Clinicopathological features and prognosis of drug rash with eosinophilia and systemic symptoms: a study of 30 cases in Taiwan.

BACKGROUND: Drug rash with eosinophilia and systemic symptoms (DRESS), a group of non-blistering severe cutaneous adverse drug reactions (SCADRs), is characterized by skin rash and multiorgan involvement. Details of this reaction have not been reported in the literature so far. AIM: We investigate clinical and pathological features and prognosis of DRESS and hope this study will provide data concerning this disorder in Taiwan. METHODS: From January 2001 to June 2006, a total of 30 patients, diagnosed with DRESS, were enrolled and evaluated for demographic characteristics, pathological findings, complications and outcome. RESULTS: Patient ages ranged from 13 to 78, with an equal sex ratio. The most common offending drug was allopurinol followed by carbamazepine. Pathologic changes observed were lichenoid dermatitis, erythema multiforme, pseudolymphoma and vasculitis. Impairment of liver and renal functions and blood dyscrasia were frequent complications. Active infection or reactivation of HHV-6 was observed in 7 of 11 patients studied serologically. Two patients developed type 1 diabetes mellitus. The mortality rate was 10% (3 of 30). CONCLUSIONS: DRESS is a heterogeneous group of life-threatening conditions. The leading drug in DRESS in Taiwan is allopurinol. High eosinophil count and multiple underlying diseases are poor prognostic factors in patients with DRESS.

Disseminated xanthogranulomas associated with adult T-cell leukaemia/lymphoma: a case report and review the association of haematologic malignancies.

Xanthogranuloma (XG) is rarely observed in adults and has been reported to be associated with chronic myelogenous leukaemia (CML) and/or neurofibromatosis type 1 (NF1). A 68-year-old woman with adult T-cell leukaemia/lymphoma (ATLL) gradually developed disseminated XGs over the 3 years since disease onset. Histopathological examination of a skin biopsy revealed the presence of histiocytes in the dermis with a few Touton giant cells admixed with lymphoid cells. The lesions of XGs persisted despite chemotherapy with prednisolone and chlorambucil for her ATLL. This is the first report of disseminated XGs associated with ATLL. The association of disseminated XGs with haematologic malignancies was reviewed and the possible pathogenesis of this association will be discussed.

Helicobacter pylori inhibits activity of cdc2 kinase and delays G2/M to G1 progression in gastric adenocarcinoma cell line.

BACKGROUND: Helicobacter pylori is a bacterial pathogen strongly associated with ulcer diseases and gastric cancer. The bacterial-induced alteration of cell-cycle control in host cells may play a role in the pathogenetic mechanisms. The aims of this study were to define the effect of H. pylori on the G2/M to G1 transition in a gastric cell line. METHODS: Cultured gastric cells, AGS, were synchronized in the S/early G2 phase and treated with intact H. pylori. The cell-cycle distribution of AGS cells was determined by flow cytometry. The activity of cdc2 kinase, as well as of some parameters that affect the kinase activity, was also examined. RESULTS: H. pylori delays cell-cycle progression at the G2/M phase in AGS cells. The G2/M delay was associated with reduced activity of cdc2 kinase. Both down-regulation of cell-cycle regulators (p34cdc2, cyclin B1 and cdc25C) and decreased association between p34cdc2 and cyclin B1 were found to be associated with the activity of cdc2 kinase abated after the H. pylori infection. In addition, the H. pylori-induced G2/M delay required direct contact between the bacteria and host cells. CONCLUSIONS: H. pylori inhibits G2/M to G1 progression and causes a reduction of cell division in gastric epithelial cells.

Helicobacter pylori infection induced alteration of gene expression in human gastric cells.

BACKGROUND: Helicobacter pylori, a human pathogen responsible for many digestive disorders, induces complex changes in patterns of gene expression in infected tissues. cDNA expression arrays provide a useful tool for studying these complex phenomena. AIM: To identify genes that showed altered expression after H pylori infection of human gastric cells compared with uninfected controls. METHODS: The gastric adenocarcinoma cell line AGS was cocultivated with H pylori. Growth of infected cells was determined by trypan blue exclusion assay. Complementary DNA probes derived from H pylori treated and untreated cells were hybridised to two identical Atlas human cDNA expression arrays, and those genes with altered expression levels were identified. A real time quantitative reverse transcription-polymerase chain reaction assay was used to better define expression patterns of these genes in endoscopically gastric mucosal biopsies with and without H pylori infection. RESULTS: Over 24 hours, coincubation with H pylori inhibited AGS cell growth but did not cause a noticeable degree of cell death. H pylori treatment altered the pattern of gene expression in AGS cells. We identified 21 overexpressed genes and 17 suppressed genes from the cDNA expression arrays. The majority of genes were transcription factors such as c-jun, BTEB2, and ETR101. Other genes were involved in signal transduction pathways, such as MAP kinase, interleukin 5, and insulin-like growth factor. Genes involved in cell cycle regulation and differentiation, such as CDC25B and NM23-H2, were also identified. In patients with H pylori infection (n=20), there was a significant difference for ERCC3, Id-2, and NM23-H2 mRNA levels in infected gastric mucosa compared with uninfected gastric mucosa in patients without peptic diseases (n=20) (ERCC3 4.75 molecules/10(4) beta-actin mRNA molecules v 13.65, p<0.001; Id-2 16.1 v 23.4, p<0.05; NM23-H2 17.5 v 45.5, p<0.001). There was no significant difference between mRNA levels of c-jun and CDC25B in H pylori colonised gastric mucosa and uninfected mucosa. CONCLUSION: We demonstrated that H pylori infection caused alteration of gene expression in AGS cells. The differential hybridisation technique of Atlas human cDNA expression array is a useful method to identify host genes involved in pathogenic mechanisms in H pylori infection.

Esophageal candidiasis in pediatric acquired immunodeficiency syndrome: clinical manifestations and risk factors.

BACKGROUND: Little is known about the epidemiology and clinical features of esophageal candidiasis (EC) in pediatric AIDS. We therefore investigated the clinical presentation and risk factors of EC in a large prospectively monitored population of HIV-infected children at the National Cancer Institute. PATIENTS AND METHODS: We reviewed the records of all HIV-infected children (N = 448) followed between 1987 and 1995 for a history of esophageal candidiasis to characterize the epidemiology, clinical features, therapeutic interventions and outcome of esophageal candidiasis. To understand further the risk factors for EC in pediatric AIDS, we then performed a matched case-control analysis of 25 patients for whom control cases were available. RESULTS: There were 51 episodes of EC documented in 36 patients with 23 male and 13 female patients (0.2 to 17 years; median CD4, count 11/microl), representing a frequency of EC of 8.0%. Concurrent oropharyngeal candidiasis (OPC) was the most common clinical presentation of EC (94%); other signs and symptoms included odynophagia (80%), retrosternal pain (57%), fever (29%), nausea/vomiting (24%), drooling (12%), dehydration (12%), hoarseness (6%) and upper gastrointestinal bleeding (6%). The causative organism documented in 36 episodes (18 from OPC, 17 from endoscopic biopsy and 1 from autopsy) was Candida albicans in all cases. Patients received treatment for EC with amphotericin B (63%), fluconazole (29%), ketoconazole (4%) or itraconazole (1%). A clinical response was documented in all 45 evaluable episodes. In 6 other cases, EC was a final event without contributing to the cause of death. By a conditional logistic regression model for matched data, the best predictor of EC was the presence of prior OPC (P<0.0001), followed by CD4 count and CD4 percentage (P = 0.0002) and use of antibacterial antibiotics (P = 0.0013). The risks associated with low CD4 count were independent of that of prior OPC. CONCLUSION: EC in pediatric AIDS is a debilitating infection, which develops in the setting of prior OPC, low CD4 counts and previous antibiotics.

New drugs and novel targets for treatment of invasive fungal infections in patients with cancer.

Invasive fungal infections have emerged as important causes of morbidity and mortality in profoundly immunocompromised patients with cancer. Current treatment strategies for these infections are limited by antifungal resistance, toxicity, drug interactions, and expense. In order to overcome these limitations, new antifungal compounds are being developed, which may improve our therapeutic armamentarium for prevention and treatment of invasive mycoses in high-risk patients with neoplastic diseases.

Expression of capsid [correction of caspid] protein VP1 for use as antigen for the diagnosis of enterovirus 71 infection.

To produce enterovirus 71 antigen for diagnostic purposes, the gene encoding the entire capsid protein VP1 was amplified by reverse transcription-polymerase chain reaction (RT-PCR), cloned and expressed in Escherichia coli as a poly-histidine fusion protein. Western blotting experiments with sera from patients with enterovirus 71 infection indicated that immunoglobulin G (IgG) and IgM antibodies bound to a single polypeptide VP1. According to these results, IgM anti-VP1 appeared in sera of patients with a symptomatic enterovirus 71 acute infection, whereas IgG anti-VP1 was present in sera of past infection. This finding suggests that detecting IgG and IgM immune responses against linear epitopes of recombinant VP1 is an effective means of determining the different phases of enterovirus 71 infection. In addition, sera containing coxsackie virus 16 (CA16) antibodies did not cross-react with the recombinant VP1 of enterovirus 71, despite the homology between VP1 proteins of both viruses. Comparison with reference PCR and neutralization assays showed these antibody tests to be appropriate for the serodiagnosis of enterovirus 71 infection.

Mutagenicity and specific mutation spectrum induced by 8-methoxypsoralen plus a low dose of UVA in the hprt gene in diploid human fibroblasts.

Exposure of cells to 8-methoxypsoralen plus a low dosage of UVA (365 nm) generates mainly monoadducts (PUVA-I treatment), while further irradiation of PUVA-I treated cells after removal of 8-methoxypsoralen (PUVA-II treatment) converts a high frequency of monoadducts to crosslinks. In this study, a comparison was made of the cytotoxicity and mutagenicity of PUVA-I-treated cells obtained here with those induced by PUVA-II treatment in our previous report. PUVA-I treatment slightly affected the colony-forming ability of cells. However, the 6-thioguanine-resistant cells were markedly increased from 3/10(6) clonable cells in UVA-irradiated populations to 47/10(6) clonable cells in PUVA-I-treated populations. Those results indicated that PUVA-I was more mutagenic than PUVA-II at equal cytotoxic doses, implying that psoralen monoadducts are less cytotoxic and as mutagenic as crosslinks. Mutations in the hypoxanthine (guanine) phosphoribosyltransferase gene of independent PUVA-I mutants were characterized by direct sequencing of cDNA and/or genomic DNA that were amplified by polymerase chain reaction. All the 30 sequenced mutants had single base substitutions. Of those mutations, 21 occurred in the coding region and the others were in the consensus sequences at exon-intron boundaries, thereby resulting in aberrant cDNA. The majority of base substitutions were T to A transversions (23/30); 22 were located at the thymine of 5'TA sites. All of the 24 T.A base pair substitutions (including one T to C) had thymine located on the non-transcribed strand. Five of the six G.C base substitutions were located at the 5' TG or 5' CA sites on the non-transcribed strand. The frequencies of mutations at 5'TA and 5'TG/5'CA sites were similar in PUVA-I- and PUVA-II-induced mutants. However, the specific kind of T.A base pair substitutions induced by PUVA-I is strikingly different from that induced by PUVA-II. While the transient misalignment-realignment model could account for PUVA-II-induced T.A base substitutions, the low cytotoxic effect and the specific T to A substitutions of PUVA-I treatment might be a result of rapid incorporation of nucleotides after insertion of an adenine or a thymine opposite the psoralen monoadducts on the template by DNA polymerases.

Mutation specificity of 8-methoxypsoralen plus two doses of UVA irradiation in the hprt gene in diploid human fibroblasts.

To investigate which specific kinds of base changes are induced by psoralen adducts in the genomic DNA of diploid human fibroblasts, cells were exposed to 8-methoxypsoralen (8-MOP) at 2-12 microM followed by one dose of UVA (365 nm) irradiation (PUVA-I treatment) or two doses of UVA (PUVA-II treatment). While PUVA-I treatment produced little effect on the induction of cytotoxicity, PUVA-II treatment significantly reduced the fibroblasts' colony-forming ability and resulted in about 10-fold increases in mutation frequency at the D0 dose. Mutations in the hypoxanthine (guanine) phosphoribosyltransferase (hprt) gene of 36 independent PUVA-II mutants were characterized by direct sequencing of cDNA amplified by the polymerase chain reaction (PCR). Seventeen mutants contained single base substitutions and the other 19 mutants either lacked one or more exons, or had deleted or gained nucleotides in the exon boundaries in their cDNA. The intron--exon boundaries of 10 of these 19 putative splicing mutants were further characterized by direct sequencing of the PCR-amplified hprt gene. The results showed that nine contained single base substitutions at the consensus splicing donor and acceptor sites. One splicing mutant possessed two base substitutions located at exon 8, whereas its splicing sites were intact. Most of the base substitutions occurred at T-A base pairs (24/29). The majority of T.A changes occurred at thymine of 5'TA and 5'ATA on the non-transcribed strand. Four of the five G.C base substitutions were located at guanines of 5'TG sites adjacent 3' to AT or TA sequences. In addition, the occurrence of a specific type of mutation was highly correlated to the 5' flanking bases of TA sites. The mutagenesis of 13 of the 16 mutational events at 5'TA sites on the non-transcribed strand can be explained by the preferential incisions of the photoadducts on the transcribed strand followed by misalignment--realignment during translesion repair synthesis of the bulky lesions on the non-transcribed strand.