Kyushu University Academic Staff Educational and Research Activities Database
List of Reports
Shouichi Ohga Last modified date:2021.07.15

Professor / Department of Clinical Medicine / Faculty of Medical Sciences

1. , Miho Maeda, Akira Morimoto, Yoko Shioda, Takeshi Asano, Yuhki Koga, Yozo Nakazawa, Hirokazu Kanegane, Kazuko Kudo, Shouichi Ohga, Eiichi Ishii, Long-term outcomes of children with extracutaneous juvenile xanthogranulomas in Japan, Pediatric Blood and Cancer, 10.1002/pbc.28381, 2020.07, Background: Juvenile xanthogranuloma (JXG) is the most common non-Langerhans cell histiocytosis in children. The mortality and morbidity of JXG with extracutaneous lesions remain unclear. Methods: Data of patients aged < 18 years who were diagnosed with JXG between 2001 and 2010 were retrospectively collected through a nationwide survey. Results: Twenty patients (11 male and nine female) had extracutaneous lesions. The median observation time was 10 years (range, 0-17). Six patients presented with symptoms at birth. The median age at diagnosis was 8.5 months (range, 0 month-13 years). Fifteen patients underwent treatment for JXG, including chemotherapy (n = 11), and five did not receive treatment. All patients except one survived; 17 were disease-free and two survived with disease. One newborn-onset patient with liver, spleen, and bone marrow involvement died of the disease. Permanent sequelae included central diabetes insipidus, growth hormone deficiency, and panhypopituitarism detected at diagnosis in three, one, and two patients, respectively. Four patients had visual impairment (optic nerve compression and intraocular invasion in two each), three had epilepsy, one had mental retardation, and one had a skin scar. Eight patients who had intracranial lesions were older at diagnosis, and had a higher frequency of disease-related comorbidities and permanent sequelae than those without intracranial involvement. Conclusions: Patients with extracutaneous JXG had good outcomes, although those with intracranial lesions had serious permanent sequelae. Effective and safe treatment regimens for patients with intracranial JXG need to be developed..
2. Kiwako Yamamoto-Hanada, Eiryo Kawakami, Mayako Saito-Abe, Miori Sato, Hiroshi Mitsubuchi, Masako Oda, Takahiko Katoh, Masafumi Sanefuji, Shouichi Ohga, Mari Kuwajima, Nathan Mise, Akihiko Ikegami, Fujio Kayama, Ayako Senju, Masayuki Shimono, Koichi Kusuhara, Shin Yamazaki, Shoji F. Nakayama, Kenji Matsumoto, Hirohisa Saito, Yukihiro Ohya, Exploratory analysis of plasma cytokine/chemokine levels in 6-year-old children from a birth cohort study, Cytokine, 10.1016/j.cyto.2020.155051, 2020.06, This study aimed to reveal a new dimension of allergy profiles in the general population by using machine learning to explore complex relationships among various cytokines/chemokines and allergic diseases (asthma and atopic dermatitis; AD). We examined the symptoms related to asthma and AD and the plasma levels of 72 cytokines/chemokines obtained from a general population of 161 children at 6 years of age who participated in a pilot birth cohort study of the Japan Environment and Children's Study (JECS). The children whose signs and symptoms fulfilled the criteria of AD, which are mostly based on questionnaire including past symptoms, tended to have higher levels of the two chemokine ligands, CCL17 and CCL27, which are used for diagnosis of AD. On the other hand, another AD-related chemokine CCL22 level in plasma was higher only in children with visible flexural eczema, which is one of AD diagnostic criteria but was judged on the same day of blood examination unlike other criteria. Here, we also developed an innovative method of machine learning for elucidating the complex cytokine/chemokine milieu related to symptoms of allergic diseases by using clustering analysis based on the random forest dissimilarity measure that relies on artificial intelligence (AI) technique. To our surprise, the majority of children showing at least any asthma-related symptoms during the last month were divided by AI into the two clusters, either cluster-2 having elevated levels of IL-33 (related to eosinophil activation) or cluster-3 having elevated levels of CXCL7/NAP2 (related to neutrophil activation), among the total three clusters. Future studies will clarify better approach for allergic diseases by endotype classification..
3. Yu Taniguchi, Shin Yamazaki, Takehiro Michikawa, Shoji F. Nakayama, Makiko Sekiyama, Hiroshi Nitta, Hidetoshi Mezawa, Mayako Saito-Abe, Masako Oda, Hiroshi Mitsubuchi, Masafumi Sanefuji, Shouichi Ohga, Nathan Mise, Akihiko Ikegami, Masayuki Shimono, Reiko Suga, Associations of dog and cat ownership with wheezing and asthma in children
Pilot study of the Japan Environment and children’s study
, PloS one, 10.1371/journal.pone.0232604, 2020.05, Objectives No previous study has used repeated measures data to examine the associations of dog/ cat ownership with wheezing and asthma prevalence among children. This prospective study used repeated measurers analysis to determine whether dog/cat ownership in childhood is an independent risk factor for wheezing and asthma, after adjustment for gestational, socio-economical, and demographical confounders confounders, in Japan. Methods We conducted a multicenter pilot study of the Japan Environment and Children’s Study (JECS) during 2009–2010. Among 440 newborn infants enrolled, 410 (52.8% males) were evaluated for dog/cat ownership in the home and history of wheezing and asthma in five follow-up questionnaire surveys (until age 6 years). Dog/cat ownership during follow-up period was categorized into four groups: 7.6% were long-term dog/cat owners, 5.9% were toddler-age owners, 5.9% were preschool-age owners, and 80.7% were never owners. Results The prevalence of wheezing during follow-up period increased from 20.8% to 35.4% and the prevalence of asthma increased from 1.3% to 16.3%. A fitted logistic generalized estimating equation models including important confounders showed no significant associations of the interaction between dog and/or cat ownership and follow-up time with the risks of wheezing and asthma. However, the risks of wheezing and asthma were slightly lower for long-term and toddler-age dog/cat owners than for preschool-age and never owners. Conclusions The present findings suggest that dog and cat ownership from toddler-age does not increase the risks of wheezing and asthma compared with never owners among Japanese children..
4. Shoji F. Nakayama, Tomohiko Isobe, Miyuki Iwai-Shimada, Yayoi Kobayashi, Yukiko Nishihama, Yu Taniguchi, Makiko Sekiyama, Takehiro Michikawa, Shin Yamazaki, Hiroshi Nitta, Masako Oda, Hiroshi Mitsubuchi, Masafumi Sanefuji, Shouichi Ohga, Nathan Mise, Akihiko Ikegami, Reiko Suga, Masayuki Shimono, Poly- and perfluoroalkyl substances in maternal serum
Method development and application in Pilot Study of the Japan Environment and Children's Study
, Journal of Chromatography A, 10.1016/j.chroma.2020.460933, 2020.05, Poly- and perfluoroalkyl substances (PFAS) have been investigated in a number of cohort studies due to concern over their adverse health effects. The aim of this study was to develop a reliable, high throughput and cost-effective analytical method for a broad range of PFAS in human serum. Protein precipitation, automatic solid phase extraction (SPE) pre-treatment and column-switching LC-MS/MS were employed. The optimised and validated method was then used to analyse the levels of 28 PFAS in 339 maternal serum samples from Pilot Study of the Japan Environment and Children's Study. Perfluorooctanoic acid (PFOA), perfluorononanoic acid (PFNA), perfluoroundecanoic acid (PFUnA) and perfluorooctane sulphonic acid (PFOS) were detected in all 339 samples at median (range) concentrations of 1.9 (0.46–15), 1.5 (0.32–10), 1.3 (0.25–4.5) and 3.7 (0.43–15) ng/ml, respectively. These levels are comparable to those reported in previous studies using samples collected from various parts of the world. With a few exceptions, the remainder of the PFAS examined had lower detection rates but were found at concentrations similar to those reported in previous studies. The sensitivity and throughput ability of the method developed here are sufficient for its application in a large-scale biomonitoring study..
5. Keishiro Kinoshita, Yoshito Ishizaki, Hiroyuki Yamamoto, Motoshi Sonoda, Kousuke Yonemoto, Ryutaro Kira, Masafumi Sanefuji, Akihiko Ueda, Hirotaka Matsui, Yukio Ando, Yasunari Sakai, Shouichi Ohga, De novo p.G696S mutation in COL4A1 causes intracranial calcification and late-onset cerebral hemorrhage
A case report and review of the literature COL4A1-associated vasculopathy
, European Journal of Medical Genetics, 10.1016/j.ejmg.2019.103825, 2020.04, Background: The collagen type IV alpha 1 chain (COL4A1) is an essential component of the basement membrane in small vessels. Pathogenic variants in COL4A1 cause perinatal cerebral hemorrhages in an autosomal-dominant fashion. However, little is known about the long-term outcomes of patients with mildly affecting COL4A1 mutations. Case report: We report a 17-year-old boy, who presented with recurrent intracranial hemorrhages in the periventricular white matter. He had been followed-up as a child with cerebral palsy bearing intracranial calcifications, developmental delay and epilepsy. Screening tests in infancy provided negative results for intrauterine infections. Severe motor and cognitive deficits persisted after admission. Carbazochrome was introduced on day 19 of admission, which appeared to prevent extension and reactivation of cerebral hemorrhages for over 6 months after discharge. Results: Targeted sequencing of NOTCH3 and TREX1 excluded causal mutations in these genes. The whole-exome sequencing revealed that he carried a de novo mutation in COL4A1 (p.Gly696Ser). An overview of the literature for 345 cases with COL4A1 mutations supported evidence that p.Gly696Ser is associated with the unique phenotype of late-onset hemorrhage among patients with COL4A1-associated cerebral angiopathy. Conclusions: This case first demonstrates that infants with COL4A1-associated leukoencephalopathy and calcifications have a risk for developing the rupture of small vessels in the cerebral white matter after 10 years of age..
6. Kei Nishiyama, Mari Kurokawa, Michiko Torio, Yasunari Sakai, Mitsuru Arima, Shoko Tsukamoto, Satoshi Obata, Shogo Minamikawa, Kandai Nozu, Noriyuki Kaku, Yoshihiko Maehara, Koh Hei Sonoda, Tomoaki Taguchi, Shouichi Ohga, Gastrointestinal symptoms as an extended clinical feature of Pierson syndrome
A case report and review of the literature
, BMC Medical Genetics, 10.1186/s12881-020-01019-9, 2020.04, Background: Pierson syndrome (PS) is a rare autosomal recessive disorder, characterized by congenital nephrotic syndrome and microcoria. Advances in renal replacement therapies have extended the lifespan of patients, whereas the full clinical spectrum of PS in infancy and beyond remains elusive. Case presentation: We present the case of a 12-month-old boy with PS, manifesting as the bilateral microcoria and congenital nephrotic syndrome. He was born without asphyxia, and was neurologically intact from birth through the neonatal period. Generalized muscle weakness and hypotonia were recognized from 3 months of age. The infant showed recurrent vomiting at age 5 months of age, and was diagnosed with gastroesophageal reflux and intestinal malrotation. Despite the successful surgical treatment, vomiting persisted and led to severely impaired growth. Tulobuterol treatment was effective in reducing the frequency of vomiting. Targeted sequencing confirmed that he had a compound heterozygous mutation in LAMB2 (NM_002292.3: P.Arg550X and p.Glu1507X). A search of the relevant literature identified 19 patients with severe neuro-muscular phenotypes. Among these, only 8 survived the first 12 months of life, and one had feeding difficulty with similar gastrointestinal problems. Conclusions: This report demonstrated that severe neurological deficits and gastrointestinal dysfunction may emerge in PS patients after the first few months of life..
7. Mari Kurokawa, Michiko Torio, Kazuhiro Ohkubo, Vlad Tocan, Noriko Ohyama, Naoko Toda, Kanako Ishii, Kei Nishiyama, Yuichi Mushimoto, Ryuichi Sakamoto, Maki Nakaza, Riho Horie, Tomoya Kubota, Masanori P. Takahashi, Yasunari Sakai, Masatoshi Nomura, Shouichi Ohga, The expanding phenotype of hypokalemic periodic paralysis in a Japanese family with p.Val876Glu mutation in CACNA1S, Molecular Genetics and Genomic Medicine, 10.1002/mgg3.1175, 2020.04, Background: Hypokalemic periodic paralysis (HypoPP) is an autosomal dominant disease characterized by the episodic weakness of skeletal muscles and hypokalemia. More than half patients with HypoPP carry mutations in CACNA1S, encoding alpha-1 subunit of calcium channel. Few reports have documented the non-neuromuscular phenotypes of HypoPP. Methods: The proband is a Japanese woman who developed HypoPP at 6 years of age. An excessive insulin secretion with the oral glucose tolerance test rationalized that she had experienced frequent attacks of paralysis on high-carbohydrate diets. Results: Voglibose and acetazolamide effectively controlled her paralytic episodes. Her 8-year-old son and 2-year-old daughter started showing the paralytic symptoms from 4 and 2 years of age, respectively. Laboratory tests revealed high concentrations of creatinine kinase in serum and elevated renin activities in plasma of these children. The targeted sequencing confirmed that these three patients had an identical heterozygous mutation (p.V876E) in CACNA1S. Conclusion: Our data indicate that the p.V876E mutation in CACNA1S contributes to the early onset of neuromuscular symptoms and unusual clinical phenotypes of HypoPP..
8. Yoshihiro Azuma, Yasuo Suzuki, Seigo Okada, Chie Matsuguma, Hiroyuki Wakiguchi, Yuji Ohnishi, Takashi Furuta, Akiko Miyake, Hiroki Yasudo, Kiyoshi Ichihara, Shouichi Ohga, Shunji Hasegawa, Utility of Soluble CD163 in the Clinical Management of Patients With Kawasaki Disease, Frontiers in Pediatrics, 10.3389/fped.2020.00148, 2020.04, Objective: Intravenous immunoglobulin (IVIG) therapy is a useful first-line treatment for Kawasaki disease (KD); however, 10–20% of patients fail to respond and require additional IVIG. Soluble CD163 (sCD163) is considered a biomarker for macrophage activation. There are no reports measuring serum sCD163 in KD patients. This study aimed to explore its possible utility in the clinical management of patients with KD. Methods: Eighty-seven patients with well-defined KD were retrospectively enrolled together with 19 healthy individuals with comparable ages. KD patients were classified into three groups, Group A (initial IVIG responders), Group B (additional IVIG responders), and Group C (additional IVIG non-responders). Serum sCD163 together with complete blood counts, C-reactive protein, d-dimer, albumin, aspartate aminotransferase (AST), and alanine aminotransferase (ALT) were measured before the initial IVIG treatment in all cases, and afterward in a fraction of cases. Results: Serum sCD163 in KD patients before initial IVIG was generally much higher than the control group. The median (interquartile range) of sCD163 was as follows: Control 446 (385–521) ng/mL; Group A, 699 (478–1,072); Group B, 1,349 (1,116–1,390); and Group C, 665 (544–1,094). In general, sCD163 showed close positive correlation with ALT and AST, but none with other markers. Among the KD groups, Group B showed the highest sCD163: Group B vs. A: p = 0.0003; B vs. C: p = 0.035). Serum sCD163 was significantly increased after IVIG in Group A, while no change occurred in others. Conclusion: The serum sCD163 levels could be a useful biomarker in the clinical management of KD, especially for predicting responsiveness to IVIG..
9. Hiroki Hamano, Takeshi Matsushige, Hirofumi Inoue, Madoka Hoshide, Hikaru Kobayashi, Fumitaka Kohno, Momoko Oka, Takashi Ichiyama, Shouichi Ohga, Kazunobu Ouchi, Shunji Hasegawa, A case of acute encephalophathy with residual neurological sequelae induced by immunoglobulin A vasculitis., Journal of clinical neuroscience : official journal of the Neurosurgical Society of Australasia, 10.1016/j.jocn.2019.05.061, Vol.67, pp.270-271, 2019.09, Immunoglobulin A vasculitis (IgAV) occasionally induces central nervous system (CNS) involvement, which is usually transient with no sequelae except for hemorrhagic stroke. It is thought to be useful to measure serum and cerebrospinal fluid (CSF) cytokine levels for better understanding the pathological condition in encephalopathy, but there have been no reports in acute encephalopathy with IgAV. We describe an 8-year-old boy with IgAV who had neurological sequelae after complication of acute encephalopathy, focusing on the cytokine profiles and unique biphasic findings of magnetic resonance imaging. He presented with status epilepticus and mildly intensified area in the occipital lobe on the fluid-attenuated inversion recovery view. Arterial spin labeling (ASL) revealed the reduction of cerebral blood flow in the left hemisphere. On day 5 of illness, these abnormal findings disappeared, but delayed hyperintensity lesions on diffusion-weighted images newly emerged. Furthermore, CSF interleukin (IL)-6 levels markedly increased without elevated levels of IL-10 during the acute phase of disease. He suffered from long-lasting hemiparesis and intellectual impairment. In conclusion, acute encephalopathy with IgAV could cause neurological sequelae by prolonged seizure, and elevated IL-6 in CSF and laterality of cerebral blood flow in ASL might be useful to predict the prognosis of CNS dysfunction of IgAV..
10. Katsuhide Eguchi, Masataka Ishimura, Motoshi Sonoda, Hiroaki Ono, Akira Shiraishi, Shunsuke Kanno, Yuhki Koga, Hidetoshi Takada, Shouichi Ohga, Nontuberculous mycobacteria-associated hemophagocytic lymphohistiocytosis in MonoMAC syndrome, Pediatric Blood and Cancer, 10.1002/pbc.27017, Vol.65, No.7, 2018.07.
11. Yoshiaki Kinoshita, Yuki Koga, Ryota Souzaki, Naonori Kawakubo, Minori Ishi, Utako Oba, Hidetoshi Takada, Yuichi Shibui, Junkichi Takemoto, Kenichi Kohashi, Yoshinao Oda, Shouichi Ohga, Tomoaki Taguchi, A Review of 50 Cases of Rhabdomyosarcoma Treated Between 1990-2017: A Report from the Single Institution, PEDIATRIC BLOOD & CANCER, Vol.64, p.S59, 2017.11.
12. Katsuhide Eguchi, Masataka Ishimura, Motoshi Sonoda, Akira Shiraishi, Hidetoshi Takada, Shouichi Ohga, Hematopoietic Stem Cell Transplantation with Targeted Busulfan-containing Regimen for Diamond-Blackfan Anemia, PEDIATRIC BLOOD & CANCER, Vol.64, p.S76, 2017.11.
13. Motoshi Sonoda, Masataka Ishimura, Katsuhide Eguchi, Akira Shiraishi, Shouichi Ohga, Two Neonatal Patients with Systemic Herpes Simplex Virus-associated Hemophagocytic lymphohistiocytosis, PEDIATRIC BLOOD & CANCER, Vol.64, p.S36, 2017.11.
14. 【外科の近未来-1,000号記念】 近未来の再生医療と外科 肝再生医療の展望と乳歯歯髄幹細胞
15. Etsuro Nanishi, Hisanori Nishio, Hidetoshi Takada, Kenichiro Yamamura, Mitsuharu Fukazawa, Kenji Furuno, Yumi Mizuno, Kenjiro Saigo, Ryo Kadoya, Noriko Ohbuchi, Yasuhiro Onoe, Hironori Yamashita, Hideki Nakayama, Takuya Hara, Takuro Ohno, Yasuhiko Takahashi, Ken Hatae, Tatsuo Harada, Takayuki Shimose, Junji Kishimoto, Shouichi Ohga, Toshiro Hara, Clarithromycin Plus Intravenous Immunoglobulin Therapy Can Reduce the Relapse Rate of Kawasaki Disease: A Phase 2, Open-Label, Randomized Control Study., Journal of the American Heart Association, 10.1161/JAHA.116.005370, Vol.6, No.7, 2017.07, BACKGROUND: We previously reported that biofilms and innate immunity contribute to the pathogenesis of Kawasaki disease. Therefore, we aimed to assess the efficacy of clarithromycin, an antibiofilm agent, in patients with Kawasaki disease. METHODS AND RESULTS: We conducted an open-label, multicenter, randomized, phase 2 trial at 8 hospitals in Japan. Eligible patients included children aged between 4 months and 5 years who were enrolled between days 4 and 8 of illness. Participants were randomly allocated to receive either intravenous immunoglobulin (IVIG) or IVIG plus clarithromycin. The primary end point was the duration of fever after the initiation of IVIG treatment. Eighty-one eligible patients were randomized. The duration of the fever did not differ between the 2 groups (mean±SD, 34.3±32.4 and 31.1±31.1 hours in the IVIG plus clarithromycin group and the IVIG group, respectively [P=0.66]). The relapse rate of patients in the IVIG plus clarithromycin group was significantly lower than that in the IVIG group (12.5% versus 30.8%, P=0.046). No serious adverse events occurred during the study period. In a post hoc analysis, the patients in the IVIG plus clarithromycin group required significantly shorter mean lengths of hospital stays than those in the IVIG group (8.9 days versus 10.3 days, P=0.049). CONCLUSIONS: Although IVIG plus clarithromycin therapy failed to shorten the duration of fever, it reduced the relapse rate and shortened the duration of hospitalization in patients with Kawasaki disease. CLINICAL TRIAL REGISTRATION: URL: Unique identifier: UMIN000015437..
16. 小児外科領域の先端的医療の展開(II):先端治療開発の方向性 乳歯幹細胞を用いた肝再生研究.
17. 異臭便のMorganella morganiiに関連したスルフヘモグロビン血症疑いの早産児例.
18. 【貧血性疾患診療の進歩】 先天性溶血性貧血の遺伝子診断.
19. Nobuto Arashiki, Yuichi Takakuwa, Hiromi Ogura, Taiju Utsugisawa, Satoru Miyano, Seishi Ogawa, Seiji Kojima, Shouichi Ohga, Narla Mohandas, Hitoshi Kanno, ATP11C Encodes a Major Flippase in Human Erythrocyte and Its Genetic Defect Causes Congenital Non-Spherocytic Hemolytic Anemia, BLOOD, Vol.126, No.23, 2015.12.
20. Hiromi Ogura, Shouichi Ohga, Takako Aoki, Taiju Utsugisawa, Hidehiro Takahashi, Asayuki Iwai, Kenichiro Watanabe, Yusuke Okuno, Kenichi Yoshida, Satoru Miyano, Seishi Ogawa, Seiji Kojima, Hitoshi Kanno, COL4A1 is a Novel Causative Gene Responsible for Congenital Hemolytic Anemia, Representing Characteristic Clinical Course in Infants, BLOOD, Vol.126, No.23, 2015.12.
21. Hiroyuki Wakiguchi, Shunji Hasegawa, Hidenobu Kaneyasu, Madoka Kajimoto, Yousuke Fujimoto, Reiji Hirano, Shunsaku Katsura, Kenji Matsumoto, Takashi Ichiyama, Shouichi Ohga, Long-lasting non-IgE-mediated gastrointestinal cow's milk allergy in infants with Down syndrome, PEDIATRIC ALLERGY AND IMMUNOLOGY, 10.1111/pai.12351, Vol.26, No.8, pp.821-823, 2015.12.
22. Seigo Okada, Shunji Hasegawa, Yasuo Suzuki, Midori Wakabayashi, Takuya Ichimura, Hidenobu Kaneyasu, Maiko Shimomura, Kazuhiro Nakamura, Masao Kobayashi, Shouichi Ohga, Increased Neutrophil Counts and Serum Transforming Growth Factor-beta 1 Levels in an Infant With Autoimmune Neutropenia Who Recovered From Kawasaki Disease, CIRCULATION, Vol.131, 2015.04.
23. Seigo Okada, Shunji Hasegawa, Yasuo Suzuki, Midori Wakabayashi, Takuya Ichimura, Hidenobu Kaneyasu, Maiko Shimomura, Kazuhiro Nakamura, Masao Kobayashi, Shouichi Ohga, Increased Neutrophil Counts and Serum Transforming Growth Factor-beta 1 Levels in an Infant With Autoimmune Neutropenia Who Recovered From Kawasaki Disease, CIRCULATION, Vol.131, 2015.04.
24. Taiju Utsugisawa, Toshitaka Uchiyama, Hiromi Ogura, Takako Aoki, Isao Hamaguchi, Akira Ishiguro, Akira Ohara, Seiji Kojima, Shouichi Ohga, Etsuro Ito, Hitoshi Kanno, Elevated Red Cell Reduced Glutathione Is a Novel Biomarker of Diamond-Blackfan Anemia, BLOOD, Vol.124, No.21, 2014.12.
25. Wakato Matsuoka, Kenichiro Yamamura, Kiyoshi Uike, Hazumu Nagata, Shouichi Ohga, Toshiro Hara, Tachyarrhythmia-induced Cerebral Sinovenous Thrombosis in a Neonate Without Cardiac Malformation, PEDIATRICS AND NEONATOLOGY, 10.1016/j.pedneo.2014.02.003, Vol.55, No.5, pp.412-413, 2014.10.
26. Asahito Hama, Hideki Muramatsu, Masafumi Ito, Yoshiyuki Kosaka, Masahiro Tsuchida, Yoshiyuki Takahashi, Ryoji Kobayashi, Etsuro Ito, Hiromasa Yabe, Shouichi Ohga, Akira Ohara, Seiji Kojima, Risk Factors For Clonal Evolution Of Acquired Bone Marrow Failure After Immunosuppressive Therapy In Children, BLOOD, 10.1182/blood.V122.21.2473.2473, Vol.122, No.21, 2013.11.
27. 新鮮凍結血漿定期投与を行ったUpshaw-Schulman症候群の長期腎予後についての検討.
28. 新鮮凍結血漿定期投与を行ったUpshaw-Schulman症候群の長期腎予後についての検討.
29. 定期凍結血漿投与を行ったUpshaw-Schulman症候群3例の長期予後.
30. Etsuro Ito, Kenichi Yoshida, Yusuke Okuno, Aiko Sato-Otsubo, Tsutomu Toki, Satoru Miyano, Yuichi Shiraishi, Kenichi Chiba, Kiminori Terui, RuNan Wang, Tomohiko Sato, Yuji Iribe, Shouichi Ohga, Madoka Kuramitsu, Isao Hamaguchi, Akira Ohara, Kazuko Kudo, Isamu Kamimaki, Junichi Hara, Kanji Sugita, Kousaku Matsubara, Kenichi Koike, Akira Ishiguro, Yoshifumi Kawano, Hitoshi Kanno, Seiji Kojima, Seishi Ogawa, Identification of Two New DBA Genes, RPS27 and RPL27, by Whole-Exome Sequencing in Diamond-Blackfan Anemia Patients, BLOOD, Vol.120, No.21, 2012.11.
31. Upshaw-Schulman症候群3例における定期凍結血漿補充の長期効果.
32. 本邦における骨髄不全症候群の現況 先天性赤芽球癆(Diamond-Blackfan貧血)の効果的診断法の確立に関する研究
33. Asahito Hama, Hideki Muramatsu, Masafumi Ito, Masahiro Tsuchida, Hirotoshi Sakaguchi, Sayoko Doisaki, Makito Tanaka, Akira Shimada, Yoshiyuki Takahashi, Ryoji Kobayashi, Etsuro Ito, Hiromasa Yabe, Shouichi Ohga, Akira Ohara, Seiji Kojima, Comparison of Clinical Outcome Between Children with Aplastic Anemia and Refractory Cytopenia of Childhood Who Received Immunosuppressive Therapy with Antithymocyte Globulin and Cyclosporine, BLOOD, Vol.118, No.21, pp.26-27, 2011.11.
34. Ohga S, Ishii E, Takada H, Hara T, Stem cell transplantation for pediatric malignancyHemophagocytic lymphohistiocytosis., 15th Congress of Asia-Pacific Blood and Marrow Transplantation, 2010.10.
35. H. Yabe, A. Ohara, F. Bessyo, T. Nakahata, R. Kobayashi, M. Tsuchida, S. Ohga, Y. Kosaka, H. Mugishima, A. Morimoto, E. Ito, S. Kojima, Comparison of three preparative regimens in alternative donor transplant for aplastic anaemia in Japan, BONE MARROW TRANSPLANTATION, Vol.45, pp.S167-S168, 2010.03.
36. Yuki Konno, Tsutomu Toki, Satoru Tandai, Gang Xu, Kiminori Terui, Shouichi Ohga, Seiji Kojima, Ryu Yanagisawa, Kenichi Koike, Daiichiro Hasegawa, Yoshiyuki Kosaka, Rie Kanei, Tsuyoshi Imai, Teruaki Hongo, Myoung-Ja Park, Arata Watanabe, Etsuro Ito, Mutations in Ribosomal Protein Genes of Diamond-Blackfan Anemia Patients in Japan, BLOOD, Vol.114, No.22, pp.1241-1242, 2009.11.
38. Shinji Katsuragi, Shouichi Ohga, Neonatal Onset Hemophagocytic Lymphohistiocytosis in a Premature Infant, PEDIATRIC BLOOD & CANCER, 10.1002/pbc.21963, Vol.53, No.2, pp.244-245, 2009.08.
39. Jun Muneuchi, Shouichi Ohga, Masataka Ishimura, Kazuyuki Ikeda, Kenichiro Yamaguchi, Akihiko Nomura, Hidetoshi Takada, Yasunobu Abe, Toshiro Hara, Cardiovascular Complications Associated with Chronic Active Epstein-Barr Virus Infection, PEDIATRIC CARDIOLOGY, 10.1007/s00246-008-9343-8, Vol.30, No.3, pp.274-281, 2009.04, This study aimed to assess the outcome of cardiovascular diseases for patients with chronic active Epstein-Barr virus infection (CAEBV). The study enrolled 15 patients (7 boys and 8 girls) who fulfilled the diagnostic criteria for CAEBV, including 10 patients with T-cell type and 3 patients with natural killer (NK)-cell type. The median age at the CAEBV onset was 6.3 years (range, 1.2-17.8 years). Regular cardiologic studies were performed during the median follow-up period of 8 years (range, 2-20 years). Nine patients (60%) had cardiac diseases including coronary artery lesion (CAL) (n = 4, 44%), decreased left ventricular ejection fraction and pericardial effusion in (n = 3, 33%), complete atrioventricular block (n = 1), and sudden arrest (n = 1). The frequency of fever (78%, p = 0.04) or cytopenias (100%, p = 0.01), as the major symptom among patients with cardiac complications, was higher than among those without complications. The median time from disease onset to detection of CAL was 3.4 years (range, 1.8-8.6 years). The mean z-score increased to 3.98. Seven patients (78%) with cardiac complications died of disease progression, hematopoietic stem cell transplantation-related events, or both. In two patients, CAL regressed after allogeneic cord blood transplantation. Among CAEBV patients, CAL was the most common cardiac complication and could not be controlled without the eradication of EBV-infected T- and NK-cells..
41. T. Kamio, E. Ito, A. Ohara, Y. Kosaka, M. Tsuchida, H. Mugishima, H. Yabe, A. Morimoto, S. Ohga, H. Yagasaki, F. Bessho, T. Nakahata, S. Kojima, RELAPSE OF CHILDREN WITH APLASTIC ANEMIA AFTER IMMUNOSUPPRESSIVE THERAPY, HAEMATOLOGICA-THE HEMATOLOGY JOURNAL, Vol.94, pp.S8-S9, 2009.04.
42. Haemophilus influenzae type bによる髄膜炎からショック・DICとなり頭部CTで多発梗塞・出血を認め両下腿の紫斑および足趾壊疽の進行を認めた1例.
43. タクロリムスが奏効したSjoegren症候群関連髄膜脳脊髄炎の1例 髄液サイトカインの変化.
44. Masayuki Ochiai, Shunji Hikino, Hidetake Yabuuchi, Hideki Nakayama, Kazuo Sato, Shouichi Ohga, Toshiro Hara, A new scoring system for computed tomography of the chest for assessing the clinical status of bronchopulmonary dysplasia, JOURNAL OF PEDIATRICS, 10.1016/j.jpeds.2007.05.043, Vol.152, No.1, pp.90-95, 2008.01, Objective To develop a new scoring system for computed tomography (CT) of the chest for assessing the clinical status of patients with bronchopulmonary dysplasia (BPD) in comparison with a modified Edwards roentgenographic scoring system.
Study design Preterm infants diagnosed with BPD (n = 42) were assessed prospectively by chest CT scan at the time of discharge. Three radiologists classified the CT findings into I of 3 categories-hyperexpansion, emphysema, or fibrous/interstitial abnormalities-and developed a new scoring system. We assessed interobserver reproducibility and investigated whether this classification system reflected the severity of BPD in these patients.
Results The CT scores had acceptable reproducibility (coefficient of correlation [ee] = 0.721 to 0.839). The subgroup with a more severe form of BPD had a higher CT score. The CT score correlated with the clinical score at 36 weeks of postmenstrual age (cc = 0.367) and the duration of oxygen therapy (cc = 0.537). Patients who were discharged home on oxygen had higher CT scores than patients who were not.
Conclusions The new chest CT scoring system may have higher objectivity and accuracy in terms of predischarge assessment of clinical status as well as prediction of the prognosis of patients with BPD..
45. Sjoegren症候群の経過中に無菌性髄膜炎、急激な感覚障害と膀胱直腸障害を来した1例.
46. 細菌性髄膜炎 Hib髄膜炎に伴う多発脳血栓および電撃性紫斑病から診断されたヘテロ接合体プロテインC欠乏症.
47. 細菌性髄膜炎に伴う電撃性紫斑病にProtein C(PC)製剤が著効し診断に至ったヘテロ接合体PC欠乏症.
48. Purpura fulminans in meningitis as the first manifestation of heterozygous protein C deficiency.
49. Shouichi Ohga, Akihiko Nomura, Hidetoshi Takada, Naohiro Suga, Toshiro Hara, Successful self-infusion of activated prothrombin complex concentrate for prophylaxis in a child with a factor VIII inhibitor, AMERICAN JOURNAL OF HEMATOLOGY, 10.1002/ajh.20751, Vol.82, No.2, pp.145-149, 2007.02, Regular self-infusion of an activated prothrombin complex concentrate (APCC) has been successfully introduced to a 14-year-old boy with hemophilia A. The child was diagnosed as a neonate, and at age 7 years, developed a high titer (127 BU/mL) factor VIII inhibitor coincident with a protracted ankle joint bleeding. From age 7-10 years, he received on-demand therapy using a prothrombin complex concentrate (PCC), PROPLEX-ST. From age 1014 years, he received prophylaxis with PROPLEX-ST, initiated after an intracranial hemorrhage and coincident anamnestic inhibitor response. Throughout 7-year period of PCC treatment, he experienced recurrent bleeding episodes. Self-prophylaxis with APCC, FEIBA VH [Anti-inhibitor Coagulant Complex] (50 U/kg/dose three times per week) using infusion pump was initiated at 14 years of age and has continued for 2 years. There were no bleeding, thrombotic events or other adverse events after initiation of this prophylaxis, and inhibitor levels decreased to 1 BU/mL. His quality of life was improved, particularly with respect to school. Our long observation proposes a well-disciplined home-based FEIBA prophylaxis in inhibitor-positive hemophiliacs. (c) 2006 Wiley-Liss, Inc..
50. H Nagata, S Ohga, S Hattori, K Masumoto, T Taguchi, T Matsumoto, T Hara, Barium-associated appendicitis in a childhood case with Crohn's disease, ACTA PAEDIATRICA, 10.1080/08035250600599743, Vol.95, No.7, pp.889-890, 2006.07.
51. T Hara, S Ohga, S Hattori, M Hatano, N Kaku, A Nomura, H Takada, H Kokuba, K Ohshima, T Hara, Prolonged severe pancytopenia preceding the cutaneous lesions of juvenile xanthogranuloma, PEDIATRIC BLOOD & CANCER, 10.1002/pbc.20514, Vol.47, No.1, pp.103-106, 2006.07, We report a case of juvenile xanthogranuloma (JXG) having progressive pancytopenia for 6 months until the proliferating skin lesions. A 2-month-old infant presented recurrent fever, anemia, and hepatosplenomegaly mimicking hemophagocytic lymphohistiocytosis (HLH) or juvenile myelomonocytic leukemia (JMML). At 8 months of age, the biopsy of a growing papule on the elbow made the diagnosis. Bone marrow (BM) specimens showed clustering foamy cells including hemophagocytosis by histiocytes. Treatment with etoposide followed by vinblastine plus prednisolone (PSL) therapy improved the disease. Although JXG is a benign non-Langerhans cell histiocytosis, the multisystem-visceral form should be considered as a potential aggressive disease when associated with BM failure in early infancy..
52. Y Koga, S Ohga, A Nomura, H Takada, T Hara, Reduced gene expression of clustered ribosomal proteins in Diamond-Blackfan anemia patients without RPS19 gene mutations, JOURNAL OF PEDIATRIC HEMATOLOGY ONCOLOGY, 10.1097/00043426-200606000-00007, Vol.28, No.6, pp.355-361, 2006.06, Diamond-Blackfan anemia (DBA) is a rare congenital pure red cell aplasia occasionally presenting physical anomalies. Ribosomal protein S19 gene (RPS19) is one of the causative genes for DBA; however, the pathologic mechanism of erythroblastopenia and abnormal morphology has not been clarified. To assess the pathophysiology of DBA, the gene expression profile of 2 representative patients carrying no RPS19 mutations was compared with that of aplastic anemia (AA) patients.. assessed by the microarray analyses. The K-mean clustering analysis revealed the significant categorization of 28 ribosomal protein (R-P) genes into a small set of group (994 genes) (P = 2.39E-17), all of which were expressed at lower levels in DBA than in AA patients. RPS19 was categorized into the set of low expressing genes in DBA patients. No mutations were deter-mined in the promoter and coding sequences of top 10 RP genes expressed at the levels over 1.2 of the AA/DBA ratio, in 3 DBA patients. These results indicated that the lower expression of R-P gene group, even without the mutation, was a distinctive feature of DBA from AA, although the study number was small. The reduced RP gene expression, by itself, may suggest an underlying mechanism of the constitutional anemia..
53. T Matsuura, KH Sonoda, S Ohga, A Ariyama, T Nakamura, T Ishibashi, A case of chronic recurrent uveitis associated with chronic granulomatous disease, JAPANESE JOURNAL OF OPHTHALMOLOGY, 10.1007/s10384-005-0313-x, Vol.50, No.3, pp.287-289, 2006.05.
54. T Toubo, S Ohga, H Takada, N Suga, A Nomura, T Ohno, T Hara, Rheumatic fever-mimicking carditis as a first presentation of chronic active Epstein-Barr virus infection, ACTA PAEDIATRICA, 10.1080/08035250500371821, Vol.95, No.5, pp.614-618, 2006.05, A 7-y-old girl presented with prolonged fever, arrhythmia and cardiomegaly during the treatment course of group A beta-haemolytic streptococcal pharyngitis. The isolated rheumatogenic strain M1 suggested the diagnosis of rheumatic fever. However, serous pericardial effusion contained high levels of Epstein-Barr virus (EBV) DNA. Clonally proliferating EBV+ T cells were determined in the circulation. The atypical carditis without valvitis was then complicated by coronary artery dilatations. Four months after the start of prednisolone plus antiviral/bacterial therapy, EBV+ T-cell lymphoma developed in the thigh.
Conclusion: Atypical carditis may be a notable and life-threatening presentation of chronic active EBV infection to be differentiated from rheumatic fever..
55. Hidetoshi Takada, Tamami Tanaka, Akihiko Nomura, Shouichi Ohga, Rumiko Shibata, Toshiro Hara, Distinct gene expression patterns of peripheral blood cells in hyper-IgE syndrome, JOURNAL OF IMMUNOLOGY, Vol.176, p.S108, 2006.04.
56. M Hatano, H Takada, A Nomura, S Ohga, K Ohshima, Saeki, I, T Tajiri, T Taguchi, S Suita, T Hara, Epstein-Barr virus-associated bronchial leiomyoma in a boy with cellular immunodeficiency, PEDIATRIC PULMONOLOGY, 10.1002/ppul.20375, Vol.41, No.4, pp.371-373, 2006.04, Bronchial leiomyoma is a rare disease in children. Recently, the association of leiomyoma and HIV infection was reported. We describe a boy with a cellular immunodeficiency, who had endobronchial leiomyoma. The tumor cells were positive for Epstein-Barr virus-encoded RNA-1 (EBER-1) and Epstein-Barr virus-determined nuclear antigen-2, suggesting a role of Epstein-Barr virus in the pathogenesis of leiomyoma..
57. Y Kanaya, S Ohga, K Ikeda, K Furuno, T Ohno, H Takada, N Kinukawa, T Hara, Maturational alterations of peripheral T cell subsets and cytokine gene expression in 22q11.2 deletion syndrome, CLINICAL AND EXPERIMENTAL IMMUNOLOGY, 10.1111/j.1365-2249.2006.03038.x, Vol.144, No.1, pp.85-93, 2006.04, Chromosome 22q11.2 deletion syndrome is a common disorder characterized by thymic hypoplasia, conotruncal cardiac defect and hypoparathyroidism. Patients have a risk of infections and autoimmunity associated with T lymphocytopenia. To assess the immunological constitution of patients, the numerical changes and cytokine profile of circulating T cells were analysed by flow cytometry and real-time polymerase chain reaction (PCR). CD3(+), CD4(+), T cell receptor (TCR)alpha beta(+) or CD8 alpha alpha(+) cell counts were lower, and CD56(+) cell counts were higher in patients than in controls during the period from birth to adulthood. The ageing decline of CD3(+) or CD4(+) cell counts was slower in patients than in controls. The proportion of CD8 alpha alpha(+) cells increased in controls, and the slope index was larger than in patients. On the other hand, both the number and proportion of V alpha 24(+) cells increased in patients, and the slope indexes tended to be larger than in controls. The positive correlation of the number of T cells with CD8 alpha alpha(+) cells was observed only in patients, and that with V alpha 24(+) cells was seen only in controls. No gene expression levels of interferon (IFN)-gamma, interleukin (IL)-10, transforming growth factor (TGF)-beta, cytotoxic T lymphocyte antigen 4 (CTLA4) or forkhead box p3 (Foxp3) in T cells differed between patients and controls. There was no significant association between the lymphocyte subsets or gene expression levels and clinical phenotype including the types of cardiac disease, hypocalcaemia and frequency of infection. These results indicated that T-lymphocytopenia in 22q11.2 deletion patients became less severe with age under the altered composition of minor subsets. The balanced cytokine profile in the limited T cell pool may represent a T cell homeostasis in thymic deficiency syndrome..
58. Masafumi Sanefuji, Shouichi Ohga, Ryutaro Kira, Takashi Yoshiura, Hiroyuki Torisu, Toshiro Hara, Moyamoya syndrome in a splenectomized patient with β-thalassemia intermedia, Journal of Child Neurology, 10.1177/08830738060210010501, Vol.21, No.1, pp.75-77, 2006.01, We describe a 14-year-old Japanese girl with β-thalassemia intermedia who developed moyamoya syndrome after splenectomy. This patient had compound heterozygous mutations of the β-globin gene and received occasional transfusions. After splenectomy at 12 years of age, she transiently required partial exchange transfusions for leukoerythroblastosis but attained transfusion independence. Two years after the splenectomy, transient ischemic attacks occurred repeatedly with right hemiparesis or left paresthesia. Magnetic resonance imaging revealed bilateral stenosis of the internal carotid arteries and dilatation of the perforating branches with the formation of moyamoya vessels but not infarctions. The strict adherence to aspirin and dipyridamole has led to no stroke or progression of the vasculopathy for 8 years. Moyamoya disease has been reported in a patient with β-thalassemia major. Cerebral vasculopathy can be a rare but grave consequence of the thromboembolic complications in β-thalassemia major/intermedia..
59. H Takada, K Kusuhara, A Nomura, S Ohga, M Hayashi, M Furue, T Hara, A novel CIAS1mutation in a Japanese patient with chronic infantile neurological cutaneous and articular syndrome, EUROPEAN JOURNAL OF PEDIATRICS, 10.1007/s00431-005-1750-8, Vol.164, No.12, pp.785-786, 2005.12.
60. T Nagatomo, K Muta, S Ohga, M Ochiai, S Hikino, T Hara, Insulin-like growth factor II is an autocrine growth factor to prevent apoptosis as well as to enhance proliferation and maturation of erythroid progenitor cells., BLOOD, Vol.106, No.11, p.878A, 2005.11.
61. K Yamamoto, E Ishii, H Horiuchi, Ueda, I, S Ohga, M Nishi, Y Ogata, M Zaitsu, A Morimoto, T Hara, S Imashuku, T Sasazuki, M Yasukawa, Mutations of syntaxin 11 and SNAP23 genes as causes of familial hemophagocytic lymphohistiocytosis were not found in Japanese people, JOURNAL OF HUMAN GENETICS, 10.1007/s10038-005-0293-1, Vol.50, No.11, pp.600-603, 2005.11, Although mutations of perforin, MUNC13-4 and syntaxin 11 genes have been found in children with familial hemophagocytic lymphohistiocytosis (FHL), the incidence of each genetic subtype varies in different ethnic groups. We evaluated mutations of syntaxin 11 and SNAP23 genes in 30 Japanese FHL patients. The patients had no mutations and 10% had one polymorphism (146G > A) of syntaxin 11, while no mutation of SNAP23 was observed. Our results indicate that aberrations in the SNARE system may not cause FHL in Japanese families..
62. M Ishimura, S Ohga, A Nomura, T Toubo, E Morihana, Y Saito, H Nishio, M Ide, H Takada, T Hara, Successful umbilical cord blood transplantation for severe chronic active Epstein-Barr virus infection after the double failure of hematopoietic stem cell transplantation, AMERICAN JOURNAL OF HEMATOLOGY, 10.1002/ajh.20430, Vol.80, No.3, pp.207-212, 2005.11, An 11-year-old boy with severe chronic active Epstein-Barr virus infection (CAEBV) underwent successful cord blood transplantation (CBT) after consecutive failure of peripheral blood and bone marrow transplantation from his HILA-mismatched mother. CB cells from an unrelated donor were infused after conditioning with total body irradiation (12 Gy), melphalan (120 mg/m(2)), and etoposide (600 mg/m(2)). Complete remission without circulating EBV-DNA has continued for 15 months after a delayed hematologic recovery. This is the first successful report of CBT for CAEBV. CB may therefore be an alternate source of stem cells for the curative treatment of CAEBV, despite the absence of EBV-specific cytotoxic T lymphocytes..
63. H Takada, Y Saito, A Nomura, S Ohga, K Kuwano, N Nakashima, S Aishima, N Tsuru, T Hara, Bronchiolitis obliterans organizing pneumonia as an initial manifestation in systemic lupus erythematosus, PEDIATRIC PULMONOLOGY, 10.1002/ppul.20224, Vol.40, No.3, pp.257-260, 2005.09, Bronchiolitis obliterans organizing pneumonia (BOOP) is a rare complication of adult systemic lupus erythematosus (SLE). This is the first report of a pediatric patient with BOOP as an initial presentation of SLE. She had dyspnea, cough, arthralgia, and erythema on her face. Laboratory examinations revealed pancytopenia, low serum levels of complements, and positivity for anti-nuclear antibody, anti-double stranded DNA antibody, and anti-SM antibody. Her respiratory symptoms, pulmonary function tests, and radiologic findings showed significant improvement after treatment with oral prednisolone. Although it is a rare complication among the pleuro-pulmonary manifestations in SLE, BOOP can be the first presentation, even in pediatric patients..
64. M Okano, K Kawa, H Kimura, A Yachie, H Wakiguchi, A Maeda, S Imai, S Ohga, H Kanegane, S Tsuchiya, T Morio, M Mori, S Yokota, S Imashuku, Proposed guidelines for diagnosing chronic active Epstein-Barr virus infection, AMERICAN JOURNAL OF HEMATOLOGY, 10.1002/ajh.20398, Vol.80, No.1, pp.64-69, 2005.09, Since the initial report of unusual manifestations possibly associated with chronic active Epstein-Barr virus (EBV) infection (CAEBV), nearly three decades have passed. During this period, reported cases with this entity have dramatically increased in the world. Additionally, recent development of diagnostic procedures, including molecular biological and immunological techniques, have provided us with the ability to define certain diseases, especially malignant disorders. Guidelines, derived mainly from the current literature and recent experiences with CAEBV in Japan, for diagnosing CAEBV are proposed to clarify this enigmatic disease..
65. T Nagatomo, K Muta, S Ohga, M Ochiai, S Hikino, T Hara, Insulin-like growth factor II is an autocrine growth factor to prevent apoptosis as well as to enhance proliferation and maturation of erythroid progenitor cells in cord blood, EXPERIMENTAL HEMATOLOGY, Vol.33, No.7, p.79, 2005.07.
66. T Tanaka, H Takada, A Nomura, S Ohga, R Shibata, T Hara, Distinct gene expression patterns of peripheral blood cells in hyper-IgE syndrome, CLINICAL AND EXPERIMENTAL IMMUNOLOGY, 10.1111/j.1365-2249.2005.02805.x, Vol.140, No.3, pp.524-531, 2005.06, Hyper-immunoglobulin E (IgE) syndrome (HIES) is one of the primary immunodeficiency syndromes. Although the cytokine dysregulation is suggested to play a role in its pathophysiology, the causative gene has not yet been identified. To investigate the pathophysiology and candidate genes involved in this disease, we performed microarray analysis of unstimulated peripheral CD4(+) T cells and CD14(+) cells, as well as peripheral blood mononuclear cells (PBMNC) stimulated with Staphylococcus aureus isolated from HIES patients and healthy controls. By microarray analysis, 38 genes showed over 2-fold differences between the HIES patients and healthy controls in purified CD14(+) cells, although only small differences in the gene expression profiles were observed between the two groups in purified CD4(+) T cells. RGC32 expression levels showed the greatest difference between the two groups, and were significantly elevated in HIES compared with those in severe atopic dermatitis or healthy controls using real-time PCR. A significantly larger number of lysosome-related genes were up-regulated, and significantly larger number of genes related to cell growth and maintenance were down-regulated in HIES. After the stimulation of PBMNC with Staphylococcus aureus, 51 genes showed over 3-fold differences between HIES patients and healthy controls. A significantly large number of immunoglobulin-related genes were up-regulated in HIES. The distinct patterns of gene expression profiles and RGC32 expression levels will be useful for understanding the pathophysiology and for diagnosis of HIES, respectively..
67. Eiichi Ishii, Ikuyo Ueda, Ryutaro Shirakawa, Ken Yamamoto, Hisanori Horiuchi, Shouichi Ohga, Kenji Furuno, Akira Morimoto, Miyoko Imayoshi, Yoshiyasu Ogata, Masafumi Zaitsu, Masahiro Sako, Kenichi Koike, Akifumi Sakata, Hidetoshi Takada, Toshiro Hara, Shinsaku Imashuku, Takehiko Sasazuki, Masaki Yasukawa, Genetic subtypes of familial hemophagocytic lymphohistiocytosis: correlations with clinical features and cytotoxic T lymphocyte/natural killer cell functions., Blood, 10.1182/blood-2004-08-3296, Vol.105, No.9, pp.3442-8, 2005.05, Mutations of the perforin (PRF1) and MUNC13-4 genes distinguish 2 forms of familial hemophagocytic lymphohistiocytosis (FHL2 and FHL3, respectively), but the clinical and biologic correlates of these genotypes remain in question. We studied the presenting features and cytotoxic T lymphocyte/natural killer (CTL/NK) cell functions of 35 patients for their relationship to distinct FHL subtypes. FHL2 (n = 11) had an earlier onset than either FHL3 (n = 8) or the non-FHL2/FHL3 subtype lacking a PRF1 or MUNC13-4 mutation (n = 16). Deficient NK cell activity persisted after chemotherapy in all cases of FHL2, whereas some patients with FHL3 or the non-FHL2/FHL3 subtype showed partial recovery of this activity during remission. Alloantigen-specific CTL-mediated cytotoxicity was deficient in FHL2 patients with PRF1 nonsense mutations, was very low in FHL3 patients, but was only moderately reduced in FHL2 patients with PRF1 missense mutations. These findings correlated well with Western blot analyses showing an absence of perforin in FHL2 cases with PRF1 nonsense mutations and of MUNC13-4 in FHL3 cases, whereas in FHL2 cases with PRF1 missense mutations, mature perforin was present in low amounts. These results suggest an association between the type of genetic mutation in FHL cases and the magnitude of CTL cytolytic activity and age at onset..
68. E Ishii, S Ohga, S Imashuku, N Kimura, Ueda, I, A Morimoto, K Yamamoto, M Yasukawa, Review of hemophagocytic lymphohistiocytosis (HLH) in children with focus on Japanese experiences, CRITICAL REVIEWS IN ONCOLOGY HEMATOLOGY, 10.1016/j.critrevonc.2004.11.002, Vol.53, No.3, pp.209-223, 2005.03, Hemophagocytic lymphohistiocytosis (HLH) is characterized by fever and hepatosplenomegaly associated with pancytopenia, hypertriglyceridemia and hypofibrinogenemia. Increased levels of cytokines and impaired natural killer activity are biological markers of HLH. HLH can be classified into two distinct forms, including primary HLH, also referred to as familial hemophagocytic lymphohistiocytosis (FHL), and secondary HLH. Although FHL is an autosomal recessive disorder typically occurring in infancy, it is important to clarify that the disease may also occur in older patients. It is now considered that FHL is a disorder of T-cell function; moreover, clonal proliferation of T lymphocytes is observed in a few FHL patients, and cytotoxicity of these T lymphocytes for target cells is usually impaired. In 1999, perforin gene (PRF1) mutation was identified as a cause of 20-30% of FHL (FHL2) cases. In Japan, two specific mutations of PRF1 were also detected. Furthermore, in 2003, MUNC13-4 mutations were identified in some non-FHL2 patients (FHL3). Identification of other genes responsible for remaining cases is a major concern. Hematopoietic stem cell transplantation (HSCT) has been established as the only accepted curative therapy for FHL. Thus, appropriate diagnosis and prompt treatment with HSCT are necessary for FHL patients. Genetic analysis for PRFI and MUNC13-4 and functional assay of cytotoxic T lymphocytes are recommended to be performed in each patient. In those patients displaying impaired cytotoxic function but lacking genetic defects, samples should be employed for identification of unknown genes. In the near future, an entire pathogenesis should be clarified in order to establish appropriate therapies including immunotherapy, HSCT and gene therapy. (c) 2004 Elsevier Ireland Ltd. All rights reserved..
69. A Nomura, H Takada, S Ohga, N Ishii, T Inoue, T Hara, T-Cell-depleted CD34+ cell transplantation from an HLA-mismatched donor in a low-birthweight infant with X-linked severe combined immunodeficiency, JOURNAL OF PEDIATRIC HEMATOLOGY ONCOLOGY, 10.1097/01.mph.0000152859.59880.54, Vol.27, No.2, pp.80-84, 2005.02, The best strategy of hematopoietic stem cell (HSC) transplantation for low-birthweight (LBW) infants with severe combined immunodeficiency (SCID) remains to be determined. To avoid the toxicity of drugs used for the transplantation and the risk of graft-versus-host disease (GVHD), the authors performed allogeneic bone marrow HSC transplantation with a combination of CD34 selection and T-cell depletion in a LBW infant with X-linked SCID. The authors analyzed the process of T-cell reconstitution after the transplantation in this patient. The patient was born at 30 weeks and 2 days' gestational age via cesarean section. He was diagnosed as having SCID at birth. The patient received a transplant of 1 million CD34+ cells/kg body weight. Immunologic reconstitution was investigated by means of phenotypic analysis of T cells and genetic analysis of coding joint T-cell receptor rearrangement excision circle expression. Increases in donor-derived NK cells and T cells were observed 2 and 3 months after the transplantation, respectively. The patient had no infectious complications or GVHD despite the presence of SCID and prematurity-associated immunodeficiency. Analysis of T-cell regeneration pathways revealed that T cells reconstituted mainly via the thymus-dependent pathway. T-cell-depleted CD34+ cell transplantation would be a safe and useful therapy for LBW infants with SCID..
70. T Toubo, N Suga, S Ohga, A Nomura, Y Onoe, H Takada, T Hara, Successful unrelated cord blood transplantation for Epstein-Barr virus-associated lymphoproliferative disease with hemophagocytic syndrome, INTERNATIONAL JOURNAL OF HEMATOLOGY, 10.1532/IJH97.04081, Vol.80, No.5, pp.458-462, 2004.12, We report a case of successful umbilical cord blood transplantation (CBT) for Epstein-Barr virus (EBV)-associated lymphoproliferative disease (LPD) in a 6-year-old girl. The patient had hemophagocytic syndrome with excessive circulating levels of EBV DNA that was refractory to immunochemotherapy. Multiple hepatosplenic lesions favored the diagnosis of EBV-associated LPD, although the aggressive course precluded the histopathologic diagnosis. Unrelated CB cells mismatched at 1 HLA focus were infused after patient conditioning with 900 mg/m(2) etoposide, 2 g/m(2) cytarabine, 16 mg/kg busulfan, and 200 mg/kg cyclophosphamide. Complete chimeric status was obtained on day 19 posttransplantation. Drug fever and acute graft-versus-host disease of the skin (grade II) were the major complications. A transient increase of EBV DNA 1 year after CBT indicated a primary EBV infection of the donor cells. The patient is alive with no evidence of disease 27 months after CBT There has been no previous report of successful CBT for EBV-related LPD/lymphoma. CBT can be a curative treatment for the disease, even if no viral memory has been set in the stem cell source. (C) 2004 The Japanese Society of Hematology.
71. E Ishii, Ueda, I, K Yamamoto, S Ohga, K Furuno, A Morimoto, M Imayoshi, M Sako, H Takada, T Hara, S Imashuku, T Sasazuki, M Yasukawa, Classification of familial hemophagocytic lymphohistiocytosis based on genetic and immunologic analyses., BLOOD, Vol.104, No.11, p.374A, 2004.11.
72. S Ohga, A Nomura, H Takada, T Tanaka, K Furuno, Y Takahata, N Kinukawa, N Fukushima, S Imai, T Hara, Dominant expression of interleukin-10 and transforming growth factor-beta genes in activated T-cells of chronic active Epstein-Barr virus infection, JOURNAL OF MEDICAL VIROLOGY, 10.1002/jmv.20197, Vol.74, No.3, pp.449-458, 2004.11, Chronic active Epstein-Barr virus (EBV) infection is a chronic mononucleosis syndrome associated with clonal proliferation of EBV-carrying T-/natural killer (NK)-cells. High levels of circulating EBV and activated T-cells are sustained during the prolonged disease course, whereas it is not clear how ectopic EBV infection in T-/NK-cells has been established and maintained. To assess the biological role of activated T-cells in chronic active EBV infection (CAEBV), EBV DNA and cellular gene expressions in peripheral T-cells were quantified in CAEBV and infectious mononucleosis (IM) patients. In CAEBV, HLA-DR+ T-cells had higher viral load and larger amounts of IFNgamma, IL-10, transforming growth factor-beta (TGFbeta), and cytotoxic T lymphocyte antigen-4 (CTLA4) mRNA than HLA-DR-T-cells. HLA-DR+ T cells of IM patients transcribed more IFNgamma and IL-10 than their HLA-DR-T cells. Expression levels of IFNgamma and forkhead box p3 (Foxp3) in CAEBV HLA-DR+ T-cells were higher than in IM HLA-DR+ T-cells. The effective variables to discriminate the positivity of HLA-DR were IL-10, IFNgamma, CTLA4, TGFbeta, and IL-2 in the order of statistical weight. EBV load in CAEBV T-cells correlated with the expression levels of only IL-10 and TGFbeta. These results suggest that CAEBV T-cells are activated to transcribe IFNgamma, IL-10, and TGFbeta excessively, and the latter two genes are expressed preferentially in the EBV-infected subsets. The dominant expression of regulatory cytokines in T-cells may imply a viral evasion mechanism in the disease. (C) 2004 Wiley-Liss, Inc..
73. R Kobayashi, H Ayukawa, K Kato, T Kaneko, H Kigasawa, H Yabe, M Tsuchida, H Mugishima, A Ohara, A Morimoto, M Yamamoto, S Ohga, F Bessho, T Nakahata, L Tsukimoto, S Kojima, Prospective multicenter trial comparing repeated immunosuppressive therapy (IST) with stem cell transplantation (SCT) from an alternative donor as a second-line treatment for children with acquired aplastic anemia (AA)., BLOOD, Vol.104, No.11, p.770A, 2004.11.
74. K Yamamoto, E Ishii, M Sako, S Ohga, K Furuno, N Suzuki, Ueda, I, M Imayoshi, S Yamamoto, A Morimoto, H Takada, T Hara, S Imashuku, T Sasazuki, M Yasukawa, Identification of novel MUNC13-4 mutations in familial haemophagocytic lymphohistiocytosis and functional analysis of MUNC13-4-deficient cytotoxic T lymphocytes, JOURNAL OF MEDICAL GENETICS, 10.1136/jmg.2004.021121, Vol.41, No.10, pp.763-767, 2004.10, Background: Familial haemophagocytic lymphohistiocytosis (FHL) has an autosomal recessive mode of inheritance and consists of at least three subtypes. FHL2 subtype with perforin (PRF1) mutation accounts for 30% of all FHL cases, while FHL with MUNC13-4 mutation was recently identified and designated as FHL3 subtype.
Objective: To examine MUNC13-4 mutations and the cytotoxic function of MUNC13-4 deficient T lymphocytes in Japanese FHL patients
Methods: Mutations of MUNC13-4 and the cytotoxicity of MUNC13-4-deficient cytotoxic T lymphocytes (CTL) were analysed in 16 Japanese families with non-FHL2 subtype.
Results: Five new mutations of the MUNC13-4 gene were identified in six families. The mutations were in the introns 4, 9, and 18, and exons 8 and 19. Two families had homozygous mutations, while the remaining four had compound heterozygous mutations. Cytotoxicity of MUNC13-4 deficient CTL was low compared with control CTL, but was still present. Clinically, the onset of disease tended to occur late; moreover, natural killer cell activity was not deficient in some FHL3 patients.
Conclusions: MUNC13-4 mutations play a role in the development of FHL3 through a defective cytotoxic pathway..
75. T Nagatomo, S Ohga, H Takada, A Nomura, S Hikino, M Imura, K Ohshima, T Hara, Microarray analysis of human milk cells: persistent high expression of osteopontin during the lactation period, CLINICAL AND EXPERIMENTAL IMMUNOLOGY, 10.1111/j.1365-2249.2004.02549.x, Vol.138, No.1, pp.47-53, 2004.10, To continue the search for immunological roles of breast milk, cDNA microarray analysis on cytokines and growth factors was performed for human milk cells. Among the 240 cytokine-related genes, osteopontin (OPN) gene ranked top of the expression. Real-time PCR revealed that the OPN mRNA levels in colostrum cells were approximately 100 times higher than those in PHA-stimulated peripheral blood mononuclear cells (PBMNCs), and 10 000 times higher than those in PB CD14(+) cells. The median levels of OPN mRNA in early milk or mature milk cells were more than three times higher than those in colostrum cells. Western blot analysis of human milk showed appreciable expression of full-length and short form proteins of OPN. The concentrations of full-length OPN in early milk or mature milk whey continued to be higher than those in colostrum whey and plasma as assessed by ELISA. The early milk (3-7 days postpartum) contained the highest concentrations of OPN protein, while the late mature milk cells (1 years postpartum) had the highest expression of OPN mRNA of all the lactating periods. The results of immunohistochemical and immunocytochemical staining indicated that OPN-producing epithelial cells and macrophages are found in actively lactating mammary glands. These results suggest that the persistently and extraordinarily high expression of OPN in human milk cells plays a potential role in the immunological development of breast-fed infants..
76. Hideko Kajiwara, Mitsumasa Saito, Shouichi Ohga, Takeshi Uenotsuchi, Shin-Ichi Yoshida, Impaired host defense against Sporothrix schenckii in mice with chronic granulomatous disease, Infection and Immunity, 10.1128/IAI.72.9.5073-5079.2004, Vol.72, No.9, pp.5073-5079, 2004.09, We compared the immune defense of mice with chronic granulomatous disease (CGD mice) with that of wild-type C57BL/6 mice for their response to Sporothrix schenckii. A subcutaneous injection of 5 × 104 CFU S. schenckii strain IFM41598 into CGD mice resulted in systemic infection and death within 84 days. In contrast, injected C57BL/6 mice did not develop systemic infection and were able to survive through 100 days of observation. Differences in host resistance were analyzed in vitro. Neutrophils and macrophages obtained from CGD mice were found to allow greater growth of this organism than did those obtained from C57BL/6 mice. Moreover, macrophages obtained from immunized CGD mice were able to simply inhibit the growth of this fungus whereas macrophages obtained from immunized C57BL/6 mice killed the fungus within 48 h after phagocytosis. These results suggest that (i) the lack of NADPH oxidase function is a risk factor for lethal S. schenckii infection and (ii) Superoxide anion and its reactive oxidative metabolites produced by neutrophils and macrophages are involved in fungistatic and fungicidal activities..
77. Hidetoshi Takada, Shouichi Ohga, Yumi Mizuno, Akihiko Nomura, Toshiro Hara, Increased IL-16 levels in hemophagocytic lymphohistiocytosis, Journal of Pediatric Hematology/Oncology, 10.1097/01.mph.0000134465.86671.2e, Vol.26, No.9, pp.567-573, 2004.09, Serum levels of interleukin-16 (IL-16) were measured to investigate its role in the pathophysiology of hemophagocytic lymphohistiocytosis (HLH). Serum IL-16 levels in patients with acute HLH were significantly higher than those in healthy controls and patients with infectious mononucleosis. They returned to normal levels in the convalescent phase of the disease. In contrast to serum interferon-gamma (IFN-γ) levels, serum IL-16 levels showed a gradual decrease over the course of the disease. Serum IL-16 levels showed a significant positive correlation with serum levels of soluble IL-2 receptor, IFN-γ, and interleukin-18, body temperature, and serum lactic dehydrogenase (LDH) levels. An increase in IL-16 mRNA expression was detected in the liver of an HLH patient. These results suggest that IL-16 plays an important role in the pathophysiology of HLH by TH1 cell recruitment and activation at organs with inflammation..
78. Yasushi Takahata, Akihiko Nomura, Hidetoshi Takada, Shouichi Ohga, Kenji Furuno, Shunji Hikino, Hideki Nakayama, Shimon Sakaguchi, Toshiro Hara, CD25+CD4+ T cells in human cord blood: an immunoregulatory subset with naive phenotype and specific expression of forkhead box p3 (Foxp3) gene., Experimental hematology, Vol.32, No.7, pp.622-9, 2004.07, OBJECTIVE: To address the role of cord blood (CB) CD25+CD4+ T cells, the gene expressions and function of this subset were analyzed. MATERIALS AND METHODS: CD25+CD4+ T cells fractionated from CB of term and preterm infants were subjected to flow cytometry, quantitative polymerase chain reaction analysis for cytokines, costimulatory molecules, and transcription factors, and functional assays. RESULTS: Human preterm CB contained a high proportion of CD25+CD4+ T cells that declined with gestational age to the level of adult peripheral blood (PB). CD25+ or CD25-CD4+ T cells in CB had a higher frequency of CD45RA+ and CD38+ cells than in PB. CB CD25+CD4+ T cells less frequently expressed CD45RO, CD71, and HLA-DR than PB CD25+CD4+ T cells, despite similar expressions on CB and PB CD25-CD4+ T cells. No expression of IL-10, transforming growth factor-beta, interleukin-4, and interferon-gamma mRNA differed between CB CD25+CD4+ and CD25-CD4+ T cells, in contrast to the high interleukin-10 expression in PB CD25+CD4+ T cells. CTLA-4 was more transcribed in CB and PB CD25+CD4+ T cells than in the counterpart CD25-CD4+ T cells. CD28 or ICOS was similarly expressed in CB and PB T cells. CB CD25+CD4+ T cells effectively suppressed the proliferation of CB CD25-CD4+ T cells in a dose-dependent manner. Human CB and PB CD25+CD4+ T cells preferentially transcribed Foxp3, which governs the regulatory function of this subset in mice. CONCLUSIONS: These results suggest that CB contains CD25+CD4+ regulatory T cells as a functionally mature population with naive phenotype. This subset may naturally arise and decline in fetus to play a potential immunoregulatory role in intrauterine life..
79. H Takada, Y Takahata, A Nomura, S Ohga, Y Mizuno, T Hara, Increased serum levels of interferon-gamma-inducible protein 10 and monokine induced by gamma interferon in patients with haemophagocytic lymphohistiocytosis, CLINICAL AND EXPERIMENTAL IMMUNOLOGY, Vol.133, No.3, pp.448-453, 2003.09, We measured serum interferon-gamma-inducible protein 10 (IP-10) and monokine induced by gamma interferon (MIG) levels to investigate the role of these molecules in the pathophysiology of haemophagocytic lymphohistiocytosis (HLH). Serum IP-10 and MIG levels were significantly increased in patients with active HLH compared with those of healthy controls. Serum MIG levels decreased gradually during the course of disease in a patient who recovered without therapy. On the other hand, rapid reduction of MIG and IP-10 levels was observed after chemotherapy in a patient with severe HLH. IP-10 and MIG mRNA expression was enhanced in liver and spleen, and IP-10 mRNA expression was enhanced in bone marrow in the patients, suggesting activated macrophages that infiltrated in these organs as one of the main producers of these cytokines. Serum IP-10 and MIG levels showed a significant correlation with serum IFN-gamma levels. In addition, these chemokines had a significant correlation with fever and serum LDH levels, which are clinical indicators of disease activity of HLH. These results suggest that IP-10 and MIG which are produced by activated macrophages by the stimulation of IFN-gamma, play an important role in the pathophysiology of HLH, by recruitment of activated Th1 cells into the tissues or organs..
80. Y Ishizaki, J Tezuka, S Ohga, A Nomura, N Suga, R Kuromaru, K Kusuhara, Y Mizuno, N Kasuga, T Hara, Quantification of circulating varicella zoster virus-DNA for the early diagnosis of visceral varicella, JOURNAL OF INFECTION, 10.1016/S0163-4453(03)00004-5, Vol.47, No.2, pp.133-138, 2003.08, Varicella zoster virus (VZV)-DNA was quantified in peripheral blood of 2 patients with visceral varicella due to endogenous reactivation. An 18-year-old mate contracted varicella following the courses of chemotherapy for T cell lymphoma. Another 18-year-old male suffered from varicella 16 months after the complete engraftment of hematopoietic stem cell transplantation. Both patients had past VZV infection, but no recent contact with the disease. Paralytic ileus and ascites preceded the skin lesions. Quantitative real-time polymerase chain reaction reveated >200 copies of VZV per 1 ml of whole blood before or at the time when cropping vesicles emerged. The viral load reflected their prolonged clinical courses. Similar Levels of VZV-DNA were detected in primary varicella patients, but not in herpes zoster patients or immunocompromised children without varicella or zoster. Quantitative monitoring of circulating VZV-DNA may be useful for the diagnosis and assessing the treatment response of visceral varicella in immunocompromized hosts. (C) 2003 The British Infection Society. Published by Elsevier Science Ltd. All rights reserved..
81. Ohga S, Takada H, Nomura A, Hara T, Lymphoproliferative Disease in Childhood: Clinical and biological role of cytokines, 2003.01.
82. S Ohga, A Nomura, H Takada, T Hara, Immunological aspects of Epstein-Barr virus infection, CRITICAL REVIEWS IN ONCOLOGY HEMATOLOGY, Vol.44, No.3, pp.203-215, 2002.12, Epstein-Barr virus (EBV) is a member of ubiquitous gamma herpes viruses, which primarily induces acute infectious mononucleosis (IM) or subclinical infection in susceptible subjects. The host reactions account for the clinical manifestation of IM. This virus also contributes to the development of lymphoid or epithelial malignancies. The outgrowth of EBV-infected B-cells is first controlled by interferon (IFN)-gamma and natural killer (NK) cells, and later by EBV-specific cytotoxic T-lymphocytes (CTL). To overcome the host responses and establish the persistent infection, EBV conducts the protean strategies of immune evasion. Several EBV genes modulate apoptotic signals and cytokine balances to persist B-cell infection without insulting the host. Uncontrolled lymphoproliferation occurs as EBV+ B-cell lymphoproliferative disease (LPD)/Iymphoma in AIDS, posttransplant, or primary immunodeficiency diseases (PID). On the other hand, EBV+ Y/NK cells are involved in EBV-associated hemophagocytic lymphohistiocytosis (EBV-HLH) or chronic active EBV infection (CAEBV) in children having no underlying immunodeficiencies, and at times lead to the clonal evolution of T/NK-cell LPD/lymphomas. Recent advance in molecular techniques has enabled us to analyze the clonality of EBV-infected lymphocytes and to quantify the gene expression of EBV and cytokines. Dominant autocrine loop of T helper (Th) 2 and Th1 may exert in EBV+ B-LPD and T-LPD, respectively. Intensive studies on the immunological interface between effector components and EBV+ target cells will provide more information on clarifying the pathogenesis of EBV-associated lymphoid malignancies, as well as on exploiting the therapeutic and preventive strategies for the formidable EBV-associated disease in childhood. (C) 2002 Elsevier Science Ireland Ltd. All rights reserved..
83. Shouichi Ohga, Akihiko Nomura, Hidetoshi Takada, Toshiro Hara, Immunological aspects of Epstein-Barr virus infection, Critical Reviews in Oncology/Hematology, 10.1016/S1040-8428(02)00112-9, Vol.44, No.3, pp.203-215, 2002.12, Epstein-Barr virus (EBV) is a member of ubiquitous γ herpes viruses, which primarily induces acute infectious mononucleosis (IM) or subclinical infection in susceptible subjects. The host reactions account for the clinical manifestation of IM. This virus also contributes to the development of lymphoid or epithelial malignancies. The outgrowth of EBV-infected B-cells is first controlled by interferon (IFN)-γ and natural killer (NK) cells, and later by EBV-specific cytotoxic T-lymphocytes (CTL). To overcome the host responses and establish the persistent infection, EBV conducts the protean strategies of immune evasion. Several EBV genes modulate apoptotic signals and cytokine balances to persist B-cell infection without insulting the host. Uncontrolled lymphoproliferation occurs as EBV+ B-cell lymphoproliferative disease (LPD)/lymphoma in AIDS, posttransplant, or primary immunodeficiency diseases (PID). On the other hand, EBV+ T/NK cells are involved in EBV-associated hemophagocytic lymphohistiocytosis (EBV-HLH) or chronic active EBV infection (CAEBV) in children having no underlying immunodeficiencies, and at times lead to the clonal evolution of T/NK-cell LPD/lymphomas. Recent advance in molecular techniques has enabled us to analyze the clonality of EBV-infected lymphocytes and to quantify the gene expression of EBV and cytokines. Dominant autocrine loop of T helper (Th) 2 and Th1 may exert in EBV+ B-LPD and T-LPD, respectively. Intensive studies on the immunological interface between effector components and EBV+ target cells will provide more information on clarifying the pathogenesis of EBV-associated lymphoid malignancies, as well as on exploiting the therapeutic and preventive strategies for the formidable EBV-associated disease in childhood. © 2002 Elsevier Science Ireland Ltd. All rights reserved..
84. S Tsutsumi, S Ohga, A Nomura, H Takada, S Sakai, K Ohshima, K Sumimoto, T Hara, CD4(-)CD8(-) T-cell polymyositis in a patient with chronic active Epstein-Barr virus infection, AMERICAN JOURNAL OF HEMATOLOGY, 10.1002/ajh.10207, Vol.71, No.3, pp.211-215, 2002.11, We describe a 17-year-old woman with chronic active Epstein-Barr virus infection (CAEBV), who developed EBV*CD4(-)CD8(-) T-cell polymyositis. At 14 years of age, CAEBV was diagnosed with fever, cytopenia, liver dysfunction, and hepatosplenomegaly. Despite the transient remission of interferon-alpha therapy, migratory lesions emerged in back and extremities. MRI indicated polymyositis. Biopsy specimens revealed intramuscular infiltration of CD3*, CD4(-), CD8(-), CD56(-), and EBV-encoded RNA 1(+) cells. Circulating CD4(-)CDS(-)Vdelta2/Vgamma9 cells increased. gammadeltaT-cells contained 20-200 times higher EBV-DNA (2 x 10(4) copies/mugDNA) than alphabetaT-cells or NK-cells. The ominous polymyositis might denote the musculotropic invasion of EBV(+)gammadeltaT-cell lymphoproliferative disease as a consequence of CAEBV. (C) 2002 Wiley-Liss, Inc..
85. S Kojima, A Ohara, R Kobayashi, S Nishimura, K Sugita, M Maeda, M Sako, S Hibi, K Fujisawa, S Ohga, Y Toyoda, H Mugishima, T Nakahata, Tsukimoto, I, K Yamamoto, Participation in clinical trials is a favorable prognostic factor for children with aplastic anemia, BLOOD, Vol.100, No.11, p.16B, 2002.11.
86. S Ohga, A Ohara, S Hibi, S Kojima, F Bessho, S Tsuchiya, Y Ohshima, N Yoshida, Y Kashii, S Nishimura, K Kawakami, K Nishikawa, Treatment responses of childhood aplastic anaemia with chromosomal aberrations at diagnosis, BRITISH JOURNAL OF HAEMATOLOGY, 10.1046/j.1365-2141.2002.03582.x, Vol.118, No.1, pp.313-319, 2002.07, The clinical outcome of childhood aplastic anaemia (AA) with aberrant cytogenetic clones at diagnosis was surveyed. Among 198 children with newly diagnosed AA registered with the AA Committee of the Japanese Society of Paediatric Hematology between 1994 and 1998, cytogenetic studies of bone marrow (BM) cells were completed in 159 patients. Apart from one Robertsonian translocation, seven patients (4.4%) showed clonal chromosomal abnormalities in hypoplastic BM without myelodysplastic features. The patients included six girls and one boy with a median age of 11 years (range 5-14 years). Sixpatients had del(6), del(5), del(13), del(20), or -7, and one showed add(9). Four patients responded to the first immunosuppressive therapy (IST: cyclosporin A plus anti-thymocyte globulin) and one obtained a spontaneous remission. Cytogenetic abnormalities remained in two patients with an IST response. On the other hand, two patients showed no IST response. One did not respond to repeat IST and died of acute graft-versus-host disease after an unrelated-BM transplant. Another obtained a complete response after a successful BM transplant. No haematological findings at diagnosis predicted the treatment response. No significant morphological changes developed during the course of the illness. A literature review revealed that half of 24 AA patients with chromosomal abnormalities responded to the first IST, and that +6 was the sole predictable marker for IST unresponsiveness. These results suggest that IST can be applied as the initial therapy for AA with cytogenetic abnormalities in the absence of completely matched donors..
87. M Yamamoto, S Ohga, Y Ohnishi, H Inomata, Optic disk vasculitis associated with chronic active Epstein-Barr virus infection, OPHTHALMOLOGICA, Vol.216, No.3, pp.221-225, 2002.05, Purpose: To report two cases of optic disk vasculitis associated with chronic active Epstein-Barr virus infection (CAEBV). Method: We examined the eyes of two patients with CAEBV. Results: In the first case, a 6-year-old boy, visual acuity was 20/20 in both eyes. Papillary and peripapillary exudates were observed in the right eye. Fluorescein angiography showed hyperfluorescence of the optic disk and a leakage from the peripapillary retinal vessels in the right eye. Two months later, the exudates increased and preretinal hemorrhages appeared in the right eye. Visual acuity decreased to 20/60. He was treated with systemic administration of corticosteroid, globulin and acyclovir. Visual acuity returned to 20/20, but peripapillary exudates remained in the right eye. In the second case, a 16-year-old girl, visual acuity was 20/20 in both eyes. The right eye showed optic disk swelling and dilated retinal veins. Fluorescein angiography showed hyperfluorescence of the optic disk but no leakage from the retinal vessels. Visual field examination revealed an enlarged blind spot in the right eye in both cases. These ocular manifestations are compatible with those of optic disk vasculitis, which shows swelling of the optic disk and dye leakage on and around the optic disk in fluorescein angiography, with an almost normal visual acuity and an enlargement of the blind spot. Conclusion: Persistent Epstein-Barr virus infection may cause optic disk vasculitis. Copyright (C) 2002 S. KargerAG, Basel..
88. Ohga S, Nomura A, Takada H, Hara T, Epstein-Barr virus associated diseases in childhood.-Immunological aspects of Epstein-Barr virus infection, 2002.01.
89. S Ohga, A Nomura, H Takada, H Terao, N Harada, T Hara, Expansion of trisomy 8 and Sweet syndrome in a prolonged course of aplastic anemia, JOURNAL OF PEDIATRIC HEMATOLOGY ONCOLOGY, 10.1097/00043426-200201000-00017, Vol.24, No.1, pp.64-68, 2002.01, We describe a 17-year-old boy with aplastic anemia who had Sweet syndrome develop with increasing expansion of trisomy 8. The diagnosis of aplastic anemia was made at 6 years of age. Cytopenias partially responded to danazol therapy. Cytogenetic studies of bone marrow (BM) cells were normal until the detection of trisomy 8 at 14 years of age. This clone increased with the progression of cytopenias. Cell sorting and fluorescence in situ hybridization analysis revealed that trisomy 8 was present only in nonlymphoid elements. When the patient was 17 years of age, Sweet syndrome developed. BM study showed myelodysplastic features, in which trisomy 8 occupied 7410 of BM cells with additional chromosomal changes. Trisomy 8 may contribute to the late transformation of myeloid lineages in BM failure..
90. A Nomura, H Takada, CH Jin, T Tanaka, S Ohga, T Hara, Functional analyses of cord blood natural killer cells and T cells: a distinctive interleukin-18 response, EXPERIMENTAL HEMATOLOGY, 10.1016/S0301-472X(01)00689-0, Vol.29, No.10, pp.1169-1176, 2001.10, Objective. To search for the functional property of cord blood (CB) cells, the effects of interleukin-18 (IL-18) on interferon-gamma (IFN-gamma) production of T cells or natural killer (NK) cells were compared between CB and adult peripheral blood (PB).
Materials and Methods. T cells, CD45RA(+) T cells, and NK cells were purified from CB and adult PB mononuclear cells using magnetic beads or a cell sorter. After stimulation with or without IL-18 in the presence of IL-12 for 48 hours (NK cells) or 72 hours (T cells or CD45RA(+) T cells), IFN-gamma concentration was measured in each subset. Although IL-18 induced significant IFN-gamma production from both CB and adult PB T cells in the presence of IL-12, the IFN-gamma levels from CB T cells were lower than those from adult PB T cells. However, CD45RA(+) T cells from CB and from adult PB produced similar levels of IFN-gamma after stimulation with IL-18 + IL-12. On the other hand, CB NK cells exhibited higher IFN-gamma production and CD69 expression than adult PB NK cells after stimulation with IL-18 + IL-12. Cytolytic activity of CB NK cells increased to a level comparable to that of adult PB NK cells after the same IL-18/IL-12 stimulation.
Conclusions. These results suggest that a low response of CB T cells to IL-18 is due to a higher proportion of naive (CD45RA(+)) T cells in CB, which may be one of the factors responsible for the neonatal immaturity of the immune system as well as the low incidence of graft-vs-host disease in patients receiving CB stem cell transplantation. On the other hand, a high response of CB NK cells to IL-18 may contribute to the host defense during the neonatal period and antitumor effects in CB stem cell transplantation. (C) 2001 Society for Experimental Hematology. Published by Elsevier Science Inc..
91. Y Tokunaga, S Ohga, S Suita, T Matsushima, T Hara, Moyamoya syndrome with spherocytosis: Effect of splenectomy on strokes, PEDIATRIC NEUROLOGY, 10.1016/S0887-8994(01)00283-1, Vol.25, No.1, pp.75-77, 2001.07, A 3-year-old male patient with hereditary spherocytosis who developed moyamoya syndrome, presenting hemiplegia, and slurred speech is reported. Transient ischemic attacks occurred repeatedly with hemolytic crises. Magnetic resonance imaging and angiography revealed bilateral occlusion of the internal carotid and middle cerebral arteries with the formation of moyamoya vessels and multiple infarctions in the basal ganglia. Although splenectomy can increase the risk of stroke, no stroke occurred after splenectomy. On aspirin and dipyridamole therapy the patient has been free of neurologic deficits and progression of the vasculopathy for 5 years. This rare observation suggests that anemic hypoxia more greatly contributes to the progression of moyamoya syndrome than postsplenectomy thrombocytosis or reduced deformability of spherocytes. (C) 2001 by Elsevier Science Inc. All rights reserved..
92. H Takada, A Nomura, S Ohga, T Hara, Interleukin-18 in hemophagocytic lymphohistiocytosis, LEUKEMIA & LYMPHOMA, Vol.42, No.1-2, pp.21-28, 2001.06, Hemophagocytic lymphohistiocytosis (HLH) is characterized by dysregulated hyperactivation of macrophages and T helper 1 (Th1) cells accompanied by excessive secretion of inflammatory cytokines. Although TNF-alpha and IFN-gamma are known to be important factors for the development of the disease, the mechanism of their overproduction has not been clarified, yet. We measured serum IL-18 levels of patients with HLH to investigate the possible significance of IL-18 in its pathophysiology, especially in IFN-gamma production. IL-18 levels were significantly increased in all patients with HLH compared with healthy controls. A significant correlation was observed between IL-18 and IFN-gamma levels. In addition to IFN-gamma and soluble Fas ligand (sFasL), IL-18 levels significantly correlated with disease activity. IL-18 may play important roles in the pathogenesis of HLH, particularly through induction of Th1 cells. In addition, IL-18 measurement may not only be useful for the diagnosis, but also for the evaluation of disease activity..
93. T Yamaguchi, K Ihara, T Matsumoto, Y Tsutsumi, A Nomura, S Ohga, T Hara, Inflammatory bowel disease-like colitis in glycogen storage disease type lb, INFLAMMATORY BOWEL DISEASES, Vol.7, No.2, pp.128-132, 2001.05, Chronic inflammatory bowel disease (IBD)-like colitis is occasionally associated with glycogen storage disease-type 1b (GSD- Ib). We describe a 17-year old boy with GSD-1b who developed an IBD-like colitis. Roentgenography and colonoscopy showed the lead-pipe appearance of the colon and circumferential ulcers. Histopathologic examination revealed nonspecific inflammation without granulomatous lesions. High-dose granulocyte-colony stimulating factor (G-CSF) and sulfasalazine led to the resolution of the colitis, although neutropenia continued. Besides this cast, 10 published cases of GSD-lb and IBD-like colitis were reviewed. All cases had severe neutropenia and/or neutrophil dysfunction. The mean onset of bowel; disease was 12.3 years of age. Seven cases required surgical treatment. All five patients with G-CSF/GM-CSF therapy showed clinical remission. These findings suggest that IBD-like colitis is a grave complication of GSD-lb and that recurrent enteric infections due to neutrophil deficiency may contribute to the development of this bowel disease..
94. S Ohga, E Kubo, A Nomura, H Takada, N Suga, E Ishii, A Suminoe, T Inamitsu, A Matsuzaki, N Kasuga, T Hara, Quantitative monitoring of circulating Epstein-Barr virus DNA for predicting the development of posttransplantation lymphoproliferative disease, INTERNATIONAL JOURNAL OF HEMATOLOGY, Vol.73, No.3, pp.323-326, 2001.04, Epstein-Barr virus (EBV)-DNA was quantitatively measured to assess posttransplantation virus reactivation by realtime polymerase chain reaction (PCR). In the first retrospective analysis of a 7-year-old boy with lymphoproliferative dis ease (LPD) after an unrelated cord blood transplantation. serum EBV-DNA progressively increased to 4 X 10(5) copies/mL. EBV load was then prospectively monitored in peripheral blood from posttransplantation patients. The second case was an 8 year-old boy with aplastic anemia who received a CD34(+) cell transplantation. This patient died of LPD with the progression of pulmonary nodules. EBV-DNA increased to 4 X 10(4) copies/mL after the control of cytomegalovirus reactivation. On the other hand, EBV-DNA was undetectable (<200 copies/mL) in the series of all 58 samples from 10 patients who did not develop LPD after hematopoietic stem cell transplantation. Sequential monitoring of circulating EBV-DNA by quantitative PCR may be a useful indicator for predicting the development of posttransplantation LPD. <(c)> 2001 The Japanese Society of Hematology..
95. S Ohga, A Nomura, H Takada, K Ihara, K Kawakami, F Yanai, Y Takahata, T Tanaka, N Kasuga, T Hara, Epstein-Barr virus (EBV) load and cytokine gene expression in activated T cells of chronic active EBV infection, JOURNAL OF INFECTIOUS DISEASES, Vol.183, No.1, pp.1-7, 2001.01, To identify the role of T cells in chronic active Epstein-Barr virus (EBV) infection, EBV and cytokine gene expression was quantified by use of real-time polymerase chain reaction (PCR) among 6 patients who fulfilled the diagnostic criteria for chronic active EBV infection. Four of these patients showed clonal expansion of EBV-infected T cells. Quantitative PCR for EBV DNA in peripheral blood of patients with symptomatic chronic active EBV infection showed higher copy numbers of virus (mean, 1.45 x 10(5) copies/mL) than were seen in blood from patients with infectious mononucleosis (3.08 x 10(3) copies/mL) or with EBV-associated hemophagocytosis (2.95 x 10(4) copies/mL). Fractionated CD3(+) HLA-DR+ cells from patients with chronic active EBV infection contained higher copy numbers than did CD3(+) HLA-DR+ cells. Quantitative PCR for cytokines revealed that interferon-gamma, interleukin (IL)-2, IL-10, and transforming growth factor-beta genes were expressed at higher levels in HLA-DR+ than in HLA-DR- T cells. These results suggest that activated T cells in chronic active EBV-infection expressed high levels of EBV DNA and both Th1 and Th2 cytokines. EBV-infected T cells may contribute to the unbalanced cytokine profiles of chronic mononucleosis..
96. S Ohga, A Ryu, T Nagatomo, H Takada, K Ihara, K Kawamoto, T Kai, T Hara, Inflammatory bowel disease-like complication in anhidrotic ectodermal dysplasia, AMERICAN JOURNAL OF GASTROENTEROLOGY, 10.1016/S0002-9270(00)02187-0, Vol.95, No.12, pp.3651-3652, 2000.12.
97. S Ohga, A Nomura, H Takada, K Ihara, K Kawakami, F Yanai, N Kasuga, T Hara, Epstein-Barr virus (EBV) and cytokine gene expressions in activated T-cells of chronic active EBV infection., BLOOD, Vol.96, No.11, p.44B, 2000.11.
98. R Kira, S Ohga, H Takada, K Gondo, F Mihara, T Hara, MR choroid plexus sign of iron overload, NEUROLOGY, Vol.55, No.9, p.1340, 2000.11.
99. K Honda, S Ohga, H Takada, A Nomura, K Ohshima, N Kinukawa, Y Mizuno, T Hara, Neuron-specific enolase in hemophagocytic lymphohistiocytosis: A potential indicator for macrophage activation?, INTERNATIONAL JOURNAL OF HEMATOLOGY, Vol.72, No.1, pp.55-60, 2000.07, To determine the pathogenesis of hemophagocytic lymphohistiocytosis (HLH), serum levels of neuron-specific enolase (NSE) and cytokine profiles were investigated. Serum concentrations of NSE and several cytokines were measured by immunoassays, and the association was evaluated in 18 HLH patients. Serum NSE levels increased (>10 ng/mL) in 27/29 samples (93%) during the active febrile phase, the mean level of which (35.9 ng/mL) was much higher than that during the remission phase (11.2 ng/mL) (P = .001). The peak levels of NSE in 11 patients who required cytotoxic agents were higher than those in 7 patients without chemotherapy, 64.6 +/- 49.4 and 17.9 +/- 12.9, respectively (P = .265). The NSE levels correlated positively with the levels of interferon (IFN)-gamma (Pearson's correlation coefficient [r] = 0.408, P = .044), soluble interleukin-2 receptor (sIL-2R) (r = 0.464, P = .048), lactate dehydrogenase (r = 0.830, P <.00001), aspartate aminotransferase (r = 0.531, P = .003), acid ferritin (r = 0.715, P = .00001), and correlated negatively with platelet count (r = -0.422, P = .021), but not with other parameters, including tumor necrosis factor-alpha, IL-1 beta, IL-18, soluble Fas ligand and C-reactive protein. Multiple regression analysis indicated that the correlation of NSE with platelet count was independent of other correlations. Sequential NSE changes well reflected the clinical course of patients. Immunohistochemical staining revealed an appreciable number of NSE-positive histiocytes in bone marrow specimens with florid hemophagocytosis. These results suggest that the circulating NSE originated from macrophages stimulated with IFN-gamma/sIL-2R, and partly from the destruction of platelets. Serum NSE level may be a useful marker for predicting the disease progression of HLH. Int J Hematol. 2000;72:55-60. (C) 2000 The Japanese Society of Hematology..
100. A Nomura, H Takada, C Jin, S Ohga, T Hara, IL-18 response of cord blood T and NK cells., FASEB JOURNAL, Vol.14, No.6, p.A1180, 2000.04.
101. K Honda, H Takada, Y Nagatoshi, K Akazawa, S Ohga, E Ishii, J Okamura, T Hara, Thymus-independent expansion of T lymphocytes in children after allogeneic bone marrow transplantation, BONE MARROW TRANSPLANTATION, Vol.25, No.6, pp.647-652, 2000.03, The contribution of the thymus-dependent pathway and thymus-independent pathways for T cell regeneration after BRIT in children is still unclear. We analyzed the kinetics of T cell regenerative pathways after allogeneic BRIT. The number of CD4(+)CD45RA(+) T cells, a thymus-dependent population, was very low until 3 months after BRIT. The numbers of CD28(-) T cells and CD8(+) T cells expressing CD8 alpha/alpha homodimer (CD8 alpha/alpha(+) T cells), a thymus-independent population, increased shortly after BRIT, beyond the levels of healthy children in some patients. The numbers of V gamma 9(+)V delta 2(+) and V alpha 24(+) T cells, which represent populations of extrathymic development, were less than 200/mu l during the 6 months after BRIT. There was a significant inverse correlation between the percentages of CD4(+)CD45RA(+) and CD28(-) T cells at 1 month, and a positive correlation between the percentages of CD28(-) and CD8 alpha/alpha(+) T cells at 2 and 3 months after BRIT. The mean age at BRIT was higher in patients with a high level of CD8 alpha/alpha(+) T cells than in those without an increase in these cells, suggesting the influence of thymic function on the regenerative pathways. These results suggest that the thymus-independent pathway is the dominant source of T cells even in children shortly after allogeneic BMT..
102. S Ohga, Y Kanaya, H Maki, H Takada, K Ohshima, M Kanda, A Nomura, A Suminoe, A Matsuzaki, T Hara, Epstein-Barr virus-associated lymphoproliferative disease after a cord blood transplant for Diamond-Blackfan anemia, BONE MARROW TRANSPLANTATION, Vol.25, No.2, pp.209-212, 2000.01, A 7-year-old boy with Diamond-Blackfan anemia (DBA) developed lymphoproliferative disease (LPD) after a cord blood transplant (CBT), 3.1 x 10(7)/kg mononuclear cells from an HLA one-locus mismatched CB were transplanted after conditioning with total body irradiation (8 Gy), cyclophosphamide (200 mg/kg) and antithymocyte globulin (10 mg/kg), Complete engraftment occurred on day 33 post transplant, Despite the resolution of grade II graft-versus-host disease (GVHD), he died of lymphoma on day 130 post transplant. The tumor was of donor origin, indicating clonal proliferation of Epstein-Barr virus (EBV)infected B cells, This is the first report of EBV-LPD after CBT, Post-transplant LPD can be a serious EBV-associated complication of CB grafts..
103. Y Mizuno, H Takada, K Urakami, K Ihara, R Kira, A Suminoe, S Ohga, T Aoki, T Hara, Neurotrophin-3 levels in cerebrospinal fluid from children with bacterial meningitis, viral meningitis, or encephalitis, JOURNAL OF CHILD NEUROLOGY, Vol.15, No.1, pp.19-21, 2000.01, Neurotrophin-3 levels were measured in the cerebrospinal fluid of 35 patients with bacterial meningitis, viral meningitis, or encephalitis by two-site enzyme immunoassay. Elevated cerebrospinal fluid levels of neurotrophin-3 were demonstrated in 8 of 18 patients with bacterial meningitis. Follow-up examination of the eight patients at the convalescent stage showed diminished cerebrospinal fluid levels of neurotrophin-3. in contrast, none of the 17 patients with viral meningitis or encephalitis showed an elevation of neurotrophin-3 levels in cerebrospinal fluid. No relationships were observed between neurotrophin-3 levels and cerebrospinal fluid cell numbers, cerebrospinal fluid protein levels, serum C-reactive protein concentrations, or outcome in bacterial meningitis. Since neurotrophin-3 is involved in the survival of neurons and the modulation of the immune system, neurotrophin-3 could play a neuroprotective or immunomodulatory role in bacterial meningitis..
104. A Ohara, S Kojima, F Bessho, S Konishi, M Tsuchida, S Ohga, Y Toyoda, K Koike, R Hanada, S Imashuku, T Nakahata, Tsukimoto, I, Changes in the cause of death in pediatric acquired aplastic anemia in Japan: Comparison of 425 patients registered during '88-'95 and 118 patients registered during '65-'75., BLOOD, Vol.94, No.10, p.193A, 1999.11.
105. Y Sakai, H Nakayama, A Matsuzaki, Y Nagatoshi, A Suminoe, K Honda, T Inamitsu, S Ohga, T Hara, Trisomy 10 in a child with acute nonlymphocytic leukemia followed by relapse with a different clone, CANCER GENETICS AND CYTOGENETICS, 10.1016/S0165-4608(99)00087-4, Vol.115, No.1, pp.47-51, 1999.11, We report a 2-year-old Japanese boy with acute nonlymphocytic leukemia (ANLL) having trisomy 10 as the sole chromosomal abnormality. The majority of the marrow blasts had lobulated nuclei and Auer rods in their cytoplasm. The blasts were positive for peroxidase, CD13, CD15, and CD33, but negative for esterase, CD3, CD7, CD34, and HLA-DR, indicating a diagnosis of ANLL, atypical M2 in French-American-British (FAB) classification. He was treated with combination chemotherapy including anthracyclines, etoposide, and cytosine arabinoside. Four months after achieving the first remission, the disease relapsed during the consolidation therapy, and he died 9 months later. Trisomy 10 was not detected at relapse, and blasts showed phenotypes different from those at initial diagnosis. The present case suggests that the prognosis of acute leukemia with trisomy 10 in the pediatric age group may not be good, and that further studies are required to clarify the association of trisomy 10 with leukemogenesis and disease progression. (C) Elsevier Science Inc., 1999. All rights reserved..
106. M Kajiwara, S Nonoyama, M Eguchi, T Morio, K Imai, H Okawa, M Kaneko, M Sako, S Ohga, M Maeda, S Hibi, H Hashimito, A Shibuya, HD Ochs, T Nakahata, JI Yata, WASP is involved in proliferation and differentiation of human haemopoietic progenitors in vitro, BRITISH JOURNAL OF HAEMATOLOGY, 10.1046/j.1365-2141.1999.01694.x, Vol.107, No.2, pp.254-262, 1999.11, The Wiskott-Aldrich syndrome (WAS) is an X-linked recessive disorder characterized by thrombocytopenia, immunodeficiency and eczema. X-linked thrombocytopenia (XLT) is a mild form of WAS with isolated thrombocytopenia. Both phenotypes are caused by mutation of the Wiskott-Aldrich syndrome protein (WASP) gene. In this study we investigated the role of WASP in the differentiation of CD34-positive (CD34(+)) cells isolated from the bone marrow of patients with WAS (n = 5) or with XLT (n = 4), Megakaryocyte colony formation was significantly decreased in patients with WAS when compared with normal controls. The formation of granulocyte-macrophage colonies and erythroid bursts were also decreased in WAS patinets. In contrast, in XLT patients, formation of all these colonies was normal. However, in vitro proplatelet formation of megakaryocytes induced by thrombopoietin was markedly decreased in both XLT and WAS. Electron microscopic examination revealed that megakaryocytes obtained from WAS or XLT patients grown in vitro had abnormal morphologic features, which seemed to be caused by defective actin cytoskeletal organization, including labyrinth-like structures of the demarcation membrane system and deviated distribution of the alpha-granules and demarcation membrane system. These observations indicate that WASP is involved in the proliferation and differentiation of CD34(+) haemopoietic progenitor cells probably by its participation in signal transduction and in the regulation of the cytoskeleton..
107. T Nagatomo, S Ohga, M Saito, H Takada, Y Sasaki, K Okada, T Inamura, T Hara, Streptococcus intermedius-brain abscess in chronic granulomatous disease, EUROPEAN JOURNAL OF PEDIATRICS, 10.1007/s004310051231, Vol.158, No.10, pp.872-873, 1999.10.
108. S Ohga, K Okada, K Ueda, H Takada, M Ohta, T Aoki, N Kinukawa, S Miyazaki, T Hara, Cerebrospinal fluid cytokine levels and dexamethasone therapy in bacterial meningitis, JOURNAL OF INFECTION, 10.1016/S0163-4453(99)90103-2, Vol.39, No.1, pp.55-60, 1999.07, Objectives: cerebrospinal fluid (CSF) levels of interleukin (IL)-1 beta and tumor necrosis factor (TNF) alpha were measured to assess the effect and application of dexamethasone (Dex) therapy for bacterial meningitis.
Methods: associations between clinical findings and CSF parameters were first investigated, and prognosis was compared between 25 patients with Dex and 12 without Dex therapy.
Results: patients with the presence of disturbed consciousness showed higher CSF levels of TNF alpha (mean: 3015 pg/ml) or protein (mean: 215 mg/dl) than those without it (both, P<0.05). Simultaneous increase of TNF alpha (>1000 pg/ml) and protein (>100 mg/dl) was observed in 80% of patients with profoundly disturbed consciousness. Patients with Dex therapy presented higher TNF alpha/protein levels at diagnosis than those without Dex therapy (P<0.05). Despite worse conditions at diagnosis, only one of 14 Dex-treated patients whose initial CSF TNF alpha levels exceeded 1000 pg/ml developed deafness. On the other hand, two of four patients without Dex therapy who had the same TNF alpha level suffered from psychomotor retardation. The differences in the frequency of sequelae between those with and without Dex therapy were significant in patients showing high TNF alpha level (P<0.05), but not in those showing high CSF levels of IL-1 beta or protein. The logistic regression analysis indicated that high CSF protein level (P<0.0001), or no Dex therapy (P=0.0001) was the independent risk factor for sequelae.
Conclusions: although the study number was small, our observations suggested that CSF TNF alpha/protein levels reflected the neurologic severity, and implied that early Dex therapy might be beneficial for patients with prominently high TNF alpha levels..
109. S Ohga, N Kimura, H Takada, M Nagano, K Ohshima, A Nomura, K Muraoka, H Take, S Yamamori, T Hara, Restricted diversification of T-cells in chronic active Epstein-Barr virus infection: Potential inclination to T-lymphoproliferative disease, AMERICAN JOURNAL OF HEMATOLOGY, 10.1002/(SICI)1096-8652(199905)61:1<26::AID-AJH6>3.0.CO;2-R, Vol.61, No.1, pp.26-33, 1999.05, To assess the abnormal T-cell expansion in chronic active Epstein-Barr virus infection (CAEBV), T-cell antigen receptor (TCR) repertoire was analyzed in four patients with the disease. All fulfilled the diagnostic criteria of CAEBV, presenting with fever, hepatosplenomegaly, cytopenia, abnormal high titers of anti EBV-antibodies, and positive EBV genome of unknown cause. Southern blotting probed with EBV-terminal repeats and TCR C beta gene indicated clonal expansion of the infected cells in 3 and 2 patients, respectively, The number of CD4(+) HLA-DR+ cells appreciably increased in patients 1 (59%) and 2 (24%), who had a coronary aneurysm and central nervous system involvement, respectively. TCR gene expression examined by the inverse polymerase chain reaction methods revealed that VP gene usages were preferential in all patients (V beta 7 and V beta 12: patient 1, V beta 4: patient 2, V beta 13: patients 3 and 4), compared with those in healthy controls. V alpha 18 gene expression was remarkably high in patients 1 and 2. Moreover, J beta gene expression was skewing in the reigning V beta clones in all patients. V beta 4-J beta 1.5 and V beta 13-J beta 1.5 genes were clonally expressed in patients 2 and 4, respectively. These results suggest that CAEBV is associated with the restricted diversity of T-cells, which may stem from the sustained expansion of oligoclonal T-cells possibly driven by conventional viral antigens, but not, superantigens. Although the study is limited by the small number of patients, the unbalanced T-cell repertoire might contribute to the evolution of T-lymphoproliferative disease, otherwise, imply the innate defective immunity to EBV in CAEBV patients. (C) 1999 Wiley-Liss, Inc..
110. H Takada, S Ohga, K Honda, M Ikeda, M Kurimoto, T Hara, Increased interleukin-18 levels in patients with hemophagocytic lymphohistiocytosis., FASEB JOURNAL, Vol.13, No.4, p.A643, 1999.03.
111. K Ohshima, J Suzumiya, M Sugihara, S Nagafuchi, S Ohga, M Kikuchi, CD95 (Fas) ligand expression of Epstein-Barr virus (EBV)-infected lymphocytes: A possible mechanism of immune evasion in chronic active EBV infection, PATHOLOGY INTERNATIONAL, 10.1046/j.1440-1827.1999.00816.x, Vol.49, No.1, pp.9-13, 1999.01, The Epstein-Barr virus (EBV) induces infectious mononucleosis (IM) and can be associated with chronic active EBV infection (CAEBV). Cytotoxic T lymphocytes (CTL) play an important role in excluding EBV-infected cells. Two cytotoxic mechanisms of CTL have been demonstrated: one perforin/granzyme-based and the other Fas (CD95)/Fas ligand (FasL)-based. To clarify these two pathways in CAEBV, we analyzed six patients with CAEBV and four patients with IM using immunohistochemical staining of the lymph nodes. In both CAEBV and IM, CD8(+) T-cells increased in number, but CD56(+) natural killer cells were rare. In four of six cases with CAEBV, approximately half the lymphocytes were positive for T cell-restricted intracellular antigens (TIA-1), which were recognized by the cytolytic granules of CTL, In IM, the number of TIA-1 positive cells was smaller than that in CAEBV, Fas-positive lymphocytes were frequently encountered in both CAEBV and IM, However, Fast-positive lymphocytes increased in three of six patients with CAEBV, but not in patients with IM, Except for one case with CAEBV, the number of perforin- and/or granzyme-positive cells was small in number in both CAEBV and IM cases. In double-staining Fast and EBV in situ hybridization, Fast-positive EBV-infected lymphocytes were detected in CAEBV but not in IM. In CAEBV, the Fas/FasL pathway and not perforin pathways appears to play an important role in the pathogenesis, The data suggest that EBV-infected lymphocytes may evade immune attack through the expression of Fast..
112. S Ohga, H Takada, K Honda, T Inamura, K Gondo, K Ohshima, M Yamamoto, T Hara, Central nervous system T-cell lymphoproliferative disorder in a patient with chronic active Epstein-Barr virus infection, JOURNAL OF PEDIATRIC HEMATOLOGY ONCOLOGY, 10.1097/00043426-199901000-00011, Vol.21, No.1, pp.42-46, 1999.01, Purpose: Central nervous system (CNS)-T cell lymphoproliferative disorder (T-LPD) developing during the course of chronic active Epstein-Barr virus (CAEBV) infection is reported.
Patients and Methods: CAEBV was diagnosed in a 14-month-old boy with fever, cytopenia, hepatosplenomegaly, and abnormal high titers of anti-Epstein-Barr virus (EBV) antibodies. At 8 years of age, he had a splenectomy because of progressive disease.
Results: After 27 months of clinical remission, muscle weakness and paresthesia developed. Magnetic resonance imaging of his brain showed spotty T2 prolongation in left parietal, bilateral frontal, and temporal white matter with meningeal enhancement. Brain biopsy revealed the cerebral infiltration of CD3(+), CD4(+), CD8(-). CD45RO(+), CD56(-), and EBV-encoded RNA li cells.
Conclusions: The CNS involvement of EBV-associated T-LPD is a rare but serious complication in CAEBV without known underlying immunodeficiency..
113. K Ohshima, J Suzumiya, M Sugihara, S Nagafuchi, S Ohga, M Kikuchi, Clinicopathological study of severe chronic active Epstein-Barr virus infection that developed in association with lymphoproliferative disorder and/or hemophagocytic syndrome, PATHOLOGY INTERNATIONAL, 10.1111/j.1440-1827.1998.tb03864.x, Vol.48, No.12, pp.934-943, 1998.12, Chronic active Epstein-Barr virus (CAEBV) infection has been previously reported to be sometimes associated with an aggressive clinical course. However, the role of EBV in the CAEBV is not well clarified. A retrospective study was performed on nine adult and five child patients (eight males and six females). Histologically, at first admission, the presence of neoplastic lesions could not be confirmed. The lymph nodes in half of all cases revealed paracortical hyperplasia with transformed lymphocytes (hyperplastic type). Half of the cases showed non-suppurative necrosis and an increased number of histiocytes with phagocytosis (histiocytic type). Activated histiocytes with lymphokine positivity were frequently detected in the histiocytic type. In the phenotypical study, 10 of the examined 11 cases showed increased numbers of natural killer (NK) cells and/or CD8-positive T lymphocytes. In situ hybridization (ISH) showed EBV-infected lymphoid cells, but the number of EBV-infected cells varied. Double-labeling immunochemistry/ISH demonstrated EBV-infected T cells, including NK cells, but not B cells. In addition, three cases showed a monoclonal dissemination of EBV terminal repetitive sequence (TR), and two cases showed oligoclonal dissemination. From those findings, monoclonal, oligoclonal and polyclonal populations of EBV-infected T or NK cells were considered to be present in CAEBV states. During the clinical course, 12 of the 14 cases died within 5 years. Six cases died from EBV-associated hematopoietic tumors (histiocytic tumor, T cell lymphoma, B cell lymphoma, plasmacytoma, and NK cell leukemia); one from non-EBV-associated acute myelogenous leukemia, and five due to hemophagocytic syndrome. The examined EBV-associated hematopoietic tumors showed monoclonal EBV terminal repetitive sequences. There is a possibility that the monoclonal dissemination of EBV-infected cells develops from oligoclonal or polyclonal EBV-infected cells. And active histiocytes with lymphokine positivity were frequently detected in the cases with histologically histiocytic type. These findings seem to be related with the causes of death due to hemophagocytic syndrome..
114. A Ohara, S Kojima, S Hibi, H Inada, H Kigasawa, J Okamura, S Ohga, Y Toyoda, F Bessho, K Koike, S Konishi, M Tsuchida, R Hanada, S Imashuku, T Nakahata, Tsukimoto, I, Development of MDS/AML in children with hepatitis associated aplastic anemia following treatment with ALG, cyclosporine and rhG-CSF., BLOOD, Vol.92, No.10, p.427A, 1998.11.
115. M Kuroiwa, H Gondo, K Ashida, T Kamimura, T Miyamoto, Y Niho, K Tsukimori, H Nakano, S Ohga, Interferon-alpha therapy for chronic myelogenous leukemia during pregnancy, AMERICAN JOURNAL OF HEMATOLOGY, 10.1002/(SICI)1096-8652(199809)59:1<101::AID-AJH23>3.0.CO;2-D, Vol.59, No.1, pp.101-102, 1998.09.
116. Y Sakai, S Ohga, Y Tonegawa, H Takada, F Nakao, H Nakayama, T Aoki, S Yamamori, T Hara, Interferon-alpha therapy for chronic active Epstein-Barr virus infection: Potential effect on the development of T-lymphoproliferative disease, JOURNAL OF PEDIATRIC HEMATOLOGY ONCOLOGY, 10.1097/00043426-199807000-00013, Vol.20, No.4, pp.342-346, 1998.07, Purpose: A patient with aggressive chronic active Epstein-Barr virus (CAEBV) infection is described whose disease activity subsided after interferon (IFN)-alpha therapy.
Patient and Methods: The patient had intermittent fever, cytopenia, liver dysfunction, hepatosplenomegaly, abnormal titers of EBV-associated antibodies, and positive EBV genomes.
Results: Despite repeated trials of the antiviral agents prednisolone and gamma-globulin, his condition deteriorated. The administration of IFN-alpha (1 x 10(5) U/kg subcutaneously 3 times per week) led to a dramatic clinical improvement. During the IFN-alpha therapy, the rearrangement bands of T-cell antigen receptor genes disappeared assessed by Southern blotting with a decrease in the number of activated T cells, although the EBV-genome remained evident.
Conclusions: These observations suggest that IFN-alpha is useful in managing CAEBV, possibly restraining the clonal development of T-lymphoproliferative disease (LPD) and EBV-associated B-LPD, although it does not eradicate the proliferation of EBV..
117. E Ishii, S Ohga, M Tanimura, S Imashuku, M Sako, S Mizutani, S Miyazaki, Clinical and epidemiologic studies of familial hemophagocytic lymphohistiocytosis in Japan, MEDICAL AND PEDIATRIC ONCOLOGY, 10.1002/(SICI)1096-911X(199805)30:5<276::AID-MPO3>3.0.CO;2-C, Vol.30, No.5, pp.276-283, 1998.05, Background and Procedure. The etiology of familial hemophagocytic lymphohistiocytosis (FHL), which is characterized by fever, hepatosplenomegaly, pancytopenia, and coagulopathy, remains unknown. We analyzed 43 FHL patients, all with affected siblings, in 18 families who were identified during the period 1986-1995 in Japan.
Results. The presence of consanguinity was evident in two families (11%). The majority of families lived in western Japan, where the frequency of consanguineous marriage is high. The incidence of FHL was significantly higher in the western island, Kyushu, than in other areas. The segregation ratio calculated for these families was 0.35 by the Weinberg proband method, showing the autosomal-recessive inheritance of the disease. Since the diagnosis of an FHL patient without affected siblings (sporadic case) is quite difficult, we calculated the possible number of sporadic cases; approximately 122 patients could be identified as sporadic FHL cases during the same period in Japan. Most of the clinical and laboratory findings were not distinguishable from those of other types of lymphohistiocytosis. However, atypical lymphoid cells with azurophilic granules in peripheral blood were observed in half of the patients at diagnosis, suggesting the clinical importance of this parameter for early diagnosis. Despite intensive therapy, the prognosis of FHL was extremely poor; but 4 of the 8 patients who have survived had received bone marrow transplantation (BMT), indicating the effectiveness of BMT for this disorder.
Conclusions. The distribution of FHL in areas of highly frequent consanguineous marriage and the segregation analysis indicated a genetic factor in FHL. The identification of the genes for FHL is expected to contribute to a cure for this disorder, and might also enable FHL carrier detection and donor selection for BMT. (C) 1998 Wiley-Liss, Inc..
118. S Ohga, K Gondo, A Nomura, Y Onoe, A Matsuzaki, T Hara, Cerebrospinal fluid cytokine concentrations in a patient with lupus meningoencephalitis: Differences from cytokine profiles in central nervous system infections, BRITISH JOURNAL OF RHEUMATOLOGY, Vol.37, No.1, pp.111-112, 1998.01.
119. S Ohga, F Nakao, O Narazaki, N Fusazaki, T Aoki, K Kamesaki, T Hara, Hypogammaglobulinaemia in a patient with ring chromosome 21, ARCHIVES OF DISEASE IN CHILDHOOD, Vol.77, No.3, pp.252-254, 1997.09, An 8 year old boy with ring chromosome 21 who was susceptible to sinorespiratory infections due to hypogammaglobulinaemia is reported. He presented with the characteristic features of monosomy 21 syndrome, such as psychomotor retardation, hypertonia, large saccular ears, prominent nasal bridge, micrognathia, thrombocytopenia, and patent ductus arteriosus. His serum Ige concentration was less than 1.5 g/l at 3 years and 6 months of age after repeated hospitalisations with pneumonia, otitis media, and convulsions. Regular replacement of intravenous gammaglobulin effectively reduced such infectious episodes. A predisposition to infection in patients with ring chromosome 21 may be explained by hypogammaglobulinaemia and merit treatment with gammaglobulin..
120. K Ohshima, J Suzumiya, S Ohga, A Ohgami, M Kikuchi, Integrated Epstein-Barr virus (EBV) and chromosomal abnormality in chronic active EBV infection, INTERNATIONAL JOURNAL OF CANCER, 10.1002/(SICI)1097-0215(19970611)71:6<943::AID-IJC5>3.0.CO;2-Y, Vol.71, No.6, pp.943-947, 1997.06, In order to examine the role of Epstein-Barr virus (EBV) in the pathogenesis of chronic active EBV infection (CAEBV), we investigated whether or not EBV integration into the human genome is associated with any chromosonal abnormality. We therefore analyzed 4 cases of CAEBV: 2 cases showed a normal karyotype, while one had an oligo-clonal 6th chromosomal abnormality and the fourth had a clonal 6th deletion (q15q23). In addition, the case with an oligo-clonal abnormality also had oligo-clonal EBV terminal repeat (TR) bands, while the case with a clonal abnormality showed a clonal TR band. In contrast, the 2 cases with a normal karyotype showed no clonal band. Two-color fluorescence in site hybridization (FISH) was used to detect the integrated EBV and the 6th chromosomal site. The presence of integrated EBV into the 6th chromosome was not frequent in the 2 cases with a normal karyotype, but it was statistically frequent in the case with an oligo-clonal 6th abnormality. in the case with a clonal 6th deletion, integration in the 6th chromosome was also slightly higher than that in the other chromosomes. In CAEBV, integrated EBV might thus be associated both with chromosomal abnormality and with pathogenesis. (C) 1997 Wiley-Liss, Inc..
121. S Ohga, K Ikeuchi, R Kadoya, K Okada, C Miyazaki, S Suita, K Ueda, Intrapulmonary Mycobacterium avium infection as the first manifestation of chronic granulomatous disease, JOURNAL OF INFECTION, Vol.34, No.2, pp.147-150, 1997.03, A 10-month-old Japanese male infant, with no history of being prone to infections, contracted an intrapulmonary mycobacteria! infection. After 2 months of intermittent fever, radiological examinations revealed mass lesions in the lung and mediastinum. Biopsy specimens showed granulomas with caseous necrosis, from which Mycobacterium avium was isolated There was no history of mycobacteriosis or immunodeficiency diseases among his relatives. Analyses of the O-2(-) release and expression of NADPH oxidase components verified that he suffered from gp91-phox(-) chronic granulomatous disease (CGD), and that his mother was a carrier of the disease. This is a rare clinical presentation for the onset of CGD, suggesting that the invasive mycobacteriosis might result from defective intracellular killing of CGD-phagocgtes..
122. Ohga S, Miyazaki S, Idiopathic pulmonary hemosiderosis: current diagnosis and management, 1997.01.
123. S Ohga, T Kai, K Honda, H Nakayama, T Inamitsu, K Ueda, What are the essential symptoms in the Hoyeraal-Hreidarsson syndrome?, EUROPEAN JOURNAL OF PEDIATRICS, Vol.156, No.1, pp.80-81, 1997.01.
124. H Kanno, H Fujii, A Hirono, Y Ishida, S Ohga, Y Fukumoto, K Matsuzawa, S Ogawa, S Miwa, Molecular analysis of glucose phosphate isomerase deficiency associated with hereditary hemolytic anemia, BLOOD, Vol.88, No.6, pp.2321-2325, 1996.09, We report here two new cases of glucose phosphate isomerase (GPI) deficiency associated with hemolytic anemia and present the results of molecular analysis of the five Japanese GPI variants. A Japanese girl (GPI Fukuoka) had an episode of prolonged neonatal jaundice and at 3 years of age was admitted due to acute hemolytic crisis occurring with upper respiratory tract infection. Red blood cell (RBC) GPI activity was decreased to 11.8% of normal and the reduced glutathione (GSH) level of RBCs was slightly decreased. A 54-year-old Japanese man (GPI Iwate) was hospitalized due to chronic active hepatitis, and compensated hemolysis was noted. RBC GPI activity of the proband was decreased to 18.8%, and the GSH content was about half of the normal mean value. Sequencing of the reticulocyte GPIcDNA showed homozygous missense mutations 1028CAG --> CGG (343Gln --> Arg), 14ACC --> ATC (5Thr --> IIe), 671ACG --> ATG (224Thr --> Met), and 1615GAC --> AAC (539Asp --> Asn) in GPI Narita, GPI Matsumoto, GPI Iwate, and GPI Fukuoka, respectively. We also identified GPI Kinki as a compound heterozygote of 1124ACA --> AGA(375Thr --> Arg)/1615GAC --> AAC(539Asp --> Asn). Our findings, together with the previous results of other investigators, showed that the GPI gene mutations so far identified were heterogeneous, although most GPI variants had common biochemical characteristics such as heat instability and normal kinetics. Several amino acid substitutions were identified in the proximity of the catalytically important amino acid residues such as Ser/Asp 159/160, Asp341, and Lys518, which have been identified in the structural analysis of the pig GPI. The molecular characterization of human GPI variants, therefore, may provide new insights into the genotype-phenotype correlation of GPI deficiency as well as the Structure-function relationship of this enzyme. (C) 1996 by The American society of Hematology..
125. A Nomura, S Ohga, A Matsuzaki, T Kai, S Inaba, M Suda, K Ueda, Granulocyte transfusion: Stimulation of low dose granulocyte colony-stimulating factor in donors for leukapheresis, ACTA PAEDIATRICA JAPONICA, Vol.38, No.4, pp.317-321, 1996.08, In order to assess the clinical utility of granulocyte transfusions (GT), the stimulating effects of donor granulopoiesis for GT therapy were examined using either low dose recombinant human granulocyte colony-stimulating factor (rhG-CSF) or dexamethasone (DEX). The increment of leukocytes, polymorphonuclear cells (PMN) and monocytes in the subjects stimulated with rhG-CSF (0.7 mu g/kg SC) surpassed each increment in those with DEX alone (1 mg PO). The lymphocyte counts after DEX stimulation decreased in contrast to those after G-CSF stimulation. This dose of G-CSF did not enhance the priming effects on the superoxide release from PMN. The serum levels of lysozyme, but not of lactate dehydrogenase, in G-CSF stimulated donors were higher than those in DEX-treated donors. The serum macrophage/monocyte-colony stimulating factor (M-CSF) levels in DEX stimulation were lower than in either G-CSF stimulation or no stimulation. The net yield of the PMN in GT on G-CSF stimulation was practically larger than that on DEX stimulation. One of the two patients who received GT collected by DEX stimulation died of aspergillosis. Two of the five patients who received PMN mobilized by G-CSF died of fungal infections or necrotizing fasciitis, although two of the remaining patients overcame severe bacterial infections. These results suggest that low dose G-CSF effectively and safely mobilizes a sufficient quantity of PMN from GT-donors without excessive superoxide generation from the transfused cells. This low dose G-CSF stimulation may be substituted for conventional DEX stimulation for GT..
126. H Nakayama, T Inamitsu, S Ohga, T Kai, M Suda, A Matsuzaki, K Ueda, Chronic myelomonocytic leukaemia with t(8;9)(p11;q34) in childhood: An example of the 8p11 myeloproliferative disorder?, BRITISH JOURNAL OF HAEMATOLOGY, Vol.92, No.3, pp.692-695, 1996.03, We describe the case of a 10-year-old girl with chronic myelomonocytic leukaemia with the chromosomal translocation t(8;9)(p11;q34), who had developed tonsillar lymphoma as extramedullary involvement at the initial presentation. The cytogenetic study of the cells in both bone marrow and tonsils demonstrated t(8:9)(p11:q34), despite no malignant features in the bane marrow specimens. She developed acute leukaemic transformation 8 months after diagnosis during chemotherapy for lymphoma. Although etoposide reduced the number of blasts, t(8;9)(p11:q34)-bearing cells were not eradicated. Complete remission was obtained following an unrelated bone marrow transplantation. The clinical characteristics of this patient are similar to those of the patients with t(8;9)(p11;q34 or q32) or t(8:13)(p11:q11 or q12) reported previously. The unusual progression of the disease might be associated with the presence of t(8:9)(p11:q34), suggesting a part in the 8p11 myeloproliferative syndrome..
127. T KAMURA, H TSUDA, Y YAE, S HATTORI, S OHGA, Y SHIBATA, SI KAWABATA, N HAMASAKI, AN ABNORMAL FIBRINOGEN FUKUOKA-II (GLY-B-BETA-15-]CYS) CHARACTERIZED BY DEFECTIVE FIBRIN LATERAL ASSOCIATION AND MIXED DISULFIDE FORMATION, JOURNAL OF BIOLOGICAL CHEMISTRY, 10.1074/jbc.270.49.29392, Vol.270, No.49, pp.29392-29399, 1995.12, A dysfibrinogenemia was attributable to a single amino acid substitution from glycine to cysteine at residue 15 of the B beta chain in a fibrinogen molecule designated as fibrinogen Fukuoka II. The fibrinogen Fukuoka II showed prolonged thrombin and reptilase times and impaired fibrinopeptide B release by thrombin, resulting in abolition of fibrin monomer repolymerization under physiological conditions. Repolymerization of the des-(B beta 1-42)-fibrin monomers, however, was not distinguished from the normal pattern of des-(B beta 1-42)-fibrin monomers, suggesting that no other abnormality existed in fibrinogen Fukuoka II. Although an additional cysteine was substituted at residue 15 of the B beta chain, fibrinogen Fukuoka II had no free sulfhydryl group within the molecule. Instead, fibrinogen Fukuoka II formed a disulfide bond with cysteine, albumin, another mutated B beta chain within the same molecule, or intermolecular dimeric fibrinogen Fukuoka II. The mutation in fibrinogen Fukuoka II was the same as that in fibrinogen Ise published previously (Yoshida, N., Wada, H., Morita, K., Hirata, H., Matsuda, M., Yamazumi, K., Asakura, S., and Shirakawa, S. (1991) Blood 77, 1958-1963). Fibrinogen Ise, however, has been described as having prolonged thrombin time but normal reptilase time. Reasons for the discrepancy were not clear. Analysis of the B beta 1-42 fragment showed that fibrinogen was heterogeneous at position 31 of the B beta chain with respect to proline or hydroxyproline..
129. A MATSUZAKI, J OKAMURA, Y NAGATOSHI, T KAI, S OHGA, H GONDO, S INABA, K UEDA, TREATMENT OF YOUNG RELAPSED HODGKINS-DISEASE PATIENTS WITH HIGH-DOSE CHEMOTHERAPY FOLLOWED BY PERIPHERAL-BLOOD STEM-CELL TRANSPLANTATION, LEUKEMIA & LYMPHOMA, Vol.18, No.5-6, pp.505-509, 1995.08, Four patients less than 20 years of age with Hodgkin's disease, who had developed either second or third relapse, were treated with high-dose chemotherapy followed by peripheral blood stem cell transplantation (PBSCT). Peripheral blood stem cells (PBSC) were collected after the administration of high-dose cytosine arabinoside (HD-AraC, 1g/m(2)x4). The conditioning regimen for PBSCT contained cyclophosphamide (50 mg/m(2)x4), etoposide (150 mg/m(2)x6) and ranimustine (250 mg/dosex1) (CVM regimen). A significant tumor regression was thus obtained after HD-AraC in 3 cases. The amount of PBSC harvested ranged from 1.2 to 4.5 x 10(5)/kg CFU-GM. Several cycles of conventional therapy were performed prior to the transplantation. PBSCT was done only after achieving a complete remission (CR) in 3 cases, but during relapse in another case. All patients showed both a rapid and sustained hematological recovery without any critical side effects. After this treatment, the 3 patients who were in CR at transplantation maintained a CR for 27, 26, and 4 months, respectively, while another developed a bone relapse despite achieving a CR by PBSCT. These results suggest that a combination of HD-AraC and CVM followed by PBSCT is therefore considered to be beneficial in the treatment of relapsed Hodgkin's disease..
130. S OHGA, A OOSHIMA, J FUKUSHIGE, K UEDA, HISTIOCYTIC HEMOPHAGOCYTOSIS IN A PATIENT WITH KAWASAKI-DISEASE - CHANGES IN THE HYPERCYTOKINAEMIC STATE, EUROPEAN JOURNAL OF PEDIATRICS, Vol.154, No.7, pp.539-541, 1995.07, A 32-month-old Japanese boy exhibited haemophagocytic syndrome (HPS) during the recurrent course of Kawasaki disease. Despite repeated gamma-globulin therapy, he developed cytopenia with marked hepatomegaly and evidence of histiocytic haemophagocytosis in the bone marrow. Serum levels of interferon-gamma and tumour necrosis factor, but not of interleukin-1 beta, increased in parallel with his symptoms. No confirmation was obtained of the association of toxic reactions to the used drugs. No coronary lesions remained as sequelae.
Conclusion Cytopenia in Kawasaki disease could herald HPS, and the hypercytokinaemia involved in the two febrile syndromes might be of distinct nature..
132. S OHGA, E HIGASHI, A NOMURA, A MATSUZAKI, A HIRONO, S MIWA, H FUJII, K UEDA, HAPTOGLOBIN THERAPY FOR ACUTE FAVISM - A JAPANESE BOY WITH GLUCOSE-6-PHOSPHATE-DEHYDROGENASE GUADALAJARA, BRITISH JOURNAL OF HAEMATOLOGY, Vol.89, No.2, pp.421-423, 1995.02, We report the case of a 2-year-ord Japanese boy with acute favism who was treated with human haptoglobin products. He had been exhibiting chronic nonspherocytic haemolytic anaemia until the diagnosis of glucose-6-phosphate dehydrogenase (G6PD) deficiency when 14 months old. He suffered a favic crisis at 24 months of age, when the administration of haptoglobin was effective for relieving bilirubinaemia and haemoglobinuria. Serum-free Hb rapidly decreased to normal levels despite the sustained level of serum lactate dehydrogenase. His G6PD gene was G6PD Guadalajara. This is the first application of haptoglobin therapy for acute favism and the first reported case of Japanese G6PD deficiency with typical favic crisis. Haptoglobin treatment might be helpful for managing the haemolytic crisis in the disease..
133. S OHGA, A NOMURA, N SUGA, S HIKINO, R KIRA, A MATSUZAKI, K MASUDA, K UEDA, LIPOSTEROID AGAINST REFRACTORY PULMONARY HEMORRHAGE IN IDIOPATHIC PULMONARY HEMOSIDEROSIS, EUROPEAN JOURNAL OF PEDIATRICS, Vol.153, No.9, pp.687-690, 1994.09, We describe two Japanese children with idiopathic pulmonary haemosiderosis (IPH), whose refractory haemorrhages were treated with an intravenous; lipid emulsion containing dexamethasone (liposteroid). A 22-month-old boy and a 14-month-old girl have been observed with similar symptoms; periodic bouts of anaemia, reticulocytosis, diffuse infiltrates on chest X-ray and the finding of siderophages in sputum or gastric lavage fluid. The MRI of the lung was useful for the diagnosis. Methylprednisolone pulse therapy was successful in treating acute massive bleeding. Subsequent oral prednisolone could not prevent chronic recurrent haemorrhages. However, the intermittent administration of liposteroid (0.05 mg/kg/dose IV) led to a cessation of bleeding; the haemoglobin concentration rose to normal levels. This observation emphasizes the usefulness of liposteroid in the management of refractory IPH..
134. H YAMASHITA, J KUKITA, S OHGA, H NAKAYAMA, K AKAZAWA, K UEDA, SERUM ERYTHROPOIETIN LEVELS IN TERM AND PRETERM INFANTS DURING THE 1ST YEAR OF LIFE, AMERICAN JOURNAL OF PEDIATRIC HEMATOLOGY ONCOLOGY, Vol.16, No.3, pp.213-218, 1994.08, Purpose: To evaluate the kinetics of erythropoietin (EPO) production and address the pathogenesis of anemia of prematurity, we measured EPO levels in infants during the first year of life.
Patients and Methods: Using a radioimmunoassay, serum EPO levels were measured in 97 infants classified into three groups according to weight: group A, n = 40, <1,500 g; group B, n = 19, 1,500-2,499 g; and group C, n = 38, greater-than-or-equal-to 2,500 g.
Results: The serum EPO level ranged widely during the early neonatal period from days 0 to 6 (group A, <5 to 307 mU/ml; group B, 10-340 mU/ml; and group C, 9-108 mU/ ml). EPO reached its lowest level (<20 mU/ml) between days 7 and 50 in all groups. The hemoglobin concentration reached its nadir between days 51 and 150 in all groups, with the lowest concentration observed in low birth weight infants. In contrast, the EPO level during the anemic phase was approximately 20 mU/ml and was independent of birth weight. A negative correlation between serum EPO level and hemoglobin concentration was observed only in group C (r = -0.54, p < 0.05). The negative slope of the regression equation in group C exceeded that of groups A and B (p < 0.05). When the relationship between EPO and Hb was evaluated over periods of 7-50 days, 51-100 days, and > 101 days, respectively, we noted a significant correlation between values on days 7 and 50 in group A (r = -0.53, p < 0.05) and between days 51 and 100 in group B (r = -0.76, p < 0.05).
Conclusions: These data suggest the appreciable EPO production in premature infants, but its insufficient response to the depressed hemoglobin level, implying the need to administer exogenous EPO to infants with anemia of prematurity..
135. A MATSUZAKI, T INAMITSU, T WATANABE, S OHGA, E ISHII, Y NAGOTOSHI, H TASAKA, M SUDA, K UEDA, ACUTE PROMYELOCYTIC LEUKEMIA IN A PATIENT TREATED WITH ETOPOSIDE FOR LANGERHANS CELL HISTIOCYTOSIS, BRITISH JOURNAL OF HAEMATOLOGY, Vol.86, No.4, pp.887-889, 1994.04, We report a child with acute promyelocytic leukaemia (APL) who was treated with etoposide (VP16) for Langerhans cell histiocytosis (LCH). A 3-year-old Japanese girl was diagnosed as having LCH. She was treated with combination chemotherapy using VP16 and prednisolone. 56 months after beginning the chemotherapy she developed APL. Her bone marrow was occupied with atypical promyelocytes including giant granules and multiple Auer bodies. A cytogenetic analysis of the leukaemic cells showed 46,XX,11p-,14q+,t(15,17). The cumulative dose of the administered VP16 was 12120mg/m2, which suggested that VP16 may be responsible for the development of APL. The risk of developing secondary leukaemia after the administration of VP16 should therefore be considered when managing patients with LCH..
136. S OHGA, M NISHIZAKI, T NAGASHIMA, K UEDA, ASSOCIATION BETWEEN FEVER AND SERUM INTERLEUKIN-6 LEVELS IN CHILDREN WITH GROUP-A BETA-HEMOLYTIC STREPTOCOCCAL INFECTION, JOURNAL OF THERMAL BIOLOGY, Vol.19, No.2, pp.91-96, 1994.04, 1. The serum levels of interleukin (IL)-1 beta, IL-6 and granulocyte colony-stimulating factor (G-CSF) were measured in children with Group A beta-hemolytic streptococcal (GABHS) infection using sensitive immunoassays.
2. Serum IL-6 levels were elevated in 21/27 patients during the phase of GABHS antigen-detection, significantly higher than in healthy control children (P < 0.01). Levels of IL-1 were undetectable in all but one sample.
3. The IL-6 level peaked on day 3 of the infection, then decreased. The IL-6 levels were significantly associated with the duration of fever (P < 0.05) and the maximum body temperature (BT) (P < 0.05), but not with the BT at time of blood sampling, C-reactive protein levels or leukocyte counts.
4. Levels of G-CSF were slightly higher in the patients with infection than in the controls (P < 0.05), but were not correlated with any other parameter including neutrophil counts.
5. These cytokine levels neither reflected a differing T-serotype infection, nor did they vary among patients with regard to the presence of skin eruptions and the carrier state.
6. These observations suggest that IL-6, but not IL-1, is produced during the acute phase of GABHS infection, accounting for the febrile condition as an inflammatory cytokine, despite the serotype of the infecting organism or the clinical types of infection..
137. M IWATA, H NUNOI, H YAMAZAKI, T NAKANO, H NIWA, S TSURUTA, S OHGA, S OHMI, S KANEGASAKI, MATSUDA, I, HOMOLOGOUS DINUCLEOTIDE (GT OR TG) DELETION IN JAPANESE PATIENTS WITH CHRONIC GRANULOMATOUS-DISEASE WITH P47-PHOX DEFICIENCY, BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS, 10.1006/bbrc.1994.1382, Vol.199, No.3, pp.1372-1377, 1994.03, The cytosolic 47-kDa protein designated as p47-phox (phagocyte oxidase) is one of the essential components of the superoxide-generating system in phagocytes, and its defect is known to cause chronic granulomatous disease (CGD). Five unrelated CGD patients with p47-phox deficiency were found among 82 CGD patients in Japan. We sequenced the cDNAs and the genomic DNAs corresponding to p47-phox derived from these patients. In all cases examined, the defect was identified to be a GT (or TG) dinucleotide deletion at bases 75/76 (or 74/75, respectively) in the coding sequence for the protein. The same mutation was reported previously for a total of 9 alleles from 5 CGD patients in England and in the United States. It seems, therefore, that the dinucleotide GT deletion is the common mutation in 47-phox deficient CGD due to certain structural issues. (C) 1994 Academic Press, Inc..
138. S OHGA, T AOKI, K OKADA, H AKEDA, K FUJIOKA, A OHSHIMA, T MORI, MINAMISHIMA, I, K UEDA, CEREBROSPINAL-FLUID CONCENTRATIONS OF INTERLEUKIN-1-BETA, TUMOR-NECROSIS-FACTOR-ALPHA, AND INTERFERON-GAMMA IN BACTERIAL-MENINGITIS, ARCHIVES OF DISEASE IN CHILDHOOD, Vol.70, No.2, pp.123-125, 1994.02, To investigate the role of the inflammatory cytokines, the cerebrospinal fluid concentrations of interleukin (IL)-1 beta, tumour necrosis factor-alpha (TNF-alpha), and interferon gamma (IFN-gamma) were measured in 11 children with bacterial meningitis and two with mycoplasmic meningoencephalitis and compared with those in 50 children with aseptic meningitis and 15 with non-pleocytotic cerebrospinal fluid. Concentrations of IL-1 beta and TNF-alpha were each significantly higher in the cerebrospinal fluid of patients with bacterial meningitis than in those with aseptic meningitis or those with non-pleocytotic cerebrospinal fluid. IFN-gamma was detected at low concentrations in the cerebrospinal fluid of only 2/11 of those with bacterial meningitis. On the other hand, the IFN-gamma concentration was the highest in the cerebrospinal fluid of patients with aseptic meningitis. These results suggest that the inflammatory cytokines are differently released in the intrathecal space infected with viruses or bacteria..
139. S OHGA, A MATSUZAKI, M NISHIZAKI, T NAGASHIMA, T KAI, M SUDA, K UEDA, INFLAMMATORY CYTOKINES IN VIRUS-ASSOCIATED HEMOPHAGOCYTIC SYNDROME - INTERFERON-GAMMA AS A SENSITIVE INDICATOR OF DISEASE-ACTIVITY, AMERICAN JOURNAL OF PEDIATRIC HEMATOLOGY ONCOLOGY, Vol.15, No.3, pp.291-298, 1993.08, Purpose: We assayed serum interleukin-1 beta (IL-1beta), tumor necrosis factor alpha (TNF-alpha) and interferon gamma (IFN-gamma) levels in children with virus-associated hemophagocytic syndrome (VAHS) to evaluate the relationship Of these cytokines to other laboratory parameters. We also studied the role of IFN-gamma as a macrophage activator in hemophagocytic syndrome (HPS).
Patients and Methods: Interleukin-1 beta, TNF-alpha, and IFN-gamma were measured in 42 serial sera from six children with VAHS using a sensitive radioimmunoassay.
Results: The cytokine IFN-gamma or TNF was detected in 19/19 (100%) or 11/19 (69%) samples, respectively, during the active febrile phase, at much higher levels than during the remission phase of the disease (IFN: p < 0.00001; TNF: p < 0.01). In contrast, IL-1 could be detected in only two sera obtained from a patient during severe relapse. Serial cytokine examination revealed that the elevated TNF and IFN-gamma levels decreased rapidly to an undetectable level in concert with clinical improvement after an effective treatment, and that IFN-gamma, but not TNF, was detected just before a relapse marked by spiking fever. In the active phase, the CD4/8 ratio was depressed, and the total number of CD3+HLA-DR+ cells was increased. Of the activated T cells, CD8+ cells outnumbered CD4+ T cells. By the Spearman's rank sum test, the IFN-gamma level correlated positively with the peripheral leukocyte count [Correlation coefficient (CC): 0.585, p < 0.051 and serum lactate dehydrogenase level (CC: 0.538, p < 0.05) and negatively with the CD4/8 ratio (CC: - 0.618, p < 0.05), but not with any other parameter including ferritin and C-reactive protein. Although TNF and IL-1 were not statistically linked to these parameters, TNF levels were related to IFN-gamma levels (product moment CC: 0.546, p < 0.05). conclusions: These results suggest that circulating IFN-gamma is one of the most sensitive indicators of disease activity; it may act as a potent macrophage activator during the hypercytokinemic state of childhood VAHS..
140. S OHGA, M SAITO, A MATSUKAZI, T KAI, K UEDA, DISSEMINATED INTRAVASCULAR COAGULATION IN A PATIENT WITH HEMOPHILIA-B DURING FACTOR-IX REPLACEMENT THERAPY, BRITISH JOURNAL OF HAEMATOLOGY, Vol.84, No.2, pp.343-345, 1993.06, We report a case of haemophilia B, who developed disseminated intravascular coagulation (DIC) with massive bleeding following an administation of factor IX complex concentrates. A 22-year-old male with severe haemophilia B had a bone fracture of the fibula and haemorrhage in the ankle joint because of a traffic accident. Factor IX complex concentrates were given to keep the plasma factor IX level more than 80% for surgery. 60 h after the infusion he showed epistaxis, haematuria and swelling of the injured ankle with evidence of DIC. A small dose of monoclonal antibody (mAb)-purified factor IX concentrates with heparin and gabexate relieved the haemorrhage. A high dose of the mAb-purified product attained more than 90% levels of plasma factor IX without coagulopathy. This observation emphasizes that currently available factor IX concentrates have thrombogenicity to induce DIC. Highly purified factor IX concentrates are needed for the high-dose replacement in haemophilia B..
141. MINAMISHIMA, I, S OHGA, E ISHII, A MATSUZAKI, T KAI, K AKAZAWA, K UEDA, SERUM INTERLEUKIN-6 AND FEVER AT DIAGNOSIS IN CHILDREN WITH ACUTE-LEUKEMIA, AMERICAN JOURNAL OF PEDIATRIC HEMATOLOGY ONCOLOGY, Vol.15, No.2, pp.239-244, 1993.05, Patients and Methods: We examined serum interleukin (IL)-6 and tumor necrosis factor (TNF) alpha levels at initial diagnosis in acute leukemic children in order to clarify the roles of these cytokines on the febrile and hematological responses in the disease.
Results: IL-6 levels were significantly higher in 34 leukemic children than in 18 healthy controls and 15 patients with various malignant diseases in long remission (p < 0.0001). Three patients with apparent bacterial infections showed especially high IL-6 levels of > 100 pg/ml. In all the leukemic children, the high IL-6 levels at initial diagnosis had decreased to a low range at the time of complete remission, regardless of the use of antibiotics. In 10 of 14 leukemic children, TNF levels were high at diagnosis and then decreased to undetectable levels at remission. The relationship between IL-6/TNF levels and clinical/laboratory findings in leukemic children at diagnosis was also examined. Serum IL-6 significantly correlated with elevated body temperature (BT) (p < 0.001) and C-reactive protein (CRP) levels (p < 0.001), but not with other parameters such as leukocyte and platelet counts, hemoglobin levels, lactate dehydrogenase, and serum immunoglobulin. On the other hand, serum TNF did not show any statistical linkage with these parameters.
Conclusion: These data provide evidence for the role of IL-6 in the pathogenesis of tumor-related fever and other acute phase responses in acute leukemia..
143. S OHGA, C MIYAZAKI, K OKADA, K AKAZAWA, K UEDA, THE INFLAMMATORY CYTOKINES IN MEASLES - CORRELATION BETWEEN SERUM INTERFERON-GAMMA LEVELS AND LYMPHOCYTE SUBPOPULATIONS, EUROPEAN JOURNAL OF PEDIATRICS, Vol.151, No.7, pp.492-496, 1992.07, Interleukin-1 (IL-1-beta), tumour necrosis factor alpha (TNF-alpha) and interferon gamma (IFN-gamma) were measured in serum from children with measles using an immunoradiometric assay. The IFN-gamma level was increased in 52 out of 54 patients in the acute phase of measles (< 7 days of illness), and then declined to an undetectable level in the convalescent phase. Neither IL-1 nor TNF could be detected during the course of the illness. The mean serum IFN-gamma level was at its peak on day 4 and could be detected over a 7-day period after the onset of fever, coinciding with the febrile period (6.9 +/- 1.5 days). In the acute phase. the phytohaemagglutinin responses. absolute number of platelets, total lymphocyte counts. CD3+, CD4+, CD8+ cell counts and the CD4/8 ratio were depressed, while stab cell number and lactate dehydrogenase levels were higher than those in the convalescent phase. Using Spearman rank sum test, the IFN-gamma level was correlated negatively with the peripheral lymphocyte (P < 0.05), CD3+ (P < 0.05), CD4+ (P < 0.05) cell counts and the CD4/8 ratio (P < 0.05) and correlated positively with the stab cell count (P < 0.01) but not with any other parameter. When the acute phase findings were compared between 28 complicated and 40 uncomplicated patients, the former were younger (P < 0.01) and had higher maximum body temperature during the illness (P < 0.05) than the latter, there was no difference in their IFN-gamma levels. These results show that endogenous IFN-gamma appears in the circulation during the acute febrile phase of measles, but does not contribute directly to any complication of the disease..
144. K HIROMATSU, Y YOSHIKAI, G MATSUZAKI, S OHGA, K MURAMORI, K MATSUMOTO, JA BLUESTONE, K NOMOTO, A PROTECTIVE ROLE OF GAMMA-DELTA T-CELLS IN PRIMARY INFECTION WITH LISTERIA-MONOCYTOGENES IN MICE, JOURNAL OF EXPERIMENTAL MEDICINE, Vol.175, No.1, pp.49-56, 1992.01, We have previously reported that T cells bearing T cell receptors (TCRs) of gamma/delta-type appear at a relatively early stage of primary infection with Listeria monocytogenes in mice. To characterize the early-appearing gamma/delta-T cells during listeriosis, we analyzed the specificity and cytokine production of the gamma/delta-T cells in the peritoneal cavity in mice inoculated intraperitoneally with a sublethal dose of L. monocytogenes. The early-appearing gamma/delta-T cells, most of which were of CD4- CD8- phenotype, proliferated and secreted IFN-gamma and macrophage chemotactic factor in response to purified protein derivative from Mycobacterium tuberculosis, or recombinant 65-kD heat-shock protein derived from M. bovis but not to heat-killed Listeria. To further elucidate the potential role of the gamma/delta-T cells in the host-defense mechanism against primary infection with Listeria, we examined the effects of in vivo administration of monoclonal antibodies (mAbs) against TCR-gamma/delta or TCR-alpha/beta on the bacterial eradication in mice infected with Listeria. Most of alpha/beta-T cells or gamma/delta-T cells were depleted in the peripheral lymphoid organs at least for 12 d after an intraperitoneal injection of 200 gg TCR-alpha/beta-mAb or 200-mu-g TCR-gamma/delta-mAb, respectively. An exaggerated bacterial multiplication was evident at the early stage of listerial infection in the gamma/delta-T cells-depleted mice, whereas the alpha/beta-T cell-depleted mice exhibited much the same resistance level as the control mice at this stage although the resistance was severely impaired at the late stage after listerial infection. These results clearly indicated that the early-appearing gamma/delta-T cells contribute to the host defense at the early stage of infection with Listeria and confirmed previous reports that the highly evolved type of immunity mediated by Listeria-specific alpha/beta-T cells contributes to the host protection at the late stage after listerial infection..
145. MINAMISHIMA, I, S OHGA, E ISHII, C MIYAZAKI, K HAMADA, K AKAZAWA, K UEDA, ASEPTIC-MENINGITIS IN CHILDREN - CORRELATION BETWEEN FEVER AND INTERFERON-GAMMA LEVEL, EUROPEAN JOURNAL OF PEDIATRICS, Vol.150, No.10, pp.722-725, 1991.08, We studied the correlation between interleukin-1 beta (IL-1-beta), tumour necrosis factor alpha (TNF-alpha) and interferon gamma (IFN-gamma) in cerebrospinal fluid (CSF) and clinical/laboratory findings in children with aseptic meningitis. In 19/27 patients (70%), the CSF IFN level was high at initial diagnosis, and reduced to a low or undetectable level during the convalescent phase (5-14 days later) of the disease. There were no differences in IL-1-beta and TNF-alpha-levels between the acute and convalescent phase of the patients. The serum IFN-gamma-levels in the patients, which were simultaneously examined were undetectable in the acute phase. When we compared the clinical/laboratory findings between the 29 patients with detectable CSF IFN-gamma-level and the 21 patients with an undetectable CSF IFN-gamma-level in the acute phase, the former demonstrated higher body temperature (P < 0.01), and higher cell number and protein level in the CSF (P < 0.05) than the latter. On the other hand, there were no significant differences in the duration of meningeal signs, the titre of C-reactive protein, and the peripheral leucocyte count between the two groups. By the Spearman's rank sum test, the CSF IFN-gamma-levels correlated more definitively with the severity of febrile episode (maximal body temperature, duration of fever and body temperature at the first lumbar tap), and the cell number and protein level in the CSF. These results suggest that IFN-gamma produced in the inflamed intrathecal space may be associated with the pathogenesis of aseptic meningitis, especially the production of fever..
146. S OHGA, K UEDA, Y YOSHIKAI, Y TAKEDA, K HIROMATSU, K NOMOTO, KINETICS OF FEVER AND ITS RELATED CYTOKINES IN MICE AFTER INTRAPERITONEAL INFECTION WITH LISTERIA-MONOCYTOGENES, JOURNAL OF THERMAL BIOLOGY, Vol.16, No.2, pp.103-107, 1991.03, 1. We studied the kinetics of fever and its related cytokine production in mice after an intraperitoneal (i.p.) infection with a sublethal dose of viable Listeria monocytogenes. By day 2 after an inoculation of Listeria, body temperature of the infected mice rose to a higher level than that of non-treated mice. On day 3 after infection, body temperature of the mice became lower than that of non-treated mice, and was accompanied by wasting. After day 5, the mice gradually recovered from this wasting to show a similar level of body temperature to the control mice.
2. The number of peritoneal exudate cells (PEC) increased to the maximal level on day 3, when Thy1/CD3-positive cells emerged, and then the T cells increased to 35% of the non-adherent population of the PEC on day 8. By contrast, the number of IgM+- or Ly1+-positive cells was at a constant level (approximately 60% and approximately 20%, respectively) of the non-adherent PEC during the infection.
3. To characterize the productive pattern of fever-related cytokines in listeriosis, we investigated their expression in the PEC from mice during infection. In the adherent-PEC, IL-1-alpha and IL-6 mRNAs were consistently expressed from day 1 to day 8 after infection, while TNF had already been expressed at the highest level on day 1 and decreased on day 8. IFN-gamma mRNA was first detected in the non-adherent PEC on day 3 and increased on day 8.
4. These results suggest that TNF may be related to the initial febrile state and the consecutive wasting at the early phase of listeriosis, followed by the T cell-expansion producing IFN-gamma for elimination of Listeria..
147. M OGIMOTO, Y YOSHIKAI, G MATSUZAKI, S OHGA, K MATSUMOTO, K NOMOTO, DELETION OF SELF-REACTIVE T-CELLS IN THE DONOR-DERIVED T-CELLS BUT NOT IN THE HOST-DERIVED T-CELLS IN FULLY ALLOGENEIC RADIATION CHIMERAS - MLS-REACTIVE T-CELLS IN ALLOGENEIC RADIATION CHIMERAS, THYMUS, Vol.17, No.1, pp.11-22, 1991.02, Kinetics of T cells bearing V-beta-6 capable of recognizing Mls-1a were examined in the thymus and peripheral lymphoid organs of two allogeneic bone marrow chimeras; AKR/J(H-2K, Thy1.1,Mls-1a) --> C3H/He(H-2K,Thy1.2,Mls-1b) and AKR/J --> C57BL/6(H-2b,Thy1.2,Mls-1b). Sequential appearance of host- and donor-derived T cells occurred in the thymus and the peripheral lymphoid organs of both AKR --> C3H and AKR --> B6 chimeras. The first cells to repopulate the thymus were Thy1.2+ host-derived radioresistant cells, which were synchronized in their development. The host-derived cells in thymus of AKR --> B6 chimeras differentiate more rapidly than those in AKR --> C3H chimeras. An almost complete replacement from host-derived cells to donor-derived cells occurred by day 21 after reconstitution in AKR --> C3H and AKR --> B6 chimeras. In the donor-derived thymocytes, none of CD4- or CD8-single positive thymocytes expressed high density of V-beta-6 in either AKR --> C3H or AKR --> B6 chimeras, whereas the host-derived thymocytes in AKR --> B6 chimeras contained an appreciable number of CD4-single positive thymocytes bearing V-beta-6. In the peripheral lymphoid organs, T cells bearing V-beta-6 were virtually abolished in Thy1.1+ cell pool of both AKR --> C3H and AKR --> B6 chimeras. While V-beta-6+ T cells of host-origin were detected in the peripheral lymphoid organs in AKR --> B6 chimeras. These result indicated that the donor-derived mature T cells showed deletion of V-beta-6 in the thymus and the peripheral lymphoid organs in both AKR --> C3H and AKR --> B6 chimeras, whereas lack of V-beta-6 deletion was observed in the host-derived mature T cells in the AKR --> B6 chimeras. These results suggested that the host-derived thymocytes may likely to escape undergoing a negative selection against donor-phenotype in the radiation bone marrow chimeras..
148. E ISHII, S OHGA, K UEDA, K AKAZAWA, SERUM INTERLEUKIN-1 AND TUMOR-NECROSIS-FACTOR ACTIVITIES IN FEBRILE CHILDREN WITH ACUTE-LEUKEMIA, INTERNATIONAL JOURNAL OF HEMATOLOGY, Vol.54, No.1, pp.79-84, 1991.02, In order to determine whether a relationship exists between levels of serum interleukin-1 (IL-1) and tumor necrosis factor (TNF) and the incidence of fever in malignant disease and infection, IL-1 and TNF levels in 60 children with acute leukemia, 18 children with bacterial infection, and 10 children with viral infection were compared with those of 20 healthy children. IL-1 levels greater than 100 pg/ml were seen in two febrile leukemic patients and six bacteria-infected patients, and the bacteria-infected group as a whole had IL-1 levels significantly higher than those of healthy children (p < 0.05). TNF levels greater than 50 pg/ml were noted in six febrile leukemic patients and two bacteria-infected patients (both of whom were complicated by septic shock). No single group showed significantly higher levels when compared to healthy children. All patients showing high IL-1 or TNF levels had fevers at the time of diagnosis. These findings suggest that fever in bacterial infection is associated with the production of IL-1 but not TNF (except in cases of septic shock), whereas fever in acute leukemia may be associated with the production of either IL-1 or TNF. Monitoring patients with acute leukemia for IL-1 and TNF levels throughout the clinical course of disease may help clarify the causes of febrile episodes..