Fanconi anemia (FA) is an autosomal recessive disease, characterized by bone marrow failure, leukemia susceptibility and chromosome instability. There are at least eight genetically distinct groups (A, B, C, D1, D2, E, F and G). To date, seven genes (for FA-A, C, D1, D2, E, F and G) have been cloned. These FA proteins cooperate in a common molecular pathway. FANCD2, a downstream component of this pathway, interacts with BRCA1, a familial breast cancer gene product. These findings, together with recent identification of BRCA2 as the FANCD1 gene, suggest that the FA/BRCA pathway regulates homology-directed DNA repair. The present review describes a current view on the FA/BRCA pathway and highlights the genetics of FA. The FA/BRCA pathway plays an important role in the maintenance of genomic stability in hematopoietic cells. Elucidation of the molecular mechanisms of this pathway would provide new insights into the pathogenesis of acquired bone marrow failure syndromes and myeloid malignancies.

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Genetic counseling contains two factors : one is giving suitable information about the disease including natural history, recurrence risk, availability and usefulness of genetic testing and so on ; another is psychosocial support. In the field of pediatric hematology, the majority of genetic counseling seems to be a simple risk estimation for the next child and it is not related to any ethical issues. However, in some cases such as prenatal diagnosis or carrier detection, we have to resolve several serious ethical issues. Genetic counseling should be provided by an educated medical doctor at a suitable genetics clinic. In Japan, we have the Japanese Board of Medical Genetics, Clinical Geneticist as an education system in clinical genetics for medical doctors. Pediatric hematologists should know special issues of genetic information and should contact clinical geneticists in some cases.

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We evaluated stressful conditions for hospitalized children with hemato-oncological diseases. From the factor-analysis of questionnaires for nurses working in pediatric wards, we identified children's stressors during hospitalization. Stressors consisted of four categories named as physical distress, medication, restriction of hospital life, and restriction of contact with family and friends. The four categorized stressors were directly queried to nurses and children through semi-structured interviews. Nurses who were working in the pediatric ward of three different hospitals recognized that the physical distress and the medication were more important stressors than the others in hospitalized children, irrespective of the individual hospital environment. However, the rank of distress obtained from children was different from that pointed out by nurses. The intensity of distress in children was dependent on the individual hospital environment. Children in H hospital most stressfully recognized the restriction of contact with family and friends. On the other hand, children in N hospital recognized the medication as a potent stress. These findings suggest that the exact identification of stressors in the individual hospital and the reduction of stressful conditions might be important for improving the quality of life in hospitalized children with hemato-oncological diseases.

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We identified the stressors in hospitalized children with hemato-oncological diseases. Stressors consisted of four categories, namely physical distress, medication, restriction of hospital life, and restriction of contact with family and friends. Twenty-five children aged from 6 to 13 years were eligible for this study. The patients were divided into two groups based on opportunity to attend school, age, gender, and duration of hospitalization. Stress scores were evaluated comparing the two groups. The infrequent opportunity to attend elementary school in the hospital resulted in significantly high total stressor scores. The other factors, age, gender, and duration of hospitalization did not affect the total stressor scores. Furthermore, infrequent opportunity to attend school caused high stress scores against physical distress, restriction of hospital life, and restriction of contact with family and friends. The long duration of hospitalization led to high stress scores against medication and restriction of hospital life. From these observations, it can be concluded that the lack of opportunity to attend school in the hospital and the duration of hospitalization might be significantly involved in stressful conditions for children with hemato-oncological diseases.

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We here present four patients with mental problems as late effects of pediatric malignant disease and discuss these patients in terms of post-traumatic stress disorder (PTSD). Patient 1 : Wilms' tumor developed in a 9-year-old, patient had three operations and prolonged chemotherapy with severe vomiting during CDDP administration. Any slight difficulty in his life caused severe vomiting and finally, the patient died of a severe electrolyte imbalance due to frequent vomiting. Somatoform autonomic dysfunction due to PTSD was diagnosed. Patient 2 : Acute lymphocytic leukemia developed in a 12-year-old ; however, anxiety, rough language and violence were observed. Therapy was changed to an outpatient administration. The protocol was successfully completed, but many problems developed due to a generalized anxiety disorder. PTSD accompanied with personality disorder was diagnosed. Patient 3 : Non-Hodgkin lymphoma developed in a 5-year-old. After the end of therapy, she frequently complained of low-grade fever, headache, and abdominal pain. At high school, she often complained about her teacher and her mother and showed symptoms of hyperventilation, hysteria and syncope. Conversion disorder and personality disorder were diagnosed but PTSD was not. Patient 4 : At nine years old, the patient developed acute myelocytic leukemia. At 11 years old, he complained of low-grade fever, chest pain and headache and a twilight state at 14 years old. He could enter a vocational college but soon left the college since the symptoms became more severe. Dissociative disorders accompanying PTSD were diagnosed.

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Mitochondrial nuclei (a complex of DNA and histone-like proteins) have been easily visualized as compartments in the matrix of mitochondria. Thus, mitochondria division can be clearly separated into two main events : division of the organelle nuclei, and then division of the rest of the organelles (mitochondriokinesis). The mitochondriokinesis was studied by using the primitive red alga Cyanidioschyzon merolae. The mitochondrial divisions were synchronized by light/dark cycles. The results have shown that the mitochondria division is controlled by four rings, namely the ancient FtsZ ring, the inner and outer MD ring and dynamin ring, which appear in that order. Surprisingly, these FtsZ, similar inner and outer PD rings and dynamin rings also played an important role for plastid divisions, suggesting that mitochondria and plastids may rise from the same origin.

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Since the '50s, according to the progress of play support program for children in hospital and the concerted efforts of play therapists and hospital play specialists, the Family Centered Care and Preparation program also has developed considerably in European countries. In 1998 “The EACH (European Association for Children in Hospital) Charter” was drawn up and in 2002 “Information : The EACH Charter & Annotations” was published. Implementing the EACH Charter means at the same time implementing the UN Convention on the Rights of the Child. In this Charter the right of children to have their parents with them at all times in hospital, includes all situations where they need or possibly might need their parents, e.g. during the night, while having treatments and/or examinations with or without local anaesthesia, with or without sedation ; during induction of anaesthesia and immediately upon recovery ; during periods of coma or semi-consciousness ; during resuscitation, when parents must be offered full support. Prior knowledge of all measures that need to be taken is a precondition for the active involvement of children and parents in decision making. The doctors and nurses need to accept children as equal partners in all areas of health care. At the same time for the fulfillment of Family Centered Care, hospital adaptations for family to stay in hospital with their children and the education and employment of hospital play specialists who support the children and family in hospital are the urgent issues in Japan.

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In Japan, informed consent is obtained in a clinical setting from adult patients or parents of pediatric patients, and pediatric patients rarely receive sufficient explanations about their disease and the treatments to be given. Medical professionals, especially physicians, should respect the rights of pediatric patients. When a pediatric patient is considered to be able to give informed consent, the medical professional should make every effort to obtain informed consent from the patient by fully explaining the disease and treatments to be given, requesting the understanding and cooperation of the parent. Even if the patient appears to have limited ability to give informed consent, medical professionals should provide explanations by using simple terms and visual clues or pictures to inform the patients about the disease. Especially as Hemophilia is a illness which require patients to gain life-long self management skills, informed consent to be initiated in their childhood is essential in order to enhance their independence.

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In order to form a regional medical network for hemophilia care and treatment, it is very important to share the information on hemophilia care in common between medical participants and patients. Our specialist group for hemophilia care has been holding many types of medical meetings and seminars for hemophilia care and treatment in Hokkaido. In addition, cooperating with the patient and family group in Hokkaido (Do-yuu-kai), we have been participating in general meetings of the group every year and in hemophilia care seminars for hemophilia patients and families. By managing these seminars and meetings, hemophilia specialists, medical participants, the patient and family group, and pharmaceutical participants have been forming tight cooperative networks for hemophilia medicine in Hokkaido. In addition, using e-mail and a homepage, new types of medical networks for hemophilia care and treatment are now being developed in Hokkaido. Regional hemophilia specialists should act continuously to form strong networks for hemophilia care and treatment with the regional patient and family support group.

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The hemophilia treatment in Japan is mainly on-demand therapy in which a deficient coagulation factor VIII or IX is administered at the time of a bleeding episode. In recent years, however, regular replacement therapy in which a deficient enzyme is regularly administered from an extremely-early stage of childhood has been mainly used in Northern Europe and is reported to be clinically very effective. The aim of the therapy is to convert the severe form of the disorder into a milder form, thus preventing spontaneous musculoskeletal bleedings and the subsequent development of hemophilic arthropathy. Our facility has attempted this therapy since 1999 and obtained a favorable outcome. A clinical study on this therapy will soon be conducted by the Hemophilia Committee of the Japanese Society of Pediatric Hematology.

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The principle of the hemostatic treatment of hemophilia patients is replacement therapy using FYIII or FIX concentrates. However some patients develop FVIII or FIX inhibitors which are alloantibodies against FVIII or FIX in the concentrates. The development of the inhibitors is a severe complication in the treatment of hemophilia, because the antibodies neutralize the FVIII or FIX activity. Although bypassing therapy using (A) PCC has been widely used for their bleeding episodes, the efficacy is not always satisfactory. Immune tolerance induction (ITI) therapy is the most promising therapy which eliminates or reduces inhibitors. Basically three protocols of ITI have been conducted. One is the Bonn protocol using high-dose FVIII, the second is the van Creveld protocol using low-dose of FVIII, the third is the Malmö protocol using high dose FVIII and several immunosuppressant therapies. It has been accepted that the most important factor for success in ITI is inhibitor titer at the initiation of the therapy. Although many investigators believe the higher dose the better success, there is no scientific evidence supporting this. The Factor VIII and IX subcommittee of the Scientific and Standardization Committee (SSC), the International Society on Thrombosis and Haemostasis (ISTH) recently began an International, Randomised, Controlled Trial of Immune-Tolerance Induction Study. The study objectives are to compare the efficacy, response time, morbidity and economics of a high-dose and low-dose ITI and to identify predictors of successful ITI. Japan is going to participate in this international study.

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Although there have been exceptional advances in hemostatic treatment due to the popularization of home infusion therapy and the development of clotting factor concentrates including recombinants, hemophiliac arthropathy is still a serious problem for hemophiliacs. Since establishing the North Kyushu Hemophilia Center in 1984, we have set up general hemophilia outpatient consultations, and thus been comprehensively tackling the medical care of hemophilia patients in cooperation with other departments. In the present study we investigated the current state of arthropathy in pediatric hemophilia patients based on data collected at this center. Firstly, evaluation by modified De Palma method revealed a high incidence of hemophiliac arthropathy in the ankles, knees and elbows in that order. In the ankles in particular, arthropathy was evident in about half of the patients aged 20 years or younger. We next examined the predictive factors of arthropathy deterioration in pediatric hemophilia patients, but found that the age at the time of diagnosis, family history, the age at the start of replacement therapy, whether or not home infusion therapy had been introduced, whether or not secondary prophylaxis had been conducted, and the age at the start of such treatment were not significant predictors. To date we have selected either administration at the time of hemorrhage or secondary prophylaxis as the method of replacement therapy. However, in order to inhibit completely the onset of hemophiliac arthropathy, the introduction of primary prophylaxis should be examined.

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[in Japanese]

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[in Japanese]

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