A nuclear factor-κB inhibitor, dehydroxymethylepoxyquinomicin, ameliorates GVHD in allogeneic bone marrow transplantation.

GVHD is a crucial mortality factor in allogeneic bone marrow transplantation (ABMT). In this paper, we show that dehydroxymethylepoxyquinomicin (DHMEQ), a novel inhibitor of nuclear factor-κB, suppresses GVHD, resulting in an improved mortality rate in a mouse ABMT model. Bone marrow cells from C57BL/6 mice (B6 mice) were transplanted into lethally irradiated BALB/c mice. Two weeks later, spleen cells from B6 mice were transplanted into the irradiated BALB/c mice. From one week after the injection of spleen cells, when the mice started to show GVHD, the mice were also injected intraperitoneally daily with DHMEQ or vehicle only (DMSO) for 4 weeks. By 80 days after the ABMT, 6/14 of the vehicle-injected mice (43%) had died because of GVHD, whereas all DHMEQ-injected mice survived this observation period and developed milder GVHD than the vehicle-injected mice. When regulatory T cells were reduced by the injection of anti-folate receptor 4 (FR4) antibody, the effects of DHMEQ were reduced. These findings suggest that administration of DHMEQ could become a new strategy for preventing fatalities from GVHD.

Pulmonary sclerosing hemangioma with lymph node metastasis: A case report and literature review.

Pulmonary sclerosing hemangioma (SH) is an uncommon benign or low-grade malignant tumor. Multicentric SH and SH with lymph node metastasis have rarely been reported. The present report describes a case of pulmonary SH with lymph node metastasis in a middle-aged female. A nodule was found incidentally in the lower left lung. The patient underwent left lower pulmonary lobectomy and lymph node dissection. Histologically, the nodule demonstrated the characteristic features of SH and one of the resected lymph nodes contained a metastasis of this tumor. Thus, pulmonary SH has the potential to metastasize, a potential not suggested by histological features.

Home-based oral immunotherapy (OIT) with an intermittent loading protocol in children unlikely to outgrow egg allergy.

BACKGROUND: Home based oral immunotherapy (OIT) for food allergy has often been used for young children in Japan, the majority of whom are believed to outgrow the allergy by the school age, therefore the true efficacy of the therapy has been controversial. The aim of this study was to evaluate the efficacy and safety of a newly developed slow- type home-based oral immunotherapy (OIT) regimen in children with hen's egg (HE) allergy, who had low likelihood of outgrowing the allergy, with treatment involving only elimination diet. METHOD: We retrospectively reviewed the medical records of 43 children with egg allergy (30 males; median age 6) who fulfilled Burks et al.'s criteria of being unlikely to outgrow the allergy. Thirty children who agreed to start OIT were assigned to the treatment group, and 13 who did not want to participate immediately were assigned to the untreated group; the patients underwent an elimination diet for 1 year, during which they were monitored. The OIT regimen involved the intake of the maximum tolerated dose 2 to 3 times a week at home, with initial dose introduction followed by dose build-ups with medical supervision. We statistically evaluated the rate of children who changed their threshold up to 32 g of egg - defined as, oral tolerance induction- in both the groups for 1 year and in the OIT group for 2 years, as well as the rate of children who fulfilled Savage et al.'s criteria of clinical tolerance after reaching the abovementioned remission stage. RESULTS: The rate of children who achieved oral tolerance induction to 32 g of egg after 1 year in the OIT group (9/30) was significantly higher than that in the untreated group (0/13). The total rate within the OIT group was significantly increased from 9/30 at 1 year to 17/30 at two years without any severe adverse reaction; of the above 17 children, we followed 14 children, and noted that 11 of these were able to obtain clinical tolerance. CONCLUSION: The home-based OIT with an intermittent loading protocol was very safe and effective in children with a low likelihood of outgrowing egg allergy.

Bone marrow cells enhance liver regeneration after massive hepatectomy in mice.

BACKGROUND: Recent evidence indicates that transplanted autologous bone marrow cells (BMCs) can be converted into functional liver cells. BMC therapy can improve hepatic function and increase the potential for liver regeneration in patients with serious liver damage. We investigated whether BMC therapy influenced liver regeneration after massive hepatectomy in mice. METHODS: Male C57/BL6 mice underwent 70 % hepatectomy, followed by injection of BMCs via the portal vein (PV group), BMCs via the tail vein (IV group), or saline via the portal vein (control group). Analysis of serum enzyme levels and liver histology was performed on postoperative days (POD) 1, 3, and 5. RESULTS: Compared with the control group, the rate of liver regeneration on POD 3 and 5 was significantly higher in the PV group, but not in the IV group. Examination of the mitotic index and Ki-67 labeling index revealed that the increased liver regeneration resulted from stimulation of DNA synthesis. On POD 3, the serum levels of interleukin (IL)-6 and hepatocyte growth factor (HGF) were significantly higher and the expression of IL-6 and HGF mRNA in the remnant liver tended to be higher in the PV group than in the control group. Histological examination showed BMCs in the liver of the PV group, as well as conversion of BMCs into liver cells. CONCLUSIONS: Our findings indicate that the injection of BMCs via the portal vein, but not the injection of BMCs via the tail, enhances liver regeneration after massive hepatectomy in mice.

An autopsy case of pulmonary fissure induced by zygomycosis.

For immunodeficient patients, fungi are life-threatening pathogens. In this paper, we present an autopsy case of combined zygomycosis and aspergillosis. A female in her 70s on chronic hemodialysis was admitted to a hospital suffering bloody sputum, dyspnea, and fever, probably due to perinuclear anti-neutrophil cytoplasmic antibody-related vasculitis. Antibiotics were administered and immunosuppressive therapy was started, resulting in an improvement in her condition. Pneumonia later developed, followed by pulmonary bleeding and intractable pneumothorax from which she ultimately died. On autopsy, the upper lobe of the left lung was found to have hemorrhagic necrosis and showed a large longitudinal fissure. Microscopically, Zygomycota were observed in both the lungs and heart, while Aspergillus was found in the middle lobe of the right lung. Zygomycosis, which usually has a poor prognosis, is assumed to have induced hemorrhagic infarction of the lungs, inducing pulmonary bleeding and necrosis, despite the use of lipid formulations of amphotericin B, which are effective medicines against Zygomycota.

A novel nuclear factor κB inhibitor, dehydroxymethylepoxyquinomicin, ameliorates puromycin aminonucleoside-induced nephrosis in mice.

BACKGROUND/AIMS: Minimal-change nephrotic syndrome (MCNS) is a kidney disease defined by selective proteinuria and hypoalbuminemia occurring in the absence of cellular glomerular infiltrates or immunoglobulin deposits. Recent observations suggest that nuclear factor κB (NF-κB) of podocyte is strongly associated with the development of proteinuria in MCNS. Dehydroxymethylepoxyquinomicin (DHMEQ) is a novel NF-κB inhibitor that potently inhibits DNA-binding activity of NF-κB, resulting in several therapeutic effects in various pathological conditions. We conducted this study to ask whether DHMEQ may ameliorate the nephrosis in mice induced by puromycin aminonucleoside (PAN), which is considered to be an animal model for MCNS. METHODS/RESULTS: Pretreatment with DHMEQ alleviated the proteinuria and reversed the serum abnormalities in mice nephrosis induced by 450 mg/kg of PAN. Increased serum interleukin-6 level in PAN-induced nephrosis was also completely suppressed by DHMEQ. Electron microscopic analyses of glo-meruli indicated that DHMEQ can inhibit the podocyte foot process effacement via blocking the translocation of podocyte NF-κB from cytoplasm to nucleus. CONCLUSIONS: These results suggest that DHMEQ can be a potential therapeutic agent for MCNS.

Production of nitric oxide is lower in Shiga toxin-stimulated neutrophils of infants compared to those of children or adults.

Hemolytic uremic syndrome (HUS) in infants is mainly caused by the Shiga toxin (Stx), which is produced by pathogenic Escherichia coli O157:H7. Infants are prone to develop HUS in comparison to older children and adults, but its underlying mechanism remains unknown. Recent observations suggest that reactive oxygen species (ROS) and reactive nitrogen species (RNS) including nitric oxide (NO) may be involved in the pathogenesis of HUS. We therefore measured NO production by neutrophils prepared from infants (6-27 months old), children (5.3-11 years old) or adults (25-47 years old). The NO production was measured by a flow cytometric analysis with a fluorescent indicator (expressed as mean fluorescence intensity), and mRNA expression of inducible NO synthase (iNOS) was analyzed by reverse transcription-polymerase chain reaction (RT-PCR). The amount of NO produced was significantly lower in Stx-stimulated neutrophils prepared from infants (45.8 ± 23.3) than that in those from children (120.5 ± 81.5) or adults (127.7 ± 45.8) (n = 10 each group, P < 0.05). The expression level of iNOS mRNA was lower in Stx-stimulated neutrophils of the infants than the level in those of children or adults. In conclusion, Stx increased NO production in neutrophils probably via iNOS. Importantly, the degree of the Stx-mediated increase in NO production was lower in neutrophils of infants compared to those of children or adults, which may explain the higher incidence of HUS in infants. These results suggest that NO may contribute to the cellular defense mechanisms against Stx.

Predictive value of IgE/IgG4 antibody ratio in children with egg allergy.

BACKGROUND: The aim of this study was to investigate the role of specific IgG4 antibodies to hen's egg white and determine their utility as a marker for the outcome of oral challenge test in children sensitized to hen's egg METHODS: The hen's egg oral food challenge test was performed in 105 sensitized children without atopic dermatitis, and the titers of egg white-specific immunoglobulin G4 (IgG4) and immunoglobulin E (IgE) antibodies were measured. To set the cut-off values of IgG4, IgE, and the IgE/IgG4 ratio for predicting positive results in oral challenges, receiver operating characteristic curves were plotted and the area under the curves (AUC) were calculated. RESULTS: Sixty-four of 105 oral challenges with whole eggs were assessed as positive. The AUC for IgE, IgG4, and IgE/IgG4 for the prediction of positive results were 0.609, 0.724, and 0.847, respectively. Thus, the IgE/IgG4 ratio generated significantly higher specificity, sensitivity, positive predictive value (%), and negative predictive value (%) than the individual IgE and IgG4. The negative predictive value of the IgE/IgG4 ratio was 90% at a value of 1. CONCLUSIONS: We have demonstrated that the egg white-specific serum IgE/IgG4 ratio is important for predicting reactivity to egg during food challenges.

Increased urinary calcium excretion caused by ceftriaxone: possible association with urolithiasis.

The administration of ceftriaxone is known to be associated with biliary pseudolithiasis, although the development of urolithiasis has only rarely been reported. We treated a young male with bacterial meningitis complicated by urinary precipitates composed of ceftriaxone-calcium salt, which prompted us to study whether ceftriaxone administration predisposes children to the formation of urinary precipitates. The case-control study reported here included 83 children with bacterial pneumonia aged from 3 months to 8.9 years. The children were divided into one group of 43 children who received ceftriaxone (group A) and a second group of 40 children who received amoxicillin (group B). Paired samples of serum and urine before and after treatment were obtained from the patients in each group. There were no significant differences in demographic characteristics and blood biochemistry between the groups. However, the mean urinary calcium to creatinine ratio (uCa/Cr; mg/mg) was significantly higher in group A patients than in group B patients after treatment (0.19 vs. 0.09, respectively; p < 0.001), and analysis of the paired urine samples revealed that the uCa/Cr significantly increased after treatment only in group A patients(p < 0.001). There was a weak but non-significant relationship between the dose of ceftriaxone and the uCa/Cr in group A (p = 0.10, r = 0.24). Our results are the first to demonstrate that ceftriaxone has the potential to significantly increase urinary excretion of calcium, which may be linked to ceftriaxone-related urolithiasis or sludge. We therefore suggest that it is worthwhile monitoring the uCa/Cr levels in patients on ceftriaxone as they may be at greater risk for developing large stones and renal damage.

Serum albumin level accurately reflects antioxidant potentials in idiopathic nephrotic syndrome.

BACKGROUND: Recent observation revealed that serum albumin plays an important role in the host defense mechanism as it is one of the important antioxidants. This study was conducted to investigate whether hypoalbuminemia contributes to a decreased biological antioxidant potentials (BAP) in idiopathic nephrotic syndrome (INS). METHODS: Fifty three heparinised blood samples were obtained from 8 patients with INS (median 13.5 years). Eighteen samples from 6 patients with Henoch-Schönlein purpura (HSP median 7 years) were served as control. Intravenous human albumin preparation was also applied for comparison. Measurement of BAP in blood and human albumin preparation was determined by a newly developed devise called FRAS4(®). Comparison among groups and relationships between BAP and albumin concentrations or c-reactive protein (CRP) were studied by Kruskal-Wallis test and Spearman rank correlation test, respectively. RESULTS: Serum levels of BAP was significantly lower in patients with nephrotic relapse than those in patients with nephrotic remission or HSP. BAP correlated well with serum albumin levels. Positive relationship was also found between concentration of albumin in human preparation and BAP. Weakly positive CRP sera disclosed both hypoalbuminemia and low BAP. CONCLUSION: Our results suggest that decreased antioxidant potentials caused by hypoalbuminemia in INS may contribute to an aberrant immunity.

Prediction of the risk of coronary arterial lesions in Kawasaki disease by brain natriuretic peptide.

Kawasaki disease (KD) is an acute systemic vasculitis associated with the development of coronary arterial lesions (CALs) occurring in 3-5% of children treated by intravenous immune globulin (IVIG). However, a considerable number of patients who are not responding to IVIG are at much higher risk. Although studies have explored potential biomarkers to predict patients with KD who are at risk of CAL, no useful single marker exists. We hypothesized that the serum concentrations of the N-terminal moiety of brain natriuretic peptide (NT-proBNP) can be useful to predict CAL. Forty-three children with KD (29 males and 14 females) were enrolled in this study. Despite IVIG, 6 of the 43 patients developed CAL. There were, however, no significant differences in variables between children with CAL and those without CAL: These include age, gender, day of the illness, leukocyte count, and the serum levels of sodium, C-reactive protein, and albumin. The serum NT-proBNP level was significantly higher in children with CAL than those without CAL (2,611 ± 1,699 vs. 1,073 ± 1,427 pg/ml; P = 0.03): the cutoff value of 1,000 pg/ml to predict CAL produced a specificity of 0.68, sensitivity of 0.83, and an odds ratio as high as 10.4. In conclusion, NT-proBNP is increased in KD patients who are developing CAL, and patients with an elevated serum NT-proBNP >1,000 pg/ml have a risk of CAL ~10 times higher than that of patients with a modest increase.

Immunoglobulin preparations affect hyponatremia in Kawasaki disease.

Hyponatremia frequently occurs in Kawasaki disease (KD). The aim of this study was to investigate the effect of Na content of the intravenous immunoglobulin (IVIG) preparation on serum Na levels in KD. Seventy-eight subjects, of whom 27 had hyponatremia, were split up into two groups: group A receiving IVIG preparations containing high Na (0.9%) and group B receiving IVIG preparations containing trace Na. While the data before IVIG therapy revealed no significant differences in the median serum Na between the groups, an administration of IVIG preparations increased the serum levels of Na in group A (P < 0.01) but not in group B (P > 0.05). Furthermore, the median serum Na level was significantly higher in group A than that in group B (139.0 vs 137.0 mEq/L, respectively, P < 0.01). No significant difference was found in the prevalence of coronary artery lesions between the groups. In conclusion, we should keep it in mind that the IVIG products without Na have an adverse affect on hyponatremia in KD though their efficacy seems to be equivalent to those containing high Na.