Regulation of somatostatin receptor 4-mediated cytostatic effects by CD26 in malignant pleural mesothelioma.

BACKGROUND: Malignant pleural mesothelioma (MPM) is an aggressive neoplasm arising from mesothelial lining of pleura. CD26 molecules preferentially expressed on epithelioid type of MPM. This study investigates the molecular mechanisms of CD26 regulating MPM cells in vitro and in vivo. METHODS: Biochemical and cell biological approaches were used for identifying a novel molecular target of MPM. Its contribution to tumour expansion has been also assessed using animal models. The clinical samples of MPM were also assessed for its expression. RESULTS: We identify that cytostatic effects in MPM are mediated by somatostatin (SST) receptor 4 (SSTR4), being inhibited by the interaction of CD26 molecules. We also indicates that SSTR4-mediated cytostatic effects are regulated by SHP-2 PTP, and that this inhibitory effect by SST agonist is enhanced via lipid raft clustering of associated molecules following crosslinking of anti-CD26 antibody. Finally, using an in vivo xenograft model, we demonstrate that the anti-tumour effect of anti-CD26 mAb is enhanced when combined with SSTR4 agonist treatment, and that SSTR4 is highly coexpressed with CD26 on epithelioid or biphasic types of MPM tissues obtained from patients' surgical specimens. CONCLUSIONS: Combination therapy with humanised anti-CD26 mAb and SSTR4 agonist may therefore potentiate anti-tumour effect on MPM.

Episodic release of methane bubbles from peatland during spring thaw.

Methane (CH(4)) flux into the atmosphere during spring thaw was investigated in a small ombrotrophic peatland (141 degrees 48'E, 43 degrees 19'N, Japan) using the conventional chamber method. More than 50 chamber deployments on top of the snow cover were carried out and continued for more than 165h until the surface snow and underlying ice cover on top of the peat layer had thawed completely. Methane emissions were almost absent in the presence of snow cover. At the very moment the surface ice cover thawed, a large CH(4) flush (>10mgCH(4)m(-2)h(-1)) was recorded, which was on the same order of magnitude as episodic ebullition previously observed in the high-summer. Gas bubbles trapped in the ice layer on top of the waterlogged peat were preliminarily analyzed for the volumetric percentage in the total ice volume and their gas species compositions. Results showed that the bubbles occupied about 3.2% volume and that the mixing ratio of CH(4) in the bubbles was about 20%. The abundance of the bubble-form CH(4) was sufficient to explain the observed episodic CH(4) release during the thaw. Results of this study show that CH(4) emissions during the thaw season have great temporal variability; emission occurs as an episodic release of bubble-form CH(4) stored in the frozen layer. The results also imply the possibility that gas-phase CH(4) plays an important role, not only during the growing season but also in cold-season CH(4) dynamics in northern peatlands.

Evaluating stream water quality through land use analysis in two grassland catchments: impact of wetlands on stream nitrogen concentration.

We evaluated the impacts of natural wetlands and various land uses on stream nitrogen concentration in two grassland-dominated catchments in eastern Hokkaido, Japan. Analyzing land use types in drainage basins, measuring denitrification potential of its soil, and water sampling in all seasons of 2003 were performed. Results showed a highly significant positive correlation between the concentration of stream NO3-N and the proportion of upland area in drainage basins in both catchments. The regression slope, which we assumed to reflect the impact on water quality, was 24% lower for the Akkeshi catchment (0.012 +/- 0.001) than for the Shibetsu catchment (0.016 +/- 0.001). In the Akkeshi catchment, there was a significant negative correlation between the proportion of wetlands in the drainage basins and stream NO3-N concentration. Stream dissolved organic nitrogen (DON) and carbon (DOC) concentrations were significantly higher in the Akkeshi catchment. Upland and urban land uses were strongly linked to increases in in-stream N concentrations in both catchments, whereas wetlands and forests tended to mitigate water quality degradation. The denitrification potential of the soils was highest in wetlands, medium in riparian forests, and lowest in grasslands; and was significant in wetlands and riparian forests in the Akkeshi catchment. The solubility of soil organic carbon (SOC) and soil moisture tended to determine the denitrification potential. These results indicate that the water environment within the catchments, which influences denitrification potential and soil organic matter content, could have caused the difference in stream water quality between the two catchments.

A case of gain-of-function mutation in calcium-sensing receptor: supplemental hydration is required for renal protection.

AIMS: The calcium-sensing receptor (CaSR) regulates the extracellular calcium level, mainly by controlling parathyroid hormon secretion and renal calcium reabsorption. In gain-of-function CaSR mutations, the genetic abnormalities increase CaSR activity leading to the development of such clinical manifestations as hypercalciuric hypocalcemia and hypoparathyroidism. We report a Japanese case of CaSR gain-of-function mutation and represent a therapeutic intervention based on the functional characteristics of CaSR in renal tubule. METHODS AND RESULTS (CASE): DNA sequence analysis revealed a heterozygous G to T mutation identified in a 12-year-old Japanese girl presenting with sporadic onset of hypercalciuric hypocalcemia and hypoparathyroidism. The mutation is located in the N-terminal extracellular domain of the CaSR gene, one of the most important parts for the three-dimensional construction of the receptor, resulting in the substitution of phenylalanine for cysteine at amino acid 131 (C131F) in exon 3. Based on the diagnosis of the gain-of-function mutation in the CaSR, oral hydrochlorothiazide administration and supplemental hydration were started in addition to calcium supplementation. The combination therapy of thiazide and supplemental hydration markedly reduced both renal calcium excretion and urinary calcium concentration from 0.4-0.7 to less than 0.1 mg/mg (urinary calcium/creatinine ratio) and from 10-15 to 3-5 mg/dl (urinary calcium concentration), respectively. This therapy stopped the progression of renal calcification during the follow-up period. CONCLUSION: Supplemental hydration should be considered essential for the following reasons: (1) calcium supplementation activates the CaSR in the kidney and suppresses renal urinary concentrating ability, (2) the thiazide has a diuretic effect, (3) as calcium supplementation increases renal calcium excretion, the supplemental hydration decreases urinary calcium concentration by increasing urinary volume, thereby diminishing the risk of intratubular crystallization of calcium ion.

Relationship between copper, zinc and metallothionein in hepatocellular carcinoma and its surrounding liver parenchyma.

BACKGROUND/AIM: Accumulation of copper (Cu) in hepatocellular carcinoma (HCC), especially in small tumors, is greater than that in the surrounding liver parenchyma. Metallothionein (MT) is considered to be present as Cu-MT, Zn,Cu-MT or Zn-MT. The aim of this study was to determine the presence and localization of Cu-MT and Zn-MT in HCC and surrounding liver parenchyma. METHODS: In 16 HCC patients, surgically resected specimens including HCC and surrounding liver parenchyma were evaluated. RESULTS: The level of Cu present in small HCC (<4 cm in diameter) was significantly greater than that in the surrounding liver parenchyma (p<0.05). However, the level of Cu in large HCC (>4 cm in diameter) was similar to that in the surrounding liver parenchyma. Analysis by Sephadex G-75 gel filtration revealed that the peak fraction due to Cu was identical to that due to MT in 14 (87.5%) of 16 HCC, the peak fraction due to Cu and Zn was identical to that due to MT in 2 (12.5%) HCC, and the peak fraction due to Zn was identical to that of MT in none of 16 HCC. CONCLUSIONS: Accumulation of Cu in small HCC, in which Cu was present as Cu-MT or Zn, Cu-MT, was greater than that in the surrounding liver parenchyma. Cu accumulation and the presence of MT in the liver may be related to carcinogenesis of HCC, because of the similarity of these findings in the experimental data of Long-Evans rats with a cinnamon-like coat color who develop HCC spontaneously.

Accumulation of copper in the liver and hepatic injury in chronic hepatitis C.

BACKGROUND AND AIMS: Relationships between chronic liver disease and trace metals have not been clearly understood. To examine connections between severity of hepatic fibrosis in chronic hepatitis C and copper, iron and zinc we measured the contents of these metals in liver tissue and serum in the patients. METHODS: Forty-one patients (26-62 years), 13 with fibrosis representing grade F1, 16 with F2, seven with F3, and five with F4, entered this study. Metals were quantified in needle liver-biopsy specimens by particle-induced X-ray emission. In serum, metals were measured by flameless atomic absorption spectrometry. RESULTS: Hepatic copper content increased with progression of hepatic fibrosis (P < 0.05). The copper content correlated positively with bilirubin (r = 0.466, P = 0.0023), and with type IV collagen (r = 0.402, P = 0.0086) and correlated negatively with albumin (r = -0.404, P = 0.080). However, hepatic iron and zinc contents did not show a significant differences between grades of fibrosis. CONCLUSIONS: Copper accumulation in fibrotic livers caused by chronic hepatitis C may contribute to hepatic injury. The real mechanism is not known at present, but excess copper may damage the liver by oxidative stress.

Natural course of small hepatocellular carcinoma with underlying cirrhosis. A study of 30 patients.

To anticipate the prognosis and choose therapy for patients with relatively early-stage HCCs, we elucidate the natural course of such patients. Thirty cirrhotic patients with small hepatocellular carcinoma (HCC) < 3 cm in size and not receiving anti-cancer treatment were followed by sonography for periods of 6-48 mots. The growth speed varied considerably from case to case, with an average of 6.5+/-5.7 months of doubling time (DT). Growth speed of small HCC is significantly related to histological differentiation of tumors: a slow-growing HCC tends to be well-differentiated and a rapid-growing HCC moderately- or poorly-differentiated. Furthermore, there was a tendency to grow without changing from nodular type in slow-growing HCCs and to multiple nodular or massive types in intermediate- and rapid-growing HCCs. The survival rates of these untreated HCC patients showed a 1-yr survival of 90.7%, a 2-yr survival of 55.0%, and a 3-yr survival of 12.8%. Factors significantly influencing survival of these patients were serum total bilirubin level and DT. This study will provide invaluable data for diagnosing and treating for small HCCs.

Sensitivity of opioid receptor-like receptor ORL1 for chemical modification on nociceptin, a naturally occurring nociceptive peptide.

Nociceptin or orphanin FQ is a novel neuropeptide that activates an opioid-like G protein-coupled receptor ORL1. This heptadecapeptide FGGFTGARKSARKLANQ resembles kappa-opioid peptide dynorphin A but exhibits an opposite effect to make animals hyperreactive to nociceptive stimulations (Meunier, J.-C., Mollereau, C., Toll, L., Suaudeau, C., Moisand, C., Alvinerie, P., Butour, J.-L., Guillemot, J.-C., Ferrara, P., Monsarrat, B., Mazarguil, H., Vassart, G., Parmentier, M., and Costentin, J. (1995) Nature 377, 532-535; Reinscheid, R. K., Nothacker, H.-P., Bourson, A., Ardati, A., Henningsen, R. A., Bunzow, J. R., Grandy, D. K., Langen, H., Monsma, F. J., Jr., and Civelli, O. (1995) Science 270, 792-794). In the present study, it was found that guinea pig brain contains receptors to which nociceptin binds much more strongly than to ORL1 receptors expressed in human 293 cells. Although the Tyr1 --> Phe substitution for dynorphin A eliminates almost completely an ability to bind to opioid receptors, the Phe1 --> Tyr substitution in nociceptin was found to retain almost fully both receptor binding affinity and in vivo hyperalgesic activity in tail-flick assay. Nociceptin was extremely weak to bind to opioid receptors, while Tyr1-nociceptin exhibited 10-40 times increased affinity, especially for mu receptors, due to its N-terminal sequential identity to opioid peptides. Shortened analogs of dynorphin A are known to retain receptor binding ability and analgesic activity, whereas the removal of C-terminal hexa- or decapeptide from nociceptin totally abolished the affinity for the ORL1 receptor. These results indicated that the mode of interaction between nociceptin and ORL1 receptor is quite different from that between dynorphin and opioid receptor and that the C-terminal portion of nociceptin is crucial for receptor recognition.

Enhanced activation is the mechanism of negative cross-resistance to Chlorpyrifos in the Dicofol-IR strain of Tetranychus urticae (Acari: Tetranychidae).

The mechanism responsible for negative cross-resistance to chlorpyrifos was examined in isogenic dicofol susceptible (Orchard-12) and resistant (Dicofol-IR) two-spotted spider mites, Tetranychus urticae Koch. The acetylcholinesterase of both strains was equally sensitive to inhibition by chlorpyrifos oxon. However, the Dicofol-IR strain showed increased oxidative activation of chlorpyrifos to chlorpyrifos oxon relative to the Orchard-12 strain, suggesting this mechanism is responsible for the observed negative cross-resistance.

Diagnostic and pathological considerations in the popliteal artery entrapment syndrome.

Four cases of the popliteal artery entrapment syndrome including two with bilateral lesions are reported. All limbs of these patients showed classical arterial entrapment due to the anomalous course of the popliteal artery in relation to the medial head of the gastrocnemius muscle. All cases were diagnosed preoperatively, and computed tomography demonstrated apparent separation of the popliteal artery and vein at the site of the insertion of the gastrocnemius muscle. All patients complained of gradually progressive intermittent claudication except for one who revealed acute leg ischemia following long periods of driving and Japanese-style sitting. Surgical treatment resulted in complete recovery in all limbs. Pathological characteristics in the popliteal artery were: (1) the presence of longitudinal smooth muscle bundles in the medial coat adjacent to the gastrocnemius muscle, and (2) intimal thickening and/or thrombus formation adjacent to the medial condyle of the femur.

[Phase II study on peplomycin for esophageal cancer].

For the purpose of verifying the effectiveness of peplomycin, one of the derivatives of bleomycin, against carcinoma of the esophagus and the safety of it, the analysis of the data for total 113 cases collected from 25 institutions in Japan was made. The results are as follows. It was effective in 19 out of 74 evaluable cases of carcinoma of the esophagus (25.7%). In case of treatment with peplomycin alone, it was effective in 6 out of 39 cases (15.4%). In case of the combination treatment with peplomycin and some other therapy, it was effective in 13 out of 35 cases (37.1%). As for the side effects, the incidence of fever was the highest in both the cases of peplomycin alone and the combination treatment such as 39.6% and 37.0%, respectively. Anorexia, nausea, vomiting, respiratory symptoms and tiredness were found in relatively many cases. In the clinical laboratory tests, the vital capacity after the treatment tended to be lower than that before the treatment, but there was little change in the hematological tests, pulmonary function test and renal function test.

Successful resection of an aortic arch aneurysm using a temporary trifurcation bypass graft.

Resection of a syphilitic aortic arch aneurysm in a 62-year-old woman was accomplished using a trifurcation temporary bypass system. The bifurcation graft was sutured end-to-side to the ascending thoracic aorta, to the brachiocephalic trunk and to the left common carotid artery, respectively. The attached third limb end was anastomosed end-to-side to the infrarenal abdominal aorta. This technique enabled a large shunt into the abdominal aorta. Occlusion of the iliac arteries proved to be effective in coping with hypotension while attending to the bypass and the volume replacement. The post-operative recovery was uneventful and the patient has remained well after 43 months.

Multiple aneurysms of the visceral arteries with migrating vascular bruit on postural change: a case report.

Multiple aneurysms of the gastroepiploic artery and the ileocecal branch of the superior mesenteric artery were found in a 68-year-old male patient by angiography. The patient presented with one-hour postprandial epigastric pain of 10 years duration. Abdominal bruit was auscultated at the two different sites, one of which shifted downwards upon upright position. From the freely movable nature of the great omentum, this bruit, migrating upon postural change, was most likely from the gastroepiploic artery aneurysms. The aneurysms were excised and the abdominal bruit disappeared. The etiology of the aneurysms was suggested to be arterial fibrodysplasia histologically. From this experience, it was stressed that postural change should be added to a routine physical examination to rule out an aneurysm from the freely movable great omentum.

Experimental and clinical studies of the inverted autogenous vein grafts.

The vein was inverted (inside-out) and used as a new arterial substitute. Experimental study showed more than 90% patency rate and clinical experiences were satisfactory. Autogenous inverted vein grafting is a safe procedure and should be considered another way to widen the indication of the vein.

Degenerative changes of vein grafts in preparation media: preliminary studies by electron microscopy and fibrinolytic autography.

Degenerative changes of saphenous vein grafts in four preparation media (heparinized whole blood at room temperature and 4 degrees C, and heparinized normal saline at same temperatures) were examined by scanning and transmission electron microscopy and fibrinolytic autography. Following 60--90 min. storage in heparinized normal saline at room temperature, marked morphological changes were present in the media, accompanied by swelling of the endothelial cells, however the tunica media and adventitia were well preserved even after 120 minutes in all of the four preparation media. The decrease in fibrinolytic activity was comparable to the observed morphological changes. In heparinized whole blood at 4 degrees C, degenerative changes were slow and mostly of a slight nature.

Surgical treatment of juxtarenal aortic occlusion.

From 1974 to 1976, four patients with juxtarenal aortic occlusion were operated upon with no surgical mortality. Thromboendarterectomy (TEA) of the aorta with renal revascularization was performed in one patient, and TEA with grafting in three. Intraoperative renal protection was particularly important, since suprarenal aortic clamping was often required in these cases. Possible renal embolism developed in one patient postoperatively. In order to prevent renal embolism and to minimize ischemic insult to the kidney, the value of the following procedures was stressed; (a) irrigation of aortic lumen with saline after TEA under suprarenal aortic clamping with renal arteries kept occluded, and (b) re-application of aortic clamp below the renal arteries after irrigation. Since the most distal level of occlusive process was the common femoral artery in our series, the patient with this disease entity should be treated more actively.