Purpose

Viral infection is the most common aggravating factor for childhood asthma. Asthma may be a risk factor for severe respiratory symptoms in children with lower respiratory tract infections of viral etiology. Influenza A infection enhances Th2-polarization to house dust mites during the acute phase and leads to lung dysfunction in a mouse model. However, there are no data on the relationship between atopic sensitization and H1N1 (Influenza A) infection in humans. To investigate whether atopic sensitization is associated with the severity of H1N1 pneumonia, we compared clinical features and the atopic sensitization rate between children with and without H1N1 infection.

Methods

Using reverse transcription-polymerase chain reactions, we investigated H1N1 virus infection in 214 children who were hospitalized with high fever and respiratory symptoms from September 2009 to February 2010. We also performed immunoassays for total and specific IgEs to six common aeroallergens. Atopy was defined as positivity for more than one specific IgE. The clinical severity of pneumonia was evaluated based on intensive care unit admission, oxygen therapy, steroid therapy, and atelectasis.

Results

There were 70 H1N1-positive children, 42.9% of whom had pneumonia. Children with H1N1 infection were older and had a higher prevalence of atopic sensitization and pneumonia compared with H1N1-negative children. The rate of atelectasis was higher in children with H1N1 pneumonia than in children with non-H1N1 pneumonia. Among children with H1N1 viral infection, those with atopic sensitization had a higher prevalence of intensive care unit admission and oxygen therapy, and a longer duration of hospitalization than non-atopic children. There were no differences between atopic and non-atopic children without H1N1 viral infection.

Conclusions

The prevalence of H1N1-induced severe lower respiratory tract diseases is higher in children with atopic sensitization.

TRAIL [TNF (tumour necrosis factor)-related apoptosis-inducing ligand] is a promising agent for clinical use since it kills a wide range of tumour cells without affecting normal cells. We provide evidence that pretreatment with etoposide significantly enhanced TRAIL-mediated apoptosis via up-regulation of DR5 (death receptor 5 or TRAIL-R2) expression in the caspase 8 expressing neuroblastoma cell line, SK-N-MC. In addition, sequential treatment with etoposide and TRAIL increased caspases 8, 9 and 3 activation, Mcl-1 cleavage and Bid truncation, which suggests that the ability of etoposide and TRAIL to induce apoptosis is mediated through activation of an intrinsic signalling pathway. Although TRAIL-R2 expression increased in IMR-32 cells in response to etoposide treatment, cell death was not increased by concurrent treatment with TRAIL compared with etoposide alone, because the cells lacked caspase 8 expression. Restoration of caspase 8 expression by exposure to IFNγ (interferon γ) sensitizes IMR-32 cells to TRAIL. Moreover, pretreatment with etoposide increased TRAIL-induced apoptosis in caspase 8 restored IMR-32 cells through activation of a caspase cascade that included caspases 8, 9 and 3. These results indicate that the etoposide-mediated sensitization of neuroblastoma cells to TRAIL is associated with an increase in TRAIL-R2 expression and requires caspase 8 expression. These observations support the potential use of a combination of etoposide and TRAIL in future clinical trials.

Purpose

Dramatic improvement of hemangioma to propranolol has been recently reported; however, details on dose and duration of treatment, potential risks, and monitoring have not been determined. The objective of this study is to describe and analyze the use of propranolol as a first-line treatment or as a single therapy in management of complicated hemangioma.

Methods

A retrospective chart review of eight patients diagnosed with hemangioma and treated with propranolol in Kangbuk Samsung Hospital from February 2010 to April 2011 was performed.

Results

Eight patients with hemangioma with functional impairment, cosmetic disfigurement, or rapid growth were treated with propranolol. Five patients had solitary facial hemangioma. The mean age of symptoms at onset was 5 weeks. The median age for starting propranolol treatment was 5.5 months. Propranolol at 2 mg/kg/day was finally administered in divided doses with a gradual increase. Significant regression was observed in seven patients, and shrinkage in size, softening in consistency, and decrease in redness were evident within 4 weeks. Among them, six patients were still taking propranolol, and one patient had stopped after 12 months. Other one patient did not show significant improvement with satisfactory result after 3 months of propranolol use. Treatment with propranolol was well tolerated and had few side effects. No rebound growth was observed in any of the patients.

Conclusion

We observed that use of propranolol was very effective in treatment of hemangioma without obvious adverse effects or relapse.

Purpose

Obesity is a risk factor for asthma and type II diabetes. Peroxisome proliferator-activated receptor (PPAR)-γ has been suggested to regulate inflammatory responses in diabetes and asthma. We investigated whether PPAR-α, PPAR-γ, adiponectin receptors (AdipoR1, AdipoR2), leptin, and tumor necrosis factor (TNF)-α are expressed in rat lung tissues and whether the expression differs between obese Otsuka Long-Evans Tokushima Fatty (OLETF) and lean Long Evans Tokushima Otsuka (LETO) rats.

Materials and Methods

Obese and lean rats were given with a high fat diet or a 30% restricted diet for 32 weeks, and their blood glucose levels and weights were monitored. After 32 weeks, mRNA levels of PPAR-α, PPAR-γ, AdipoR1, AdipoR2, leptin, and TNF-α in lung tissues were measured using real time PCR.

Results

PPAR-α, PPAR-γ, AdipoR1, AdipoR2, leptin, and TNF-α were expressed in both obese and lean rat lung tissues. Increased serum glucose levels on intraperitoneal glucose tolerance testing and a higher weight gain at 32 weeks were observed in OLETF control rats compared to OLETF diet restricted rats. PPAR-γ expression was markedly elevated in obese control and diet restricted rats compared to lean rats, although PPAR-γ expression in obese rats was not affected by diet restriction. Leptin was highly expressed in OLETF rats compared to LETO rats. TNF-α expression was enhanced in OLETF control rats compared LETO diet restricted rats, and decreased by diet restriction. PPAR-α, AdipoR1, and AdipoR2 expression were not significantly different between obese and lean rats.

Conclusion

PPAR-γ was highly expressed in the lung tissues of obese rats and may be a novel treatment target for regulating lung inflammation associated with obesity.

To determine the impact of treatment protocols on the outcome of central nervous system germ cell tumors (CNS-GCTs), we reviewed the medical records of 53 patients who received front-line chemotherapy from September 1997 to September 2006. Pure germinoma, normal alpha-fetoprotein level and beta-human chorionic gonadotropin level <50 mIU/mL were regarded as low-risk features and the others as high-risk. Patients from different time periods were divided into 3 groups according to the chemotherapy protocols. Group 1 (n=19) received 4 cycles of chemotherapy comprising cisplatin, etoposide and bleomycin. Group 2 (n=16) and group 3 (n=18) received 4 cycles of chemotherapy with cisplatin, etoposide, cyclophosphamide and vincristine in the former and with carboplatin, etoposide, cyclophosphamide and bleomycin in the latter. In group 2 and group 3, high-risk patients received double doses of cisplatin, carboplatin and cyclophosphamide. Radiotherapy was given after chemotherapy according to the clinical requirements. The event-free survivals of groups 1, 2, and 3 were 67.0%, 93.8%, and 100%, respectively (group 1 vs. 2, P=0.06; group 2 vs. 3, P=0.29; group 1 vs. 3, P=0.02). Our data suggest that risk-adapted intensive chemotherapy may improve the outcome of patients with malignant CNS-GCTs.

Airway smooth muscle (ASM) hyperplasia and angiogenesis are important features associated with airway remodeling. We investigated the effect of IL-4 and amphiregulin, an epidermal growth factor family member, on the proliferation of human ASM cells and on the release of vascular endothelial growth factor (VEGF) and monocyte chemotactic protein (MCP)-1 from human ASM cells. Human ASM cells were growth-arrested for 48 hr and incubated with platelet-derived growth factor (PDGF)-BB, interleukin (IL)-4, amphiregulin, and VEGF to evaluate cell proliferation. The cells were treated with PDGF, IL-4 and amphiregulin to evaluate the release of VEGF, MCP-1. IL-4 suppressed unstimulated and PDGF-stimulated ASM cell proliferation. Amphiregulin stimulated ASM cell proliferation in a dose-dependent manner. VEGF did not have any influence on ASM cell proliferation. IL-4 stimulated VEGF secretion by the ASM cells in a dose-dependent manner and showed added stimulatory effects when co-incubated with PDGF. Amphiregulin did not promote VEGF secretion. IL-4 and amphiregulin showed no stimulatory effects on MCP-1 secretion. The results of this study showed that IL-4 had bifunctional effects on airway remodeling, one was the suppression of the proliferation of the ASM cells and the other was the promotion of VEGF release by the ASM cells, and amphiregulin can promote human ASM cell proliferation.

Transplantation of marrow-derived mesenchymal stem cells (MSCs), expanded by culture in addition to whole bone marrow, has been shown to enhance engraftment of human hematopoietic stem cells (HSCs). Our hypothesis was that there might be an optimum ratio range that could enhance engraftment. We examined the percent donor chimerism according to the ratio of HSCs to MSCs in non-obese diabetic/severe combined immunodeficiency (NOD/SCID) mice. We tested a series of ratios of co-transplanted CD34+-selected bone marrow cells, and marrow-derived MSCs into sublethally irradiated NOD/SCID mice. In all experiments, 1×105 bone marrow derived human CD34+ cells were administered to each mouse and human MSCs from different donors were infused concomitantly. We repeated the procedure three times and evaluated engraftment with flow cytometry four weeks after each transplantation. Serial ratios of HSCs to MSCs were 1:0, 1:1, 1:2 and 1:4, in the first experiment, 1:0, 1:1, 1:2, 1:4 and 1:8 in the second and 1:0, 1:1, 1:4, 1:8 and 1:16 in the third. Cotransplantation of HSCs and MSCs enhanced engraftment as the dose of MSCs increased. Our results suggest that the optimal ratio of HSCs and MSCs for cotransplantation might be in the range of 1:8-1:16; whereas, an excessive dose of MSCs might decrease engraftment efficiency.

This study investigated the serum vascular endothelial growth factor (VEGF) levels in children with community-acquired pneumonia. Serum VEGF levels were measured in patients with pneumonia (n=29) and in control subjects (n=27) by a sandwich enzyme-linked immunosorbent assay. The pneumonia group was classified into bronchopneumonia with pleural effusion (n=1), bronchopneumonia without pleural effusion (n=15), lobar pneumonia with pleural effusion (n=4), and lobar pneumonia without pleural effusion (n=9) groups based on the findings of chest radiographs. We also measured serum IL-6 levels and the other acute inflammatory parameters. Serum levels of VEGF in children with pneumonia were significantly higher than those in control subjects (p<0.01). Children with lobar pneumonia with or without effusion showed significantly higher levels of serum VEGF than children with bronchopneumonia. For lobar pneumonia, children with pleural effusion showed higher levels of VEGF than those without pleural effusion. Children with a positive urinary S. pneumonia antigen test also showed higher levels of VEGF than those with a negative result. Serum IL-6 levels did not show significant differences between children with pneumonia and control subjects. Serum levels of VEGF showed a positive correlation with the erythrocyte sedimentation rate in the children with pneumonia. In conclusion, VEGF may be one of the key mediators that lead to lobar pneumonia and parapneumonic effusion.

Intraocular (IO) retinoblastoma (RB) has traditionally been treated with enucleation (ENU) or external beam radiotherapy (EBRT). Recently, clinical trials are in progress to cure RB without ENU or EBRT in order to salvage the globe and to avoid unacceptable side effects of EBRT. We performed a pilot study to treat patients with advanced Reese-Ellsworth (RE) stage IO RB with initial chemotherapy (CRx) followed by local therapy (LT) and adjuvant CRx. Ten eyes (8 RE group V, 2 RE group IV) from 9 patients were enrolled from March 2001 to November 2001. All tumors responded to CRx. In 5 of 10 eyes, the RB was enough to be treated with LT after chemoreduction. One patient who underwent LT is waiting for ENU due to post-cryotherapy complication. For a median follow-up of 13 months (8-16 mo), 4 eyes that received LT and adjuvant CRx were relapse-free. A patient with bilateral RB who failed to be a candidate for LT was rescued with high-dose CRx and hematopoietic stem cell transplantation. Consequently, by treating patients according to our strategy, we were able to salvage 6 out of 10 eyes without ENU or EBRT. These results suggest that chemoreduction followed by LT and adjuvant CRx might offer the opportunity to salvage the globe and vision even in patients with advanced stage IO RB.

Double high-dose chemotherapy (HDCT) was applied to 18 patients with highrisk neuroblastoma including 14 patients who could not achieve complete response (CR) even after the first HDCT. In 12 patients, successive double HDCT was rescued with peripheral blood stem cells collected during a single round of leukaphereses and in 6 patients, second or more rounds of leukaphereses were necessary after the first HDCT to rescue the second HDCT. The median interval between the first and second HDCT (76 days; range, 47-112) in the single harvest group was shorter than that (274.5 days; range, 83-329) in the double harvest group (p<0.01). Hematologic recovery was slow in the second HDCT. Six (33.3%) treatment-related mortalities (TRM) occurred during the second HDCT but were not related to the shorter interval. Disease-free survival rates at 2 years with a median follow-up of 24 months (range, 6-46) in the single and double harvest group were 57.1% and 33.3%, respectively. These results suggest that successive double HDCT using the single harvest approach may improve the survival of high-risk patients, especially who could not achieve CR after the first HDCT despite delayed hematologic recovery and high rate of TRM during the second HDCT.