Augmentation of intrarenal angiotensin II levels in uninephrectomized aldosterone/salt-treated hypertensive rats; renoprotective effects of an ultrahigh dose of olmesartan.

Recent studies have suggested that aldosterone plays a role in the pathogenesis of renal injury. In this study, we investigated whether local angiotensin II (Ang II) activity contributes to the progression of renal injury in aldosterone/salt-induced hypertensive rats. Uninephrectomized rats were treated with 1% NaCl in a drinking solution and one of the following combinations for 6 weeks: vehicle (2% ethanol, s.c.; n=9), aldosterone (0.75 mug/h, s.c.; n=8), aldosterone+Ang II type 1 receptor blocker olmesartan (10 mg/kg/day, p.o.; n=8), or aldosterone+olmesartan (100 mg/kg/day, p.o.; n=9). Aldosterone/salt-treated hypertensive rats exhibited severe proteinuria and renal injury characterized by glomerular sclerosis and tubulointerstitial fibrosis. Aldosterone/salt-induced renal injury was associated with augmented expression of angiotensin converting enzyme and Ang II levels in the renal cortex and medullary tissues. Renal cortical and medullary mRNA expression of transforming growth factor-beta (TGF-beta) and connective tissue growth factor (CTGF) as well as the collagen contents were increased in aldosterone/salt-treated hypertensive rats. Treatment with olmesartan (10 or 100 mg/kg/day) had no effect on blood pressure but attenuated proteinuria in a dose-dependent manner. Olmesartan at 10 mg/kg/day tended to decrease renal cortical and medullary Ang II levels, TGF-beta and CTGF expression, and collagen contents; however, these changes were not significant. On the other hand, an ultrahigh dose of olmesartan (100 mg/kg/day) significantly decreased these values and ameliorated renal injury. These data suggest that augmented local Ang II activity contributes, at least partially, to the progression of aldosterone/salt-dependent renal injury.     

MRI and ultrasonography of atherosclerosis of the thoracic aorta and carotid arteries in elderly hypercholesterolemic patients]

In 53 elderly participants aged more than 60 the thoracic aorta and bilateral carotid arteries were observed with noninvasive techniques, MRI and ultra-sonography, in order to elucidate the relationship between hypercholesterolemia and atherosclerosis in the elderly. Hypercholesterolemic subjects were classified as group H (serum total cholesterol (TC) greater than 220 mg/dl), group H-I (220 mg/dl less than TC less than 250 mg/dl) and group H-II (TC greater than or equal to 250 mg/dl). Atherosclerotic changes of the thoracic aorta were observed in 46% of group H, 27% of group H-I, 60% of group H-II and 37% of normolipidemic subjects (group NL). Carotid atherosclerotic changes were observed in 19% of group H, 9% of group H-I, 27% of group H-II and 18% of group NL. In group H-I, the percentages of atherosclerotic changes in both thoracic aorta and carotid arteries were lower than those in group NL. However, atherosclerotic changes of thoracic aorta and carotid arteries were detected in 43% and 29% of the subjects showing higher apo B/Apo Al ratio than 1.0 among group H-I + NL (TC less than 250 mg/dl). These changes occurred in 32% and 13% of the subjects showing lower apo B/Apo Al ratio than 1.0 among the same groups. Namely, atherosclerotic changes of the thoracic aorta and carotid arteries were observed more frequently in the subjects showing a higher apo B/Apo Al ratio than 1.0 even if their serum cholesterol values were not higher than 250 mg/dl. We should use not only the serum cholesterol value but also the apo B/Apo Al ratio as an indicator to evaluate the roles of lipids in the development of atherosclerosis.     

ENDOSCOPIC SUBMUCOSAL DISSECTION FOR RECURRENT GASTRIC TUMORS

Endoscopic resection has been accepted as the standard treatment for intramucosal gastric tumors of differentiated type. However, the indication was limited to small tumors to achieve en bloc resection and prevent local recurrence in cases of conventional endoscopic mucosal resection (EMR) such as the strip biopsy and the cap technique. To avoid multi‐fragmental resection, we have developed endoscopic submucosal dissection (ESD) as a new endoscopic resection technique. ESD is a remarkable technique, because we make it possible to remove the lesions en bloc regardless of size, shape, coexisting ulcer, and location. However, it is difficult or impossible to resect recurrent tumors en bloc in conventional EMR owing to hard fibrosis, and some patients need laparotomy. Using ESD, we can dissect the submucosal layer as we directly look at the submucosa, and remove the lesion safely and reliably even in cases of hard fibrosis. The key to treatment of recurrent tumors in ESD are as follows: (i) using enough submucosal injection solution (we use a mixture of Glyceol and 1% 1900 kDa hyaluronic acid preparation); (ii) incising the mucosa without fibrosis; (iii) understanding characteristics of various cutting devices, and changing other devices in difficult situations. In these ways we can remove the majority of the recurrent tumors en bloc. Hence, we consider that ESD is a very effective treatment which achieves excellent en bloc and complete resection rates and enables patients with intramucosal gastric tumors to a recurrent‐free survival even in recurrent tumors.     

The effect of IL-6 on the des-gamma-carboxy prothrombin synthesis in human hepatoma cells.

Effects of several cytokines on des-gamma-carboxy prothrombin (PIVKA II) synthesis in human hepatoma cells were investigated to know the process of PIVKA II production during a liver allograft rejection. Human recombinant interleukin-6 (IL-6) significantly stimulated the PIVKA II synthesis without any influence on the cell proliferation. The effect was almost completely neutralized by the specific anti-IL-6 antibody. Neither tumor necrosis factor (TNF), interleukin-1 (IL-1) nor interferon-gamma (IFN-gamma) had such a stimulative effect. IL-6 appears to stimulate PIVKA II production, and would be a candidate of factors that enhance the production of PIVKA II during a liver allograft rejection.     

Preventive effects of intermittent administration of human parathyroid hormone on steroid-induced osteopenia in rats

The purpose of this study was to determine the preventive effect of intermittent administration of human parathyroid hormone (h-PTH) on bone change in steroid-treated rats; this was done by histomorphometric and biochemical analysis. Seven-month-old female Wistar rats were divided into four groups; in-each of the four groups one subgroup was treated for 4 weeks and one for 8 weeks. The groups consisted of: untreated controls, a steroid group (receiving prednisolone), a steroid + PTH group (predniso-lone and h-PTH administered simultaneously), and a steroid + PTH vehicle group. Prednisolone (2.5 mg/kg) and h-PTH (1–34) (6.0 μg/kg) were administered six times a week during the experimental period. At necropsy, bilateral tibiae were collected: one was used for preparing undecalcified sections after Villanueva bone staining, and the other for decalcified tartrate-resistant acid phosphatase (TRAP) stained sections. Biochemical analysis showed that steroids increased urinary calcium at the 8th week; however, such bone metabolic markers as serum 1,25-(OH)₂D and urinary deoxypyridinoline did not change in any treatment group. Histomorphometrically, steroid-induced osteopenia was established at the 8th week by inhibition of both bone formation and bone resorption. The simultaneous intermittent administration of PTH plus steroid, however, increased both bone formation and bone resorption, resulting in increases in bone volume beginning at 4 weeks. These results suggest that the simultaneous intermittent administration of PTH with steroid prevents steroid-induced low-turnover osteopenia by stimulating bone turnover.     

Distribution characteristics of immunosuppressants FK506 and cyclosporin A in the blood compartment

Using two representative immunosuppressants, FK506 (FK) and cyclosporin A (CyA), of which the mechanism of pharmacological action is the same although there is a great difference in the pharmacological intensity, the distribution characteristics were studied in both in vivo and in vitro experiments using rat, dog, and human blood. Blood samples were fractionated by means of sedimentation in Ficoll-Paque®, and the drug contents in the diluted plasma fraction, erythrocyte fraction, and lymphocyte fraction were measured by an HPLC method. FK distributes to the lymphocyte fraction to a level about three times greater than that of CyA, while CyA distributes to the erythrocyte fraction to a level ten times that of FK. The distribution pattern of these fractions was independent of the drug concentration and species after correcting the drug concentration in each fraction with the blood drug concentration. The uptakes of FK and CyA in the isolated lymphocytes obtained from the rat spleen and human peripheral blood were also studied. The amount of FK taken up by the spleen lymphocytes is five times greater than that of CyA. In the case of the uptake study using human peripheral blood lymphocytes, the concentration of FK in the lymphocyte is 100-fold higher than that of CyA. This difference in the lymphocyte level between the two immunosuppressants is thought to be one of the reasons why FK is more potent than CyA, a difference of about 100-fold in the in vitro pharmacological study and about tenfold in the in vivo organ transplantation experiments.