Redistribution of fibroblasts and macrophages as micrometastases develop into established liver metastases

Fibroblastic tissue is an important component of malignant tumors, involved in the establishment of metastatic foci from micrometastases, and thought to prevent invasion of metastatic tumor cells into surrounding tissue. However, experimental models of fibrosis during the growth of micrometastasis into established metastases were not previously available. In the present paper, we performed immunohistochemical studies on experimental hepatic metastasis with colon 38 mouse colon carcinoma cells injected into syngeneic C57BL/6 mice. Early and late stages of metastatic nodules were examined for the distribution of endothelial cells, fibroblasts, and macrophages by the use of markers of these cells. One week after intrasplenic injection of colon 38 cells, micrometastases mainly appeared in the region of sinusoids accompanied with invasion of F4/80-positive Kupffer cells. Transitional metastases can be defined based on the histological appearance and intensive infiltration of both macrophages and fibroblasts. These transitional metastases were connected by protrusions of fibroblast-rich tissues co-localized with collagen-rich matrix and CD31-positive cells. This protrusion preceded fibrosis formation characteristics to established metastases associated with angiogenesis and segregation of tumor cells from host cells. Three stages can thus be classified during the development of hepatic metastasis in this syngeneic experimental system: micrometastasis, transitional metastasis, and established metastasis. This revised version was published online in July 2006 with corrections to the Cover Date.     

Pathological examination of the placenta in small for gestational age (SGA) children with or without postnatal catch-up growth

Background/objective: Approximately 10% of small for gestational age (SGA) infants fail to catch up. The relationship between postnatal growth and placental pathology in SGA infants remains unclear. Our aim was to assess the involvement of placental pathology in postnatal growth of SGA infants.

Methods: We retrospectively evaluated placental pathology and postnatal growth in single-pregnancy infants born after 37 gestational weeks in our institution, with both birth weight and length below ?2 standard deviation scores (SDS) of the normal weight and length. “Catch-up” was defined as height reaching ?2 SDS before the second birthday. Pathology of the placenta was classified into: abnormality due to maternal factors or fatal factors, villitis of unknown etiology (VUE), other abnormalities and no abnormality.

Results: Of the 33?084 infants, 142 met our criteria and 49 of them had analyzable data. The overall catch-up rate was 84%. Catch-up growth took place in all infants with no placental abnormality and only 57% of infants with abnormality due to fatal factors. There was no significant relationship between catch-up rate and other factors.

Conclusion: Placental pathology is associated with postnatal growth in SGA children born at term. Placental abnormality due to fetal factors is related to poor catch-up rate.     

A novelde novo mutation in HPRT gene responsible for Lesch-Nyhan syndrome (HPRTosaka)

Summary A virtually complete deficiency of hypoxanthine guanine phosphoribosyltransferase (HPRT) causes Lesch-Nyhan syndrome. A novel mutation of HPRT gene in a Japanese Lesch-Nyhan family has been identified using mRNA and genomic DNA from peripheral blood cells. A single nucleotide substitution of T to C in exon 3 resulted in a mis-sensemutation, CTC (Leu) to CCC (Pro), at codon 65. Utilizing anMnlI restriction site which was lost in the mutation as an indicator,a family study showed that the mother was normal not having the mutant gene. The mutation was ade novo event that had occurred in the germ cells of the mother or in the proband during the early phase of fetal development.     

Interleukin-1 receptor antagonist attenuates airway hyperresponsiveness following exposure to ozone

The role of an interleukin (IL)-1 receptor antagonist (IL-1Ra) on the development of airway hyperresponsiveness (AHR) and airway inflammation following acute O(3) exposure in mice was investigated. Exposure of C57/BL6 mice to O(3) at a concentration of 2.0 ppm or filtered air for 3 h resulted in increases in airway responsiveness to inhaled methacholine (MCh) 8 and 16 h after the exposure, and an increase in neutrophils in the bronchoalveolar lavage (BAL) fluid. IL-1beta expression, assessed by gene microarray, was increased 2-fold 4 h after O(3) exposure, and returned to baseline levels by 24 h. Levels of IL-1beta in lung homogenates were also increased 8 h after O(3) exposure. Administration of (human) IL-1Ra before and after O(3) exposure prevented development of AHR and decreased BAL fluid neutrophilia. Increases in chemokine levels in lung homogenates, tumor necrosis factor-alpha, MIP-2, and keratinocyte chemoattractant following O(3) exposure were prevented by IL-1Ra. Inhalation of dexamethasone, an inhibitor of IL-1 production, blocked the development of AHR, BAL fluid neutrophilia, and decreased levels of IL-1 following O(3) exposure. In summary, acute exposure to O(3) induces AHR, neutrophilic inflammation, epithelial damage, and IL-1. An IL-1Ra effectively prevents the development of altered airway function, inflammation, and structural damage.     

Differentiation of mouse and human embryonic stem cells into hepatic lineages

We recently reported a novel method to induce embryonic stem (ES) cells differentiate into an endodermal fate, especially pancreatic, using a supporting cell line. Here we describe the modified culture condition with the addition and withdrawal of secreted growth factors could induce ES cells to selectively differentiate into a hepatic fate efficiently. The signaling of BMP and FGF that have been implicated in hepatic differentiation during normal embryonic development are shown to play pivotal roles in generating hepatic cells from the definitive endoderm derived from ES cells. Moreover, the expression of AFP, Albumin or a biliary molecular marker appeared sequentially thus suggested the differentiation of ES cells recapitulated normal developmental processes of liver. The ES cell-derived differentiated cells showed evidence of glycogen storage, secreted Albumin, exhibited drug metabolism activities and expressed a set of cytochrome or drug conjugate enzymes, drug transporters specifically expressed in mature hepatocytes. With the same procedure, human ES cells also gave rise to cells with mature hepatocytes' characteristics. In conclusion, this novel procedure for hepatic differentiation will be useful for elucidation of molecular mechanisms of hepatic fate decision at gut regionalization, and could represent an attractive approach for a surrogate cell source for pharmaceutical studies such as toxicology.     

Establishment and characterization of a murine model for allergic asthma using allergen-specific IgE monoclonal antibody to study pathological roles of IgE

Allergen-specific IgE has long been regarded as a major molecular component of allergic asthma. Although IgE plays a central role in the early asthmatic response, its roles in the chronic phase, such as the late asthmatic response, airway hyperresponsiveness (AHR), and airway remodeling (goblet cell hyperplasia and subepithelial fibrosis) have not yet been defined well. In this study, we investigated the hypothesis that chronic responses could be induced by IgE-dependent mechanisms. BALB/c mice passively sensitized with an ovalbumin (OVA)-specific IgE monoclonal antibody (mAb) were repeatedly challenged with intratracheal administration of OVA. The first challenge induced early phase airway narrowing without any late response, but the fourth challenge caused not only an early but also a late phase response, AHR, and goblet cell hyperplasia. Macrophages, lymphocytes and neutrophils, but not eosinophils, were significantly increased in the lung 24 h after the fourth challenge. Interestingly, levels of OVA-specific IgG1 in serum increased by multiple antigen challenges. A C3a receptor antagonist inhibited the late asthmatic response, AHR, and infiltration by neutrophils. In contrast, no late response, goblet cell hyperplasia, inflammatory cells, or production of IgG1 was observed in severe combined immunodeficient mice. On the other hand, seven challenges in BALB/c mice induced subepithelial fibrosis associated with infiltration by eosinophils. In conclusion, the allergic asthmatic responses induced by passive sensitization with IgE mAb can provide a useful model system to study the pathological roles of IgE in acute and chronic phases of allergic asthma.     

Pregnancy Outcomes in 2 Women Born with Complex Anorectal Malformations: Challenges and Considerations

BackgroundComplex anorectal malformations (ARMs) are a group of rare congenital malformations involving numerous anomalies that require reconstruction and can affect sexuality, fertility, and pregnancy outcomes. Few cases of pregnancy in complex ARM patients have been reported.CasesWe report on 2 patients with ARMs who delivered 3 term infants, all by cesarean section with successful collaboration between pediatric urologists and obstetricians. Both patients fully recovered with no long-term consequences after experiencing maternal morbidities including urinary infections, clitoral abscesses, vaginal lacerations, extensive adhesive disease, bladder injury, and maternal hemorrhage.Summary and ConclusionIn managing pregnancies and deliveries in women with complex ARMs, coordination between obstetricians, pediatric urologists, and pediatric surgeons is crucial.