A pharmacologic study on the mechanism of action of Kakkon-to: body temperature elevation and phagocytic activation of macrophages in dogs

OBJECTIVE: The phagocytic activity of macrophages as a novel approach to scientific elucidation of the effects of Chinese medicines was studied through administration of a kampo preparation, by measuring the rise in body temperature, which is thought to stimulate innate defensive functions of organisms and enhance the immune systems. DESIGN: Using dogs as experimental models, a rise in body temperature following administration of Kakkon-to was observed, and the average number and average rate of phagocytosis of macrophages in blood using latex micro-particles was investigated. RESULTS: The body temperature of the treated animals significantly increased 30 minutes after administration (p<0.01), and remained elevated for more than 5 hours. A comparison of body temperatures before and after administration showed significant increases over controls from 1 to 11 hours, p<0.01; and at 12 hours, p<0.05 after administration. The average number and the average rate of phagocytosis were significantly increased 1 (p<0.05) and 2 (p<0.01) hours after administration. The mean number of phagocytized cells significantly increased (p<0.05) at 1 hour after administration compared with that before administration, and the mean phagocytic rate also increased significantly (p<0.01) 2 hours after administration. Increases (p<0.01) in both the rate of phagocytosis and the number of cells phagocytized were found at every measurement point from 2 to 24 hours after administration. Significant increases (p<0.01) were also observed in both the rate of phagocytosis and the number of cells phagocytized 3 hours after administration, when compared with the control group. CONCLUSION: This paper demonstrates that ingestion of Kakkon-to not only increases the body temperature but also enhances the phagocytic activity of macrophages, an in vivo defense mechanism, suggesting that Kakkon-to contributes to the suppression of multiplication of common cold viruses and influenza viruses, which consequently results in improvement of various symptoms during infection with common cold viruses.     

Renal Arteriovenous Fistula with Rapid Blood Flow Successfully Treated by Transcatheter Arterial Embolization: Application of Interlocking Detachable Coil as Coil Anchor

A 70-year-old woman presented to our outpatient clinic with a large idiopathic renal arteriovenous fistula (AVF). Transcatheter arterial embolization (TAE) using interlocking detachable coils (IDC) as an anchor was planned. However, because of markedly rapid blood flow and excessive coil flexibility, detaching an IDC carried a high risk of migration. Therefore, we first coiled multiple loops of a microcatheter and then loaded it with an IDC. In this way, the coil was well fitted to the arterial wall and could be detached by withdrawing the microcatheter during balloon occlusion (pre-framing technique). Complete occlusion of the afferent artery was achieved by additional coiling and absolute ethanol. This technique contributed to a safe embolization of a high-flow AVF, avoiding migration of the IDC.     

Multi-detector row helical CT of the liver: quantitative assessment of iodine concentration of intravenous contrast material on multiphasic CT--a prospective randomized study

PURPOSE: The purpose of this study was to assess the quantitative effects of contrast material concentration on hepatic parenchymal and vascular enhancement in multiphasic computed tomography (CT), using multi-detector row helical CT. MATERIALS AND METHODS: We designed a prospective randomized study to test two different concentrations of contrast material on five phasic scans of the liver. One hundred patients were randomly assigned to two groups: an iodine concentration of 300 mg/mL in group A and 370 mg/mL in group B. All patients received a fixed volume of 100 mL at a 4 mL/sec injection rate. Enhancement values for the hepatic parenchyma and aorta at three levels (upper, middle, and lower level of the liver), and values for portal and hepatic veins were statistically compared between the two groups. RESULTS: Hepatic parenchymal enhancement values at all levels of the liver in portal phase (PP) and equilibrium phase (EP) were significantly higher in group B than in group A (p<0.01). Aortic enhancement values at two levels of the liver (middle and lower) in early hepatic arterial phase (EAP) were significantly higher in group B than in group A (p<0.05), however, there was no significant difference between groups A and B in aortic enhancement during the delayed hepatic arterial phase (DAP). Portal and hepatic venous enhancement values in PP and EP were significantly higher in group B than in group A (p<0.01). CONCLUSION: On multiphasic dynamic CT, the use of a higher iodine concentration of contrast material results in higher hepatic parenchymal enhancement and aortic enhancement, as well as higher portal and hepatic venous enhancement.     

Recording of surgery with two crane-type tripods and video cameras

At medical meetings, a video-recorded surgical procedure can be more persuasive than an oral or poster presentation. Because operating rooms generally have limited space, video setups must be efficient and effective. Patients undergoing hepatectomy and rectal resection were recorded using two sectional crane-type tripods and video cameras placed in different positions. Both small crane-type tripods and video cameras could record surgical procedures from different angles and were easily controlled. Surgical procedures by the surgeon and first assistant were recorded independently. Videotaping surgical procedures with two video cameras can make presentations at medical meetings more effective.     

Myogenesis in Wilms Tumors Is Associated with Mutations of the <Emphasis Type="Italic">WT1</Emphasis> Gene and Activation of Bcl-2 and the Wnt Signaling Pathway

Wilms tumors with WT1 mutations [WT1(–)] have a stromal-predominant histology with varying extents of rhabdomyogenesis. These tumors also frequently have mutations in the beta-catenin gene (CTNNB1). We have investigated the molecular events that may explain the origins of rhabdomyogenesis in WT1(–) tumors. Of 35 Wilms tumors, we identified 12 with WT1 mutations, of which 9 carried CTNNB1 mutations. We compared WT1 wild-type tumors [WT1(+)] with WT1(–) tumors for histological features, localization of beta-catenin, Bcl-2 expression, and apoptosis using an in-situ end-labeling technique. WT1(+) tumors showed triphasic and blastemal- and epithelial predominant-histology. Expression of WT1, beta-catenin, and Bcl-2 recapitulated those of normal kidney epithelial development. Localization of beta-catenin was observed in the cytoplasm and cytoplasmic membrane of early glomerular epithelial structures. Bcl-2 is also expressed in condensing blastema and early glomerular epithelial structures which had little apoptosis. WT1(–) tumors, regardless of whether CTNNB1 mutations were detected or not, showed a stromal-rich phenotype with abundant expression of beta-catenin in the nucleus of the rhabdomyoblasts. Bcl-2 was expressed in rhabdomyoblasts, but not in blastemal cells undergoing apoptosis, suggesting that WT1 regulates Bcl-2 positively in the epithelial pathway, but negatively in the myogenic pathway. These data indicate that mutations in WT1 might alter the Wnt signaling pathway and Bcl-2 related-apoptosis. In WT1(–) tumors, the nuclear accumulation of beta-catenin and Bcl-2 expression are associated with rhabdomyogenesis, and dysregulation of Bcl-2 may be a mechanism by which the histogenesis (loss of blastemal component, muscle differentiation) may be explained.     

Laparoscopic correction of congenital portosystemic shunt in children

Congenital portosystemic shunt is a rare clinical entity that may progress to jaundice, severe encephalopathy, and pulmonary hypertension and require surgical correction or coil embolization. We present a novel approach to the management of children with congenital portosystemic shunt by means of a minimally invasive surgical technique. Congenital portosystemic shunts were identified between the superior mesenteric vein and inferior vena cava in case 1 and between the splenic vein and left renal vein in case 2. Both of them were successfully ligated by laparoscopic approach, and catheters were subsequently replaced to monitor portal venous pressure. The patients tolerated the procedure well, and short-term results were excellent. Laparoscopic ligation of congenital portosystemic shunt is technically feasible and less invasive to the management of patients with congenital portosystemic shunts, preventing late onset, life-threatening complications.     

A novel nonpeptide ligand for formyl peptide receptor-like 1

Formyl peptide receptor-like 1 (FPRL1) is a G protein-coupled receptor that binds natural and synthetic peptides as well as lipoxin A(4) and mediates important biological functions. To facilitate its pharmacological characterization, we screened a compound library and identified a substituted quinazolinone (Quin-C1, 4-butoxy-N-[2-(4-methoxy-phenyl)-4-oxo-1,4-dihydro-2H-quinazolin-3-yl]-benzamide) as a ligand for FPRL1. Quin-C1 induces chemotaxis and secretion of beta-glucuronidase in peripheral blood neutrophils with a potency of approximately 1/1000 of that of the peptide agonist WKYMVm. In studies using transfected rat basophilic leukemia (RBL) cell lines expressing either formyl peptide receptor or FPRL1, Quin-C1 induced enzyme release from RBL-FPRL1 but not RBL-FPR cells. Likewise, Quin-C1 selectively stimulates calcium mobilization in RBL-FPRL1 cells, a response that was markedly inhibited by pertussis toxin. Quin-C1 also stimulates phosphorylation of extracellular signal-regulated protein kinases 1 and 2 and induces internalization of an FPRL1 fused to green fluorescent protein. In degranulation assays, both the FPRL1-selective peptide agonist MMK1 and Quin-C1 exhibited lower efficacy and potency than WKYMVm, with EC(50) values of 7.17 x 10(-8) M and 1.88 x 10(-6) M, respectively, compared with the EC(50) value for WKYMVm (2.29 x 10(-8) M). However, Quin-C1 did not induce neutrophil superoxide generation at up to 100 microM. Based on these results, we conclude that Quin-C1 is a novel nonpeptide ligand that binds to FPRL1 and selectively stimulates FPRL1-mediated functions. Quin-C1 is a prototype of substituted quinazolinones based on which further structural modifications may be made to improve its efficacy and potency for FPRL1.     

Disability of development of tolerance to morphine and U-50,488H, a selective kappa-opioid receptor agonist, in neuropathic pain model mice

We examined the analgesic and anti-allodynic effects of morphine and U-50,488H (trans-(+/-)-3,4-dichloro-N-methyl-N-(2-[1-pyrrolidinyl]-cyclohexyl)-benzeneacetamide methanesulfonate salt), a selective kappa-opioid receptor agonist, and the development of tolerance to their effects in neuropathic pain model mice induced by sciatic nerve ligation (SNL). In the tail-pinch method, morphine at 10 mg/kg, s.c. produced a weak analgesic effect in SNL mice; however, U-50,488H at 5 mg/kg, s.c. produced an analgesic effect equipotent to that in normal mice. In contrast, morphine produced an adequate analgesic effect when given either intracerebroventricularly (i.c.v.) or intrathecally (i.t.), but U-50,488H only produced analgesia when given i.t. Repeated administration of morphine (either i.c.v. or i.t.) or U-50,488H (either s.c. or i.t.), did not induce tolerance to the effect. In the static allodynia test with an application of von Frey filaments, both compounds given s.c. suppressed the allodynic effect, but in the dynamic allodynia test involving lightly stroking the plantar surface with a cotton bud, only U-50,488H produced an anti-allodynic effect. Repeated administrations of both compounds did not develop tolerance to these anti-allodynic effects. Thus, U-50,488H was found to be a highly effective at blocking hyperalgesia and allodynia in nerve injury, and these findings suggest that kappa-opioid receptor agonists are attractive pharmacological targets for the control of patients with neuropathic pain.     

A case of lymph node metastasis after 7 years from Hartmann's operation for stage IV sigmoid colon carcinoma

The case was a 49-year-old woman. In 1995, she underwent Hartmann's operation for sigmoid colon carcinoma. Histological stage was IV [se, n4(+), P0, H0, M(-)]. Adjuvant chemotherapy was performed by MMC and 5'-DFUR. After 7 years from the surgery, she had a lumbar pain. CT examination revealed a retroperitoneal tumor-like shadow and Para-aortic lymph nodes were swelling. In 2002, she underwent probe laparotomy. There were massive lymph nodes metastasis, and tumor resection was impossible. Following several systemic chemotherapies such as UFT/CPT-11 and TS-1, the tumor progressed and liver metastasis appeared. After 9 years from the first operation, she is still able to eat and her performance status is 1.     

Effects of endothelin-1 eyedrops on the retina in rats

Eye disorder accompanied with chronic retinal microvascular obstruction, such as diabetic retinopathy, exists in many diseases. However, it is difficult to produce this model experimentally in the animal eye. Endothelin-1 eyedrops were prepared in order to examine whether the eyedrops affect the rat retina and whether we can produce an obstruction model. Endothelin-1 eyedrops diluted by artificial tears in seven stages from 4 x 10(-5) M to 4 x 10(-11) M were arranged. We administered this solution three times a day in the left eye of male Sprague-Dawley rats. Artificial tears alone were applied to the right eye as a control vehicle. After 2 weeks, rats were sacrificed under anesthesia and the retinal tissues were isolated. As an index to the action of endothelin- 1 eyedrops to the retina, the expressions of endothelin-A (ETA) and endothelin-B (ETB) receptors in the retina were compared in both eyes. Frozen sections of the retina were immunostained to reveal the distribution of the ETA and ETB receptors. We also examined ETA and ETB mRNA expression by quantitative real-time polymerase chain reaction. As a result, the expressions of ETA and ETB receptors are reduced with both immunostaining and the mRNA levels in the left eye, in which endothelin-1 eyedrops were applied at 4 x 10(-5) M. It is suggested that endothelin-1 eyedrops affected the retina and the possibility of producing the experimental model of chronic microvascular obstruction in the rat retina.