Severe aplastic anemia in a patient with primary immunodeficiency

This paper reports the case of a 6 year old boy with primary immunodeficiency disease, whose marrow cells showed dyshematopoietic features, that was subsequently transformed to severe aplastic anemia. He was first diagnosed as having congenital immunodeficiency comprising deficiency of immunoglobulin A (IgA), IgG2 and IgG4, depressed mitogen responses, lymphopenia with inverted CD4/CD8 ratio and an increased proportion of T-cell receptor γ/δ-bearing cells. Cytogenetic study of the peripheral blood showed a normal karyotype of 46, XY, but that of the marked hypoplastic marrow demonstrated one cell with monosomy 7 and another with trisomy 8 in the 20 cells examined.     

The outbreak of mumps in a small island in Japan

A major mumps outbreak occurred on a small island, Ikeshima, in Nagasaki Prefecture from August 1994 to February 1995. There were 236 patients with the mumps at Ikeshima Miners' Hospital during that period. The Measles-Mumps-Rubella (MMR, Toitsukabu) vaccination coverage in the 43 children at the nursery school was 65.1% and it was 61.9% in the 21 children aged 4–5 years not attending the nursery school. Coverage was 66.6% in the 63 kindergarten students and 53.7% in 56 first-graders. The overall MMR vaccination coverage among these children was 61.7% (113/183) from 1989 to 1992. Children from the second grade to junior high school received monovalent mumps vaccine, Torii strain. None received Zishakabu MMR. The age of the patients ranged from 1 to 43 years, with a mean of 9.1 years. The majority (77.5%) were primary school children. The attack rates for vaccinated and unvaccinated children in grades one to six were: 6.7% (2/30) and 88.5% (23/26), 25% (3/12) and 44.1% (30/68), 11.1% (1/9) and 64.4% (29/45), 25% (2/8) and 60% (45/79), 22.2% (2/9) and 35.9% (28/78), 0% (0/5) and 24.7% (18/73), respectively. The overall frequency in the primary school was 41.4% (183/442 children). The frequency in the nursery school for children aged 4–5 years was 14.0% (6/43). It was 17.5% (11/63) in children aged 5–6 years in the kindergarten, 5.2% (11/213) in children not attending school with an age range of 1–5 years, and 4.2% (10/237) in junior high school students. Although the frequencies of MMR coverage for the nursery school children and kindergarteners were not high enough to eradicate mumps outbreaks, the MMR vaccination program was thought to have influenced the low frequency of mumps among the children. Close physical interactions among the first-graders would have contributed to their high frequency of mumps. Some patients presented with suspected mumps parotitis several times, but no such serological confirmation of reinfection was obtained.     

Myeloid differentiation is impaired in transgenic mice with targeted expression of a dominant negative form of retinoid X receptor β

To investigate the in vivo function of retinoid X receptor (RXR) on myelopoiesis, we generated transgenic (Tg) mice with targeted expression of a dominant negative form of RXR β in myeloid cells. In these Tg mice the transgene is expected to suppress the function of heterodimeric receptors composed of RXR and its counterparts, such as retinoic acid receptor. Out of 12 mice analysed, one Tg mouse exhibited a severe maturation arrest at the promyelocytic stage. Three other Tg mice showed a mild inhibition of myeloid differentiation, which was further augmented when mice were treated with 5-fluorouracil (5-FU). Furthermore, four Tg mice showed impaired myeloid differentiation in response to the treatment by 5-FU or granulocyte-colony stimulating factor (G-CSF), although they exhibited apparently normal myelopoiesis in the untreated state. The phenotype of Tg mice observed after G-CSF treatment correlated with the expression level of the transgene, although the correlation was not found in untreated mice. These results indicated that myeloid differentiation is perturbed in the Tg mice by the dominant negative effect of the transgenic RXR, indicating that RXR plays a role in myelopoiesis.     

Characterization of a Novel Missense Mutation in the Pore of HERG in a Patient with Long QT Syndrome

INTRODUCTION: A new strategy to elucidate the molecular mechanisms underlying the long QT syndrome (LQTS) is now available with genetic mutational analyses and characterization of ion channel mutations. METHODS AND RESULTS: In a 26-year-old woman with LQTS, we identified a novel missense mutation in the pore of HERG by using polymerase chain reaction/single-strand conformation polymorphism (PCR/SSCP) and sequencing of her genomic DNA. The mutation resulted in an amino acid substitution of a positively charged lysine for a highly conserved uncharged asparagine at codon 629 (N629K). Whole cell, patch clamp studies were conducted in COS7 cells by transfecting with wild-type (WT) and/or the mutant N629K HERG. The WT HERG produced an I(Kr)-like, E-4031-sensitive conductance with an inward rectification. In contrast, the cells transfected with the N629K HERG did not display any time-dependent current. Cotransfection of WT and N629K HERG (at a ratio of 1:1) produced a significantly smaller conductance when compared with WT HERG (WT 59.9 +/- 7.3 pA/pF [n = 22] vs WT+N629K 5.5 +/- 2.3 pA/pF [n = 11]; P < 0.01), but did not alter K+ ion selectivity and tail current-voltage dependence. Because aprindine hydrochloride was effective in preventing ventricular tachycardias, we also tested the effect of the drug on WT HERG (I(Kr)) and KvLQT1/KCNE1 (I(Ks)) currents expressed in COS7. CONCLUSION: Functional analyses of a novel missense mutation in the pore of HERG suggest that the mutation causes marked reduction of I(Kr) via a dominant negative effect.     

New treatment modalities for paediatric kidney disease

Summary: The new modalities of treating nephrotic syndrome, chronic renal insufficiencies, renal osteodystrophy and the use of recombinant human growth hormone and insulin-like growth factors are reviewed in order to provide the nephrologist caring for children an informed choice of therapies.     

Defective Leukocyte Interferon Response in Children with Recurrent Infections Accompanied by Arthralgia

ABSTRACT. Children with recurrent and/or unusually severe infections were investigated for possible defects in the interferon (IFN)-natural killer (NK) cell system. Two series, each of 13 children, were examined, one in 1982 and one in 1983. Healthy children, seven in 1982 and eight in 1983, served as controls. Peripheral blood mononuclear leukocytes were examined for IFN production induced by the IFN-α inducers Sendai virus and Escherichia coli and by the IFN-γ inducers Concanavalin A and Lens culinaris lectin. None of these inducers discriminated patients from controls. However, the bacteria Staphylococcus aureus Cowan I (SACol), inducers of atypical IFN in null lymphocytes, yielded significantly lower IFN production in infection-prone children than in controls, particularly in children with recurrent infections accompanied by arthralgia. No differences in basal NK activity or in the in vitro enhancement of such activity by IFN-α were found between patients and controls.     

Inappropriate use of emergency ambulance services and the implications for primary health care in Japan

The number and per-capita emergency transports by public ambulancesand the percentage of transports of patients with non-emergencyconditions has been increasing in Japan, especially in urbanareas. Public ambulance services are, of course, essential fortransporting patients with crucial health problems. However,inappropriate ambulance use by patients who do not need emergencytreatment, but who need primary health care, means that thesepatients cannot get suitable health care, and diminishes theeffectiveness and efficiency of emergency medical-care servicesystems. The purposes of this study were to identify the factorsrelating to usage of public ambulance services in urban areas,to determine how to make these services more effective and moreefficient, and to discuss how to provide primary health-careservices so as to reduce the inappropriate use of public ambulanceservices. We investigated the accessibility of primary health-careservices, the characteristics of public ambulance service utilization,and the potential needs of the elderly for emergency-care servicesin two Tokyo wards: Edogawa andSetagaya. There were less healthresources, such as clinics, hospital beds and physicians, percapita in Edogawa than in Setagaya. Both the percentage of ambulancetransports of patients suffering from mild problems and thepercentage of ambulance transports on Sundays were higher inEdogawa than in Setagaya. Our survey showed that the percentagesof the elderly who would call for ambulances for each of threespecific health problems (fever, chest pain and ankle sprain)were all higher in Edogawa than in Setagaya. In both wards,elderly people living with their children and/or grandchildrenwere more likely to choose different health resources accordingto the specific problem being experienced than were elderlypeople living with other aged persons but without young people.The insufficient development of primary healthcare resourcesand systems increased the inappropriate use of high-cost emergencyambulance services by the elderly living in urban areas, wherefamily support is weakening. Health systems therefore need tobe reoriented so as to enhance accessibility to primary healthcareservices.     

贝伐单抗联合放射方案的实验研究

Objective To evaluate the impact of the hypoxia induced by bevacizumab on the antitumor effect in combining with irradiation in CNI-H441 xenografts in mice. Methods Bevacizumab of 5 mg/kg mouse for groups of control, bevacizumab alone, irradiation alone, earlier combination (EC), and later combination (LC) were initially injected peritoneally. Single irradiation of 14 Gy (122Sc γ-ray) was given at the 4th hour for the group of irradiation alone, 24th hour for EC group, and 72nd hour for LC group after the initial injection. Tumor hypoxia, micro vessels density and permeability of tumor vasculature,pathological responses, apoptosis, and tumor growth delay curve were evaluated after using bevacizumab and/or irradiation. Results Although it was lower than the control at the 24 hr after using bevacizumab (3. 1 × 106: 6.1 × 106 ;t = - 1.73 ,P > 0. 05), the HIF-1α rapidly increased to 3 - 4 times and 2 - 3 times of the control at day 3 (7.4 × 106: 20. 4 × 106; t = 2. 36, P < 0. 05) and lasted until day 10, which was consistent with the changes of tumor function vessels count. The count of residual micro vessel density count in LC group was higher than that in groups of EC and irradiation at day 3 after irradiation (9. 33: 3. 17;t =- 2. 43, P < 0. 05). The apoptotic count of tumor cells was lower in LC group than that in EC group (23.33: 43.83; t= 2.54, P< 0.05, at day 3 after radiation). Tumor growth delay time of LC groupwas shorter than that of EC groups (10. 5 days vs. 23. 0 days , t = 2. 67 , P < 0. 05) . Conclusions Hypoxia level induced by bevacizumab decreases the antitumor effect in later combination of bevacizumab and irradiaion. It shows a time window that determines whether the combination of bevacizumab and irradiation will be benefit or diverse.