IntroductionMast cells are the major effector cell type in immunoglobulin E (IgE)-mediated immediate hypersensitivity, chronic allergic diseases, and the defense against certain parasites and bacteria. Traditionally, it is thought that mast cells bound to antigen-specific IgE via the high-affinity receptor (Fc⑀RI) encounter multivalent antigen (the stimulation mode hereafter termed IgEϩAg), and then IgE-bound receptors are aggregated, leading to cellular activation. 1 Activated mast cells secrete preformed and newly synthesized proinflammatory mediators, such as histamine, proteases, lipids, cytokines, and chemokines.The mouse Fc⑀RI consists of an IgE-binding ␣ subunit, a ␤ subunit, and 2 molecules of signal-generating ␥ subunit. 2 Fc⑀RI aggregation leads to phosphorylation of the immunoreceptor tyrosine-based activation motifs (ITAMs) of the ␤ and ␥ subunits by Lyn, and recruitment of Syk to the tyrosine-phosphorylated ITAMs of the ␥ subunit results in the activation of this proteintyrosine kinase (PTK). 3 Activated Lyn and Syk as well as Fyn eventually lead to the activation of multiple signaling pathways, including phosphatidylinositol 3-kinase (PI3K), phospholipase C-␥/Ca 2ϩ /protein kinase C (PKC), and mitogen-activated protein (MAP) kinases. 4 Cell-extracellular matrix interactions mediated by integrins play a critical role in multiple cellular functions including cell adhesion and migration. Activation of mast cells by Fc⑀RI aggregation and stem cell factor (SCF) induces adhesion to fibronectin (FN) 5 predominantly via integrin ␣5␤1. 6-8 Upon Fc⑀RI aggregation and SCF stimulation, FN-adherent cells exhibit stronger effector functions such as histamine release and cytokine production than nonadherent cells. 7 We and others recently demonstrated that monomeric IgE can promote mast cell survival. 9,10 This observation, together with earlier studies showing that IgE in the absence of antigen can increase the surface expression of Fc⑀RI, [11][12][13] has transformed the traditional view of IgE-mast cell binding as a "sensitization" step prior to receptor aggregation with antigen or other crosslinking reagents into a new one that monomeric IgE can induce survival and "activation" of mast cells. 14 We also found that IgE molecules display heterogeneity in that different IgE molecules induce varied levels of activation; at one extreme end of the spectrum, some IgE molecules, termed highly cytokinergic (HC) IgEs, induce the production and secretion of various cytokines and other activation events including degranulation, whereas other IgE molecules, termed poorly cytokinergic (PC), do so very inefficiently. 15 Mast cells accumulate at local inflammatory mucosal tissues, as seen in allergic rhinitis and asthma. Interestingly, class switch recombination and somatic hypermutation of the immunoglobulin gene and eventually IgE synthesis and secretion occur at such inflammatory mucosae. [16][17][18][19][20][21] In an allergic individual, local IgE production persists for a long period in the absence of allergen. 20 A va...

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Background: Dystrophin Dp71 is one of the isoforms produced by the DMD gene which is mutated in patients with Duchenne muscular dystrophy (DMD). Although Dp71 is expressed ubiquitously, it has not been detected in normal skeletal muscle. This study was performed to assess the expression of Dp71 in human skeletal muscle. Methods: Human skeletal muscle RNA and tissues were obtained commercially. Mouse skeletal muscle was obtained from normal and DMDmdx mice. Dp71 mRNA and protein were determined by reverse-transcription PCR and an automated capillary Western assay system, the Simple Western, respectively. Dp71 was over-expressed or suppressed using a plasmid expressing Dp71 or antisense oligonucleotide, respectively. Results: Full-length Dp71 cDNA was PCR amplified as a single product from human skeletal muscle RNA. A ca. 70 kDa protein peak detected by the Simple Western was determined as Dp71 by over-expressing Dp71 in HEK293 cells, or suppressing Dp71 expression with antisense oligonucleotide in rhabdomyosarcoma cells. The Simple Western assay detected Dp71 in the skeletal muscles of both normal and DMD mice. In human skeletal muscle, Dp71 was also detected. The ratio of Dp71 to vinculin of human skeletal muscle samples varied widely, indicating various levels of Dp71 expression. Conclusions: Dp71 protein was detected in human skeletal muscle using a highly sensitive capillary Western blotting system.

A Japanese woman aged in her late 30s with severe insulin resistance and bodily features including a triangular face, prominent forehead, small chin, large and low‐set ears, and ocular depression was investigated. A similar phenotype was not observed in other family members with the exception of her son, suggesting that the condition was caused by a de novo mutation that was transmitted from mother to son. Exome analysis showed the presence in the proband and her son of a c.1945C>T mutation in PIK3R1, a common mutation associated with SHORT (short stature, hyperextensibility of joints and/or inguinal hernia, ocular depression, Rieger anomaly, and teething delay) syndrome. Administration of a sodium–glucose cotransporter 2 inhibitor lowered the proband's hemoglobin A1c level and allowed a reduction in her insulin dose without treatment‐related adverse events including ketoacidosis, exaggerated loss of body mass or hypoglycemia. Sodium–glucose cotransporter 2 inhibitors might thus offer an additional option for the treatment of genetic syndromes of severe insulin resistance.

We have identified two central neurocytomas which contained cells co-expressing glial fibrillary acidic protein and synaptophysin defined by double-label immunostaining. Dual-positive cells were mostly polygonal in shape and with a morphological appearance similar to that of reactive astrocytes. This distinct morphology could be used to distinguish cells expressing glial fibrillary acidic protein from cells with round and clear cytoplasm which did not express glial fibrillary acidic protein and which composed the majority of the tumor. Samples containing polygonal cells were selected for electron microscopy from toluidine blue-stained semithin sections. Ultrastructural findings were similar in both neurocytomas, with both being composed predominantly of round cells with clear cytoplasm corresponding to the clear cells identified by light microscopy. Dense-core vesicles and clear vesicles were frequently observed in the cell processes. Apart from these clear cells, polygonal cells with electron-dense cytoplasm were noted. Paralleling the result of double immunostaining, these polygonal cells contained both dense-core vesicles and intermediate, presumably glial filaments. Microtubules and lipofuscin granules were also observed. These results suggest that cells expressing glial fibrillary acidic protein in central neurocytoma include tumor cells with both neuronal and glial characteristics.

In contrast to the inner structure, three-dimensional structure of psammona bodies in meningiomas is not well defined. This study examined three cultured meningiomas, in which surface observation of psammoma bodies might be easier than in the tumor tissues since influence of interposing connective tissue is minimized in tissue culture. Early culture revealed that psammoma bodies with frank calcification were suspended in the tissue culture medium, and so were they collected, centrifuged, and then processed for electron microscopy. Ultrastructurally, psammoma bodies were mostly spherical in shape and composed of a core of dense calcification and surrounding collagen fiber bundles. Apart from psammoma bodies, round bodies with concentric lamination like a transversely cut onion were frequently noted by light microscopy. These bodies were composed mainly of tangles of collagen fibers emerged from surrounding tumor cell processes. The results suggest that psammoma bodies in meningiomas arise in part from meningothelial whorls due to collagen production by tumor cells followed by obliteration and disappearance of tumor cell processes, although some of the alternative pathways for psammoma body formation proposed by other investigators cannot be ruled out by this study.