Diminished toll-like receptor response in febrile infection-related epilepsy syndrome (FIRES).

BACKGROUND: Defective human TLR3 signaling causes recurrent and refractory herpes simplex encephalitis/encephalopathy. Children with febrile infection-related epilepsy syndrome with refractory seizures may have defective TLR responses. METHODS: Children with febrile infection-related epilepsy syndrome were enrolled in this study to evaluate TLR1-9 responses (IL-6, IL-8, IL-12p40, INF-α, INF-γ, and TNF-α) in their peripheral blood mononuclear cells (PBMCs) and monocyte-derived dendritic cells (MDDCs), compared to those with febrile seizures and non-refractory epilepsy with/without underlying encephalitis/encephalopathy. RESULTS: Adenovirus and enterovirus were found in throat cultures of enrolled patients (2-13 years) as well as serologic IgM elevation of mycoplasma pneumonia and herpes simplex virus, although neither detectable pathogens nor anti-neural autoantibodies in the CSF could be noted. Their PBMCs and MDDCs trended to have impaired TLR responses and significantly lower in cytokine profiles of TLR3, TLR4, TLR7/8, and TLR9 responses but not other TLRs despite normal TLR expressions and normal candidate genes for defective TLR3 signaling. They also had decreased naïve T and T regulatory cells, and weakened phagocytosis. CONCLUSION: Children with febrile infection-related epilepsy syndrome (FIRES) could have impaired TLR3, TLR4, TLR7/8, and TLR9 responses possibly relating to their weakened phagocytosis and decreased T regulatory cells.

6-Gingerol modulates proinflammatory responses in dextran sodium sulfate (DSS)-treated Caco-2 cells and experimental colitis in mice through adenosine monophosphate-activated protein kinase (AMPK) activation.

BACKGROUND: 6-gingerol has been reported to have anti-inflammatory effects in different experimental settings. The present study aimed at evaluating the effect of 6-gingerol on dextran sodium sulfate (DSS)-induced barrier impairment and inflammation in vitro and in vivo. METHODS: a differentiated Caco-2 monolayer was exposed to DSS and treated with different concentrations of 6-gingerol (0, 1, 5, 10, 50, and 100 µM). Changes in intestinal barrier function were determined using transepithelial electrical resistance (TEER). The anti-inflammatory activity of 6-gingerol was examined as changes in the expression of proinflammatory cytokine using quantitative real-time PCR. Western blotting was employed to determine the activation of adenosine monophosphate-activated protein kinase (AMPK). Mice with DSS-induced colitis were given different oral dosages of 6-gingerol daily for 14 days. Body weight and colon inflammation were evaluated, and level of proinflammatory cytokines in colon tissues was measured. RESULTS: 6-gingerol treatment was shown to restore impaired intestinal barrier function and to suppress proinflammatory responses in DSS-treated Caco-2 monolayers. We found that AMPK was activated on 6-gingerol treatment in vitro. In animal studies, 6-gingerol significantly ameliorated DSS-induced colitis by restoration of body weight loss, reduction in intestinal bleeding, and prevention of colon length shortening. In addition, 6-gingerol suppressed DSS-elevated production of proinflammatory cytokines (IL-1ß, TNFα, and IL-12). CONCLUSION: our findings highlight the protective effects of 6-gingerol against DSS-induced colitis. We concluded that 6-gingerol exerts anti-inflammatory effects through AMPK activation. It is suggested that 6-gingerol has a promising role in treatment of IBD.

Intestinal obstruction caused by potato bezoar in infancy: a report of three cases.

We present a report of three young infants with unusual intestinal obstruction caused by potato bezoar. They presented with vomiting, irritable crying, and abdominal distention. Barium gastrointestinal series clearly revealed intraluminal filling defect in the duodenum in two cases and ileum in one. Those bezoars in the pylorus and duodenal bulb were all successfully retrieved endoscopically. The patient's abdominal symptoms subsided after the bezoars were eliminated; no subsequent gastrointestinal events occurred in the following months. The authors believe that the occurrence of these cases suggest that feeding mashed potato to young infants (≤4 months) should be prohibited because it can result in bezoar formation.

Overexpression of kappa-actin alters growth properties of hepatoma cells and predicts poor postoperative prognosis.

UNLABELLED: Since Rho-mediated signaling can regulate liver cancer cell proliferation, amino acid sequence changes of its downstream targets, actins, might alter the properties of cell growth. Here, we investigated the function of a novel class of actins, named κ-actins, in hepatocellular carcinoma (HCC). MATERIALS AND METHODS: Alexander cells overexpressing an HCC-derived κ-actin (Alex-κ cells) were established to study growth property changes. κ-actin expression was also determined in tumor and noncancerous tissues from 72 HCC patients. Survival analysis was conducted to evaluate the prognostic predictive value of κ-actin expression. RESULTS: Phylogenetic analysis showed that κ-actin sequences constituted 94.7% and 17.6% of actin transcripts in Alex-κ and naive Alexander cells, respectively. Alex-κ cells exhibited serum-independent cell growth with increased anchorage-independent colony formation and BrdU incorporation upon serum deprivation. Cox proportional hazard analysis showed that κ-actin expression in both cancerous and noncancerous tissues predicted poorer postoperative disease-free survival (p=0.004). CONCLUSION: Overexpression of κ-actin altered growth properties of hepatoma cells, contributing to poor postoperative prognosis.

Distribution, clinical features and treatment in Taiwanese patients with symptomatic primary immunodeficiency diseases (PIDs) in a nationwide population-based study during 1985-2010.

Primary immunodeficiency diseases (PIDs) are a group of rare diseases with wide geographic and ethnic variations in incidence, prevalence, and distribution patterns. The aim of this study was to examine the distribution pattern and clinical spectrum of PIDs in Taiwan at a national referral institute. From 1985 to 2010, 215 patients from 183 families were diagnosed and grouped according to the updated classification of PIDs. Eighty-one (37.7%) patients had "other well-defined immunodeficiency syndromes", followed by "predominantly antibody deficiencies" (54 patients; 25.1%), "T- and B-cell immunodeficiencies" (34; 15.8%), "congenital defects of phagocytes" (25; 20.2%), "complement deficiencies" (15; 7.0%), and "disease in immune dysregulation" (5; 2.3%). The last category included two patients with Chediak-Higashi syndrome, and one each with familial hemophagocytosis, IPEX, and hypogammaglobulinemia and albinism. One female had cold-induced auto-inflammatory disease. There were no cases of "defects in innate immunity". Pseudomonas and Streptococcus pneumoniae were the two most identified microorganisms in septicemia (42.7%; 44/103 episodes). Stem cell transplantation was successful in 13 of 22 patients, while 34 patients (15.8%) died. Molecular defects were identified in 109 individuals (from 90 families). There were relatively fewer cases of "predominantly antibody deficiencies" due to there being only a few patients with adult-onset PIDs, implying certainty bias rather than ethnic variation. Awareness of under-diagnosis among physicians rather than pediatricians is vital for timely diagnosis and consequently adequate treatment.

SLC25A13 gene mutations in Taiwanese patients with non-viral hepatocellular carcinoma.

Mutations of the SLC25A13 gene, which encodes citrin, result in adult-onset type II citrullinemia (CTLN2). Because CTLN2 has been associated with hepatocellular carcinoma (HCC) and may be involved in hepatocarcinogenesis, the objective of this study was to assess the frequency of SLC25A13 mutations in patients with non-viral HCC. A retrospective review of 154 patients with HCC, who underwent total tumor resection from July 1998 to August 2005, was conducted. After exclusion of 137 patients infected with hepatitis B and/or C viruses, 17 patients were analyzed. Genomic DNA from stored tumor and normal hepatic samples was analyzed for the SLC25A13 gene mutation. In addition, the clinicopathological and histopathological features of patients with and without the SLC25A13 gene mutation were compared. The SLC25A13 mutation was observed in two patients (12%), and the carrier rate was approximately 1 in 8 patients. The IVS6+5G>A mutation was heterozygous in both normal hepatic and tumor tissues for case 1. On the other hand, the c.851del4 mutation was heterozygous in normal tissue but homozygous in tumor tissue for case 2. No significant differences in patient characteristics were observed. Further analyses of patients with SLC25A13 gene mutations may elucidate the relationship between the citrin gene and susceptibility of HCC.

Clinical aspects and genetic analysis of taiwanese patients with wiskott-Aldrich syndrome protein mutation: the first identification of x-linked thrombocytopenia in the chinese with novel mutations.

BACKGROUND: Wiskott-Aldrich syndrome (WAS) is an X-linked immunodeficiency characterized by microthrombocytopenia, eczema, and recurrent infections. However, the more than 500 patient mutations described are mainly based on Caucasian and Japanese populations. This study investigated Taiwanese patients with WASP mutations since 1985 as part of a long-term comprehensive study in primary immunodeficiency diseases (PIDs) covering 23 million inhabitants. METHODS: Clinical manifestations, immunologic functions, and WASP gene sequencing and expressions were analyzed in WAS patients. And, those patients with idiopathic thrombocytopenic purpura and "small" thrombocytopenia were enrolled. RESULTS: Of 16 patients studied in 1993-2009, 12 presented as classic WAS phenotype and four had X-linked thrombocytopenia (XLT). Almost all correlated to the WASP expression level and severity of infections. Causes of mortality in the 12 classic WAS patients were mass bleeding, Staphylococcus aureus sepsis, and cytomegalovirus (CMV) pneumonitis in three non-transplant cases, and EBV-associated lymphoproliferative disorder and CMV pneumonitis in two non-engrafted transplant patients. Splicing mutations of Int 8 (+5) G>A in cousins and insertion of 1023 C in unrelated families presented as both XLT and classic WAS phenotype in the same mutations. Four XLT patients, including two novel mutations of 1023 Ins C (in 2) and "double" missense mutations of 1378 C>T and 1421 T>C had relatively higher CD4+ memory cells and/or activated lymphocytes (CD3+CD69+) compared with those of classic WAS patients. CONCLUSIONS: The lower ratio of XLT to classic WAS patients underestimates the burden of Taiwanese patients with WASP mutations, especially the XLT phenotype. A clustering pattern on exon 1 and five unique mutations (deletion of 45-48 ACCA, IVS 1 (-1) G>C, large deletion of promoter and exon 1 and 2, insertion 1023 C, and 1378 C>T and 1421 T>C) explain the genetic variations in different ethnic groups, despite the possibility of selection and ascertainment bias.

Probiotics have clinical, microbiologic, and immunologic efficacy in acute infectious diarrhea.

BACKGROUND: Acute infectious diarrhea is a major cause of childhood morbidity and economic burden for families. We evaluate the clinical, microbiologic, and immunologic effects of probiotics in acute infectious diarrhea. METHODS: Children (n = 304) aged 3 months to 6 years hospitalized for acute diarrhea were randomized to receive Bio-three (a mixture of Bacillus mesentericus, Enterococcus faecalis, and Clostridium butyricum) or placebo orally 3 times daily for 7 days. Fecal samples were homogenized for bacterial culture and blood cells were isolated for cell culture and cytokine analysis. This study is registered (NCT00463190). RESULTS: The mean duration of diarrhea after start of therapy was 60.1 hours in the probiotics group versus 86.3 hours in the placebo group (P = 0.003). Hospital stay was shorter in the probiotics group than in the placebo group (P = 0.009). Counts of Bifidobacteria and Lactobacillus species were elevated in stool culture of the probiotics (Bio-three) group. IL-10 was increased in the serum and supernatants of cell culture in the probiotics group, and tumor necrosis factor-alpha values were down-regulated. Interferon- gamma and IL-12 were mildly elevated in the probiotics group, compared with the placebo group. CONCLUSIONS: This probiotics mixture reduced the severity of diarrhea and length of hospital stay in children with acute diarrhea. In addition to restoring beneficial intestinal flora, probiotics may enhance host protective immunity such as down-regulation of pro-inflammatory cytokines and up-regulation of anti-inflammatory cytokines.

Fibrolamellar hepatocellular carcinoma- report of a case.

Fibrolamellar hepatocellular carcinoma (FLH) is a variant of hepatocellular carcinoma (HCC) with distinct clinical, histologic and prognostic features different from conventional HCC. Herein, we present a 14-year-old girl with a palpable mass over the right upper -quadrant of the abdomen. A well-defined mass in the left liver with heterogeneous density and a central linear band was demonstrated by ultrasound and computed tomogram. FLH was proved by the histopathology study of a liver specimen taken from an echo-guided liver core needle biopsy before surgery and from a left hepatectomy. No tumor recurrence was detected by ultrasound in the 2-year follow-up.

The impact of constipation on growth in children.

The observation on the impact of constipation on nutritional and growth status in healthy children was never reported. During a 4-y period, we evaluated the consequence of constipation on growth in children. The enrolled children were aged between 1 and 15 y with constipation. Medical response of constipation to treatment was evaluated by the scoring of constipation symptoms. The correlation of therapeutic effect of constipation with growth status at 12 wk and 24 wk was statistically evaluated. About 2426 children (1284 boys, 1142 girls) with a mean age of 7.31 +/- 3.65 (range 1.1-14.9) y were enrolled. After 12-wk treatment, significant increase of z-scores of height-for-age, weight-for-age, and body mass index-for-age were all found in patients with good medical responses (1377 cases) than in those with poor medical responses (1049 cases). The 1049 patients with poor medical response received advanced medications; significant increase of z-scores of height-for-age, weight-for-age, and body mass index were also found in these patients. A marked increase of appetite was significantly correlated with better gain on height and weight after treatment. We conclude that chronic constipation may retard growth status in children, and a long-term medication for constipation in children appears beneficial to their growth status.

Clinical aspects and molecular analysis of Chinese patients with Wiskott-Aldrich syndrome in Taiwan.

BACKGROUND: Wiskott-Aldrich syndrome (WAS) is an X-linked immunodeficiency, characterized by microthrombocytopenia, eczema and recurrent infections. More than 441 patient mutations have been described all over the world, mainly based on Caucasian and Japanese people. There have been few reported cases involving Chinese WAS patients. OBJECTIVE: We investigated Chinese WAS patients in Taiwan since 1980. METHODS: All WAS patients met the diagnosis criteria. Clinical manifestations, immunological functions, gene sequencing and the WAS protein (WASP) expression were analyzed. RESULTS: Eleven male Chinese WAS patients were enrolled, presenting as classic WAS phenotype, correlative to the expression level of WASP and the severity of infections. Seven patients had autoimmune disorders, encompassing autoimmune hemolysis in 4, lymphoproliferative disorders in 2 and ulcerative colitis in 1 patient. As well as prophylactic monthly intravenous immunoglobulin infusion, splenectomy was performed on 2 patients. Five patients received hematopoietic stem cell transplantation. The causes of mortality were mass bleeding, sepsis and Epstein Barr virus-associated lymphoproliferative disorders in 3 nontransplant patients and acute graft failure and cytomegalovirus pneumonitis in 2 transplant patients. Nine patients received genetic analysis and revealed 4 unique mutations. None had the X-linked thrombocytopenia phenotype. CONCLUSIONS: All of the recognized Chinese WAS patients had the classic phenotype. Most mutations involved exon 1 of the WASP gene and none had the X-linked thrombocytopenia phenotype. This may be attributable to genetic variation, although selection bias may exist.

Early transplantation of unrelated cord blood in a two-month-old infant with Wiskott-Aldrich syndrome.

This report exemplified a success of unrelated CBT in a two-month-old boy with Wiskott-Aldrich Syndrome. Umbilical cord blood was chosen as the stem-cell source because of its immediate availability and reduced tendency to cause GVHD. The conditioning regimen was cyclophosphamide, busulfan, and antithymocyte globulin. GVHD prophylaxis consisted of cyclosporin and methylprednisolone. The patient received an HLA 1-locus-mismatched cord blood unit, and the total number of infused nucleated cells was 11.14 x 10(7)/kg. Neutrophil engraftment was achieved on day +11, and a platelet count greater than 50 x 10(9)/L was achieved on day +71. He is currently alive and doing well at nine months post-transplant and free of any bleeding episodes. This case suggests that unrelated donor CBT may be safe and technically feasible, even in early infancy, when an appropriately matched related or unrelated donor is unavailable.

Identification of a novel actin isoform in hepatocellular carcinoma.

OBJECTIVE: Altered actin isoform expression occurs in some pathological conditions including muscular malignancies. This study was to investigate whether a similar event occurs in hepatocellular carcinoma. METHODS: Cellular RNA was extracted from cancerous and non-cancerous hepatoma tissues. Reverse transcription (RT)-PCR followed by cloning and sequencing was performed to obtain populations of actin sequences. Phylogenetic analysis was carried out to identify novel actin isoforms. Interaction between the novel actin isoform and other cellular proteins was examined by the yeast two-hybrid system. The relative amounts of the novel actin isoform in the cancerous and non-cancerous tissues were further assayed using real-time PCR with specific primers. RESULTS: When compared between the cancerous and non-cancerous tissues, the proportion of non-beta-actins in the cancerous parts increased significantly in three of four cases included. Among the non-beta-actins, a novel group of isoforms was identified, temporarily named kappa-actins. Two genetically closely related sequences, FKSG30 and an actin-like sequence in the Cat Eye syndrome region, were found to cluster with the kappa-actins. Protein interaction assay indicated that the interaction between kappa-actin and prefoldin 2 was greatly diminished. The relative amounts of kappa-actin increased in 12 of 20 cancerous tissues assayed. CONCLUSIONS: A novel class of actin isoforms was expressed in some hepatocellular carcinoma tissues, replacing beta-actins to become the major constituents of actin cytoskeleton.

Molecular diagnosis of Wiskott-Aldrich syndrome in Taiwan.

The spectrum of Wiskott-Aldrich syndrome (WAS) mutation in Han Chinese residing in Taiwan has not been previously reported. We describe a multidisciplinary approach to the molecular diagnosis of WAS which could be applied to clinical diagnosis, carrier prediction, and prenatal diagnosis. A total of 6 male patients, from 6 independent families, were referred for the molecular diagnosis of WAS. The respective methylation status of the 6 X chromosomes in peripheral blood leukocytes from obligatory female carriers was analyzed initially, followed by analysis of the level of expression of WAS protein (WASP) in peripheral leukocytes from patients, using a Western blotting technique. The analysis of the specific WAS gene mutation was done by direct sequencing. Mutations were identified in the WAS gene of all patients. Mutations identified included p.R13X, p.R41X, p.S82P, IVS1-1 G --> C, p.L342TFsX493, and a large deletion. Four patients had no WASP expression in peripheral leukocytes obtained before bone marrow transplantation. Several female carriers in the families of the 6 patients with such mutations were confirmed. One prenatal diagnosis was made in a fetus and he did not inherit the mutation. The importance of mutations in the first 2 exons of the WAS gene was demonstrated in this study, which represented 5 of the 6 mutations identified in 6 patients. The use of a multidisciplinary approach including DNA and protein analysis is required for molecular diagnosis and genetic counseling of WAS.

Shigella flexneri sepsis in an infant.

Shigellosis continues to be an important public health problem in developed countries, since communication in the world village has become more frequent. In addition, this disease is difficult to be prevented because only a small number of bacteria are required to cause infection, and it has exhibited steady trends towards multiple drug resistance. This report describes a 7-month-old female infant with Shigella flexneri sepsis presenting initially with a high fever, watery diarrhea, and dehydration. She was successfully treated with ceftriaxone for 7 days. This case illustrates that Shigella should be included in the differential diagnosis of sepsis associated with diarrhea particularly in young infants traveling to or living in an endemic area. The choice of antimicrobial therapy and the optimal duration for treatment should be carefully evaluated because of the emergence of multidrug-resistant Shigella.

Association between levels of TNF-alpha and TNF-alpha promoter -308 A/A polymorphism in children with Kawasaki disease.

BACKGROUND AND PURPOSE: Tumor necrosis factor-alpha (TNF-alpha) has been shown to play a central role in the pathogenesis of vasculitis in Kawasaki disease (KD). We investigated the serum levels of TNF-alpha and soluble TNF receptor 1 (STNFR1) levels, and genetic polymorphisms of the TNF-alpha promoter gene in children with KD to delineate the genetic basis of KD. METHODS: A total of 18 children (12 boys and 6 girls) with KD were studied, 9 of whom had the complication of coronary artery lesion (CAL) within 30 days after the onset of symptoms. Serum levels of TNF-alpha and STNFR1 were assayed by enzyme-linked immnosorbent assay, and DNA polymorphisms of the 5' flanking region of TNF-alpha promoter gene at position -308 [guanine (G) to adenine (A)] and -238 (G to A) were studied by direct nucleotide sequencing. RESULTS: The serum TNF-alpha level in KD patients was 113 +/- 209.9 pg/mL (range, 2.0 to 756.9 pg/mL; median, 24.7 pg/mL; normal, < 10 pg/mL). The serum levels of STNFR1 in KD (4255 +/- 2425 pg/mL) were higher than those of the control group (160 +/- 116 pg/mL). Allele frequencies of -308A and -238A were 11.1% and 0% in the KD patients, and 0% and 3.1% in the control group. Neither TNF-alpha promoter polymorphism nor any significant risk factor for CAL was identified in KD patients. One patient, who was homozygous for -308A, showed the highest TNF-alpha level and elevated STNFR1 level but had no evidence of CAL. Positive correlations were found between serum levels of STNFR1 and C-reactive protein (r = 0.731, p = 0.007), and between STNFR1 and leukocyte counts at admission (r = 0.620, p = 0.008). CONCLUSIONS: Increased serum levels of TNF-alpha and STNFR1 were found in KD patients but there was no correlation between these levels. The relationship between the pathogenesis of KD and TNF-alpha gene promoter -308G to A mutation towards cytokine production remains to be clarified.

Idiopathic pulmonary fibrosis in a child.

Idiopathic pulmonary fibrosis (IPF) is a rare disease of unknown etiology and is usually associated with a poor prognosis. Up to the present, less than 50 cases of IPF in children have been reported in the English literature, and no case has ever been reported from Taiwan. Herein we report on a 2-year-old boy with IPF presenting with a rapid onset of dyspnea followed by respiratory failure. The diagnosis of IPF was verified with an open lung biopsy. Despite intravenous methylprednisolone pulse therapy and empiric nitric oxide treatment, he expired on the 35th day after admission due to profound hypoxemia. A diagnosis of IPF should be included in the differential diagnosis for patients presenting with unexplained shortness of breath and pulmonary interstitial infiltrations.

Idiopathic hypertrophic pyloric stenosis in identical twins.

Idiopathic hypertrophic pyloric stenosis (IHPS) was thought to be a congenital disease traditionally, even though several published reports assumed IHPS was an acquired disease. The pathogenesis and inheritance patterns of IHPS are not fully understood. Except for the familial recurrence of IHPS, concordance of IHPS in monozygotic or dizygotic twins was also noted, but occurrence in female twins is rare. From July 1992 through June 2000, 130 patients were diagnosed with IHPS in our hospital including one pair of female twins. We present the finding in the twins and review the associated articles about the pathogenesis and inheritance patterns of IHPS.

Acute hypermagnesemia: a rare complication of antacid administration after bone marrow transplantation.

INTRODUCTION: We reported a case of hypermagnesemia in whom hypotension, hypothermia, and coma developed after repetitive doses of a seemingly harmless antacid for epigastric pain following bone marrow transplantation. METHODS: For this case, serial electrolytes, blood urea nitrogen, creatinine, calcium, and magnesium were obtained. Issues addressed were the restoration of normal hydration by normal saline, together with forced diuresis to hasten the renal excretion of magnesium, and eventual changes in its levels. RESULTS: The highest measured magnesium concentration was 5.9 mmol/l. She recovered without dialysis. The patient's condition improved with intravenous doses of calcium gluconate, saline solution infusion, and cardiovascular support. CONCLUSION: Hypermagnesemia is rare in allogeneic stem cell recipients receiving cyclosporine therapy for prevention of acute graft-vs.-host disease (GVHD). A posttransplant status with possible GVHD, poor nutritional intake, impaired intestinal absorption, dehydration, and the use of aluminum magnesia oral suspension may have resulted in magnesium imbalance. This case report highlights several associated nonrenal risk factors for hypermagnesemia, which include gastrointestinal tract disease, dehydration, and concomitant medications, particularly, the antacids that contain magnesium.