山本 博徳

Lipophilic hormones of steroidal origin such as the sex hormones and 1,25-dihydroxy vitamin D-3 (1,25[OH](2)D-3) function by regulating patterns of gene expression in cells. The mediators of such actions are nuclear receptors that recognize these ligands with high affinity and selectivity and function through several mechanisms as gene specific transcription factors. As a result of the mechanistic complexity of nuclear receptor action, recent studies have revealed that both synthetic analogs as well as novel mimetics of a receptor's natural hormonal ligand are capable of modulating functional responses in both cell- and gene-selective manners. These findings have given rise to the term selective receptor modulators, typified by such synthetic estrogen receptor ligands as tamoxifen and raloxifene. A number of vitamin D analogs have been prepared that appear to exhibit tissue-selective activity-most notable through their inability to induce levels of hypercalcemia typical of the activity of the natural hormone 1,25(OH)(2)D-3. Because this debilitating yet normal feature of the natural ligand limits its usefulness in a variety of clinical indications, including its application to prevent bone disease caused by secondary hyperparathyroidism, this feature of many of the new analogs is especially welcome. This article discusses what constitutes a selective receptor modulator and whether the current vitamin D analogs represent such entities. (C) 2002 by the National Kidney Foundation, Inc.

Our aim was to understand the mechanism of immunological changes associated with the use of an adsorptive-type extracorporeal device (Adacolumn) that has been developed for selective adsorption of granulocytes and monocytes/macrophages from peripheral blood of patients with active ulcerative colitis. The column is filled with carriers (G-1 beads) that have a diameter of 2 mm and are made of cellulose diacetate. In peripheral blood treated with the G-1 beads or peripheral blood from patients with active ulcerative colitis following granulocyte and monocyte adsorption apheresis, a significant suppression of proinflammatory cytokines (tissue necrosis factor-alpha, interleukin-1beta, interleukin-6, and interleukin-8) production by leukocytes, neutrophil chemotaxis, down-regulation of leukocyte adhesion molecule (L-selectin) and neutrophil adhesion to interleukin-1beta-activated endothelial cells were observed. Furthermore, after granulocyte adsorption therapy, the number of CD10-negative premature granulocytes increased, indicating increased turnover of these cells in the circulation. Our observations suggest that selective granulocyte and monocyte adsorption is associated with modified peripheral blood leukocyte function favorable to patients with ulcerative colitis and possibly other autoimmune disorders which reflect leukocyte hyperactivity.

The awareness of phosphorus intake is important because hyperphosphatemia and hypophosphatemia both impair bone metabolism. Phosphorus consumption from food was obtained from values in the Food Balance Sheet (FBS) of Japan from 19 60 to 1995. The amounts of phosphorus calculated from the FBS increased gradually from 1,243 mg/d in 1960 to 1,332 mg/d in 1975 and to 1,421 mg/d in 1995. This is explained by the increased consumption of cow's milk and milk products, meat, and chicken eggs. The main foods supplying phosphorus in 1995 were cereals, milk and milk products, fishes and shellfishes, and vegetables; their contributions were 24.4, 15.8, 14.2, and 10.9%, respectively. The phosphorus-to-calcium ratio calculated from the FBS was 3.5.1. in 1960, which decreased to 2.89 in 1975 and 2.44 in 1995. Therefore total phosphorus consumption in 1995 was presumably more than 1,500 mg/d when imported food containing phosphorus and the consumption of phosphorus-containing food additives in Japan are also considered. These findings suggest that the phosphorus consumption estimated from the FBS is increasing and that more attention should be paid to the maintenance of healthy bones in Japan, where the average amount of calcium intake is less than 600 mg/d.

Background: Deep insertion of an enteroscope by use of a push technique is difficult. A new method of enteroscopy was developed, a double-balloon method, to improve the access to the small intestine. Methods:The new method uses 2 balloons, one attached to the tip of the endoscope and another at the distal end of an overtube. By using these balloons to grip the intestinal wall, the endoscope can be inserted further without forming redundant loops in the small intestine. This method was tried with a standard upper endoscope in 3 patients and with a longer enteroscope in 1 patient. Results: Despite its short length the upper endoscope was successfully inserted as far as 30 to 50 cm beyond the ligament of Treitz in the 3 patients. In the fourth patient the longer enteroscope was successfully inserted beyond the ileo-cecal valve. Conclusions: The double-balloon method facilitates endoscopic access to the small intestine.

Instability of beta(2)-microglobulin in acidic urine was investigated by identifying an associated protease from normal urine. Degradation was completely blocked by pepstatin, an aspartic protease inhibitor, and the counterpart of the inhibitor was thus sought. The molecular weight of the counterpart was similar to that of the inhibitor, while its cleavage site on beta(2)-microglobulin was identical in three products generated in purified beta(2)-microglobulin in normal acidified urine (pH 5.0-5.5) and those generated by direct reaction between puri fled beta(2)-microglobulin and cathepsin D in acetic acid (pH 5.0). On Western blotting, the presence of cathepsin D was demonstrated immunochemically in urine, and its urinary concentration correlated well with degree of beta(2)-microglobulin degradation. All these findings strongly suggest that cathepsin D is a major urinary acid protease involved in the degradation of beta(2)-microglobulin.

Background: Saline-assisted endoscopic resection is an established therapeutic method. However, it is sometimes difficult to maintain a desired level of tissue elevation after injection of saline. Therefore we decided to use a mucinous substance such as sodium hyaluronate instead of saline. Methods: Two resected porcine stomachs and five dogs were used for the study. The elevations, made by submucosal injections of sodium hyaluronate, were compared with those produced with normal saline. Sodium hyaluronate-assisted mucosal resections were compared with the saline-assisted resections. Results: Mucosal elevations created by submucosal injections of sodium hyaluronate remained for a longer time with a clearer margin compared to those made by saline injection. Endoscopic mucosal resections were performed safely with the assistance of sodium hyaluronate. Conclusions: Use of sodium hyaluronate instead of saline for endoscopic mucosal resection could make the procedure easier and more reliable.

Aim: To evaluate the efficacy and safety of two 1-week low-dose triple-therapy drug regimens involving antisecretory drugs for Helicobacter pylori infection, 99 patients with H. pylori infection were treated with either lansoprazole or ranitidine used together with clarithromycin and metronidazole. Methods: The drug combination and administration periods in the proton pump inhibitor group were lansoprazole 30 mg o.m., clarithromycin 200 mg b.d. and metronidazole 250 mg b.d., all given for 7 days (LCM group). The ranitidine group received ranitidine 150 mg b.d., clarithromycin 200 mg b.d. and metronidazole 250 mg b.d. also for 7 days (RCM group). The presence or absence of H. pylori was determined from gastric biopsy specimens taken from both the antrum and the body, by smear, culture and tissue section (Giemsa stain). Cure was defined as failure to find evidence of H. pylori infection 4 weeks after antimicrobial therapy had ended. Results: The cure of H. pylori infection was 88% in the LCM group (44 of 50;95% confidence interval (CI) = 79-97%) and 92% in the RCM group (45 of 49; 95% CI = 84-99%). The incidence of adverse events was 16% and 18% for the two groups, respectively. Conclusions: No significant differences in cure rate and safety profiles were noted between the two regimens, suggesting that moderate acid inhibition using an H-2-blocker is sufficient to achieve optimal H. pylori eradication.

We modified a novel topical therapeutic method for the treatment of Helicobacter pylori infection to increase its effectiveness and tolerability. Sixty-six patients (with nonulcer dyspepsia, inactive ulcer, or active ulcer) were given lansoprazole (30 mg, h.s.) and pronase (18000 tyrosine units, b.i.d.) orally for 2 days before the topical therapy. One hundred milliliters of 7% sodium bicarbonate solution containing bismuth subnitrate, amoxicillin, metronidazole (at two different regimens), and pronase was instilled into the stomach through an endoscope. A double-lumen tube with a balloon at the tip was inserted into the duodenum along with the endoscope. The balloon was inflated with 25 ml of air and was lodged postbulbarly. The solution was kept in the stomach for 2h, and the patient's position was changed every 14 min from the sitting to the supine, prone, and right lateral position, each position to the supine, prone, and right lateral position, each position being maintained twice, to expose the entire gastric mucosa. The solution was aspirated at the end of the procedure. H. pylori infection was cured in 16/22 (72.7%) of patients with nonulcer dyspepsia, in 21/26 (80.7%) of patients with inactive ulcer, and in 1/18 (5.6%) patients with active ulcer. H. pylori eradication was confirmed 4 weeks after the therapeutic procedure by smear, culture, and histology of antral and corpus biopsy specimens. side effects (loose stools) were observed in two patients only, and one patient had loss of appetite. These effects were transient. This endoscopic topical therapy for H. pylori infection is a safe, effective, and well tolerated procedure. With further modifications of the drug regimens and the method itself, this procedure could be of interest as anti-H. pylori therapy.