Stromal tumor of the pancreas with expression of c-kit protein: report of a case

We report on a case of a stromal tumor, similar to a gastrointestinal stromal tumor, originating from the pancreas. The patient was a 54-year-old woman, who was seen at the Kofu Municipal Hospital because of an abdominal tumor. On abdominal computed tomography and splenic arteriography, the tumor was detected in the pancreatic tail. The patient underwent distal pancreatectomy with splenectomy. Macroscopically, the cut surface of the tumor showed almost completely surrounded by the normal pancreatic tissue. Microscopically, the tumor composed of spindle-shaped cells that were immunoreactive for vimentin, CD34, and c-kit protein. Therefore, the tumor was diagnosed as a stromal tumor of the pancreas. The expression of c-kit protein suggests that this pancreatic stromal tumor may originate from primitive mesenchymal cells which can be a logical candidate for the origin of gastrointestinal stromal tumors and extra-gastrointestinal stromal tumors.     

Selective cyclooxygenase-2 inhibitor prevents reduction of trabecular bone mass in collagen-induced arthritic mice in association with suppression of RANKL/OPG ratio and IL-6 mRNA expression in synovial tissues but not in bone marrow cells

We performed this study to clarify whether celecoxib, a selective cyclooxygenase-2 (COX-2) inhibitor, prevents trabecular bone mass reduction by suppressing arthritis-related increase of bone resorption, and to discriminate differences in actions on bone among celecoxib, SC-58560 (a selective COX-1 inhibitor), and indomethacin. Eight-week-old DBA/1J male mice were divided into six groups as follows. Control untreated (Normal) and collagen-induced arthritic (CIA) mice were compared with four treatment groups: celecoxib was orally administered to CIA mice at doses of 0 (Vehicle), 16 (COX2L), and 75 (COX2H) mg/kg, in addition to two groups of mice treated with SC-58560 (COX1) or indomethacin (IND). Histomorphometry showed a significant decrease in tibial trabecular bone volume in arthritic mice, which was corrected by COX2H. The increased osteoclast surface and number in the Vehicle group were suppressed by COX2L, COX2H, and IND. The decreased bone formation rate in Vehicle was elevated by COX2H without statistical significance. A high ratio of mRNA expression of receptor activator of NF-κB ligand (RANKL)/osteoprotegerin (OPG) in Vehicle synovial tissue was suppressed by COX2L and COX2H. The increased expression of interleukin (IL)-6 mRNA in Vehicle was suppressed by COX2L, COX2H, and IND, although no difference in this expression was observed in bone marrow cells among all groups. In conclusion, in CIA mice, celecoxib suppresses arthritis-related increase in bone resorption at low and high doses and prevents trabecular bone mass reduction at high doses in association with suppression of osteoclast development in bone marrow through inhibition of RANKL/OPG ratio and IL-6 mRNA expression in inflammatory synovial tissue.     

Importance of transient receptor potential vanilloid 4 (TRPV4) in epidermal barrier function in human skin keratinocytes

The state of the skin changes drastically depending on the ambient temperature. Skin epidermal keratinocytes express thermosensitive transient receptor potential vanilloid (TRPV) cation channels, TRPV3 and TRPV4. These multimodal receptors are activated by various kinds of chemical and physical stimuli, including warm temperatures (>30°C). It has been suggested that TRPV4 is involved in cell–cell junction maturation; however, the effect of temperature fluctuations on TRPV4-dependent barrier homeostasis is unclear. In the present study, we demonstrated that activation of TRPV4 was crucial for barrier formation and recovery, both of which were critical for the prevention of excess dehydration of human skin keratinocytes. TRPV4 activation by physiological skin temperature (33°C), GSK1016790A or 4α-PDD allowed influx of Ca²⁺ from extracellular spaces which promoted cell–cell junction development. These changes resulted in augmentation of intercellular barrier integrity in vitro and ex vivo. TRPV4 disruption reduced the increase in trans-epidermal resistance and increased intercellular permeation after a Ca²⁺ switch. Furthermore, barrier recovery after the disruption of the stratum corneum was accelerated by the activation of TRPV4 either by warm temperature or a chemical activator. Our results suggest that physiological skin temperatures play important roles in cell–cell junction and skin barrier homeostasis through TRPV4 activation.     

Exertional Oscillatory Ventilation During Cardiopulmonary Exercise Test in Fontan Patients with Total Cavopulmonary Connection

Exertional oscillatory ventilation (EOV) has been noted during cardiopulmonary exercise testing (CPX) in patients with heart failure. EOV is a predictor of poor prognosis in adult patients with heart failure. The objective of this study was to clarify the incidence and influence of EOV in Fontan patients. Symptom-limited CPX was performed in 36 Fontan patients at 12.3 ± 4.3 (6.5–24.4) years of age or 5.9 ± 2.0 (3.0–11.2) years after total cavopulmonary connection (TCPC). Mean age at the time of TCPC was 6.3 ± 3.3. All 36 TCPC patients were classified as New York Heart Association classification I or II. They also underwent cardiac catheterization subsequently. EOV was defined as cyclic fluctuations in minute ventilation at rest that persist during effort lasting ≥60% of the exercise duration, with an amplitude ≥15% of the average resting value. EOV was noted in 21 of 36 Fontan patients (58%) with good clinical status. Univariable analysis between Fontan patients with and those without EOV showed significant differences in age at TCPC (p < 0.05), age at CPX (p < 0.02), weight at CPX (p < 0.02), follow-up duration between TCPC and CPX (p < 0.04), ventricular morphology (p < 0.05), and metabolic equivalents (p < 0.05) and peak minute oxygen uptake (VO₂) per body weight (p < 0.05). Multivariable analysis showed that EOV was significantly related to peak VO₂ per kilogram. In conclusion, EOV was frequently noted during exercise in Fontan patients with good clinical status. EOV during exercise seems to be related to higher peak VO₂ per kilogram and younger age at TCPC, which is a contrary result to those for adult patients with chronic heart failure. EOV is a remarkable phenomenon during exercise to compensate for impaired cardiopulmonary function in Fontan patients.     

Calcium regulating hormones and bone mineral content in patients after subtotal gastrectomy

Twenty-nine men who had undergone Billroth I gastrectomy and 19 men who had undergone Billroth II gastrectomy were studied to examine the changes in their calcium regulating hormones and bone mineral content following surgery. The serum calcium and phosphate concentrations in the patients with Billroth I and Billroth II were normal. The Billroth II group had an elevated level of serum alkaline phosphatase and reduced bone mineral content. The 24,25(OH)₂D concentration was reduced (P<0.01) and 25(OH)D and 1,25(OH)₂D concentrations were increased (P<0.01,P<0.05, respectively) in the Billroth II group. It was suggested by our study that the Billroth II patients had a reduced bone mineral content and an elevated 1,25(OH)₂D concentration. Therefore, the pathophysiology of postgastrectomy bone metabolic disease is not due to vitamin D deficiency, but may instead be due to reduced calcium absorption in the intestine.     

Role of membrane microdomains in PTH-mediated down-regulation of NaPi-IIa in opossum kidney cells

BACKGROUND: Parathyroid hormone (PTH) rapidly down-regulates type IIa sodium-dependent phosphate transporter (NaPi-IIa) via an endocytic pathway. Since the relationship between PTH signaling and NaPi-IIa endocytosis has not been explored, we investigated the role of membrane microdomains in this process. METHODS: We examined the submembrane localization of NaPi-IIa in opossum kidney (OK-N2) cells that stably expressed human NaPi-IIa, and searched for a PTH-induced specific phosphorylating substrate on their membrane microdomains by immunoblotting with specific antibody against phospho substrates of protein kinases. RESULTS: We found that NaPi-IIa was primarily localized in low-density membrane (LDM) domains of the plasma membrane; PTH reduced the levels of immunoreactive NaPi-IIa in these domains. Furthermore, PTH activated both protein kinase A (PKA) and protein kinase Calpha (PKCa) and increased the phosphorylation of 250 kD and 80 kD substrates; this latter substrate was identified as ezrin, which a member of the ezrin-radixin-moesin (ERM) protein family. In response to PTH, ezrin was phosphorylated by both PKA and PKC. Dominant negative ezrin blocked the reduction in NaPi-IIa expression in the LDM domains that was induced by PTH. CONCLUSION: These data suggest that NaPi-IIa and PTH-induced phosphorylated proteins that include ezrin are compartmentalized in LDM microdomains. This compartmentalization may play an important role in the down-regulation of NaPi-IIa via endocytosis.