Infantile T cell acute lymphoblastic leukemia complicated by thrombotic microangiopathy and human herpes virus 6 infection after allogeneic peripheral blood stem cell transplantation using CD34-positive cells]

We report on a 19-month-old boy with refractory T-cell acute lymphoblastic leukemia who underwent allogeneic peripheral blood stem cell transplantation using positively selected CD34 cells from his HLA two-loci mismatched mother. The conditioning regimen consisted of busulfan (140 mg/m2/d for 2 days), total body irradiation (12 Gy) and melphalan (210 mg/m2). The patient received cyclosporin A for graft-versus-host disease (GVHD) prophylaxis. The CD34-positive cells were separated using an immunomagnetic cell-separation system (Isolex 50). The number of infused CD34-positive cells was 4.4 x 10(6)/kg. Successful engraftment was confirmed on day 14 by fluorescent in situ hybridization of X chromosomes. The patient experienced severe diarrhea due to thrombotic microangiopathy (TMA) following acute GVHD, and died on day 71 of human herpes virus type 6 pneumonitis. Stem cell transplantation using CD34 positively selected cells from HLA-mismatched related donors may be a useful treatment with low incidence of severe GVHD, but many problems remain to be overcome, including severe viral infections and TMA.     

Estimated sleep debt and work stress in Japanese white-collar workers.

Sleep debt on weekdays in Japanese white-collar workers, estimated using a questionnaire, was associated with age, overtime, and self-rated workload.     

Clinical manifestations of influenza a myocarditis during the influenza epidemic of winter 1998-1999.

OBJECTIVES: The clinical features of myocarditis that developed during the influenza epidemic of winter 1998-1999 were investigated to emphasize the need for medical attention to this disease. METHODS: Nine patients were treated under diagnoses of acute myocarditis during the winter of 1998-1999. Five (two males and three females, mean age 52 +/- 18 years) were examined with myocarditis associated with influenza A. The diagnosis of influenza A myocarditis was based on electrocardiographic and echocardiographic abnormalities, increased creatine kinase levels and at least a four-fold increase in influenza A virus titers using paired sera. RESULTS: All patients had preceding flu-like symptoms and fever. Cardiac involvement developed between 4 and 7 days after the onset of influenza symptoms. Dyspnea progressively worsened in three patients, one went into shock and one had persistent fever, cough and mild dyspnea without apparent cardiac symptoms. Three patients had ST elevation associated with Q waves and one had complete left bundle branch block. The creatine kinase levels were abnormally increased and global wall motion of the left ventricle on echocardiography was decreased in all patients. Two patients had diagnoses of fulminant myocarditis. One patient died of pneumonia following cerebral infarction, but the left ventricular dysfunction normalized in the remaining four patients. CONCLUSIONS: Cardiac involvement occurred between 4 and 7 days after the onset of influenza symptoms, and worsening dyspnea was the most common symptom. Electrocardiography, echocardiography and creatine kinase levels should be checked to determine the potential for cardiac involvement when patients present with suspected influenza associated with worsening dyspnea or prolonged weakness. Increasing the awareness of influenza myocarditis may help in the earlier identification and treatment of this disease during influenza epidemics.     

Neocerebellar hypoplasia with systemic combined olivo-ponto-dentatal degeneration in a 9-day-old baby: contribution to the problem of relations between malformation and systemic degeneration in early life

Three different cerebral alterations, apparently formed consecutively, were observed in a 9-day-old baby. Marked cortico-neocerebellar hypoplasia was seen in a relatively well-developed paleocortex. Its teratological stage was apparently the 3rd fetal month. Almost total nerve cell loss and marked proliferation of protoplasmic and fibrous astrocytes were found in the nuclei pontis and inferior olive. Perihypoglossal and pararaphal nuclei, which are related to the cerebellum, were also affected. This degenerative process must have resulted from neuronal deprivation or inactivity, as the pertinent cortico-cerebellar area was hypoplastic, and therefore any neuronal imput was impossible (olivo-ponto-dentatal degeneration due to cortico-cerebellar hypoplasia). Massive symmetrical necrosis in the cerebral white and grey matter, basal ganglia, midbrain and bulbus, is interpreted as hypoxic damage due to perinatal convulsive attacks and cessation of respiration.     

Essential role of IRAK-4 protein and its kinase activity in Toll-like receptor-mediated immune responses but not in TCR signaling

Interleukin-1 receptor-associated kinase 4 (IRAK-4) was reported to be essential for the Toll-like receptor (TLR)- and T cell receptor (TCR)-mediated signaling leading to the activation of nuclear factor kappaB (NF-kappaB). However, the importance of kinase activity of IRAK family members is unclear. In this study, we investigated the functional role of IRAK-4 activity in vivo by generating mice carrying a knockin mutation (KK213AA) that abrogates its kinase activity. IRAK-4(KN/KN) mice were highly resistant to TLR-induced shock response. The cytokine production in response to TLR ligands was severely impaired in IRAK-4(KN/KN) as well as IRAK-4(-/-) macrophages. The IRAK-4 activity was essential for the activation of signaling pathways leading to mitogen-activated protein kinases. TLR-induced IRAK-4/IRAK-1-dependent and -independent pathways were involved in early induction of NF-kappaB-regulated genes in response to TLR ligands such as tumor necrosis factor alpha and IkappaBzeta. In contrast to a previous paper (Suzuki, N., S. Suzuki, D.G. Millar, M. Unno, H. Hara, T. Calzascia, S. Yamasaki, T. Yokosuka, N.J. Chen, A.R. Elford, et al. 2006. Science. 311:1927-1932), the TCR signaling was not impaired in IRAK-4(-/-) and IRAK-4(KN/KN) mice. Thus, the kinase activity of IRAK-4 is essential for the regulation of TLR-mediated innate immune responses.