Essential role of Src-family protein tyrosine kinases in NF-kappaB activation during B cell development

The nature of signals that govern the development of immunoglobulin heavy chain-dependent B cells is largely unknown. Using mice deficient for the B cell-expressed Src-family protein tyrosine kinases (SFKs) Blk, Fyn and Lyn, we show an essential role of these kinases in pre-B cell receptor (pre-BCR)- mediated NF-kappaB activation and B cell development. This signaling defect is SFK specific, as a deficiency in Syk, which controls pre-B cell development, does not affect NF-kappaB induction. Impaired NF-kappaB induction was overcome by the activation of protein kinase C (PKC)-lambda, thus suggesting the involvement of PKC-lambda in pre-BCR-mediated SFK-dependent activation of NF-kappaB. Our data show the existence of a functionally distinct SFK signaling module responsible for pre-BCR-mediated NF-kappaB activation and B cell development.     

Two Cases of Peritoneal Serous Papillary Adenocarcinoma

Two cases of peritoneal papillary carcinoma are reported. The patient in the first case was a 71-year-old woman with symptoms of obstructive ileus. Laparotomy revealed a tumor in the omentum involving the transverse colon, and several small tumors in the peritoneum and pelvic wall. However, no primary site of the tumor was seen in the ovary, pancreas, or gastrointestinal tract. The patient in the second case was a 44-year-old woman with carcinomatous peritonitis. Postmortem examination revealed multiple tumors in the peritoneum, omentum, and pelvic wall. Tumors were also found in the cortex with mild invasion of the underlying parenchyma of the bilateral ovaries, although these lesions were thought to be metastatic. The histologic features of the tumor in both cases were those of tubulopapillary adenocarcinoma containing scattered psammoma bodies. The cells were positive with the PAS D technique, but negative with alcian blue staining. In both cases, the serum levels of CA-125 were considerably elevated, and the tumor cells showed positivity for CA-125, S 100 protein, cytokeratin and EMA by im-munohistochemistry. The present cases were most likely peritoneal serous papillary adenocarcinoma derived from extraovarian peritoneal mesothelium with miillerian potential, being different from the usual type of diffuse malignant mesothelioma. Acta Pathol Jpn 41: 642-646, 1991.     

A new liver metastatic and peritoneal dissemination model established from the same human pancreatic cancer cell line: analysis using cDNA macroarray

To elucidate the mechanisms of metastasis, we established two sublines HPC-1H5 with a highly liver metastatic cell line and HPC-1P5a with a highly peritoneal disseminating cell line, which were sequentially selected from the parental pancreatic cancer cell line HPC-1. Using these three cell lines, we investigated several biological properties and mRNA levels of differentially-expressed genes involved in cancer metastasis by cDNA macroarray. Microscopic findings for the three cell lines were the same. The tumorigenicity, in vitro growth ability, motile activity, adhesive activity and the production of IL-8 of metastatic sublines were higher than those of parental HPC-1 cells. Particularly, HPC-1H5 cells showed clearly higher levels of IL-8 expression and tumors of HPC-1H5 cells grew faster and bigger than those of HPC-1P5a cells. In cDNA macroarray analysis of HPC-1H5 cells, 22 genes were up-regulated and 44 genes were down-regulated compared with parental HPC-1 cells. In HPC-1P5a cells, 9 genes were up-regulated and 28 genes were down-regulated compared with parental HPC-1 cells. This study provides a demonstration of global gene expression analysis of pancreatic cancer cells with liver metastasis and peritoneal dissemination. Furthermore, our results provide a new insight into the study of liver metastasis and peritoneal dissemination of human pancreatic cancer. This revised version was published online in July 2006 with corrections to the Cover Date.     

Constitutive Expression of a Bacterial Pattern Recognition Receptor, CD14, in Human Salivary Glands and Secretion as a Soluble Form in Saliva

Saliva contains a number of proteins and glycoproteins that protect oral tissues, but little is known about the role of human saliva in innate immunity. Here we showed that human major salivary gland cells constitutively expressed a bacterial pattern recognition receptor, CD14, by immunohistochemistry. Human salivary gland cells in culture express CD14 mRNA and a 55-kDa CD14 protein in, but not on the cells, and secrete a soluble form with the same molecular mass. Human whole saliva contains a 55-kDa CD14, and the concentration of parotid saliva was 10-fold higher than whole saliva, which is comparable to that of serum CD14. Levels of CD14 in unstimulated whole and parotid saliva were unchanged before and after a meal and between unstimulated and stimulated saliva, indicating that saliva CD14 is constitutively secreted into the oral cavity. In contrast, lipopolysaccharide (LPS)-binding protein was below the detectable level. The saliva CD14 is functionally active in that it mediated the activation of CD14-lacking intestinal epithelial cells by LPS in a Toll-like receptor 4-dependent manner. These results suggested that saliva CD14 is important for the maintenance of oral health and possibly intestinal homeostasis.     

Endolymphatic perfusion with EGTA-acetoxymethyl ester inhibits asphyxia- and furosemide-induced decrease in endocochlear potential in guinea pigs

We examined the effect of the Ca(2+) concentration in the endolymph ([Ca](e)) or in the endolymphatic surface cells ([Ca](i)) on the endocochlear potential (EP) by using an endolymphatic or perilymphatic perfusion technique, respectively. (i) A large increase in [Ca](e) up to approximately 10(-3) M with a fall in the EP was induced by transient asphyxia ( approximately 2 min) or by the intravenous administration of furosemide (60 mg/kg), and a significant correlation was obtained between the EP and p[Ca](e) (= -log [Ca](e), r = 0.998). (ii) Perfusion of the endolymph with 10 mM EGTA for 5 min neither produced any significant change in the EP nor altered the asphyxia-induced change in EP (DeltaEP(asp)), suggesting that neither [Ca](e) nor the Ca(2+) concentration gradient across the stria vascularis contributed directly to the generation of the EP in the condition of low [Ca](e). In contrast, endolymphatic perfusion with high Ca(2+) (more than 10 mM) produced a decrease in EP and a significant correlation was obtained between the EP and the Ca(2+) concentration of perfusion solution (r = 0.982), suggesting that Ca(2+) permeability may exist across the stria vascularis. (iii) The administration of a Ca(2+) chelator, EGTA-acetoxymethyl ester (AM, 0.3 mM), to the endolymph, which produced a gradual increase in EP, suppressed significantly, by 60-80%, DeltaEP(asp) or furosemide-induced changes in EP. In contrast, perilymphatic administration of 0.5 mM EGTA-AM caused no significant suppression of the DeltaEP(asp). These findings suggest that [Ca](i) plays an important role in generating/maintaining a large positive EP.     

Intravenous ulinastatin therapy for Stevens-Johnson syndrome and toxic epidermal necrolysis in pediatric patients. Three case reports

BACKGROUND: More effective therapy is needed for the treatment of Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN). The clinical efficacy of intravenous ulinastatin therapy was investigated in 3 Japanese pediatric patients with SJS or TEN. METHODS: Ulinastatin was given to 1 pediatric SJS patient and 2 pediatric TEN patients within 7 days (patient 1; SJS), 6 days (patient 2; TEN), or 4 days (patient 3; TEN) after the onset of the skin rash. Ulinastatin was administered intravenously at a dose of 7,500 U/kg/day (maximum dose: 300,000 U/day). No corticosteroids were given. After the skin lesions resolved, the ulinastatin dose was reduced to between 2,500 and 5,000 U/kg/day as maintenance therapy and then the drug was withdrawn. RESULTS: Erythema, fatigue, and fever improved within 12-36 h of starting the ulinastatin infusion, and the skin lesions resolved completely after 4-7 days of ulinastatin therapy. None of the patients had cutaneous or ocular sequelae. No patient developed secondary infection or relapse and ulinastatin therapy caused no side effects. CONCLUSION: Ulinastatin dramatically reduced the febrile period with no adverse effects and was very safe in this study. Ulinastatin appears to be a useful and effective therapy for controlling SJS and TEN without sequelae.     

HLA class I distribution in Japanese patients with schizophrenia

Several Caucasian studies and one Japanese study have observed associations between human leukocyte antigen (HLA) class I specificities, including A24 (9) and A26 (10) and schizophrenia. Most of those studies were conducted in 1970s and early 1980s, when the typing technique of HLA was not adequately reliable. Also, an operational diagnostic system was not employed in many of the studies. The present study investigated frequencies of HLA-A specificities in schizophrenia patients (ICD-10 and DSM-III-R, n=98) and sex-matched healthy controls (n=392) from population in the southwestern part of Japan. HLA-B and -C specificities were studied in addition. Frequencies of subjects possessing A24 and A26 were not different between the patients and controls (54% and 24% in the patients and 62% and 24% in the controls, respectively). No significant difference was found in frequencies of other class I (A, B, and C) specificities between the patients and the controls. Thus, the present study provided no evidence for an association between the HLA class I specificities, including A24, A26, and others, and schizophrenia in the Japanese population.     

Follow-up study in a patient with Setleis syndrome

We report on an 8-year-old Japanese boy with Setleis syndrome. The patient had a very characteristic “coarse” facial appearance, bitemporal “forceps marks,” skin aplasia, sparse hair, and skin hypo- and hy-perpigmentation. He also had previously undescribed manifestations, including an aberrant hair pattern of the forehead, linear skin lesions on the forehead, short palpebral fissures, a small skin tag on the right cheek, cone-shaped teeth, and pectus carinatum. Dermatoglyphic studies documented aberrant distal palmar creases (simian crease variant), 8 arches, and reduced total finger ridge count. When serial photographs were reviewed, his facial characteristics became more obvious with increasing age. © 1995 Wiley-Liss, Inc.     

Clinical features of oral allergy syndrome to plant foods allergens in Kanto regions]

BACKGROUND: Recently, it is recognized that the patients of oral allergy syndrome (OAS) to fruits are increasing. However, there are little knowledges of the background, character, and seriousness about these patients in Kanto regions. OBJECTIVE: We aimed to investigate the clinical features of OAS patients to plant origin foods in Kanto regions. METHODS: The patient, who visited Sagamihara National Hospital from 2000 to 2005 and developed some allergic symptoms to plant origin foods, were studied by a questionary survey. RESULTS: As for the 42 subjects, average age are 36 years old, male:female=8:34, merger of other allergic disease is 35 allergic rhinitis of 42 subjects (83%), 34 of asthma (81%), 14 of atopic dermatitis (33%). The causes of OAS symptoms are 32 rose-family fruits, 34 non-rose family fruits, 14 vegetables, 11 nuts, 2 grains subjects. As for the symptom, only in the oral and pharynx symptoms are found in 12, the systemic symptoms is 29, anaphylaxis is 11 subjects. Allergic rhinitis preceded on the 90% subjects with pollinosis, very high rate. On the other hand, the 20% of all subjects have no symptoms of allergic rhinitis. CONCLUSION: A nasal catarrh symptoms went ahead in most of the OAS subjects in Kanto regions. In addition, considering from some patients have no black alder pollinosis and/or are allergic to many non-rose-family fruits at high frequency, there might be a broad cross-reactivity between many pollens other than alder and plant origin foods.     

Processing and major histocompatibility complex class II presentation of Legionella pneumophila antigens by infected macrophages

To better understand interactions between the intracellular pathogen Legionella pneumophila and macrophages (Mphis), host and bacterial determinants important for presentation of antigens on major histocompatibility complex class II molecules (MHC-II) were investigated. It was determined that immune CD4 T-cell responses to murine bone marrow-derived Mphis (BMphis) infected with wild-type L. pneumophila were higher than the responses to avirulent dotA mutant bacteria. Although this enhanced response by immune T cells required modulation of vacuole transport mediated by the Dot/Icm system, it did not require intracellular replication of L. pneumophila. Intracellular cytokine staining identified a population of immune CD4 T cells that produced gamma interferon upon incubation with BMphis infected with wild-type L. pneumophila that did not respond to Mphi infection with dotA mutant bacteria. Endocytic processing was required for presentation of L. pneumophila antigens on MHC-II as determined by a defect in CD4 T-cell responses when the pH of BMphi endosomes was neutralized with chloroquine. Investigation of MHC-II presentation of antigens by BMphis infected with L. pneumophila icmR, icmW, and icmS mutants indicated that these mutants have an intermediate presentation phenotype relative to those of wild-type and dotA mutant bacteria. In addition, it was found that antigens from dot and icm mutants are presented earlier than antigens from wild-type L. pneumophila. Although immune CD4 T-cell responses to proteins secreted by the L. pneumophila Lsp system were not detected, it was found that the Lsp system is important for priming L. pneumophila-specific T cells in vivo. These data indicate that optimal antigen processing and MHC-II presentation to immune CD4 T cells involves synthesis of L. pneumophila proteins in an endoplasmic reticulum-derived compartment followed by transport to lysosomes.