Mother-to-infant transmission of the carcinogenic colibactin-producing bacteria.

BACKGROUND: The Escherichia coli strain that is known to produce the genotoxic secondary metabolite colibactin is linked to colorectal oncogenesis. Therefore, understanding the properties of such colibactin-positive E. coli and the molecular mechanism of oncogenesis by colibactin may provide us with opportunities for early diagnosis or prevention of colorectal oncogenesis. While there have been major advances in the characterization of colibactin-positive E. coli and the toxin it produces, the infection route of the clb + strain remains poorly characterized. RESULTS: We examined infants and their treatments during and post-birth periods to examine potential transmission of colibactin-positive E. coli to infants. Here, analysis of fecal samples of infants over the first month of birth for the presence of a colibactin biosynthetic gene revealed that the bacterium may be transmitted from mother to infant through intimate contacts, such as natural childbirth and breastfeeding, but not through food intake. CONCLUSIONS: Our finding suggests that transmission of colibactin-positive E. coli appears to be occurring at the very early stage of life of the newborn and hints at the possibility of developing early preventive measures against colorectal cancer.

Using optical coherence tomography angiography to guide myopic choroidal neovascularization treatment: a 3-year follow-up study.

PURPOSE: To report the long-term changes of the size of myopic choroidal neovascularization (mCNV) using optical coherence tomography angiography (OCTA). METHODS: This was a retrospective, observational case study of eleven eyes in eleven patients with mCNV followed with OCTA for a minimum of 3 years. The flow area of mCNV on OCTA, the size of chorioretinal atrophy (CRA) and central choroidal thickness were analyzed. The relationship between the changes of mCNV size and recurrences treated with anti-vascular endothelial growth factor (VEGF) agents was also assessed. RESULTS: Three eyes out of eleven eyes showed enlargement of the mCNV over 3 years. In two of the three eyes, the mCNV recurrences had not been treated immediately (the examination intervals were 4 months and 5 months, respectively), and we found obvious enlargement of the mCNV. In three eyes, the mCNV size decreased in 1 year and was stable thereafter without recurrences. In five eyes, mCNV size did not show remarkable changes for 3 years. In three of the five eyes, no recurrences were detected and two of the five eyes underwent prompt treatments against recurrences. CONCLUSION: Regular examination and prompt treatments against recurrences are critical to prevent enlargement of mCNV.

Maternal ω3 docosapentaenoic acid inhibits infant allergic dermatitis through TRAIL-expressing plasmacytoid dendritic cells in mice.

BACKGROUND: Maternal dietary exposures are considered to influence the development of infant allergies through changes in the composition of breast milk. Cohort studies have shown that ω3 polyunsaturated fatty acids (PUFAs) in breast milk may have a beneficial effect on the preventing of allergies in infants; however, the underlying mechanisms remain to be investigated. We investigated how the maternal intake of dietary ω3 PUFAs affects fatty acid profiles in the breast milk and their pups and reduced the incidence of allergic diseases in the pups. METHODS: Contact hypersensitivity (CHS) induced by 2,4-dinitrofluorobenzene (DNFB) and fluorescein isothiocyanate was applied to the skin in pups reared by mother maintained with diets mainly containing ω3 or ω6 PUFAs. Skin inflammation, immune cell populations, and expression levels of immunomodulatory molecules in pups and/or human cell line were investigated by using flow cytometric, immunohistologic, and quantitative RT-PCR analyses. ω3 PUFA metabolites in breast milk and infant's serum were evaluated by lipidomics analysis using LC-MS/MS. RESULTS: We show that maternal intake of linseed oil, containing abundant ω3 α-linolenic acid, resulted in the increased levels of ω3 docosapentaenoic acid (DPA) and its 14-lipoxygenation products in the breast milk of mouse dams; these metabolites increased the expression of TNF-related apoptosis-inducing ligand (TRAIL) on plasmacytoid dendritic cells (pDCs) in their pups and thus inhibited infant CHS. Indeed, the administration of DPA-derived 14-lipoxygenation products to mouse pups ameliorated their DNFB CHS. CONCLUSION: These findings suggest that an inhibitory mechanism in infant skin allergy is induced through maternal metabolism of dietary ω3 PUFAs in mice.

[Dermatitis in early infancy as a risk factor for sensitization and allergic diseases during the first year of life].

BACKGROUND: A recent study hypothesized that a skin-mediated immune response leads to atopic sensitization. However, prospective studies investigating sensitization during infancy are limited. METHODS: This cohort study included unselected infants born at NTT Medical Center Tokyo between March 2008 and February 2009. At age 3, 6, 9, and 12 months, they underwent physical examinations and a skin prick test (SPT). Associations of predictor variables with sensitization, atopic dermatitis (AD), and food allergy (FA) at ≤1 year were analyzed. RESULTS: Of 317 infants, the SPT was positive in 25 (8%) at 3 months and 133 (42%) at least once. Of the SPT-positive infants at 3 months, 19 (76%) had atopic diseases at ≤1 year (OR, 13.9; 95% 95%CI, 5.3-36.6). The presence of dermatitis at ≤3 months was significantly associated with sensitization (aOR, 3.0; 95%CI, 1.8-5.0), AD (aOR, 13.0; 95%CI, 4.5-37.3), and FA (aOR, 28.4; 95%CI, 3.3-240.6) by the age of 1 year. Point prevalence of sensitization paralleled the incidence of dermatitis. Almost all FA infants had experienced dermatitis at ≤3 months. In infants with dermatitis at ≤3 months, breast-feeding was significantly associated with sensitization (OR, 2.5; p=0.005) and FA (OR, 3.0; p=0.004). Infants without eczema at ≤3 months rarely developed AD or FA. CONCLUSIONS: The presence of dermatitis in the first few months after birth is a strong risk factor for atopic sensitization and FA during the first year of life.

Cadmium, lead, and selenium in cord blood and thyroid hormone status of newborns.

Cadmium (Cd), lead (Pb), and selenium (Se) concentrations in cord whole blood, sampled from 24 women at the time of delivery in a hospital in Tokyo in 2005, were determined by inductively coupled plasma mass spectrometry with a reaction cell. Signal enhancement caused by nonspectroscopic interference for Se was evident and the standard addition technique was essential for correcting the interference. Median concentration in cord bloods was 0.20 ng/g, 6.7 ng/g (0.67 microg/dL), and 191 ng/g for Cd, Pb and Se, respectively. Lead concentration was lower, whereas Se concentration was higher, than those reported in other countries. The trace element concentration was related to the levels of thyroid stimulating hormone (TSH) and free thyroxin (fT4) in the neonatal blood sampled at 4-6 days postpartum. A significantly negative correlation was observed between Cd concentrations in cord blood and TSH concentration in neonatal blood. The result indicated the possible effect of in utero Cd exposure on thyroid hormone status of newborns and that Cd exposure level should be assessed as a covariate in the survey on the relationship between in utero chemicals (e.g., PCBs) exposure and thyroid hormone status.

Thyroid hormone status of newborns in relation to in utero exposure to PCBs and hydroxylated PCB metabolites.

The associations between in utero exposure to polychlorinated biphenyls (PCBs) or hydroxylated PCB metabolites (OH-PCBs), and free thyroxin (fT4) or thyroid-stimulating hormone (TSH) status in the newborn were investigated as a pilot study of a large-scale epidemiologic study on in utero PCB or OH-PCB exposure and thyroid function of the newborns. Umbilical cord tissue was used as the media for the biological monitoring of PCBs/OH-PCBs exposure in utero. For the measurement of fT4 and TSH, a heel-prick blood sample spotted on filter paper, which is called Guthrie card, is collected from each neonate at day 4-6 postpartum for this study when the mass screening sampling was performed. We showed that the concentration of total OH-PCBs and one of the OH-PCB congeners (OH-PCB 187) was related significantly to higher fT4 level of newborns. On the other hand, the concentration of total PCBs and PCB congeners (PCB 118, 138, 153, and 180) showed no relationship with fT4 and TSH level of the newborns. The results obtained in this pilot study indicated the possibility that in utero OH-PCBs exposure affects thyroid hormone status of newborns.

Development of a support tool for multi-agent based biological modeling.

In late years physiomic modeling of biological organisms are performed flourishingly. However enormous labor is required for performing such a large-scale and complicated biological model development. We were aimed at developing a software tool which could reduce a burden of the model developers who try to build such a model. At first we defined the data structure that could describe structure and functions of modules consisting of biological organisms. Then we designed the base classes which expressed the data structure. A whole model would be realized by connecting a number of modules that realize the functioning of the base classes. By applying our tool to concrete model developments for a cardiac cell and a single ionic channel, we examined utility and effectiveness of the tool for modeling on a multi-scale.

Efficacy and safety of immunization for pre- and post- liver transplant children.

BACKGROUND: Infection is a serious complication after liver transplantation. Immunization is one means of controlling infections. The objective of this study was to investigate the efficacy and safety of simultaneous administration of several vaccines before transplantation and the efficacy and safety of administration under immunosuppressive conditions after transplantation. METHODS: Fifty-eight patients who underwent living-related liver transplantation between April 1994 and March 2000 were included in this study. Simultaneous administration of a maximum of six vaccines was performed in a short period of time before transplantation. We also readministered vaccines to 15 patients with waning antibody titers after transplantation from June 1999. We investigated whether patients could seroconvert for measles, rubella, mumps, and varicella after immunization and how long antibody titers could be retained by measuring them several times throughout the period before and after transplantation. We also examined side effects caused by immunization. RESULTS: The rates of seroconversion against measles, rubella, mumps, and varicella after the pretransplantation vaccination were 82%, 100%, 90%, and 95%, respectively. The rates of reseroconversion against measles, rubella, mumps, and varicella after the posttransplantation revaccination were 85%, 100%, 100%, and 71%, respectively. Although antibody titers against these viruses generally waned with time, no patient exhibited any serious illness or side effects. CONCLUSION: Although 12 of 58 patients (21%) had an infection, pretransplantation immunization was effective to prevent serious illness, especially for the 6 months after transplantation. Posttransplantation live-vaccine administration under immunosuppressive conditions is effective and safe.

Kawasaki disease before kawasaki at Tokyo university hospital.

OBJECTIVE: Kawasaki disease (KD) was first reported by Tomisaku Kawasaki in 1967 in Japan. Large-scale nationwide epidemiologic surveys have been conducted continuously by the Japan Kawasaki Disease Research Committee; however, there were very few reports of KD before 1967. This study was performed to clarify when KD appeared in Japan. DESIGN: We investigated the medical charts of patients who had been hospitalized at Tokyo University Hospital between 1940 and 1965. RESULTS: We identified 10 patients whose clinical signs fulfilled the criteria for KD. The ages of the patients ranged from 8 months to 5 years, and their final diagnoses were Stevens-Johnson syndrome, allergic toxic erythema, Izumi fever, scarlet fever, and cervical lymphadenitis. These 10 patients presented between 1950 and 1964, and no confirmed cases were seen between 1940 and 1949. CONCLUSIONS: Our findings suggested that KD patients were rare before 1950 in Japan.

Novel NUP98-HOXC11 fusion gene resulted from a chromosomal break within exon 1 of HOXC11 in acute myeloid leukemia with t(11;12)(p15;q13).

The NUP98 gene has been reported to be fused to 11 partner genes in hematological malignancies with 11p15 translocations. Among NUP98 fusion partner genes, HOXA and HOXD clusters have been reported thus far; however, no HOXC or HOXB clusters have been reported. We identified a novel NUP98-HOXC11 fusion gene in a pediatric patient with de novo acute myeloid leukemia having t(11;12)(p15;q13). The breakpoint of NUP98 was located within a LINE repetitive sequence (HAL1) in intron 12, and the breakpoint of HOXC11 was located within exon 1, resulting in a NUP98-HOXC11 in-frame fusion transcript containing exon 12 of NUP98 fused to a part of exon 1 of HOXC11 with an 8-bp insertion derived from the intron sequence just 5' of the breakpoint of NUP98. The NUP98-HOXC11 fusion protein consists of the NH2-terminal phenylalanine-glycine repeat motif of NUP98 and the COOH-terminal homeodomain of HOXC11. Although the frequency of HOXC11 expression was not high in leukemia cell lines, its expression was significantly more frequent in myeloid than lymphoid leukemia cell lines. These data suggest that the NUP98-HOXC11 fusion protein plays a role in the pathogenesis of myeloid malignancies.

The HOXD11 gene is fused to the NUP98 gene in acute myeloid leukemia with t(2;11)(q31;p15).

The nucleoporin gene, NUP98, has been reported to be fused to seven partner genes in hematological malignancies with 11p15 translocations. We report here a novel NUP98 partner gene, HOXD11, not HOXD13, in a pediatric patient with de novo AML having t(2;11)(q31;p15), using a cDNA panhandle PCR. The HOXD11 gene is one of the HOXD cluster genes and contains 2 exons, encoding a protein of 338 amino acids with a homeodomain. Reverse transcription (RT)-PCR analysis showed that two alternatively spliced 5'-NUP98 transcripts were fused in frame to the HOXD11 gene. Both proteins consist of an NH(2)-terminal phenylalanine-glycine repeat motif of NUP98 and COOH-terminal homeodomain of HOXD11. RT-PCR analysis in various leukemic cell lines showed that expression of the HOXD11 gene was significantly more frequent in BCR-ABL-positive than in BCR-ABL-negative leukemic cell lines (P = 0.028). Our results revealed that t(2;11)(q31;p15) was not a single chromosomal abnormality and that the NUP98-HOXD fusion genes encode similar fusion proteins, which suggests that the NUP98-HOXD11 as well as NUP98-HOXD13 fusion protein play a role in leukemogenesis through similar mechanisms.