Serum Levels of Free Insulin-Like Growth Factor (IGF)-I in Normal Children

Serum levels of free insulin-like growth factor (IGF)-I were measured by immunoradiometric assay (IRMA) in fasting sera of 137 normal boys and 120 normal girls aged from 8 to 15 yr to study relationships between free IGF-I levels and ages, total IGF-I, IGF binding protein (IGFBP)-1, IGFBP-3, and acid-labile subunit (ALS) levels. In both sexes, serum free IGF-I levels and the ratios of free IGF-I to total IGF-I were significantly higher in the pubertal age groups than in the prepubertal age groups. Serum levels of free IGF-I showed a significant positive correlation with those of total IGF-I, IGFBP-3 and ALS, while they showed a significant negative correlation with those of IGFBP-1. These observations suggest that increase in serum free IGF-I levels during puberty is caused by a dramatic increase in total IGF-I, rather than IGFBP-3, and a decrease in IGFBP-1. Also, high free IGF-I levels may play an important role in pubertal growth spurt.     

Encephalomyocarditis (EMC) virus-induced sialodacryoadenitis in mice

The mode of occurrence of the D variant of encephalomyocarditis (EMC-D) virus-induced acute sialodacryoadenitis was investigated using three strains of mice differing in their sensitivity to EMC-D virus-induced diabetes (C57BL/6: resistant; BALB/c: moderately sensitive; DBA/2: highly sensitive). Mice were intranasally inoculated with high (10(5) PFU/mouse) or low dose (10(2) PFU/mouse) of EMC-D virus. Although there were individual differences, the blood virus titer generally reached the peak earlier in the high-dose group than in the low-dose group. Signals of viral RNA and histopathological changes were seen in parotid glands and intraorbital and extraorbital lachrymal glands. In these glands, signals of viral RNA and histopathological changes were detected only in acinar cells and initial lesions were characterized by pyknosis of acinar cells. Coagulative necrosis with interstitial inflammatory cell infiltration developed later in parotid glands of BALB/c mice of the high-dose group and in intraorbital and extraorbital lachrymal glands of all groups except for C57BL/6 mice of the low-dose group. Such changes were not observed in epithelial cells of the ductal system. The present results indicate that EMC-D virus shows clear tissue and cell tropism within the salivary and lachrymal glands, probably due to the distribution of receptors for EMC virus.     

Airway hyper-reactivity mediated by B-1 cell immunoglobulin M antibody generating complement C5a at 1 day post-immunization in a murine hapten model of non-atopic asthma

Contact skin immunization of mice with reactive hapten antigen and subsequent airway challenge with the same hapten induces immediate airflow obstruction and subsequent airway hyper‐reactivity (AHR) to methacholine challenge, which is dependent on B cells but not on T cells. This responsiveness to airway challenge with antigen is elicited as early as 1 day postimmunization and can be adoptively transferred to naïve recipients via 1‐day immune cells. Responses are absent in 1‐day immune B‐cell‐deficient JH^?/? mice and B‐1 B‐cell‐deficient xid male mice, as well as in recipients of 1‐day immune cells depleted of cells with the B‐1 cell phenotype (CD19⁺ B220⁺ CD5⁺). As B‐1 cells produce immunoglobulin M (IgM), we sought and found significantly increased numbers of anti‐hapten IgM‐producing cells in the spleen and lymph nodes of 1‐day immune wild‐type mice, but not in xid mice. Then, we passively immunized naive mice with anti‐hapten IgM monoclonal antibody and, following airway hapten challenge of the recipients, we showed both immediate airflow obstruction and AHR. In addition, AHR was absent in complement C5 and C5a receptor‐deficient mice. In summary, this study of the very early elicited phase of a hapten asthma model suggests, for the first time, a role of B‐1 cells in producing IgM to activate complement to rapidly mediate asthma airway reactivity only 1 day after immunization.     

From anticipation to action, the role of dopamine in perceptual decision making: an fMRI-tyrosine depletion study

During simple sensorimotor decision making, neurons in the parietal cortex extract evidence from sensory information provided by visual areas until a decision is reached. Contextual information can bias parietal activity during the task and change the decision-making parameters. One type of contextual information is the availability of reward for correct decisions. We tested the hypothesis that the frontal lobes and basal ganglia use contextual information to bias decision making to maximize reward. Human volunteers underwent functional MRI while making decisions about the motion of dots on a computer monitor. On rewarded trials, subjects responded more slowly by increasing the threshold to decision. Rewarded trials were associated with activation in the ventral striatum and prefrontal cortex in the period preceding coherent dot motion, and the degree of activation predicted the increased decision threshold. Decreasing dopamine transmission, using a tyrosine-depleting amino acid mixture, abolished the reward-related corticostriatal activation and eliminated the correlation between striatal activity and decision threshold. These observations provide direct evidence that some reward-related functional MRI signals in the striatum are the result of dopamine neuron activity and demonstrate that mesolimbic dopamine transmission can influence perceptual and decision-making neural processes engaged to maximize reward harvest.     

Tissue-specific functions based on information content of gene ontology using cap analysis gene expression

Gene expressions differ depending on tissue types and developmental stages. Analyzing how each gene is expressed is thus important. One way of analyzing gene expression patterns is to identify tissue-specific functions. This is useful for understanding how vital activities are performed. DNA microarray has been widely used to observe gene expressions exhaustively. However, comparing the expression value of a gene to that of other genes is impossible, as the gene expression value of a condition is measured as a proportion of that for the same gene under a control condition. We therefore could not determine whether one gene is more expressed than other genes. Cap analysis gene expression (CAGE) allows high-throughput analysis of gene expressions by counting the number of cDNAs of expressed genes. CAGE enables comparison of the expression value of the gene to that of other genes in the same tissue. In this study, we propose a method for exploring tissue-specific functions using data from CAGE. To identify tissue-specificity, one of the simplest ways is to assume that the function of the most expressed gene is regarded as the most tissue-specific. However, the most expressed gene in a tissue might highly express in all tissues, as seen with housekeeping genes. Functions of such genes cannot be tissue-specific. To remove these from consideration, we propose measuring tissue specificity of functions based on information content of gene ontology terms. We applied our method to data from 16 human tissues and 22 mouse tissues. The results from liver and prostate gland indicated that well-known functions of these tissues, such as functions related to signaling and muscle in prostate gland and immune function in liver, displayed high rank.     

Negative regulation by SHPS-1 of Toll-like receptor-dependent proinflammatory cytokine production in macrophages

SHPS-1 is a transmembrane protein predominantly expressed in macrophages. The possible role of SHPS-1 in regulation of Toll-like receptor (TLR)-dependent production of proinflammatory cytokines by macrophages has remained unknown, however. We now show that expression either of a mutant version of mouse SHPS-1 (SHPS-1–4F) in which the four tyrosine phosphorylation sites in the cytoplasmic region are replaced by phenylalanine or of a chimeric protein comprising the extracellular and transmembrane regions of human CD8 fused to the cytoplasmic region of SHPS-1–4F (CD8–4F) markedly promoted the production of tumor necrosis factor-α (TNF-α) or interleukin-6 (IL-6) induced by lipopolysaccharide (LPS) or polyinosinic-polycytidylic acid [poly(I : C)] in RAW264.7 macrophages. In contrast, expression of a mutant form of SHPS-1 that lacks most of the cytoplasmic region did not promote such responses. Expression of SHPS-1–4F promoted the LPS- or poly(I : C)-induced activation of NF-κB. LPS and poly(I : C) each induced the tyrosine phosphorylation of SHPS-1 through a Src family kinase and the association of SHPS-1 with SHP-1 and SHP-2. These results suggest that LPS or poly(I : C) induces tyrosine phosphorylation of SHPS-1 and the association of SHPS-1 with SHP-1 and SHP-2 in a manner dependent on a Src family kinase. SHPS-1 then negatively regulates TLR4- or TLR3-dependent cytokine production through inhibition of NF-κB-dependent signaling.     

Characterization of pancreatic islet cell tumors and renal tumors induced by a combined treatment of streptozotocin and nicotinamide in male SD rats

We herein investigated the histopathological features, including proliferative activity and immunoexpression, of pancreatic islet cell tumors (ICTs) in male SD rats induced by streptozotocin (STZ) and nicotinamide (NA), and discussed their relevance to biological behaviors and prognoses. A total of 70 and 43% of rats developed ICTs 37–45 weeks after the treatment with STZ (50 or 75 mg/kg, i.v.) and NA (350 mg/kg, twice, p.o.), respectively. Among the islet tumors observed in the STZ/NA-treated groups, 75% were adenomas, while 25% were carcinomas. Most STZ/NA-induced carcinomas were characterized by well-differentiated tumor cells with/without local invasion into the surrounding tissues, and weak proliferative activity. No outcome such as distance metastasis and death was noted. All of the ICTs strongly expressed insulin, part of which had hormone productivity; however there were no hypoglycemia-related clinical signs such as convulsion in these rats 36 weeks after the treatment. These results suggested that rat ICTs induced STZ/NA have small impact on biological activity or prognosis. STZ/NA treatment significantly increased of focal proliferative lesions in the kidney, liver and adrenal glands other than pancreatic islets. Of the STZ/NA-induced kidney tumors, more than 60% were renal cell adenomas, and many of them were basophilic type. The incidence of eosinophilic or clear cell type of tumors was less than 10%, respectively. Immunohistochemical analyses revealed that many of the STZ/NA-induced basophilic type of renal tumors were derived from proximal tubules, whereas the clear cell and eosinophilic types were derived from collecting tubules.     

RECTAL GRANULAR‐CELL TUMOR DIFFICULT TO DISTINGUISH FROM CARCINOID TUMOR

A 60‐year‐old man had a positive fecal occult‐blood test on a medical check‐up. Colonoscopy revealed a yellowish‐white submucosal tumor 8 mm in diameter in the rectum. Endoscopic ultrasonography showed a well‐demarcated mass with a homogeneous, low‐level, internal echo in the second to third layers of the rectal wall. A carcinoid tumor was suspected, and the mass was resected endoscopically. Histopathological examination revealed a granular‐cell tumor. Gastrointestinal granular‐cell tumors rarely arise in the rectum, and the preoperative diagnosis of small lesions is often difficult. In our patient, granular‐cell tumor was difficult to differentially diagnose because the endoscopic and endoscopic ultrasonographic findings closely resembled those of carcinoid tumor. Interestingly, the endoscopic characteristics of the rectal granular‐cell tumor in our patient resembled those of a carcinoid tumor.     

Relationship of Th1/Th2 cell balance with the immune response to influenza vaccine during pregnancy

To determine the optimal timing for influenza vaccination in pregnant women, we measured alterations in the types 1 and 2 T helper cell (Th1/Th2) balance during pregnancy, monitored specific immunity to inoculated antigens after vaccination with inactivated influenza vaccine, evaluated the relevance of the Th1/Th2 ratio and immune responses to the vaccination, monitored the maintenance of high antibody titers until delivery and measured the transplacental antibody transfer rate. No significant alterations of the Th1/Th2 balance were noted in the 65% of pregnant women among whom the Th1/Th2 ratio was lower than 9.9% in the first trimester. In those groups with a ratio higher than 10% in the first trimester, there was a tendency for the ratio to decrease as gestation advanced. The efficiency of immunization was not influenced by the Th1/Th2 status or by the stage of gestation. The antibody titer decreased steadily with time from 1 month after vaccination to the time of delivery. Conversely, the transfer rate of antibodies from maternal to fetal blood at the time of delivery increased with the duration of gestation after vaccination. Nevertheless, the antibody titers in both maternal and fetal blood were sufficient to afford protection against infection. Thus, efficient influenza vaccination can be undertaken at any stage of pregnancy. J. Med. Virol. 81:1923–1928, 2009. © 2009 Wiley‐Liss, Inc.