forced exogenous gene expression has been well characterized as an effective method for directing both cellular differentiation and dedifferentiation. However, transgene expression is not amenable for therapeutic application due to potential insertional mutagenesis. Protein-based techniques provide a safe alternative, but current protein delivery methods are quite limited by labor-intensive purification processes, low protein yield, and inefficient intracellular targeting. Such limitations may be overcome by using a naturally occurring bacterial protein injection system, called the type III secretion system (T3SS), which injects bacterial proteins directly into the eukaryotic cell cytoplasm. Using a genetically attenuated strain of Pseudomonas aeruginosa, we have previously described the ability of this system to easily deliver a high quantity of protein to both differentiated and pluripotent cells. MyoD is a key muscle regulatory factor, the overexpression of which is able to induce transdifferentiation of numerous cell types into functional myocytes. Here we demonstrate transient injection of MyoD protein by P. aeruginosa to be sufficient to induce myogenic conversion of mouse embryonic fibroblasts. In addition to clear morphological changes, muscle-specific gene expression has been observed both at mRNA and protein levels. These studies serve as a foundation for the bacterial delivery of transcription factors to efficiently modulate concentration-dependent and temporal activation of gene expression that directs cell fate without jeopardizing genomic integrity.

DOI： 10.1089/cell.2012.0058

PubMed

Publishing type：Research paper (scientific journal)  

糖原病(GSD)Ia型の長期観察例3例(44歳男、36歳女、19歳男)を提示し、年長例に対する治療管理の問題について考察した。3例とも成人するまでの食事療法による血糖管理は良好で、症状・検査所見の改善が維持できていた。しかし就職した2例では、社会的要因により食事管理が十分にできず、腎機能低下や高血圧が進行した。また、このうち1例で原因不明の多発神経炎から代謝不全をきたしたが、GSD用フォーミュラの持続注入によって良好なコントロールが得られた。GSD Ia型患者の成人期には予期できない合併症を契機とした臓器障害が急速に進行する危険性があるため、小児科と成人科が連携したフォローアップの体制作りが必要と考えられた。

Publishing type：Research paper (scientific journal)  

糖原病(GSD)Ia型の長期観察例3例(44歳男、36歳女、19歳男)を提示し、年長例に対する治療管理の問題について考察した。3例とも成人するまでの食事療法による血糖管理は良好で、症状・検査所見の改善が維持できていた。しかし就職した2例では、社会的要因により食事管理が十分にできず、腎機能低下や高血圧が進行した。また、このうち1例で原因不明の多発神経炎から代謝不全をきたしたが、GSD用フォーミュラの持続注入によって良好なコントロールが得られた。GSD Ia型患者の成人期には予期できない合併症を契機とした臓器障害が急速に進行する危険性があるため、小児科と成人科が連携したフォローアップの体制作りが必要と考えられた。

糖原病(GSD)Ia型の長期観察例3例(44歳男、36歳女、19歳男)を提示し、年長例に対する治療管理の問題について考察した。3例とも成人するまでの食事療法による血糖管理は良好で、症状・検査所見の改善が維持できていた。しかし就職した2例では、社会的要因により食事管理が十分にできず、腎機能低下や高血圧が進行した。また、このうち1例で原因不明の多発神経炎から代謝不全をきたしたが、GSD用フォーミュラの持続注入によって良好なコントロールが得られた。GSD Ia型患者の成人期には予期できない合併症を契機とした臓器障害が急速に進行する危険性があるため、小児科と成人科が連携したフォローアップの体制作りが必要と考えられた。

Publishing type：Research paper (scientific journal)  

Publishing type：Research paper (scientific journal)  

Publishing type：Research paper (scientific journal)  

Publishing type：Research paper (scientific journal)  

Publishing type：Research paper (scientific journal)  

Publishing type：Research paper (scientific journal)  

Publishing type：Research paper (scientific journal)  

Publishing type：Research paper (scientific journal)  

Fractional exhaled nitric oxide (FeNO) is a useful marker of airway inflammation in asthmatics. Nitric oxide synthase (NOS) requires tetrahydrobiopterin as a cofactor and produces superoxide during NO generation. Therefore, we investigated the relationship of FeNO to pteridine biosynthesis and oxidative stress in pediatric asthma patients. We recruited 67 asthmatic children for FeNO measurement and examined neopterin, biopterin, and Diacron-reactive oxygen metabolites (d-ROMs) as an oxidative stress marker in both summer and winter. Although d-ROMs levels did not show significant correlation with FeNO levels in summer, d-ROMs and FeNO were positively correlated in winter (p < 0.05). Both neopterin and biopterin levels in the blood tended to be lower in patients who showed higher FeNO. Multivariate analysis revealed that increased IgE levels correlated with increased FeNO (p < 0.01) and decreased neopterin (p < 0.05) levels. This data supports a mechanism by which decreased levels of pteridines promote reactive oxygen species production upon NO generation, resulting in airway injury in asthmatic patients. Correlation with IgE level indicates that Th2-mediated allergic inflammation is involved in this process.

Publishing type：Research paper (scientific journal)  

Fractional exhaled nitric oxide (FeNO) is a useful marker of airway inflammation in asthmatics. Nitric oxide synthase (NOS) requires tetrahydrobiopterin as a cofactor and produces superoxide during NO generation. Therefore, we investigated the relationship of FeNO to pteridine biosynthesis and oxidative stress in pediatric asthma patients. We recruited 67 asthmatic children for FeNO measurement and examined neopterin, biopterin, and Diacron-reactive oxygen metabolites (d-ROMs) as an oxidative stress marker in both summer and winter. Although d-ROMs levels did not show significant correlation with FeNO levels in summer, d-ROMs and FeNO were positively correlated in winter (p < 0.05). Both neopterin and biopterin levels in the blood tended to be lower in patients who showed higher FeNO. Multivariate analysis revealed that increased IgE levels correlated with increased FeNO (p < 0.01) and decreased neopterin (p < 0.05) levels. This data supports a mechanism by which decreased levels of pteridines promote reactive oxygen species production upon NO generation, resulting in airway injury in asthmatic patients. Correlation with IgE level indicates that Th2-mediated allergic inflammation is involved in this process.

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Publishing type：Research paper (scientific journal)  

Publishing type：Research paper (scientific journal)  

Publishing type：Research paper (scientific journal)  

DOI： 10.1074/jbc.M112.388181

PubMed

Publishing type：Research paper (scientific journal)  

Nanog or Gata6-positive cells co-exist and are convertible within the inner cell mass of murine blastocysts and embryonic stem (ES) cells. Previous studies demonstrate fibroblast growth factor receptor 2 (FGFR2) triggers Nanog gene down-regulation and differentiation to primitive endoderm (PE); however, the underlying mechanisms responsible for reversible and fluctuating cell fate are poorly understood. Using an inducible FGFR2 dimerization system in ES cells, we demonstrate that FGFR2 activation rapidly down-regulated Nanog gene transcription through activation of the Mek pathway and subsequently differentiated ES cells into PE cells. FGFR2 rather selectively repressed the Nanog gene with minimal effect on other pluripotency genes, including Oct4 and Sox2. We determined the Nanog promoter region containing minimum Oct4/Sox2 binding sites was sufficient for this transcriptional down-regulation by FGFR2, when the reporter transgenes were integrated with insulators. Of interest, FGFR2-mediated Nanog transcriptional reduction occurred without dissociation of RNA polymerase II, p300, Oct4, Sox2, and Tet1 from the Nanog proximal promoter region and with no increase in repressive histone methylation marks or DNA methylation, implying the gene repression is in the early and transient phase. Furthermore, addition of a specific FGFR inhibitor readily reversed this Nanog repression status. These findings illustrate well how FGFR2 induces rapid but reversible Nanog repression within ES cells.

DOI： 10.1074/jbc.M112.388181

PubMed

Publishing type：Research paper (scientific journal)  

DOI： 10.4161/org.20209

PubMed

Publishing type：Research paper (scientific journal)  

Introduction: To address transplant organ shortage, a promising strategy is to decellularize kidneys in a manner that the scaffold retains signals for seeded pluripotent precursor cells to differentiate and recapitulate native structures: matrix-to-cell signaling followed by cell-cell and cell-matrix interactions, thereby remodeling and replacing the original matrix. This would reduce scaffold antigenicity and enable xeno-allografts.
Results: DAPI-labeled cells in arterial vessels and glomeruli were positive for both endothelial lineage markers, BsLB4 and VEGFR2. Rat scaffold's basement membrane demonstrated immunolabeling with anti-mouse laminin beta 1. Labeling intensified over time with 14 day incubations.
Conclusion: We provide new evidence for matrix-to-cell signaling in acellular whole organ scaffolds that induces differentiation of pluripotent precursor cells to endothelial lineage. Production of mouse basement membrane supports remodeling of host (rat)-derived scaffolds and thereby warrants further investigation as a promising approach for xenotransplantation.
Methods: We previously showed that murine embryonic stem cells arterially seeded into acellular rat whole kidney scaffolds multiply and demonstrate morphologic, immunohistochemical and gene expression evidence for differentiation. Vascular cell endothelialization was now further tested by endothelial specific BsLB4 lectin and anti-VEGFR2 (Flk1) antibodies. Remodeling of the matrix basement membranes from rat to mouse ("murinization") was assessed by a monoclonal antibody specific for mouse laminin beta 1 chain.

DOI： 10.4161/org.20209

PubMed

Publishing type：Research paper (scientific journal)  

DOI： 10.1038/labinvest.2011.85

PubMed

Publishing type：Research paper (scientific journal)  

Recent advances in DNA sequencing technologies and subsequent progress in genome-wide association study (GWAS) are rapidly changing the landscape of human diseases. Our knowledge on disease-gene linkage has been exponentially growing, and soon we will obtain complete maps of SNPs and mutations linked to nearly all major disease conditions. These studies will undoubtedly lead us to a more comprehensive understanding of how multiple genetic modifications link to human pathobiology. But what comes next after we discover these genetic linkages? To truly understand the mechanisms of how polygenic modifications identified through GWAS lead to disease conditions, we need an experimental interface to study their pathobiological effects. In this study, induced pluripotent stem cells (iPSCs), retaining all the genetic information from patients, will likely serve as a powerful resource. Indeed, pioneering studies have demonstrated that disease-specific iPSCs are useful for understanding disease mechanisms. Moreover, iPSC-derived cells, when recapitulating some disease phenotypes in vitro, can be a fast track screening tool for drug discovery. Further, with GWAS information, iPSCs will become a valuable tool to predict drug efficacy and toxicity for individuals, thus promoting personalized medicine. In this review, we will discuss how patient-specific iPSCs will become a powerful biomedical interface in clinical translational research. Laboratory Investigation (2011) 91, 972-977; doi:10.1038/labinvest.2011.85; published online 9 May 2011

DOI： 10.1038/labinvest.2011.85

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Publishing type：Research paper (scientific journal)  

DOI： 10.1371/journal.pone.0019250

PubMed

Publishing type：Research paper (scientific journal)  

The adenine nucleotide translocase (ANT) mediates the exchange of ADP and ATP across the inner mitochondrial membrane. The human genome encodes multiple ANT isoforms that are expressed in a tissue-specific manner. Recently a novel germ cell-specific member of the ANT family, ANT4 (SLC25A31) was identified. Although it is known that targeted depletion of ANT4 in mice resulted in male infertility, the functional biochemical differences between ANT4 and other somatic ANT isoforms remain undetermined. To gain insight into ANT4, we expressed human ANT4 (hANT4) in yeast mitochondria. Unlike the somatic ANT proteins, expression of hANT4 failed to complement an AAC-deficient yeast strain for growth on media requiring mitochondrial respiration. Moreover, overexpression of hANT4 from a multi-copy plasmid interfered with optimal yeast growth. However, mutation of specific amino acids of hANT4 improved yeast mitochondrial expression and supported growth of the AAC-deficient yeast on non-fermentable carbon sources. The mutations affected amino acids predicted to interact with phospholipids, suggesting the importance of lipid interactions for function of this protein. Each mutant hANT4 and the somatic hANTs exhibited similar ADP/ATP exchange kinetics. These data define common and distinct biochemical characteristics of ANT4 in comparison to ANT1, 2 and 3 providing a basis for study of its unique adaptation to germ cells.

DOI： 10.1371/journal.pone.0019250

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Publishing type：Research paper (scientific journal)  

DOI： 10.1371/journal.pone.0016465

PubMed

Publishing type：Research paper (scientific journal)  

Numerous Gram negative pathogens possess a type III secretion system (T3SS) which allows them to inject virulent proteins directly into the eukaryotic cell cytoplasm. Injection of these proteins is dependent on a variable secretion signal sequence. In this study, we utilized the N-terminal secretion signal sequence of Pseudomonas aeruginosa exotoxin ExoS to translocate Cre recombinase containing a nuclear localization sequence (Cre-NLS). Transient exposure of human sarcoma cell line, containing Cre-dependent lacZ reporter, resulted in efficient recombination in the host chromosome, indicating that the bacterially delivered protein was not only efficiently localized to the nucleus but also retained its biological function. Using this system, we also illustrate the ability of P. aeruginosa to infect mouse embryonic stem cells (mESC) and the susceptibility of these cells to bacterially delivered Cre-NLS. A single two-hour infection caused as high as 30% of the mESC reporter cells to undergo loxP mediated chromosomal DNA recombination. A simple antibiotic treatment completely eliminated the bacterial cells following the delivery, while the use of an engineered mutant strain greatly reduced cytotoxicity. Utility of the system was demonstrated by delivery of the Cre-NLS to induced pluripotent stem cells to excise the floxed oncogenic nuclear reprogramming cassette. These results validate the use of T3SS for the delivery of transcription factors for the purpose of cellular reprogramming.

DOI： 10.1371/journal.pone.0016465

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DOI： 10.1371/journal.pone.0029690

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DOI： 10.1371/journal.pone.0023122

PubMed

Publishing type：Research paper (scientific journal)  

Background: Cytoplasmic filamentous rods and rings (RR) structures were identified using human autoantibodies as probes. In the present study, the formation of these conserved structures in mammalian cells and functions linked to these structures were examined.
Methodology/Principal Findings: Distinct cytoplasmic rods (similar to 3-10 mu m in length) and rings (similar to 2-5 mu m in diameter) in HEp-2 cells were initially observed in immunofluorescence using human autoantibodies. Co-localization studies revealed that, although RR had filament-like features, they were not enriched in actin, tubulin, or vimentin, and not associated with centrosomes or other known cytoplasmic structures. Further independent studies revealed that two key enzymes in the nucleotide synthetic pathway cytidine triphosphate synthase 1 (CTPS1) and inosine monophosphate dehydrogenase 2 (IMPDH2) were highly enriched in RR. CTPS1 enzyme inhibitors 6-diazo-5-oxo-L-norleucine and Acivicin as well as the IMPDH2 inhibitor Ribavirin exhibited dose-dependent induction of RR in &gt;95% of cells in all cancer cell lines tested as well as mouse primary cells. RR formation by lower concentration of Ribavirin was enhanced in IMPDH2-knockdown HeLa cells whereas it was inhibited in GFP-IMPDH2 overexpressed HeLa cells. Interestingly, RR were detected readily in untreated mouse embryonic stem cells (&gt;95%); upon retinoic acid differentiation, RR disassembled in these cells but reformed when treated with Acivicin.
Conclusions/Significance: RR formation represented response to disturbances in the CTP or GTP synthetic pathways in cancer cell lines and mouse primary cells and RR are the convergence physical structures in these pathways. The availability of specific markers for these conserved structures and the ability to induce formation in vitro will allow further investigations in structure and function of RR in many biological systems in health and diseases.

DOI： 10.1371/journal.pone.0029690

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Publishing type：Research paper (scientific journal)  

Most vertebrates have three paralogous genes with identical intron-exon structures and a high degree of sequence identity that encode mitochondrial adenine nucleotide translocase (Ant) proteins, Ant1 (Slc25a4), Ant2 (Slc25a5) and Ant3 (Slc25a6). Recently, we and others identified a fourth mammalian Ant paralog, Ant4 (Slc25a31), with a distinct intron-exon structure and a lower degree of sequence identity. Ant4 was expressed selectively in testis and sperm in adult mammals and was indeed essential for mouse spermatogenesis, but it was absent in birds, fish and frogs. Since Ant2 is X-linked in mammalian genomes, we hypothesized that the autosomal Ant4 gene may compensate for the loss of Ant2 gene expression during male meiosis in mammals. Here we report that the Ant4 ortholog is conserved in green anole lizard (Anolis carolinensis) and demonstrate that it is expressed in the anole testis. Further, a degenerate DNA fragment of putative Ant4 gene was identified in syntenic regions of avian genomes, indicating that Ant4 was present in the common amniote ancestor. Phylogenetic analyses suggest an even more ancient origin of the Ant4 gene. Although anole lizards are presumed male (XY) heterogametic, like mammals, copy numbers of the Ant2 as well as its neighboring gene were similar between male and female anole genomes, indicating that the anole Ant2 gene is either autosomal or located in the pseudoautosomal region of the sex chromosomes, in contrast to the case to mammals. These results imply the conservation of Ant4 is not likely simply driven by the sex chromosomal localization of the Ant2 gene and its subsequent inactivation during male meiosis. Taken together with the fact that Ant4 protein has a uniquely conserved structure when compared to other somatic Ant1, 2 and 3, there may be a specific advantage for mammals and lizards to express Ant4 in their male germ cells.

DOI： 10.1371/journal.pone.0023122

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DOI： 10.1364/AO.48.006716

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Publishing type：Research paper (scientific journal)  

DOI： 10.1681/ASN.2008111196

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Publishing type：Research paper (scientific journal)  

The scarcity of transplant allografts for diseased organs has prompted efforts at tissue regeneration using seeded scaffolds, an approach hampered by the enormity of cell types and complex architectures. Our goal was to decellularize intact organs in a manner that retained the matrix signal for differentiating pluripotent cells. We decellularized intact rat kidneys in a manner that preserved the intricate architecture and seeded them with pluripotent murine embryonic stem cells antegrade through the artery or retrograde through the ureter. Primitive precursor cells populated and proliferated within the glomerular, vascular, and tubular structures. Cells lost their embryonic appearance and expressed immunohistochemical markers for differentiation. Cells not in contact with the basement membrane matrix became apoptotic, thereby forming lumens. These observations suggest that the extracellular matrix can direct regeneration of the kidney, and studies using seeded scaffolds may help define differentiation pathways.

DOI： 10.1681/ASN.2008111196

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Publishing type：Research paper (scientific journal)  

DOI： 10.1158/1541-7786.MCR-09-0018

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Publishing type：Research paper (scientific journal)  

DNA methylation is an epigenetic mark essential for mammalian development, genomic stability, and imprinting. DNA methylation patterns are established and maintained by three DNA methyltransfereses: DNMT1, DNMT3A, and DNMT3B. Interestingly, all three DNMTs make use of alternative splicing. DNMT3B has nearly 40 known splice variants expressed in a tissue- and disease-specific manner, but very little is known about the role of these splice variants in modulating DNMT3B function. We describe here the identification and characterization of a novel alternatively spliced form of DNMT3B lacking exon 5 within the NH(2)-terminal regulatory domain. This variant, which we term DNMT3B3 Delta 5 because it is closely related in structure to the ubiquitously expressed DNMT3B3 isoform, is highly expressed in pluripotent cells and brain tissue, is downregulated during differentiation, and is conserved in the mouse. Creation of pluripotent iPS cells from fibroblasts results in marked induction of DNMT3B3 Delta 5. DNMT3B3 Delta 5 expression is also altered in human disease. with tumor cell lines displaying elevated or reduced expression depending on their tissue of origin. We then compared the DNA binding and subcellular localization of DNMT3B3 Delta 5 versus DNMT3B3, revealing that DNMT3B3 Delta 5 possessed significantly enhanced DNA binding affinity and displayed an altered nuclear distribution. Finally, ectopic overexpression of DNMT3B3 Delta 5 resulted in repetitive element hypomethylation and enhanced cell growth in a colony formation assay. Taken together, these results show that DNMT3B3 Delta 5 may play an important role in stem cell maintenance or differentiation and suggest that sequences encoded by exon 5 influence the functional properties of DNMT3B. (Mol Cancer Res 2009;7(10):1622-34)

DOI： 10.1158/1541-7786.MCR-09-0018

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Publishing type：Research paper (scientific journal)  

DOI： 10.1016/j.bbagrm.2008.12.005

PubMed

Publishing type：Research paper (scientific journal)   International / domestic magazine：International journal  

Adenine nucleotide translocase (Ant) mediates the exchange of ADP and ATP across the inner mitochondrial membrane in eukaryotes. Mice possess three distinct but highly homologous Ant isoforms, encoded by independent genes, whose transcription depends upon tissue type. Ant1 is expressed selectively in heart and skeletal muscles, Ant2 is ubiquitously expressed in most tissues but lower in skeletal muscle and testis, while Ant4 is exclusively expressed in the testis. Of interest, each of these Ant genes contains CpG islands in their proximal promoter regions. We investigated the methylation status of the three Ant genes in various tissues with active and inactive transcription. In contrast to the Ant4 gene in which CpG island methylation is essential for gene repression, the CpG islands of Ant1 and Ant2 are hypomethylated regardless of the gene expression status throughout the tissues of male mice. Despite the tissue specific expression profile of Ant1, CpG methylation is unlikely involved in the regulation of the gene. Consistent with these findings, addition of a CpG-demethylating agent, 5-aza-2'-deoxycitidine, to fibroblasts increased the expression of Ant4 but not Ant1 or Ant2 genes. This study provides insight regarding the differential regulation of Ant isoforms in mammals, whereby both the Ant1 and Ant2 genes are capable of expression, but the Ant4 gene is completely repressed throughout somatic tissues. To the best of our knowledge, this is a first example to clearly demonstrate a differential usage of CpG island methylation within a family of genes.

DOI： 10.1016/j.bbagrm.2008.12.005

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Publishing type：Research paper (scientific journal)  

DOI： 10.1634/stemcells.2007-0126

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Publishing type：Research paper (scientific journal)  

Nanog is a critical homeodomain factor responsible for maintaining embryonic stem ( ES) cell self-renewal and pluripotency. Of interest, Nanog expression is not homogeneous in the conventional culture of murine ES cells. A Nanog-high population expresses markers for pluripotent ES cells, whereas a Nanog-low population expresses markers for primitive endoderm, such as Gata6. Since the inner cell mass of early blastocysts has recently been reported to be heterogeneous in terms of Nanog and Gata6 expression, ES cells appear to closely resemble the developing stage from which they originate. We further demonstrate that Nanog can directly repress Gata6 expression through its binding to the proximal promoter region of the Gata6 gene and that overexpression of Nanog reduces heterogeneity during ES cell maintenance. Interestingly, Nanog heterogeneity does not correlate with the heterogeneous expression of stage-specific embryonic antigen-1, suggesting that multiple but overlapping levels of heterogeneity may exist in ES cells. These findings provide insight into the factors that control ES cell self-renewal and the earliest lineage commitment to primitive endoderm while also suggesting methods to promote homogeneity during ES cell maintenance.

DOI： 10.1634/stemcells.2007-0126

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Publishing type：Research paper (scientific journal)  

DOI： 10.1091/mbc.E07-01-0070

PubMed

Publishing type：Research paper (scientific journal)  

Gene silencing using small interfering RNA (siRNA) is a valuable laboratory tool and a promising approach to therapeutics for a variety of human diseases. Recently, RNA interference (RNAi) has been linked to cytoplasmic GW bodies (GWB). However, the correlation between RNAi and the formation of GWB, also known as mammalian processing bodies, remains unclear. In this report, we show that transfection of functional siRNA induced larger and greater numbers of GWB. This siRNA-induced increase of GWB depended on the endogenous expression of the target mRNA. Knockdown of GW182 or Ago2 demonstrated that the siRNA-induced increase of GWB required these two proteins and correlated with RNAi. Furthermore, knockdown of rck/p54 or LSm1 did not prevent the reassembly of GWB that were induced by and correlated with siRNA-mediated RNA silencing. We propose that RNAi is a key regulatory mechanism for the assembly of GWB, and in some cases, GWB may serve as markers for RNAi in mammalian cells.

DOI： 10.1091/mbc.e07-01-0070

PubMed

Publishing type：Research paper (scientific journal)  

DOI： 10.1161/CIRCULATIONAHA.106.642298

PubMed

Publishing type：Research paper (scientific journal)  

Background - Embryonic stem cell (ESC)-derived cardiomyocytes are anticipated to serve as a useful source for future cell-based cardiovascular disease therapies. Research emphasis is currently focused on determining methods to direct the differentiation of ESCs to a large population of cardiomyocytes with high purity. To this aim, understanding the molecular mechanisms that control ESC-to-cardiomyocyte differentiation should play a critical role in the development of this methodology. The Wnt/beta-catenin signaling pathway has been implicated in both embryonic cardiac development and in vitro ESC differentiation into cardiomyocytes. Chibby is a recently identified nuclear protein that directly binds to beta-catenin and antagonizes its transcriptional activity.
Methods and Results - Chibby was ubiquitously expressed in early stages of ESC differentiation but upregulated during cardiomyocyte specification. Of interest, the Chibby gene promoter has multiple binding sites for the cardiac-specific homeodomain protein Nkx2.5, and its promoter activity was indeed positively regulated by Nkx2.5. Furthermore, overexpression of Chibby increased cardiac differentiation of ESCs, whereas loss of Chibby by RNAi impaired cardiomyocyte differentiation.
Conclusions - These data illustrate the regulation and function of Chibby in facilitating cardiomyocyte differentiation from ESCs. By revealing molecular mechanisms that control ESC-to-cardiomyocyte differentiation, this study will allow for the future development of technologies to improve cardiomyocyte differentiation from ESCs.

DOI： 10.1161/CIRCULATIONAHA.106.642298

PubMed

Publishing type：Research paper (scientific journal)  

DOI： 10.1002/jbm.a.30942

PubMed

Publishing type：Research paper (scientific journal)  

Biomaterial scaffolds are fundamental components of strategies aimed at engineering a wide range of tissues. Scaffolds possessing uniform, oriented microtubular architectures could be ideal for multiple tissues, but are challenging to produce. Therefore, we developed hydrogel scaffolds possessing regular, tubular microstructures from self-assembled copper-capillary alginate gel (CCAG). To abrogate the rapid dissolution of CCAG in cell culture media, we treated it with oligochitosan and created a stable oligochitosan-CCAG (OCCAG) polyelectrolyte complex. Fourier transform infrared spectroscopy confirmed polyelectrolyte complexation between alginate and oligochitosan. OCCAG retained capillary morphology, shrank anisotropically in bulk, lost Cu2+ ions, and maintained (71.9 +/- 5.65)% of its mass in cell culture media. Next, we seeded mouse embryonic stem (ES) cells within OCCAG scaffolds, and examined cell morphology and quantified cell growth and viability over four days. ES cells were guided to form cylindrical structures of staggered cells within scaffold capillaries. Analysis of the total cells recovered from the scaffolds revealed exponential cell growth (normalized to day 0) that was statistically similar to gelatinized-plate controls. OCCAG-cultured ES cell viability was also not significantly different from controls at day 4. CCAG-derived scaffolds can therefore serve as a unique platform for stem cell-based tissue engineering. (c) 2006 Wiley Periodicals, Inc.

DOI： 10.1002/jbm.a.30942

PubMed

Publishing type：Research paper (scientific journal)  

DOI： 10.1128/MCB.00508-06

PubMed

Publishing type：Research paper (scientific journal)  

The homeobox gene Nanog is a key intrinsic determinant of self renewal in embryonic stem (ES) cells, and its repression leads ES cells to selectively differentiate into primitive endoderm. Although Nanog repression occurs at the outermost layer of ES cell aggregates independent of the leukemia inhibitory factor (LIF)/STAT3 pathway, it is largely undetermined what external cues and intracellular signals cause the event. Of interest, addition of the tyrosine phosphatase inhibitor, sodium vanadate, selectively repressed Nanog transcription without any detectable changes in upstream transcriptional regulators Oct3/4 and Sox2. Furthermore, sodium vanadate induced primitive endoderm differentiation, even in the inner cells of ES cell aggregates. Expression of Gata6 and Zfp42, two putative downstream Nanog effectors, was also increased and decreased by the addition of sodium vanadate, respectively, but these changes were eliminated by exogenous Nanog expression. The effects of sodium vanadate were abrogated by Grb2 deficiency or by the addition of the Mek inhibitor, PD98059. Indeed, PD98059 prevented Nanog repression induced by ES cell aggregation as well. Furthermore, transfection of a constitutive active Mek mutant into ES cells induced Nanog repression and primitive endoderm differentiation. These data indicate that the Grb2/Mek pathway primarily mediates Nanog gene repression upon ES cell differentiation into primitive endoderm.

DOI： 10.1128/MCB.00508-06

PubMed

Publishing type：Research paper (scientific journal)  

DOI： 10.1634/stemcells.2005-0119

PubMed

Publishing type：Research paper (scientific journal)  

The capacity for cellular differentiation is governed not only by the repertoire of available transcription factors but by the accessibility of cis-regulatory elements. Studying changes in epigenetic modifications during stem cell differentiation will help us understand how cells maintain or lose differentiation potential. We investigated changes in DNA methylation during the transition of pluripotent embryonic stem cells (ESCs) into differentiated cell types. Using a methylation-sensitive restriction fingerprinting method, we identified a novel adenine nucleotide (ADP/ATP) translocase gene, Ant4, that was selectively hypomethylated and expressed in undifferentiated mouse ESCs. In contrast to other pluripotent stem cell-specific genes such as Oct-4 and Nanog, the Ant4 gene was readily derepressed in differentiated cells after 5-aza-2'-deoxycytidine treatment. Moreover, expression of de novo DNA methyltransferases Dnmt3a and Dnmt3b was essential for repression and DNA methylation of the Ant4 gene during ESC differentiation. Although the deduced amino acid sequence of Ant4 is highly homologous to the previously identified Ant isoforms, the expression of Ant4 was uniquely restricted to developing gametes in adult mice, and its promoter hypomethylation was observed only in testis. Additionally, Ant4 was expressed in primordial germ cells. These data indicate that Ant4 is a pluripotent stem cell- and germ cell-specific isoform of adenine nucleotide translocase in mouse and that DNA methylation plays a primary role in its transcriptional silencing in somatic cells.

DOI： 10.1634/stemcells.2005-0119

PubMed

Publishing type：Research paper (scientific journal)  

DOI： 10.1038/sj.onc.1208540

PubMed

Publishing type：Research paper (scientific journal)  

The deoxycytidine analog 5-aza-2'-deoxycitidine (5-aza-dC) is a potent chemotherapeutic agent effective against selective types of cancer. The molecular mechanism by which 5-aza-dC induces cancer cell death, however, is not fully understood. It has been accepted that the mechanism of toxicity is due to the covalent binding between the DNA methyltransferase (Dnmt) and 5-aza-dC-substituted DNA. In order to de. ne which member of the Dnmt family plays a dominant role in the cytotoxicity, we examined the effect of 5-aza-dC on cell growth and apoptosis in various Dnmt null mutant embryonic stem (ES) cells. Of interest, Dnmt3a - Dnmt3b double null ES cells were highly resistant to 5-aza-dC when compared to wild type, Dnmt3a null, Dnmt3b null, or Dnmt1 null ES cells. The cellular sensitivity to 5-aza-dC correlated well with the expression status of Dnmt3 in both undifferentiated and differentiated ES cells. When exogenous Dnmt3a or Dnmt3b was expressed in double null ES cells, the sensitivity to 5-aza-dC was partially restored. These results suggest that the cytotoxic effect of 5-aza-dC may be mediated primarily through Dnmt3a and Dnmt3b de novo DNA methyltransferases. Further, the ability to form Dnmt-DNA adducts was similar in Dnmt1 and Dnmt3, and the expression level of Dnmt3 was not higher than that of Dnmt1 in ES cells. Therefore, Dnmt3-DNA adducts may be more effective for inducing apoptosis than Dnmt1-DNA adducts. These results imply a therapeutic potential of 5-aza-dC to cancers expressing Dnmt3.

DOI： 10.1038/sj.onc.1208540

PubMed

Total pages：150   Responsible for pages：p77-82   Book type：Scholarly book

フェニルケトン尿症(PKU)は,新生児マススクリーニングにて血中のフェニルアラニン(Phe)高値を指標に発見される。新生児期に診断し,速やかに血中Phe値を適正範囲内に下げ,維持することで,不可逆的な知的障がいの発症を防ぐことができるようになった。PKUは乾燥濾紙血を用いた血中Pheの測定法の開発により新生児スクリーニングの契機となった代表疾患である。本稿では,PKU研究の歴史的な背景と日本での診断方法と診療の現状,今後の課題について概説する。(著者抄録)

フェニルケトン尿症(PKU)は,新生児マススクリーニングにて血中のフェニルアラニン(Phe)高値を指標に発見される。新生児期に診断し,速やかに血中Phe値を適正範囲内に下げ,維持することで,不可逆的な知的障がいの発症を防ぐことができるようになった。PKUは乾燥濾紙血を用いた血中Pheの測定法の開発により新生児スクリーニングの契機となった代表疾患である。本稿では,PKU研究の歴史的な背景と日本での診断方法と診療の現状,今後の課題について概説する。(著者抄録)

症例は生後9ヵ月の女児。周産期に異常所見を認めず、1ヵ月健診まで体重増加は良好であった。3ヵ月健診時に体重増加不良を、6ヵ月時には頻脈、発疹を指摘されるも心雑音なく、食物アレルギーの疑いで小麦、牛乳の除去食を行っていた。9ヵ月時に体重増加不良が改善せず、胸部聴診異常を認め、精査目的に当院へ紹介となった。胸部CT検査にて左胸腔内に腸管の逸脱像を認め、横隔膜ヘルニアと診断した。待機的に胸腔鏡下横隔膜ヘルニア修復術が施行され、術後経過は問題なく、術後5日目に退院となった。手術後3年になるが、再発はなく体重増加も順調となり、問題なく経過している。先天性横隔膜ヘルニアは生後早期に発症する早発型と、生後30日以降に発症する遅発性先天性横隔膜ヘルニア(以下本症)に分類される。本症は先天性横隔膜ヘルニアの5%程度と稀であるのに加え、呼吸器症状や循環不全などの症状を呈さない症例が多く、診断には時間を要することが多いとされる。また、一般的に予後は良好であるが、急激に悪化し死に至った報告もあり、注意を要する疾患である。自験例では乳幼児健診での胸部聴診という一般的な身体診察の異常が診断の契機となった。症状が続く場合にはフォローをとぎらせず、慎重に身体所見を確認し、必要に応じて精査を行うことの重要性が再確認された。稀な疾患ではあるが鑑別すべき疾患の一つであると再認識されたため、文献的考察を加え報告する。(著者抄録)

症例は11歳5ヵ月女児。9歳頃から成長率が低下していたが近医や学校をはじめ誰からも指摘されていなかった。11歳3ヵ月時より頭痛が出現、11歳4ヵ月時に右眼視力低下を自覚し、眼科で右眼水平下半盲を認めた。頭部MRIでトルコ鞍上部に3cm大の腫瘍性病変を認め、PRL高値のためプロラクチノーマの疑いで当院を紹介された。受診時に右眼視力が著しく低下しており緊急に経鼻内視鏡下腫瘍摘出術が施行され、組織診断によりプロラクチノーマと診断された。術後、PRL高値が残存したためドパミン作動薬による追加治療を開始した。術後にTSH・GH・LH・FSH分泌の回復は得られなかった。経過中に尿崩症の合併はなく、視機能障害は完全に回復した。早期に腫瘍の圧迫を解除すれば視機能は回復する可能性が高い。成長率低下や視機能低下を認めた場合は頭蓋内病変の迅速な精査を考慮すべきと考える。(著者抄録)

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Publishing type：Article, review, commentary, editorial, etc. (scientific journal)   Kind of work：Single Work  

●アミノ酸代謝異常症は、関係するアミノ酸の種類により病態が大きく異なる。●国内での頻度はフェニルケトン尿症・高フェニルアラニン血症が高く、メープルシロップ尿症、ホモシスチン尿症はきわめて低い。●診断方法も個々の疾患において異なることに注意が必要。●治療は、代謝できないアミノ酸を除去した特殊ミルクの使用が原則だが、特異的な補酵素を大量に補充する治療に反応する病型も存在する。(著者抄録)

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●アミノ酸代謝異常症は、関係するアミノ酸の種類により病態が大きく異なる。●国内での頻度はフェニルケトン尿症・高フェニルアラニン血症が高く、メープルシロップ尿症、ホモシスチン尿症はきわめて低い。●診断方法も個々の疾患において異なることに注意が必要。●治療は、代謝できないアミノ酸を除去した特殊ミルクの使用が原則だが、特異的な補酵素を大量に補充する治療に反応する病型も存在する。(著者抄録)

●アミノ酸代謝異常症は、関係するアミノ酸の種類により病態が大きく異なる。●国内での頻度はフェニルケトン尿症・高フェニルアラニン血症が高く、メープルシロップ尿症、ホモシスチン尿症はきわめて低い。●診断方法も個々の疾患において異なることに注意が必要。●治療は、代謝できないアミノ酸を除去した特殊ミルクの使用が原則だが、特異的な補酵素を大量に補充する治療に反応する病型も存在する。(著者抄録)

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我々は極低出生体重児SGAの1歳半時点の神経学的予後をAGAと比較検討した。当院NICUに2010年から2016年の間に入院した極低出生体重児76例(AGA26例、SGA50例)を対象とし、診療録を後方視的に検討した。修正1歳半時点の新版K式発達検査における発達指数(DQ)を全領域、姿勢・運動、認知・適応、言語・社会の各々で検討したところ、姿勢・運動のみSGA群が有意に低い結果となった(100.7 vs 90.5;p=0.037)。またAGA群は全例、全項目でDQ70以上であったが、SGA群は全項目においてDQ70未満を呈する症例を認めた。DQ85未満の割合は全領域、姿勢・運動においてSGA群の方が高い傾向にあった。また、多変量解析を行いDQ85未満に寄与する周産期因子について検討した結果、SGAが神経学的予後に影響を及ぼすことが示唆された。特に、在胎週数が30週未満のSGA群では出生体重-2.5SDを境界に発達に強く影響のある可能性が示唆された。(著者抄録)

【背景】スギ花粉舌下免疫療法(SLIT)導入後にトマトの花粉-食物アレルギー症候群(PFAS)を発症した報告はこれまで認めない。【症例】12歳男児。スギ花粉症と気管支喘息、リンゴ、キウイ、アボカドのPFASあり。トマトは無症状で摂取可能であった。スギ花粉症に対しSLIT開始1ヵ月後、ミニトマトを2個摂取した直後に咽頭そう痒感と呼吸苦を認めた。SLIT開始前と比べ5ヵ月後のスギ、トマト特異的IgE抗体価は共に上昇を認め、トマトのprick-to-prick testは陰性から陽性に変化した。SLIT開始5ヵ月後の食物経口負荷試験はミニトマト1個摂取直後に咽頭そう痒感を認めた。なおトマトの加熱加工品は症状なく摂取可能であった。以上からトマトのPFASを発症したと考え、生のトマトは除去するよう指導した。【結語】スギSLITによりトマトに対する感作が増強され、トマトのPFASを発症した可能性が考えられる。SLITを行う上で、対象となる花粉と交差反応性のある食物を摂取する際は注意が必要かもしれない。(著者抄録)

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Small for gestational age(SGA)の成因は様々で半数程度が原因不明とされてきた。しかし近年の遺伝学的検査の進歩により、原因不明のSGAの原因が同定できることがある。今回、SGA性低身長症として成長ホルモン治療中に、サブテロメアfluorescence in situ hybridization(FISH)法において5番染色体短腕欠失と19番染色体長腕重複が判明した症例を経験した。5p-症候群としては典型症状に乏しく、17歳4ヵ月と年長で診断された。アレイcomparative genomic hybridization(CGH)解析で5pの欠失領域は狭く、さらに19q重複を合併していたことから、本症例の臨床像は説明されると考えられた。SGAという多彩な病態を含む状態に対し遺伝学的診断をつけることで、養育者に正しい知識や予後予測の情報提供ができる利点がある。(著者抄録)

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14歳10ヵ月の女子。母方叔父が潰瘍性大腸炎、母方いとこがCrohn病。両足関節の腫脹と両下腿の結節性紅斑が出現し、腹痛や下痢、体重増加不良はなかった。血液検査では白血球数10,400/μL、CRP5.12mg/dLと炎症所見がみられ、抗dsDNA抗体等の自己抗体は陰性を示し、ベーチェット病の鑑別目的に実施したHLA検査においてB*35、B*39が陽性であった。経過中、肛門周囲膿瘍がみられ、家族歴も含め炎症性腸疾患を疑い内視鏡検査を施行した。胃には竹の節状所見、小腸から大腸にはびらんを散在性に認めた。大腸の生検組織には非乾酪性類上皮細胞肉芽腫を認めCrohn病と診断した。関節症状は非ステロイド性消炎鎮痛薬により軽減が得られたが、弛張熱が持続するため経口5-ASA製剤・ステロイド製剤を併用し、アザチオプリンとインフリキシマブにより寛解導入した。HLA-B*35は1型末梢性関節炎を合併するCrohn病に、B*39は日本人におけるHLA-B*27陰性脊椎関節炎に陽性率が高いとされる。HLA所見と本症例の病態との関連について考察を加えた。(著者抄録)

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Publishing type：Article, review, commentary, editorial, etc. (scientific journal)   Kind of work：Single Work  

Publishing type：Article, review, commentary, editorial, etc. (scientific journal)  

Publishing type：Article, review, commentary, editorial, etc. (scientific journal)   Kind of work：Single Work  

＜Key Points＞(1)BH4・1回負荷試験はPhe制限食を開始する前に負荷試験を施行できることが望ましい。(2)BH4負荷試験にはこれまでに重大な副作用は認められておらず、とくに禁忌併用薬はなく、検査前の食事制限もない。(3)負荷試験は血中Phe値の変化で判定するため、試験期間中は一定の食事内容、Phe摂取量を維持することが重要である。(著者抄録)

＜Key Points＞(1)BH4・1回負荷試験はPhe制限食を開始する前に負荷試験を施行できることが望ましい。(2)BH4負荷試験にはこれまでに重大な副作用は認められておらず、とくに禁忌併用薬はなく、検査前の食事制限もない。(3)負荷試験は血中Phe値の変化で判定するため、試験期間中は一定の食事内容、Phe摂取量を維持することが重要である。(著者抄録)

Publishing type：Article, review, commentary, editorial, etc. (scientific journal)  

＜Key Points＞(1)BH4・1回負荷試験はPhe制限食を開始する前に負荷試験を施行できることが望ましい。(2)BH4負荷試験にはこれまでに重大な副作用は認められておらず、とくに禁忌併用薬はなく、検査前の食事制限もない。(3)負荷試験は血中Phe値の変化で判定するため、試験期間中は一定の食事内容、Phe摂取量を維持することが重要である。(著者抄録)

Publishing type：Article, review, commentary, editorial, etc. (scientific journal)  

Publishing type：Article, review, commentary, editorial, etc. (scientific journal)  

Publishing type：Article, review, commentary, editorial, etc. (scientific journal)   Kind of work：Single Work  

赤ちゃんは自分では何もできない状態で生まれ、一般的な主訴があって受診する成人での診療と全くことなる医療が必要となる。この新生児期には、不可逆的な障がいを引き起こす前に診断ができる大きな可能性を秘めている。その代表的な疾患は、フェニルケトン尿症(Penylketonuria;PKU)である。日本では1977年に新生児マススクリーニングが開始となり、これまでに600人以上の患者が、重篤な精神発達遅滞を免れることができた。しかし、未だ新生児スクリーニングに加えられない疾患があり、稀少な疾患であるが故に診断が遅れ、新規治療法があるにもかかわらず、治療の機会が失われている。近年のゲノム解析技術の革新により、これまで未診断であった患者の診断が可能となってきた。2015年、日本で未診断疾患イニシアチブ(Initiative on Rare and Undiagnosed Diseases;IRUD)が立ち上がり、多くの稀少疾患専門医との連携診療体制が整いつつある。ゲノム解析技術の進歩により、個々の遺伝子の多型による健康への影響や、薬に対する反応性を予測することも可能になってきた。一方、ゲノム情報の総体としての表現型を評価することは現在も困難であり、一つのツールとして、iPS細胞を用いた疾患モデルが注目されており、ゲノム研究からの成果から推測される分子メカニズムを実証することが期待される。(著者抄録)

Publishing type：Article, review, commentary, editorial, etc. (scientific journal)  

赤ちゃんは自分では何もできない状態で生まれ、一般的な主訴があって受診する成人での診療と全くことなる医療が必要となる。この新生児期には、不可逆的な障がいを引き起こす前に診断ができる大きな可能性を秘めている。その代表的な疾患は、フェニルケトン尿症(Penylketonuria;PKU)である。日本では1977年に新生児マススクリーニングが開始となり、これまでに600人以上の患者が、重篤な精神発達遅滞を免れることができた。しかし、未だ新生児スクリーニングに加えられない疾患があり、稀少な疾患であるが故に診断が遅れ、新規治療法があるにもかかわらず、治療の機会が失われている。近年のゲノム解析技術の革新により、これまで未診断であった患者の診断が可能となってきた。2015年、日本で未診断疾患イニシアチブ(Initiative on Rare and Undiagnosed Diseases;IRUD)が立ち上がり、多くの稀少疾患専門医との連携診療体制が整いつつある。ゲノム解析技術の進歩により、個々の遺伝子の多型

赤ちゃんは自分では何もできない状態で生まれ、一般的な主訴があって受診する成人での診療と全くことなる医療が必要となる。この新生児期には、不可逆的な障がいを引き起こす前に診断ができる大きな可能性を秘めている。その代表的な疾患は、フェニルケトン尿症(Penylketonuria;PKU)である。日本では1977年に新生児マススクリーニングが開始となり、これまでに600人以上の患者が、重篤な精神発達遅滞を免れることができた。しかし、未だ新生児スクリーニングに加えられない疾患があり、稀少な疾患であるが故に診断が遅れ、新規治療法があるにもかかわらず、治療の機会が失われている。近年のゲノム解析技術の革新により、これまで未診断であった患者の診断が可能となってきた。2015年、日本で未診断疾患イニシアチブ(Initiative on Rare and Undiagnosed Diseases;IRUD)が立ち上がり、多くの稀少疾患専門医との連携診療体制が整いつつある。ゲノム解析技術の進歩により、個々の遺伝子の多型による健康への影響や、薬に対する反応性を予測することも可能になってきた。一方、ゲノム情報の総体としての表現型を評価することは現在も困難であり、一つのツールとして、iPS細胞を用いた疾患モデルが注目されており、ゲノム研究からの成果から推測される分子メカニズムを実証することが期待される。(著者抄録)

Publishing type：Article, review, commentary, editorial, etc. (scientific journal)   Kind of work：Single Work  

Publishing type：Article, review, commentary, editorial, etc. (scientific journal)  

Publishing type：Article, review, commentary, editorial, etc. (scientific journal)   Kind of work：Single Work  

Publishing type：Article, review, commentary, editorial, etc. (scientific journal)   Kind of work：Single Work  

Publishing type：Article, review, commentary, editorial, etc. (scientific journal)  

Publishing type：Article, review, commentary, editorial, etc. (scientific journal)  

Publishing type：Article, review, commentary, editorial, etc. (scientific journal)   Kind of work：Single Work  

ムコ多糖症(MPS)は、造血幹細胞移植療法や酵素補充療法により治療可能な疾患であり、早期診断が望まれる。全身性の疾患で、幅広い診療科にわたり受診する機会があり、当該疾患を疑うことができれば早期診断は可能である。受診する契機となる症状としては、鼠径・臍ヘルニア、発達の遅れ、とくに言葉の遅れや多動、頭囲拡大や骨・関節の変形、繰り返す中耳炎や難聴、心雑音、角膜混濁、肝腫大、低身長(ただし乳幼児期は過成長)。丁寧な病歴、家族歴の聴取によりこれら共通する症状の有無を確認し、身体診察では、広範な蒙古斑、ヘルニア、粗な顔貌、関節所見、肝腫大が参考になる。MPSを疑えば、全身骨単純X線検査、尿中ウロン酸分析にて蓄積物質を特定する。確定診断には病型別で欠損する酵素の活性を測定する。遺伝子解析は、重症度や治療法の選択において有益な情報が得られる。現在、中枢病変、骨病変へのより効果的な治療法の開発がすすめられている。(著者抄録)

Publishing type：Article, review, commentary, editorial, etc. (scientific journal)  

ムコ多糖症(MPS)は、造血幹細胞移植療法や酵素補充療法により治療可能な疾患であり、早期診断が望まれる。全身性の疾患で、幅広い診療科にわたり受診する機会があり、当該疾患を疑うことができれば早期診断は可能である。受診する契機となる症状としては、鼠径・臍ヘルニア、発達の遅れ、とくに言葉の遅れや多動、頭囲拡大や骨・関節の変形、繰り返す中耳炎や難聴、心雑音、角膜混濁、肝腫大、低身長(ただし乳幼児期は過成長)。丁寧な病歴、家族歴の聴取によりこれら共通する症状の有無を確認し、身体診察では、広範な蒙古斑、ヘルニア、粗な顔貌、関節所見、肝腫大が参考になる。MPSを疑えば、全身骨単純X線検査、尿中ウロン酸分析にて蓄積物質を特定する。確定診断には病型別で欠損する酵素の活性を測定する。遺伝子解析は、重症度や治療法の選択において有益な情報が得られる。現在、中枢病変、骨病変へのより効果的な治療法の開発がすすめられている。(著者抄録

ムコ多糖症(MPS)は、造血幹細胞移植療法や酵素補充療法により治療可能な疾患であり、早期診断が望まれる。全身性の疾患で、幅広い診療科にわたり受診する機会があり、当該疾患を疑うことができれば早期診断は可能である。受診する契機となる症状としては、鼠径・臍ヘルニア、発達の遅れ、とくに言葉の遅れや多動、頭囲拡大や骨・関節の変形、繰り返す中耳炎や難聴、心雑音、角膜混濁、肝腫大、低身長(ただし乳幼児期は過成長)。丁寧な病歴、家族歴の聴取によりこれら共通する症状の有無を確認し、身体診察では、広範な蒙古斑、ヘルニア、粗な顔貌、関節所見、肝腫大が参考になる。MPSを疑えば、全身骨単純X線検査、尿中ウロン酸分析にて蓄積物質を特定する。確定診断には病型別で欠損する酵素の活性を測定する。遺伝子解析は、重症度や治療法の選択において有益な情報が得られる。現在、中枢病変、骨病変へのより効果的な治療法の開発がすすめられている。(著者抄録)

Publishing type：Article, review, commentary, editorial, etc. (scientific journal)  

J-GLOBAL

Publishing type：Article, review, commentary, editorial, etc. (scientific journal)  

J-GLOBAL

J-GLOBAL

Publishing type：Article, review, commentary, editorial, etc. (scientific journal)  

J-GLOBAL

J-GLOBAL

Publishing type：Article, review, commentary, editorial, etc. (scientific journal)   Kind of work：Single Work  

Publishing type：Article, review, commentary, editorial, etc. (scientific journal)  

Publishing type：Article, review, commentary, editorial, etc. (scientific journal)  

Publishing type：Article, review, commentary, editorial, etc. (scientific journal)  

CiNii Article

J-GLOBAL

Publishing type：Article, review, commentary, editorial, etc. (scientific journal)   Kind of work：Single Work  

＜Key Points＞(1)新生児マス・スクリーニングの精査では、高Phe血症の程度にかかわらず、PKUとBH4欠損症の鑑別のためプテリジン分析およびDHPR活性測定が全例必要である。(2)初診時のBH4・1回負荷試験は、血中Phe値が6mg/dL以上では初診時に施行すべきである。(3)Phe治療開始後1ヵ月以後も乳児期は長くとも月1回程度、幼児期は1〜2ヵ月に1回程度血中Phe値を測定して、Phe摂取量の調節を行う。(4)Phe摂取制限する際、カロリーや蛋白質が不足しがちとなり、異化亢進により血中Phe値のコントロールが不良となるため、十分なカロリーと適切な蛋白質の摂取量確認が必要である。(著者抄録)

Publishing type：Article, review, commentary, editorial, etc. (scientific journal)  

＜Key Points＞(1)新生児マス・スクリーニングの精査では、高Phe血症の程度にかかわらず、PKUとBH4欠損症の鑑別のためプテリジン分析およびDHPR活性測定が全例必要である。(2)初診時のBH4・1回負荷試験は、血中Phe値が6mg/dL以上では初診時に施行すべきである。(3)Phe治療開始後1ヵ月以後も乳児期は長くとも月1回程度、幼児期は1〜2ヵ月に1回程度血中Phe値を測定して、Phe摂取量の調節を行う。(4)Phe摂取制限する際、カロリーや蛋白質が不足しがちとなり、異化亢進により血中Phe値のコントロールが不良となるため、十分なカロリーと適切な蛋白質の摂取量確認が必要である。(著者抄録)

＜Key Points＞(1)新生児マス・スクリーニングの精査では、高Phe血症の程度にかかわらず、PKUとBH4欠損症の鑑別のためプテリジン分析およびDHPR活性測定が全例必要である。(2)初診時のBH4・1回負荷試験は、血中Phe値が6mg/dL以上では初診時に施行すべきである。(3)Phe治療開始後1ヵ月以後も乳児期は長くとも月1回程度、幼児期は1〜2ヵ月に1回程度血中Phe値を測定して、Phe摂取量の調節を行う。(4)Phe摂取制限する際、カロリーや蛋白質が不足しがちとなり、異化亢進により血中Phe値のコントロールが不良となるため、十分なカロリーと適切な蛋白質の摂取量確認が必要である。(著者抄録)

J-GLOBAL

J-GLOBAL

Publishing type：Article, review, commentary, editorial, etc. (scientific journal)   Kind of work：Single Work  

Publishing type：Article, review, commentary, editorial, etc. (scientific journal)  

Publishing type：Article, review, commentary, editorial, etc. (scientific journal)   Kind of work：Single Work  

Publishing type：Article, review, commentary, editorial, etc. (scientific journal)  

Publishing type：Article, review, commentary, editorial, etc. (scientific journal)  

Publishing type：Article, review, commentary, editorial, etc. (scientific journal)  

ヒトの老化研究にiPS細胞を利用して研究する人のために、できるだけ有用な情報を提供することを目的として、現在までに報告された主要論文「iPS細胞を用いた老化疾患モデル:ハッチンソン・ギルフォード・プロジェリア症候群の場合」の概要を紹介し、iPS技術でこれから一体何ができるかについて述べた。さらに、iPS細胞で老化やアンチエイジングの研究を試みるときに最も大切な基礎知識であるリプログラミングで、細胞の一体何が「若返る」のかについて、最新の知見を交えて考察した。

Publishing type：Article, review, commentary, editorial, etc. (scientific journal)  

日本発のテクノロジーであるiPS細胞は瞬く間に世界に拡がり、現在その臨床応用に向けて熾烈な競争がなされている。その1つが疾患iPS細胞を用いての病態解明および治療法の開発で、iPS細胞研究の中では現在最も臨床に近い分野である。米国ではすでに多数の主要大学病院でiPS coreが設立され、患者からの疾患iPS細胞の樹立が日常的に行われている。また、本邦では昨年12月、京都大学医学部附属病院iPS細胞臨床開発部いわゆる"iPS外来"が開設され、さまざまな分野の研究者が疾患iPS細胞を利用できる基盤が整ってきた。本稿では、さらに多くの研究者・医療従事者が疾患iPS細胞の特徴と利点を広く共有できるように、iPS細胞を用いた疾患研究のこれまでの応用例と今後の展望を紹介したい。(著者抄録)

Publishing type：Article, review, commentary, editorial, etc. (scientific journal)  

ヒトの老化研究にiPS細胞を利用して研究する人のために、できるだけ有用な情報を提供することを目的として、現在までに報告された主要論文「iPS細胞を用いた老化疾患モデル:ハッチンソン・ギルフォード・プロジェリア症候群の場合」の概要を紹介し、iPS技術でこれから一体何ができるかについて述べた。さらに、iPS細胞で老化やアンチエイジングの研究を試みるときに最も大切な基礎知識であるリプログラミングで、細胞の一体何が「若返る」のかについて、最新の知見を交えて考察した。

日本発のテクノロジーであるiPS細胞は瞬く間に世界に拡がり、現在その臨床応用に向けて熾烈な競争がなされている。その1つが疾患iPS細胞を用いての病態解明および治療法の開発で、iPS細胞研究の中では現在最も臨床に近い分野である。米国ではすでに多数の主要大学病院でiPS coreが設立され、患者からの疾患iPS細胞の樹立が日常的に行われている。また、本邦では昨年12月、京都大学医学部附属病院iPS細胞臨床開発部いわゆる"iPS外来"が開設され、さまざまな分野の研究者が疾患iPS細胞を利用できる基盤が整ってきた。本稿では、さらに多くの研究者・医療従事者が疾患iPS細胞の特徴と利点を広く共有できるように、iPS細胞を用いた疾患研究のこれまでの応用例と今後の展望を紹介したい。(著者抄録)

Publishing type：Article, review, commentary, editorial, etc. (scientific journal)  

日本発のテクノロジーであるiPS細胞は瞬く間に世界に拡がり、現在その臨床応用に向けて熾烈な競争がなされている。その1つが疾患iPS細胞を用いての病態解明および治療法の開発で、iPS細胞研究の中では現在最も臨床に近い分野である。米国ではすでに多数の主要大学病院でiPS coreが設立され、患者からの疾患iPS細胞の樹立が日常的に行われている。また、本邦では昨年12月、京都大学医学部附属病院iPS細胞臨床開発部いわゆる&quot;iPS外来&quot;が開設され、さまざまな分野の研究者が疾患iPS細胞を利用できる基盤が整ってきた。本稿では、さらに多くの研究者・医療従事者が疾患iPS細胞の特徴と利点を広く共有できるように、iPS細胞を用いた疾患研究のこれまでの応用例と今後の展望を紹介したい。(著者抄録)

ヒトの老化研究にiPS細胞を利用して研究する人のために、できるだけ有用な情報を提供することを目的として、現在までに報告された主要論文「iPS細胞を用いた老化疾患モデル:ハッチンソン・ギルフォード・プロジェリア症候群の場合」の概要を紹介し、iPS技術でこれから一体何ができるかについて述べた。さらに、iPS細胞で老化やアンチエイジングの研究を試みるときに最も大切な基礎知識であるリプログラミングで、細胞の一体何が「若返る」のかについて、最新の知見を交えて考察した。

Publishing type：Article, review, commentary, editorial, etc. (scientific journal)  

iPS細胞(induced pluripotent stem cell)は、線維芽細胞など体細胞を初期化(リプログラミング)することにより樹立できる多能性幹細胞である。初期胚から樹立されるES細胞(embryonic stem cell)と同等の性質を有し、体内のあらゆる細胞に分化する能力をもつことから、ヒトでは採取が困難な神経や心筋などの細胞をiPS細胞からin vitroで作製することができる。この技術の応用のひとつとして、さまざまな疾患の患者からiPS細胞を樹立し、さらには疾患関連細胞へと分化することで、個々の患者の病態を細胞レベルで再現することができるようになってきた。本稿では、iPS細胞を利用した新しい疾患モデル作製の現状と今後の展望について概説する。(著者抄録)

Publishing type：Article, review, commentary, editorial, etc. (scientific journal)  

iPS細胞(induced pluripotent stem cell)は、線維芽細胞など体細胞を初期化(リプログラミング)することにより樹立できる多能性幹細胞である。初期胚から樹立されるES細胞(embryonic stem cell)と同等の性質を有し、体内のあらゆる細胞に分化する能力をもつことから、ヒトでは採取が困難な神経や心筋などの細胞をiPS細胞からin vitroで作製することができる。この技術の応用のひとつとして、さまざまな疾患の患者からiPS細胞を樹立し、さらには疾患関連細胞へと分化することで、個々の患者の病態を細胞レベルで再現することができるようになってきた。本稿では、iPS細胞を利用した新しい疾患モデル作製の現状と今後の展望について概説する。(著者抄録)