Nitric oxide confers cisplatin resistance in human lung cancer cells through upregulation of aldo-keto reductase 1B10 and proteasome.

In this study, we show that exposure of human lung cancer A549 cells to cisplatin (cis-diamminedichloroplatinum, CDDP) promotes production of nitric oxide (NO) through generation of reactive oxygen species (ROS) and resulting upregulation of inducible NO synthase (iNOS). The incubation of the cells with a NO donor, diethylenetriamine NONOate, not only reduced the CDDP-induced cell death and apoptotic alterations (induction of CCAAT-enhancer-binding protein homologous protein and caspase-3 activation), but also elevated proteolytic activity of 26S proteasome, suggesting that the activation of proteasome function contributes to the reduction of CDDP sensitivity by NO. Monitoring expression levels of six aldo-keto reductases (AKRs) (1A1, 1B1, 1B10, 1C1, 1C2, and 1C3) during the treatment with the NO donor and subsequent CDDP sensitivity test using the specific inhibitors also proposed that upregulation of AKR1B10 by NO is a key process for acquiring the CDDP resistance in A549 cells. Treatment with CDDP and NO increased amounts of nitrotyrosine protein adducts, indicative of peroxynitrite formation, and promoted the induction of AKR1B10, inferring a relationship between peroxynitrite formation and the enzyme upregulation in the cells. The treatment with CDDP or a ROS-related lipid aldehyde, 4-hydroxy-2-nonenal, facilitated the iNOS upregulation, which was restored by increasing the AKR1B10 expression. In contrast, the facilitation of NO production by CDDP treatment was hardly observed in AKR1B10-overexpressing A549 cells and established CDDP-resistant cancer cells (A549, LoVo, and PC3). Collectively, these results suggest the NO functions as a key regulator controlling AKR1B10 expression and 26S proteasome function leading to gain of the CDDP resistance.

Activation of Na+-independent Mg2+ efflux by 20-hydroxyeicosatetraenoic acid in rat renal epithelial cells.

Renal epithelial cells may have Mg(2+) transport pathways that regulate intracellular free Mg(2+) concentration ([Mg(2+)](i)) and reabsorption into the body. In mag-fura 2 fluorescent measurement, extracellular Mg(2+) removal induced a Na(+)-independent [Mg(2+)](i) decrease. The [Mg(2+)](i) decrease was suppressed by methyl arachidonyl fluorophosphonate, a cytosolic and Ca(2+)-independent phospholipase A(2) (iPLA(2)) inhibitor, and bromoenol lactone, an iPLA(2) inhibitor, but it was not suppressed by a secretory phospholipase A(2) inhibitor. On the contrary, the [Mg(2+)](i) decrease was enhanced by the addition of exogenous arachidonic acid (AA). Next, we examined the effect of AA metabolite inhibitors on the [Mg(2+)](i) decrease. 17-octadecynoic acid inhibited the [Mg(2+)](i) decrease, but indomethacin and nordihydroguaiaretic acid did not. In the 17-octadecynoic acid-treated cells, 20-hydroxy-(5Z,8Z,11Z,14Z)-eicosatetraenoic acid (20-HETE) recovered the [Mg(2+)](i) decrease. Nicardipine inhibited both the basal and the 20-HETE-enhanced [Mg(2+)](i) decrease. These results suggest that 20-HETE is a key mediator in the activation of Na(+)-independent Mg(2+) efflux.

Polyvalent cation-sensing mechanism increased Na(+)-independent Mg(2+) transport in renal epithelial cells.

Extracellular Ca(2+)/polyvalent cation-sensing receptor (CaSR) is capable of monitoring changes in extracellular polyvalent cation concentrations. In the present study, we investigated whether CaSR agonists reinforce the decrease of intracellular free Mg(2+) concentration ([Mg(2+)](i)) induced by extracellular Mg(2+) plus Na(+) removal. Interestingly, exposure of NRK-52E renal epithelial cells to increasing extracellular Mg(2+) concentrations from 0.8 to 15 mM for 1-2 days resulted in a twofold increase in the levels of CaSR mRNA and protein. By fluorophotometer (with mag-fura 2 fluorescent dye) and atomic absorption spectrophotometer, we confirmed that activation of CaSR by neomycin (0.5 mM) or gadolinium (1 mM) reinforced the decrease of [Mg(2+)](i) induced by Mg(2+) removal in the cells cultured in 10 mM Mg(2+)-containing medium. The neomycin-induced [Mg(2+)](i) decrease was inhibited by nicardipine (50 microM), but not by verapamil (50 microM) or amiloride (0.1 mM). These results indicate that CaSR monitors extracellular Mg(2+) concentration, and probably cause activation of Na(+)-independent Mg(2+)-transport system.

Differential regulation of Na(+),K(+)-ATPase and the Na(+)-coupled glucose transporter in hypertensive rat kidney.

Several Na(+) transporters are functionally abnormal in the hypertensive rat. Here, we examined the effects of a high-salt load on renal Na(+),K(+)-ATPase and the sodium-coupled glucose transporter (SGLT1) in Dahl salt-resistant (DR) and salt-sensitive (DS) rats. The protein levels of Na(+),K(+)-ATPase and SGLT1 in the DS rat were the same as those in the DR rat, and were not affected by the high-salt load. In the DS rat, a high-salt load decreased Na(+),K(+)-ATPase activity, and this decrease coincided with a decrease in the apparent Mechaelis constant (K(m)) for ATP, but not with a change of maximum velocity (V(max)). On the contrary, a high-salt load increased SGLT1 activity in the DS rat, which coincided with an increase in the V(max) for alpha-methyl glucopyranoside. The protein level of phosphorylated tyrosine residues in Na(+),K(+)-ATPase was decreased by the high-salt load in the DS rat. The amount of phosphorylated serine was not affected by the high-salt load in DR rats, and could not be detected in DS rats. On the other hand, the amount of phosphorylated serine residues in SGLT1 was increased by the high-salt load. However, the phosphorylated tyrosine was the same for all samples. Therefore, we concluded that the high-salt load changes the protein kinase levels in DS rats, and that the regulation of Na(+),K(+)-ATPase and SGLT1 activity occurs via protein phosphorylation.

Is rabbit CLCA1 related to the basolateral Ca2+ -dependent Cl- channel of gastric parietal cells?

An expression of mRNA coding the calcium-activated Cl- channel-1 (CLCA1) in rabbit gastric parietal cells was examined to verify the possibility that the CLCA1 mediates housekeeping Cl- channels in the basolateral membrane. In whole-cell voltage-clamp experiments of rabbit parietal cells, A23187 (2 microM), a Ca2+ ionophore, activated the basolateral Cl- channels. The partial cDNA fragment of rabbit CLCA1 could be amplified from the total RNA of tracheal epithelium. A Northern blot analysis showed that rabbit CLCA1 mRNA of 3.4 kb is highly expressed in the tracheal epithelium, but not in the gastric parietal cells. Even in a more sensitive detection of rabbit CLCA1 mRNA by RT-PCR, no signal could be observed in the gastric parietal cells. These results suggest that the CLCA1 protein may not be a subunit of the housekeeping Ca2+ -dependent Cl- channel in the basolateral membrane of rabbit gastric parietal cells.

Mobilization of intracellular Ca(2+) by thromboxane A(2) does not affect Ca(2+)-activated K(+) channels in rat colonic crypt cells.

The effects of 9,11-epithio-11,12-methano-thromboxane A(2) (STA(2)), a stable thromboxane A(2) analogue, and carbachol on colonic Ca(2+)-activated K(+) channels were studied. In indo-1-loaded single cells in isolated rat colonic crypts, both STA(2) (0.1 microM) and carbachol (10 microM) transiently increased intracellular free Ca(2+) concentration ([Ca(2+)](i)) by 136 and 155 nm, respectively. In whole-cell current-clamp experiments of the colonic crypt cells with Cl(-)-free solutions, carbachol (10 microM) hyperpolarized the cell by 19.7 mV, while STA(2) (0.1 microM) did not affect the membrane potential. In the isolated colonic mucosa that was permeabilized mucosally by a monovalent ionophore nystatin in the presence of a serosally directed K(+) gradient, carbachol (10 microM) transiently elicited K(+) current, but STA(2) (0.1 microM) did not. These results indicate that STA(2) elevates [Ca(2+)](i) in rat colonic crypt cells but does not activate basolateral Ca(2+)-activated K(+) channels.

Inhibition of thromboxane A(2)-induced Cl(-) secretion by antidiarrhea drug loperamide in isolated rat colon.

The antitumor drug irinotecan clinically causes severe diarrhea as a side effect. Thromboxane A(2) (TXA(2)), released by irinotecan, has been shown to be a novel physiological stimulant of Cl(-) secretion in the rat colon. Herein, we examined the effect of loperamide, an antidiarrhea drug, on Cl(-) secretion induced by irinotecan; 9, 11-epithio-11,12-methano-thromboxane A(2) (STA(2)), a stable TXA(2) analog; and prostaglandin E(2) (PGE(2)) by using isolated mucosae of the rat colon. In the presence of atropine, loperamide in a concentration-dependent manner inhibited the Cl(-) secretion induced by irinotecan, STA(2), and PGE(2). However, the drug inhibited more effectively the irinotecan- and STA(2)-induced secretion (IC(50) = 0. 7 and 1.2 microM, respectively) than the PGE(2)-induced secretion (IC(50) = 23 microM). Naloxone, an opiate antagonist, did not affect the antisecretory action of loperamide. Similar to the case for loperamide, W-7, a specific calmodulin antagonist, inhibited more effectively the STA(2)-induced Cl(-) secretion (IC(50) = 5 microM) than the PGE(2)-induced secretion (IC(50) = 36 microM). W-5, a low-affinity calmodulin antagonist (a dechlorinated control analog of W-7), also inhibited the STA(2)-induced secretion, but this effect was much less than that of W-7. STA(2)-induced increase in the intracellular free Ca(2+) concentration of single colonic crypt cells was not affected by loperamide. We suggest that loperamide efficiently inhibits the TXA(2)-induced secretion by blocking the calmodulin system in the colonic epithelium. The present results may explain why coadministration of loperamide with irinotecan is clinically efficient for avoiding the irinotecan-induced side effect of diarrhea.

Prostaglandin E(2)-activated housekeeping Cl(-) channels in the basolateral membrane of rat gastric parietal cells.

Cl(-) channels in the basolateral membrane of parietal cells within isolated rat gastric glands were studied by the whole-cell patch-clamp technique. The membrane potential (E(m)) of non-stimulated parietal cells changed as a function of the basolateral extracellular Cl(-) concentration (46 mV per decade), but E(m) did not change significantly as a function of the K(+) concentration. The extracellular addition of prostaglandin E(2) (PGE(2); 10 microM) increased the whole-cell Cl(-) current. A bifunctional prostaglandin EP3 agonist/EP1 antagonist, 5(Z)-7-[(1S, 2S,3S,5R)-3-(trans-beta-styren)sulfonamido-6,6-dimethylbi cyclo-(3.1. 1)hept-2-yl]-5-heptenoic acid (ONO-NT-012; 10 microM), also increased the Cl(-) current. Basal Cl(-) currents and the PGE(2)- and ONO-NT-012-increased Cl(-) currents were voltage-independent and inhibited by a Cl(-) channel blocker, 5-nitro-2-(3-phenylpropylamino)-benzoate (NPPB), at 500 microM. The single Cl(-) channel conductance was estimated to be 0.29 picosiemens (pS) by variance noise analysis. Both PGE(2) and ONO-NT-012 increased intracellular free Ca(2+) concentration in the fura-2-loaded parietal cell transiently. The present study has shown that housekeeping sub-pS Cl(-) channels are present in the basolateral membrane of rat parietal cell, and that the channels are regulated positively by PGE(2) via the EP3 receptor.

Thromboxane A2 receptor linked with the Ca2+ pathway in rat colonic crypt cells.

To clarify the presence of thromboxane A2 (TXA2) receptor in the colonic epithelium, we examined the effect of 9,11-epithio-11, 12-methano-thromboxane A2 (STA2), a stable analogue of TXA2, on intracellular free Ca2+ concentration ([Ca2+]i) of indo-1-loaded single cells in isolated rat colonic crypts by laser confocal microscopy. STA2 increased [Ca2+]i in a concentration-dependent manner with a transient peak phase and a subsequent plateau phase. The EC50 values at peak and plateau phases were 1 and 32 nM, respectively. The STA2-induced increase in [Ca2+]i was completely blocked by two selective TXA2 receptor antagonists, KW-3635 and ONO-3708. These antagonists did not affect both the basal [Ca2+]i and the carbaco-induced increase in [Ca2+]i. Prostaglandin E2 did not increase [Ca2+]i. These results indicate that the STA2-elicited increase in [Ca2+]i is mediated specifically by a TXA2 receptor in colonic crypt cells This is the first report showing the presence of a TXA2 receptor that is associated with Ca2+ mobilization in the colon.

Cyclic GMP-dependent cytoprotection against ethanol-induced damage in rabbit isolated gastric parietal cells.

Prostaglandin E2 stimulates a nitric oxide/cyclic GMP (NO/cGMP) pathway which activates basolateral Cl- channels in rabbit gastric parietal cells. We examined whether the NO/cGMP pathway protects parietal cells from ethanol (EtOH)-induced cytotoxicity, using a parietal cell-rich suspension purified from rabbit gastric mucosa. Cytotoxicity was assayed by measuring the release of a fluorescent dye from the cells. N2,O2-dibutyryl guanosine 3',5'-cyclic monophosphate (DBcGMP) showed a concentration-dependent protective effect against EtOH-induced cytotoxicity. The half-maximal effect of DBcGMP was observed at 24 microM. DBcGMP in a concentration-dependent manner opened the basolateral Cl- channels of parietal cells, the EC50 value being 44 microM. The EtOH-induced cytotoxicity decreased as the Cl- concentration of medium decreased. A 30-s treatment with 5-nitro-2-(3-phenylpropylamino)-benzoate (NPPB), an inhibitor of the Cl- channel, had a cytotoxic effect which was not prevented by pre-incubation with DBcGMP. The cytotoxic effects of EtOH and NPPB were additive and the NPPB effects did not depend on the medium Cl- concentration. The present study showed that cGMP protects the gastric parietal cell from EtOH-induced cytotoxicity, and this cytoprotection is related to basolateral Cl- channel activity in the plasma membrane via an unknown mechanism(s).

[Assessment method for supporting programs for social activities of the elderly by city, town and village governments in Japan].

OBJECTIVES: The authors developed a questionnaire to assess the activities of supporting programs for social activities for the elderly conducted by city, town and village governments, based on the number of such programs. This study aims to examine the validity of the questionnaire. METHODS: We conducted a study of 145 cities, towns and villages from two prefectures in Japan using the questionnaire. The questionnaire asks government officers whether they had each of 32 programs, and the number of programs in total, as well as each of four domains of social activities (i.e., employment, social participation/volunteering, education/training, individual activities) were calculated. They were also asked to classify each of the programs into one of four domains of social activity to which the programs were most related; they were asked to rate how active the programs were for each domain in their community. To examine the validity of the questionnaire, the following indicators were assessed: (1) proportion of reported programs which were not covered by the questionnaire; (2) concordance of classification of programs into four domains of social activity with those judged by government officers; (3) correlations between number of programs and self-rated activity levels by government officers; and (4) correlations of number programs with characteristics of cities, towns or villages. RESULTS: The results indicated that the list of programs covered most of the programs. Proposed classification of programs into four domains of social activities which they are most related to agreed with judgments by officials. The number of programs positively correlated with self-rated activity levels by officers for employment and education/training domains in both prefectures; and for social participation/volunteering and individual activities in one of the prefecture. The numbers of programs for employment of the elderly positively correlated with the total population of the community, number of staffs, proportion of people employed in the tertiary industries and total budget for social welfare of the elderly; it negatively correlated with proportion of people employed in the primary industries. CONCLUSION: It is suggested that the list of programs in the questionnaire is applicable and assessment based on the number of programs by four social activity domains is valid to some extent in either prefecture. The questionnaire can be improved further, e.g., by adding other programs to the list.

Protein kinase C-mediated up-regulation of Na+/Ca2+-exchanger in rat hepatocytes determined by a new Na+/Ca2+-exchanger inhibitor, KB-R7943.

The regulatory mechanism of the plasma membrane Na+/Ca2+-exchanger in isolated rat hepatocytes was studied using microspectrofluorometry and 45Ca2+ uptake methods. Exposure of single hepatocytes to low-Na+ solutions induced an increase in the intracellular Ca2+ concentration ([Ca2+]i) which depended on the presence of extracellular Ca2+. 2-[2-[4-(4-nitrobenzyloxy)phenyl]ethyl]isothiourea methanesulfonate (KB-R7943), a novel selective inhibitor of Na+/Ca2+-exchangers, inhibited the initial rate of [Ca2+]i increase induced by exposure to the low-Na+ solution (IC50 = 2 microM). KB-R7943 also reduced the initial rate of 45Ca2+ uptake (IC50 = 4 microM). The increase in [Ca2+]i induced by exposure to the low-Na+ solution was inhibited by pre-incubation with 1-(5-isoquinolinesulfonyl)-2-methylpiperazine (H-7, 50 microM), but not with N-[2-(methylamino)ethyl]-5-isoquinolinesulfonamide (H-8, 60 microM) or a tyrosine kinase inhibitor, genistein (100 microM). Furthermore, taurocholate and phorbol-12,13-dibutyrate, both of which activate protein kinase C, promoted the increase in [Ca2+]i. These [Ca2+]i increases were sensitive to KB-R7943. Our results indicate that the Na+/Ca2+-exchanger is up-regulated via protein kinase C. The activity of Na+/Ca2+-exchangers is not evident under normal physiological conditions, suggesting that the exchanger may be activated under pathophysiological conditions.

Thromboxane A2, released by the anti-tumour drug irinotecan, is a novel stimulator of Cl- secretion in isolated rat colon.

1. A camptothecin derivative, irinotecan (Cpt-11), is a topoisomerase I inhibitor and has a strong activity against a broad range of human cancer. One of the side-effects of this drug is diarrhoea. Here, we tried to determine the mediator of the irinotecan-induced Cl- secretion which may underlie this diarrhoea, using isolated mucosae of rat distal colon. 2. Irinotecan increased Cl- secretory current in a concentration-dependent manner across the mucosa, set between Ussing chambers. Thromboxane A2 (TXA2) has not been reported to date as a physiological stimulant of Cl- secretion in the distal colon. However, the major part of the present irinotecan-induced current was inhibited by selective thromboxane A2 receptor antagonists (KW-3635 and ONO-3708), and a selective thromboxane synthase inhibitor (Y-20811). In fact, we found that irinotecan stimulated the release of TXA2 in a concentration-dependent manner from the isolated mucosa into the bathing solutions. 3. Furthermore, 9,11-epithio-11,12-methano-thromboxane A2 (STA2), a stable analogue of TXA2, induced Cl- secretion, which was almost completely inhibited by the TXA2 receptor antagonists. 4. In single cells of isolated crypts, STA2 depolarized the cell and increased the membrane conductance, indicating that STA2 opened the apical Cl- channel of the crypt cells. 5. We conclude, therefore, that the irinotecan-induced endogenous TXA2 is a novel stimulant of the Cl- secretion from the crypt cells of distal colon.

ATP, thapsigargin and cAMP increase Ca2+ in rat hepatocytes by activating three different Ca2+ influx pathways.

The intracellular Ca2+ concentration ([Ca2+]i) in single isolated rat hepatocytes was measured using fura-2. Extracellular ATP induced La(3+)-sensitive and verapamil-insensitive Ca2+ influx together with Ca2+ release from intracellular Ca2+ stores. Incubation of hepatocytes with 2 microM thapsigargin produced a large prolonged increase in [Ca2+]i, which was insensitive to both 100 microM La3+ and 40 microM verapamil. Incubation with 1 mM dibutyryl cAMP increased [Ca2+]i in the presence of extracellular Ca2+ but did not in the absence of extracellular Ca2+, indicating that dibutyryl cAMP induces Ca2+ influx which was found to be sensitive to both La3+ and verapamil, without mobilizing Ca2+ from the intracellular pools. This study shows the presence of at least 3 different Ca2+ influx pathways in the plasma membrane: that is, 1) the ATP-induced, La(3+)-sensitive and verapamil-insensitive pathway; 2) the thapsigargin-induced, La(3+)-insensitive and verapamil-insensitive pathway; and 3) the cAMP-induced, La(3+)-sensitive and verapamil-sensitive pathway.

[Development of index of social activities for the elderly].

In order to develop indices of social activities for the elderly, two surveys with 2 year intervals were conducted on the same 5,201 elderly subjects in four areas in Japan using a self-administered questionnaire. Social activities were defined as "activities which required contact with society" and were measured by 4 major facets of social activities, which were based on 21 questions relating to job activity, socially-plated activities, learning activities, and personal activities. The results were as follows; 1. The Wilcoxon scores in indices for 4 facets were given in sex and age groups. 2. Means of scores of indices increased with the degree of social activities from a subjective judgment. 3. Rank correlation coefficients between indices in two surveys were 0.60-0.71 for the persons whose answers were "no" to the question "did degrees of your activities change over the two years?" 4. Differences between indices in two surveys were higher in the persons with answers of "increase" to the above question than those with answers of "no", and were lower in those with answers of "decrease". These findings suggest that indices are available for assessing social activities as indicated by the reproducibility, validity and responsiveness found in this study.

A cyclic GMP-dependent housekeeping Cl- channel in rabbit gastric parietal cells activated by a vasodilator ecabapide.

1. The membrane potential of rabbit gastric parietal cells is dominated by a Cl- channel with a subpicosiemens single channel conductance in the basolateral membrane. The effects of 3-[[[2-(3,4-dimethoxyphenyl)ethyl]carbamoyl]amino-N-methylbenzamide++ + (DQ-2511: ecabapide), a vasodilator, on the opening of this Cl-1 channel, the cyclic GMP content and the intracellular free Ca2+ concentration ([Ca2+]i) of parietal cells were investigated by whole-cell patch-clamp technique, enzyme immunoassay and Fura 2-fluorescence measurement. 2. Ecabapide stimulated the opening of the Cl-1 channel as determined by the reversal potential. This stimulation was concentration-dependent, and its EC50 value was 0.2 microM. Both the basal and ecabapide-induced openings of the channel were inhibited by 5-nitro-2-(3-phenylpropylamino)-benzoate (NPPB, 500 microM), a Cl- channel blocker. Another Cl- channel blocker, niflumic acid (500 microM) was much less effective. 3. The power spectra of the currents before and after the addition of ecabapide (10 microM) were analysed. Both spectra contained only one Lorentzian (1/f2) component. 4. 6-Anilino-5,8-quinolinedione (LY83583; 5 microM) which prevents activation of soluble guanylate cyclase, significantly inhibited both the basal and ecabapide (10 microM)-induced openings of the Cl- channel. 5. Ecabapide (0.01-100 microM) concentration-dependently elevated the cyclic GMP content in the parietal cell-rich suspension. The EC50 value was 0.2 microM. 6. In single Fura 2-loaded parietal cells, ecabapide (10-100 microM) did not increase [Ca2+]i. 7. These results indicate that ecabapide stimulates an intracellular production of cyclic GMP in the parietal cell without increasing [Ca2+]i, and leads to an activation of the housekeeping Cl- channel.

Lifestyle determinants for social activity levels among the Japanese elderly.

We conducted a self-administered questionnaire survey to a total of 5239 elderly persons in four areas in Japan in 1993, which inquired about past lifestyles and present social activities. Based on the survey data, we first developed social activity measures, and then examined associations of the present total social activity measure with past lifestyles and physical conditions. The lifestyles significantly associated with high social activity after 65 years of age were 'high educational attainment'; having been 'healthy', 'plump', 'physically active' and 'having had hobbies' at about 50 years of age; and having 'frequent intake of many kinds of foods' during 30-50 years of age. Intake during 30-50 years of age of Japanese-style foods (rice, soybean paste soup, bean curd, pickles), noodles, beans, plant roots and potatoes was not significantly linked with the social activity levels at old age in either males or females. The same was true for smoking and drinking habits at about 50 years of age. Our findings essentially suggest the importance of a positive attitude at middle age to maintain and promote health status and improve lifestyles in order to attain high social activity at old age.

[Social activities in the elderly].

In order to clarify the status of social activities in the elderly, and to investigate an association between social activities and age, ADL, and geographical area, a self-administered questionnaire survey was conducted on the aged population in four areas in Japan. Social activities was defined as "activities which required contact with society" and was measured by 4 major facets of social activity, which were based on 21 questions on job activity, socially-related activities, learning activities, and personal activities. A total index was also developed by summarizing the 4 major facets as an indicator of whether the elderly is socially active or not as a whole. The following major findings emerged from this survey: (1) Rank correlation coefficients between each item which comprised 4 major activities were relatively high; (2) Excluding two activities, "shopping" and "attending senior school", aged men were more actively involved than women; (3) Trend in degrees of social activities differed by age among the 4 major facets, i.e., (a) job activity decreased with age, (b) socially-related activities and learning activities increased up to about 75 years old, and decreased thereafter, (c) personal activities were unaltered up to about 80 years old, and then decreased, and; (4) The elderly with low ADL had the lowest representation among the "highly active" in 4 major facets and total index as well.

A prospective study of atrophic gastritis and stomach cancer risk.

The relation of atrophic gastritis, other gastric lesions and lifestyle factors to stomach cancer risk was prospectively studied among 3,914 subjects who underwent gastroscopic examination and responded to a questionnaire survey at the Aichi Cancer Center Hospital. During 4.4 years of follow-up on average, 45 incident cases of stomach cancer were identified at least three months after the initial examination. If the baseline endoscopic findings indicated the presence of atrophic gastritis, the risk of developing stomach cancer was increased 5.73-fold, compared with no indication at the baseline. The risk further increased with advancing degree of atrophy and increasing extension of atrophy on the lesser curvature. These trends in the relative risks were statistically significant (P = 0.027 and P = 0.041, respectively). The risk of developing stomach cancer was statistically significantly increased among subjects with gastric polyps, but not among those with gastric ulcer. Stomach cancer cases tended to consume more cigarettes, alcohol, rice, pickles and salted fish gut/cod roe and less fruits and vegetables and to have more family histories of stomach cancer than noncases, although these differences were not statistically significant. The results of the present study provide additional evidence on the relation between atrophic gastritis and stomach cancer and suggest a need for intensive follow-up of patients with atrophic gastritis and gastric polyps.

The risk and predictive factors for developing liver cancer among patients with decompensated liver cirrhosis.

Patients with decompensated liver cirrhosis (n 1441) and those with post-transfusion hepatitis (n 343), whose medical expenses were subsidized by the Aichi Prefectural Government, were followed up for three years by record linkage with the Aichi Cancer Registry. During the follow-up period, 122 incident cases of liver cancer were identified. Compared with the general population, patients with decompensated liver cirrhosis were at a 64.9 times greater risk (50.5 times in males and 100.4 times in females) and those with post-transfusion hepatitis were at a 9.4 times greater risk (8.9 times in males and 13.7 times in females) of developing liver cancer. Information on prognostic factors for 1,068 patients with decompensated liver cirrhosis was also collected in a questionnaire survey by the physicians in charge. Patients positive to hepatitis B surface antigen (HBs Ag) and those positive to HBe Ag had a significantly increased risk of subsequent liver cancer. The risk of developing liver cancer was positively associated with base-line levels of GPT and AFP and age and, inversely associated with total alcohol intake and female sex. In multivariate analyses, the associations with HBe Ag, AFP, sex and age remained statistically significant, whereas the associations with GPT, total alcohol intake and HBs Ag were of borderline significance.