Cbl-b DEFICIENCY AND MACROPHAGE ACTIVATION

We previously reported the potential involvement of casitas B-cell lymphoma-b (Cbl-b) in aging-related murine insulin resistance. Because obesity also induces macrophage recruitment into adipose tissue, we elucidated here the role of Cbl-b in obesity-related insulin resistance. Cbl-b+/+ and Cbl-b-/- mice were fed a high-fat diet (HFD) and then examined for obesity-related changes in insulin signaling. The HFD caused recruitment of macrophages into adipose tissue and increased inflammatory reaction in Cbl-b-/- compared with Cbl-b+/+ mice. Peritoneal macrophages from Cbl-b-/- mice and Cbl-b–overexpressing RAW264.7 macrophages were used to examine the direct effect of saturated fatty acids (FAs) on macrophage activation. In macrophages, Cbl-b suppressed saturated FA-induced Toll-like receptor 4 (TLR4) signaling by ubiquitination and degradation of TLR4. The physiological role of Cbl-b in vivo was also examined by bone marrow transplantation and Eritoran, a TLR4 antagonist. Hematopoietic cell-specific depletion of the Cbl-b gene induced disturbed responses on insulin and glucose tolerance tests. Blockade of TLR4 signaling by Eritoran reduced fasting blood glucose and serum interleukin-6 levels in obese Cbl-b-/- mice. These results suggest that Cbl-b deficiency could exaggerate HFD-induced insulin resistance through saturated FA-mediated macrophage activation. Therefore, inhibition of TLR4 signaling is an attractive therapeutic strategy for treatment of obesity-related insulin resistance

〈Cases Reports〉Recurrent focal intestinal perforation in extremely-low-birth-weight infant

[Abstract] In recent years, the incidence of focal intestinal perforation (FIP) has been increasing, as the survival rate of extremely-low-birth-weight(ELBW) infants has been rising. We present a case of an ELBW infant who suffered three recurrences of FIP in a very short period of time. The patient was a female infant who was born at 24 weeks and 2 days of gestation, with a birth weight of 579 g. On her 22^nd day of life, abdominal X-rays revealed free air, which suggested intestinal perforation, and an intraperitoneal drainage tube was placed. Intraperitoneal lavage was performed on day 28 of life,and the drained fluid was turbid with feces, suggesting a recurrence of perforation. On day 30 of life, laparotomy revealed a perforation of approximately 1cm in diameter located at 6 cm from the ileocecum on the oral side. The X-ray taken on day 34 again revealed free air, and, through another laparotomy, a new perforation was found at about 15 cm from the stoma on the oral side. This case provides suggestions that may shed light on our approach to determine the pathogenesis of FIP, especially since no other case of FIP recurring three times has ever been reported

Data from: High cell density upregulates calcium oscillation by increasing calcium store content via basal mitogen-activated protein kinase activity

Calcium releases of non-excitable cells are generally a combination of oscillatory and non-oscillatory patterns, and factors affecting the calcium dynamics are still to be determined. Here we report the influence of cell density on calcium increase patterns of clonal cell lines. The majority of HeLa cells seeded at 1.5 x 104/cm2 showed calcium oscillations in response to histamine and ATP, whereas cells seeded at 0.5 x 104/cm2 largely showed transient and sustained calcium increases. Cell density also affected the response of HEK293 cells to ATP in a similar manner. High cell density increased the basal activity of the mitogen-activated protein (MAP) kinase and calcium store content, and both calcium oscillation and calcium store content were down-regulated by a MAP kinase inhibitor, U0126. Thus, MAP kinase-mediated regulation of calcium store likely underlie the effect of cell density on calcium oscillation. Calcium increase patterns of HeLa cells were conserved at any histamine concentrations tested, whereas the overexpression of histamine H1 receptor, which robustly increased histamine-induced inositol phospholipid hydrolysis, converted calcium oscillations to sustained calcium increases only at high histamine concentrations. Thus, the consequence of modulating inositol phospholipid metabolism was distinct from that of changing cell density, suggesting the effect of cell density is not attributed to inositol phospholipid metabolism. Collectively, our results propose that calcium increase patterns of non-excitable cells reflect calcium store, which is regulated by the basal MAP kinase activity under the influence of cell density

Laparoscopy of a splenic flexure volvulus

Splenic flexure volvulus (SFV) is a very rare condition that is unlikely to be suspected even when a patient has repeated episodes of abdominal pain and dyschezia. We describe the case of SFV diagnosed and treated laparoscopically in the non-volvulus condition. A 14-year-old boy with no medical history had severe left upper abdominal pain and dyschezia for approximately 1 year. Although contrast enema examination revealed no characteristic findings of volvulus, such as a bird-beak sign, a redundant part of the colon was found to be the site of abdominal pain. We suspected that this part of the colon was the cause of the left upper abdominal pain and performed laparoscopic exploration. The colon at the splenic flexure formed a long loop and was predisposed to twisting; therefore, we performed resection and functional anastomosis of this redundant colon. The postoperative course was uneventful, and the left upper abdominal pain and dyschezia did not recur. Laparoscopic exploration can play a role in patients who are suspected to have recurrent colonic volvulus with radiographic evidence of a redundant portion of the colon, as indicated in our case. Keywords: Splenic flexure volvulus, Child, Laparoscop

High Cell Density Upregulates Calcium Oscillation by Increasing Calcium Store Content via Basal Mitogen-Activated Protein Kinase Activity.

Calcium releases of non-excitable cells are generally a combination of oscillatory and non-oscillatory patterns, and factors affecting the calcium dynamics are still to be determined. Here we report the influence of cell density on calcium increase patterns of clonal cell lines. The majority of HeLa cells seeded at 1.5 x 104/cm2 showed calcium oscillations in response to histamine and ATP, whereas cells seeded at 0.5 x 104/cm2 largely showed transient and sustained calcium increases. Cell density also affected the response of HEK293 cells to ATP in a similar manner. High cell density increased the basal activity of the mitogen-activated protein (MAP) kinase and calcium store content, and both calcium oscillation and calcium store content were down-regulated by a MAP kinase inhibitor, U0126. Thus, MAP kinase-mediated regulation of calcium store likely underlie the effect of cell density on calcium oscillation. Calcium increase patterns of HeLa cells were conserved at any histamine concentrations tested, whereas the overexpression of histamine H1 receptor, which robustly increased histamine-induced inositol phospholipid hydrolysis, converted calcium oscillations to sustained calcium increases only at high histamine concentrations. Thus, the consequence of modulating inositol phospholipid metabolism was distinct from that of changing cell density, suggesting the effect of cell density is not attributed to inositol phospholipid metabolism. Collectively, our results propose that calcium increase patterns of non-excitable cells reflect calcium store, which is regulated by the basal MAP kinase activity under the influence of cell density