Efficacy and safety of micafungin for the prophylaxis of invasive fungal infection during neutropenia in children and adolescents undergoing allogeneic hematopoietic SCT.

The objective of this study was to evaluate the efficacy and safety of micafungin for the prevention of invasive fungal infection (IFI) during the neutropenic phase of allogeneic hematopoietic SCT (allo-HSCT) in children and adolescents. This was a prospective, multicenter, open-label, single-arm study. Micafungin was administered i.v. at a dose of 1 mg/kg/day (max 50 mg) from the beginning of conditioning until neutrophil engraftment. Treatment success was defined as the absence of proven, probable, possible or suspected IFI through to 4 weeks after therapy. From April 2010 to December 2011, 155 patients were enrolled from 11 institutions in Korea, and 147 patients were analyzed. Of the 147 patients, 121 (82.3%) completed the protocol without premature interruption. Of the 132 patients in whom micafungin efficacy could be evaluated, treatment success was achieved in 119 patients (90.2%). There was no proven fungal infection in any patient. The number of patients with probable, possible and suspected IFI was two, two and nine, respectively. Thirty-five patients (23.8%) experienced 109 adverse events (AEs) possibly related to micafungin. No patients experienced grade IV AEs. Two patients (1.4%) discontinued micafungin administration due to adverse effects. None of the deaths were related to the study drug.

Differential expression patterns of IRF3 and IRF7 in pediatric lymphoid disorders.

Interferon regulatory factors (IRFs) are multifunctional transcriptional factors. To define the role of IRFs in lymphoid disorders, we determined the expression patterns of IRF3 and IRF7 by immunohistochemistry in 5 normal lymph nodes, 12 reactive hyperplastic lymph nodes, and 27 pediatric lymphomas. IRF3 was prominently expressed in the nuclei of the histiocytes, and was expressed very weakly in the cytoplasm of most of the lymphocytes of the normal lymph nodes. However, IRF7 was expressed strongly in the nuclei of over 50% of the lymphocytes throughout the normal lymph nodes, but the histiocytes and fibroblasts were spared. In the reactive hyperplastic lymph nodes, the number of IRF3- and IRF7- positive cells in the nuclei was elevated. In the lymphomas, the number of IRF3-positive cells in the nucleus appeared to have decreased, and the cells were scattered throughout the lymphoma tissue in no specific pattern. However, in most cases the number of IRF7-positive cells was elevated. These results suggested that IRF3 was activated principally in the histiocytes and T cells under inflammatory conditions, but IRF3 activation was attenuated in cases of lymphoma. However, the number of IRF7-positive cells was found to be elevated in the reactive hyperplastic lymph nodes and pediatric lymphoma.

Transfusion-induced malaria in a child after open heart surgery in Korea.

We had an opportunity to evaluate a child who developed fever approximately two to three weeks after the open heart surgery for tetralogy of Fallot. His peripheral blood smear showed rings and various stages of Plasmodium vivax. The patient had received packed red blood cells during the surgery and postoperative care, one unit of which was later proved sero-positive for malaria. The possibility of malaria should be included in the differential diagnosis of the patients with unexplained fever after multiple blood product transfusions for the open heart surgery.

Human erythrocyte protein L-isoaspartyl methyltransferase: heritability of basal activity and genetic polymorphism for thermal stability.

Protein L-isoaspartyl methyltransferase (PIMT) is believed to play an important role in the disposition of age-damaged proteins by catalyzing the repair of abnormal isoaspartyl linkages resulting from the spontaneous deamidation of asparaginyl residues or isomerization of aspartyl residues. As a step toward testing the hypothesis that human disease- or age-related pathology might be associated with a deficiency in PIMT, we investigated basal activity and thermal stability of PIMT in erythrocyte lysates from 299 U.S. family members. Thermal stability was measured because it is a sensitive measure of variation in amino acid sequence. Basal activity was normally distributed with a mean+/-SD of 558+/-43 units/ml erythrocytes. Statistical analysis of the data revealed that basal PIMT activity exhibited a high degree of heritability. Enzyme thermal stability showed a skewed bimodal frequency distribution, and segregation analysis of family member pedigrees was consistent with Mendelian inheritance of two major alleles. No DNA was available from the family samples, so we tested two additional population samples for a known Ile/Val polymorphism at codon 119 and for PIMT activity and thermal stability, using blood donated by 25 Norwegians and by 20 Koreans. Single-stranded conformational polymorphism analysis using polymerase chain reaction revealed a 100% correlation between thermal stability grouping and this polymorphism. The high thermal stability samples were all homozygous Ile, the low thermal stability samples were all homozygous Val, and the intermediate thermal stability samples were all heterozygous. Furthermore, this polymorphism was responsible, in part, for the variation observed in basal erythrocyte PIMT activity. These results will help provide a foundation for future studies aimed at correlating levels of PIMT activity, or other properties of this enzyme, with human disease.

Human thiopurine methyltransferase pharmacogenetics: gene sequence polymorphisms.

Thiopurine methyltransferase (TPMT) catalyzes the S-methylation of thiopurine drugs. TPMT activity is regulated by a common genetic polymorphism that is associated with large individual variations in thiopurine toxicity and efficacy. We previously cloned the functional gene for human TPMT and reported a common variant allele for low enzyme activity, TPMT*3A, that contains point mutations at cDNA nucleotides 460 and 719. In the present study, we set out to determine the number, types, and frequencies of TPMT variant alleles associated with low enzyme activity in clinical laboratory samples in the United States and to compare those results with data obtained from two different ethnic groups. We identified a total of six different variant alleles for low TPMT activity in the 283 clinical laboratory samples studied. The most common variant was *3A; the second most frequent variant allele, *3C, contained only the nucleotide 719 polymorphism; and four other variant alleles were detected. TPMT*3A also appeared to be the most common variant allele in a Norwegian white population sample, but it was not found in a population sample of Korean children. However, *3C was present in samples from the Korean children, as was novel allele, *6. Characterization of variant alleles for low TPMT enzyme activity will help make it possible to assess the potential clinical utility of deoxyribonucleic acid-based diagnostic tests for determining TPMT genotype.

Thiopurine methyltransferase activity in a Korean population sample of children.

Thiopurine methyltransferase (TPMT) is a cytoplasmic enzyme that catalyzes the S-methylation of the cytotoxic drugs 6-mercaptopurine and azathioprine. Red blood cell (RBC) TPMT activity is subject to genetic polymorphism, and we have previously demonstrated an interethnic difference in TPMT activity. To investigate whether there was a race-related difference in RBC TPMT activity, TPMT was measured in a Korean population sample of 309 healthy children. Mean TPMT activity in healthy Korean children was 12.4 +/- 2.4 units/ml RBC, which is similar to the earlier reported TPMT activities in white populations. In contrast to the bimodal or trimodal frequency distributions of RBC TPMT activity in most other population samples, the frequency distribution histogram, the probit plot, and the Shapiro-Wilk test supported a normal distribution of TPMT activity in this Korean population sample of healthy children. Mean RBC TPMT activity showed a tendency to decrease with age, but it was not statistically significant. No gender-related difference in RBC TPMT activity was found.