Intensive cardiac management in patients with trisomy 13 or trisomy 18.

Intensive cardiac management such as pharmacological intervention for ductal patency (indomethacin and/or mefenamic acid for closure and prostaglandin E1 for maintenance) and palliative or corrective surgery is a standard treatment for congenital heart defects. However, whether it would be a treatment option for children with trisomy 13 or trisomy 18 syndrome is controversial because the efficacy on survival in patients with these trisomies has not been evaluated. We retrospectively reviewed 31 consecutive neonates with trisomy 13 or trisomy 18 admitted to our neonatal ward within 6 hr of birth between 2000 and 2005. The institutional management policies differed during three distinct periods. In the first period, both pharmacological ductal intervention and cardiac surgery were withheld. In the second, pharmacological ductal intervention was offered as an option, but cardiac surgery was withheld. Both strategies were available during the third period. The median survival times of 13, 9, and 9 neonates from the first, second, and third periods were 7, 24, and 243 days, respectively. Univariate and multivariate analyses confirmed that the patients in the third period survived significantly longer than the others. Intensive cardiac management consisting of pharmacological intervention for ductal patency and cardiac surgery was demonstrated to improve survival in patients with trisomy 13 or trisomy 18 in this series. Therefore, we suggest that this approach is a treatment option for cardiac lesions associated with these trisomies. These data are helpful for clinicians and families to consider in the optimal treatment of patients with these trisomies.

Interferon-alpha induces transient upregulation of c-FLIP through NF-kappaB activation.

Interferon-alpha (IFN-alpha) induces apoptosis in some cell types and promotes cell survival in other cell types, but the molecular mechanisms underlying distinct IFN-alpha-induced cell behaviours remain poorly understood. In the present study, we show that IFN-alpha induced the cellular FLICE (FADD-like interleukin-1 beta-converting enzyme) inhibitory protein (c-FLIP), which serves as a promoter of cell survival in human B lymphoma cells. IFN-alpha induction of transient upregulation of c-FLIP was partially abrogated by the NF-kappaB inhibitor BAY11-7082 (BAY). Pretreatment with BAY sensitized both Daudi and U266 cells to the IFN-alpha-induced loss of mitochondrial membrane potential (DeltaPsi(m)). IFN-alpha phosphorylated the PKC isoform PKCalpha at a threonine residue, and the PKCalpha/betaI inhibitor Go6976 abrogated upregulation of IFN-alpha-induced NF-kappaB activity, leading to sensitization of cells to IFN-alpha-induced apoptosis. To analyze the role of PKCalpha in the IFN-alpha-induced signaling, Daudi cells overexpressing a constitutively active mutant of PKCalpha (caPKCalpha) were used. The caPKCalpha-expressing Daudi cells were partially resistant to the IFN-alpha-induced loss of DeltaPsi(m), concomitant with elevated levels of c-FLIP protein. Together, these results demonstrate that IFN-alpha causes a transient upregulation of c-FLIP expression, at least through PKCalpha-mediated activation of NF-kappaB. The balance between IFN-alpha-induced pro-apoptotic and survival signals determines the cell fate. Thus, therapeutic intervention in this balance may be effective for treatment of patients with IFN-alpha-refractory tumours.

Interferon-alpha-induced apoptosis via tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-dependent and -independent manner.

IFN-alpha regulates tumor cell growth at least through induction of apoptosis. We have recently demonstrated that IFN-alpha causes apoptosis through upregulation of TNF-related apoptosis-inducing ligand (TRAIL) in Daudi B lymphoma and U266 myeloma cells. However, other cell lines such as Ramos and RPMI 8226 underwent apoptosis without any apparent involvement of TRAIL following IFN-alpha stimulation. In this study, we examined whether the IFN-alpha-induced upregulation of TRAIL is essential for the induction of apoptosis. IFN-alpha-induced early phase (48 h) of loss of DeltaPsim was substantially prevented in Daudi B lymphoma cells overexpressing the dominant-negative form of Fas-associated death domain (dnFADD) compared with vector control, whereas a late phase (72 h) of DeltaPsim was comparable to the control. The IFN-alpha-induced early phase of apoptosis was also reduced in the dnFADD-expressing cells, while the late phase of apoptosis was unaffected. IFN-alpha-induced upregulation of TRAIL protein in the dnFADD-expressing Daudi or U266 cells was comparable to their control cells, suggesting that FADD is not involved in the IFN-alpha-induced upregulation of TRAIL. Moreover, the early phase of mitochondrial depolarization was severely prevented by the presence of fusion protein of TRAIL receptor 1 and Fc portion of immunoglobulin (TRAIL-R1:Fc) and TRAIL-R2:Fc. Together, IFN-alpha induces apoptosis in a TRAIL-dependent or -independent manner, depending on the course of the apoptotic process.

IFN-alpha sensitizes daudi B lymphoma cells to anti-IgM induced loss of mitochondrial membrane potential through activation of c-Jun NH(2)-terminal kinase.

Interferon-alpha (IFN-alpha) regulates multiple biologic functions, including antiviral activity, immune regulation, cell differentiation, and cell survival or death, in a variety of cell types. We and others have recently demonstrated that IFN-alpha induces cell death through activation of c-Jun NH(2)-terminal kinase (JNK) in human Daudi B lymphoma and U266 myeloma cells. Moreover, the IFN-alpha-induced signaling pathway has been shown to cross talk with the antigen receptor-mediated signaling cascade. In the present study, we examined whether IFN-alpha affects cell death after engagement of membrane immunoglobulin (mIg) using anti-IgM. Daudi cells pretreated with low concentrations of IFN-alpha (25 or 250 U/mL) for 24 h were stimulated with anti-IgM (1-10 microg/mL) for 24 h. The cells were assayed for JNK activation, mitochondrial membrane potential (DeltaPsim) by Western blotting, and DiOC(6) staining, respectively. The IFN-alpha-primed Daudi cells showed an increased sensitivity to subsequent stimulation with anti-IgM, as assessed by JNK activation and DeltaPsim. Moreover, Daudi cells overexpressing the constitutively active or dominant-negative form of JNK were substantially susceptible or resistant to anti-IgM-induced DeltaPsim, respectively, compared with cells overexpressing the control vector alone. Taken together, these results indicate that IFN-alpha renders Daudi B lymphoma cells susceptible to anti-IgM-induced apoptosis, probably through upregulation of JNK activation.

Sudden infant death syndrome due to parainfluenza virus 2 associated with hemophagocytic syndrome.

We report a child with Sudden Infant Death Syndrome (SIDS), aged 16 months. The histological findings of tonsils, spleen, and bone marrow revealed many hemophagocytic cells. Parainfluenza virus type 2 (PIV2) was cultured in the nasopharynx and detected by reverse-transcription (RT)-PCR in liver tissue and bone marrow. His laboratory data of elevated level of ferritin and IL-6 suggested hemophagocytic syndrome (HPS). It is suspected that PIV2 infection in infants is a risk factor for SIDS.