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Patients with gout frequently have low urinary pH, though the underlying mechanism has not been identified. Recently, nephrolithiasis has been reported to be involved with renal manifestation of metabolic syndrome. The present study was conducted to clarify the mechanism of low urinary pH in gout patients. The relationships between urine pH and factors contributing to metabolic syndrome were investigated. In addition, the effects of PPAR alpha agonists on urine pH were examined. Patients with 24-hour urine samples below a level of pH 5.5 showed higher values for factors constituting metabolic syndrome, compared with those with 24-hour urine pH equal to or greater than 5.5. Multiple regression analysis demonstrated that HOMA index was the only contributing factor to low urinary pH in gout patients, except for serum uric acid. Administrations of PPAR alpha agonists significantly raised 24-hour urine pH levels in gout patients in accordance with a reduction in serum triglyceride concentration, probably through their activities to improve insulin resistance. Our results suggest that insulin resistance plays an important role in the development of low urinary pH in patients with gout and that PPAR alpha agonist is preferable for raising urinary pH of the gout patients with hypertriglyceridemia.

To determine the effects of allopurinol on beer-induced increases in plasma and urinary excretion of purine bases (hypoxanthine, xanthine, and uric acid), we performed three experiments on five healthy study participants. In the first experiment (combination study), the participants ingested beer (10 ml/kg body weight) eleven hours after taking allopurinol (300 mg). In the second experiment (beer-only study), the same participants ingested beer (10 ml/kg body weight) alone, while in the third experiment (allopurinol-only study), they took allopurinol (300 mg) alone. There was a two-week interval between each of the studies. Beer-induced increases in plasma concentration and urinary excretion of hypoxanthine in the combination study were markedly higher than those in the beer-only study. On the other hand, the sum of increases in plasma concentrations of purine bases in the beer-only study was greater than in the combination study, whereas the increase in plasma uridine concentration in the combination study did not differ from the beer-only study. In addition, allopurinol administration inhibited the beer-induced increase in plasma concentration of uric acid. These results suggest that abrupt adenine nucleotide degradation may increase plasma concentration and urinary excretion of hypoxanthine under conditions of low xanthine dehydrogenase activity, which is mostly ascribable to allopurinol. Further, the difference in the sum of increases in plasma concentrations of purine bases between the combination study and beer-only study was largely ascribable to a greater increase in urinary excretion of hypoxanthine in the combination study. In addition, allopurinol intake seems to be effective in controlling the rapid increase in plasma uric acid caused by ingestion of alcoholic beverages.

The means of measurement of adenosine and deoxyadenosine in urine was developed by separating adenosine and deoxyadenosine from other compounds using high-performance liquid chromatography with column switchings. This method is simple and convenient since no pretreatment of the urine is needed. Using this method, it could be demonstrated that urinary adenosine was higher in an adenosine deaminase (ADA) deficient patient who had a bone marrow transplant treatment (1.97 micromol/mmol creatinine) and in a heterozygote who had a markedly low erythrocyte ADA activity (1% of control ADA activity) (1.33 micromol/mmol creatinine) as compared to normal subjects (0.22+/-0.09 micromol/mmol creatinine, n=11). It was also noted that urinary deoxyadenosine was below the detection limits in the ADA-deficient bone marrow transplant patient, but it was detected in the heterozygote (3.7 micromol/mmol creatinine). Furthermore, it was also demonstrated that a fructose infusion increased the urinary concentration of adenosine from 0.21+/-0.03 to 2.66+/-1.21 micromol/mmol creatinine in five normal subjects.

Psoriatic arthritis (PA) is an immune disease associated with HLA-A2 in the Japanese population. To investigate mechanisms the association between HLA-A2 and PA, we examined in vivo immune responsiveness to Streptococcus pyogenes. Recombinant M proteins for the subtype specific N-terminal half (AB region) and conserved C-terminal half (C region) were produced separately. IgG antibody level against each region was measured by ELISA in 31 PA patients, 88 patients with psoriasis vulgaris, 6 patients with rheumatoid arthritis and 77 healthy controls. We found that IgG antibody levels against the C region were markedly higher in the PA patient group than in the other disease groups or controls. Further, IgG antibody levels were higher in PA patients with spondylitis and polyarticular arthritis than in PA patients with rheumatoid-like arthritis and arthritis mutilans. In contrast, no significant difference in the IgG antibody levels against the AB region was observed among the tested groups. HLA-A2 DNA typing showed that HLA-A*0207 was associated with PA (RR = 17.6; pcorr < 0.01) and the IgG antibody responses to the C region correlated well with the presence of HLA-A*0207. These results suggest that streptococcal infection may be involved in the pathogenesis of PA by participating in the HLA-linked immune responsiveness.

Using logistic regression analysis, we investigated whether or not excessive alcohol intake and increased BMI, both of which are known causes of lipid metabolism abnormality, are associated with increased serum triglyceride, apolipoprotein B concentrations and decreased high-density lipoprotein cholesterol (HDL-C), high-density lipoprotein 2 cholesterol (HDL2-C) levels in patients with gout. Serum triglyceride levels were significantly higher in patients with gout than in normal subjects. In contrast, serum levels of HDL-C and HDL2-C were significantly lower in patients with gout than in normal subjects. These results were further analysed using stepwise logistic regression. This analysis demonstrated that both serum triglyceride levels and alcohol consumption discriminated subjects with gout from controls but BMI, HDL-C and HDL2-C did not, suggesting that increased serum triglyceride levels exist intrinsically in gout, while decreased concentrations of HDL-C and HDL2-C may be attributed to hypertriglyceridaemia.

When treating gout patients, we have incidentally found elevated serum levels of adiponectin in some after administration of benzbromarone. In the present study, we determined whether benzbromarone increases the serum level of adiponectin in gout patients and investigated the mechanism involved. Sixty-nine patients with gout were separated into two groups, and then treated for 1 year with uric acid-lowering therapy using benzbromarone or allopurinol. After overnight fasting, blood samples were drawn before and at 1 year after beginning of treatment. In an in vitro study, 3T3L1 cells were incubated in medium containing benzbromarone, allopurinol, pioglitazone, or uric acid, after which real time PCR assays were performed for messenger RNA of adiponectin, aP2, and CD36. Furthermore, 3T3L1 cells were incubated in medium containing GW9662 (PPARgamma antagonist) together with benzbromarone or pioglitazone, after which real-time PCR assays were performed for messenger RNA of adiponectin. In the in vivo study, benzbromarone increased the serum concentration of adiponectin in the subjects, whereas allopurinol did not. In vitro, benzbromarone and pioglitazone each increased the levels of messenger RNA of adiponectin, aP2, and CD36 in 3T3 cells, whereas allopurinol and uric acid did not. Also, GW9662 suppressed the increase in adiponectin mRNA induced by benzbromarone as well as that by pioglitazone. Together, our results suggest that benzbromarone enhances the production of adiponectin via activation of PPARgamma, which is a weak agonist for PPARgamma.

To investigate the long-term effects of beer ingestion on plasma concentrations of purine bases (hypoxanthine, xanthine, and uric acid), ten healthy males ingested beer (15 ml/kg body weight) every evening for three months. Blood and 24-hour urine samples were collected in the morning on one day before and one, two, and three months after starting the experiment to determine the plasma concentrations and urinary excretion of uric acid, hypoxanthine, and xanthine. Plasma concentrations and urinary excretion of uric acid, hypoxanthine, and xanthine in five of the participants that did not regularly ingest beer at a quantity of more than 15 ml/kg body weight in a single day prior to the experiment were not increased during the experimental period. In contrast, plasma concentrations and urinary excretion of uric acid were increased in five participants who regularly ingested more than 15 ml/kg body weight of beer in a single day prior to the experiment, although hypoxanthine and xanthine levels were not significantly increased during the experimental period. In both groups, uric acid clearance and purine ingestion were not significantly different throughout the study. Our results suggest that the production of uric acid caused by ethanol ingestion from beer is a significant contributor to the increase in plasma uric acid concentration in patients that regularly consume more than 15 ml/kg body weight of beer each day. Therefore, patients with gout should be encouraged to refrain from drinking large amounts of beer on a daily basis.

To determine whether purine-free and regular low-malt liquor beverages (happo-shu) increase the plasma concentration and urinary excretion of purine bases (hypoxanthine, xanthine, uric acid) and uridine, 6 healthy males were given regular (10 ml/kg of body weight) and purine-free happo-shu (10 ml/kg of body weight). Plasma concentration-time curves were plotted, and the areas under the curves for uric acid and total purine bases (the sum of hypoxanthine, xanthine, and uric acid) were greater in the regular than in the purine-free happo-shu ingestion experiment (both p < 0.05). In addition, the total urinary excretion of xanthine, total purine bases, and uridine was greater in the regular than in the purine-free happo-shu ingestion experiment (p < 0.05 in all cases), although the total urinary excretion of hypoxanthine and uric acid was no different between the regular and the purine-free happo-shu ingestion experiments. These results suggest that uridine contained in regular happo-shu might contribute to an increase in the urinary excretion of uridine along with ethanol, and that the purines contained in regular happo-shu may contribute to the increase in plasma concentration of uric acid due to purine degradation.

A 64-year-old man was admitted to our hospital because of general fatigue and drowsiness. On admission, a physical examination disclosed dehydration and a laboratory investigation revealed the following values: plasma glucose, 1309 mg/dl; serum sodium, 160 mmol/l; potassium, 3.0 mmol/l; urea nitrogen, 65 mg/dl; creatinine, 2.73 mg/dl; and plasma osmolarity, 403 mOsm/kg. Urine ketone bodies were negative. A diagnosis of hyperosmolar non-ketotic diabetic syndrome was made, and hydration with an infusion of hypotonic saline (0.45%) and insulin therapy were immediately started. However, despite adequate rehydration and correction of blood glucose, his serum creatinine level increased to 3.1 mg/dl, while oliguria and myoglobinuria developed on the 4th hospital day, with serum creatine kinase increasing up to a maximum level of 16,749 IU/l, suggesting rhabdomyolysis. A final diagnosis of hyperosmolar non-ketotic diabetic syndrome associated with rhabdomyolysis and acute renal failure was made. His renal function gradually improved without hemodialysis, though acute renal failure due to rhabdomyolysis with hyperosmolar non-ketotic diabetic syndrome can sometimes be fatal. This rare case is presented along with a review of literature.

To investigate whether fenofibrate increases the clearance of purine bases (hypoxanthine, xanthine, uric acid) and oxypurinol.We administered fenofibrate (150 mg) 3 times a day for 3 days, and then allopurinol (300 mg) 4 h after the last administration of fenofibrate, to 5 healthy subjects. Ten hours later, a clearance study was done.Following 3 day administration of fenofibrate, fractional clearance of xanthine, uric acid, and oxypurinol increased by 41% (p0.05), 101% (p0.01), and 51% (p0.01), respectively, compared to baseline values, while the respective plasma concentrations decreased by 46% (p0.05), 46% (p0.05), and 19% (p0.05).Our results suggest that fenofibrate, fenofibric acid, or fenofibrate derivatives can increase fractional clearance of xanthine, uric acid, and oxypurinol by acting on their common renal pathways. It is suggested that the hypouricemic effect of combination therapy using allopurinol and fenofibrate may be less than additive.

Aldehyde oxidase (EC 1.2.3.1) is a xenobiotic metabolizing enzyme that catalyzes a variety of organic aldehydes and N-heterocyclic compounds. However, its precise pathophysiological function in humans, other than its xenobiotic metabolism, remains unknown. In order to gain a better understanding of the role of this enzyme, it is important to know its exact localization in human tissues. In this study, we investigated the distribution of aldehyde oxidase at the cellular level in a variety of human tissues by immunohistochemistry. The enzyme was found to be widespread in respiratory, digestive, urogenital, and endocrine tissues, though we also observed a cell-specific localization in the various tissues studied. In the respiratory system, it was particularly abundant in epithelial cells from the trachea and bronchium, as well as alveolar cells. In the digestive system, aldehyde oxidase was observed in surface epithelia of the small and large intestines, in addition to hepatic cells. Furthermore, the proximal, distal, and collecting tubules of the kidney were immunostained with various intensities, while glomerulus tissues were not. In epididymus and prostate tissues, staining was observed in the ductuli epididymidis and glandular epithelia. Moreover, the adrenal gland, cortex, and notably the zona reticularis, showed strong immunostaining. This prevalent tissue distribution of aldehyde oxidase in humans suggests some additional pathophysiological functions besides xenobiotic metabolism. Accordingly, some possible roles are discussed.

Uric acid overexcretion in patients with gout is frequently assessed by the measurement of 24 hour urinary uric acid excretion, which is cumbersome with ambulatory patients, and requires accurate timing and complete collection of the specimen. We assessed whether uric acid to creatinine ratio (Uua/Ucr) in spot urine is useful for the estimation of uric acid overexcretion in patients with gout.One hundred thirty male patients with gout and 33 non-gout male control subjects were studied. Early morning urine and/or a portion of 24 h collected urine (24 h urine) were used as spot urine samples. Uric acid overexcreters were defined as those with a 24 h urinary uric acid excretionor = 1000 mg/day, while uric acid underexcreters were defined as those with uric acid clearance6 ml/min.There was a significant relationship between 24 h urinary uric acid excretion and early morning urine Uua/Ucr in patients with gout, while no such relationship was observed in controls. No significant difference in Uua/Ucr was observed between patients with gout and controls, or in Uua/Ucr between gout uric acid overexcreters and underexcreters in early morning urine. A significant difference in this value was observed between the 2 groups in the 24 h urine specimens. Although the diagnostic accuracy of gout uric acid overexcretion was 87.2% using early morning urine and 89.6% using 24 h urine, the sensitivity of gout uric acid overexcretion was only 25.0% when using early morning urine and 25.0% when using 24 h urine, when the cutoff value of Uua/Ucr was 0.63 and 0.64, respectively.Uua/Ucr using spot urine, especially early morning urine, is not an accurate indicator of uric acid overexcretion in patients with gout.

Opportunities of observing patients with recurrent early gastric cancer are rare. Assessment of prognostic factors for the recurrence of early gastric cancer is important for determining adequate strategies for managing early gastric cancer.Clinicopathologic variables were compared in 8 patients with and 453 without recurrence who were followed for over 5 years after curative resection. Expression of mutant p53 and Ki-67 was evaluated in 16 patients with n2 or above.Eight patients died of gastric cancer with recurrence. There were no inter-group differences in mean diameter, histologic classification, patterns of infiltrating growth, or cancer-stroma relationship; but macroscopic appearance, depth of invasion, lymphatic invasion, venous invasion and lymph node metastases were significantly more frequent on univariate analysis in those with recurrence. Lymph node metastases was an independent prognostic factor by the Cox proportional hazards regression model. In patients with n2 or above, mutant p53 expression was higher in recurrent than in nonrecurrent cases.Lymph node metastasis was the only independent prognostic factor for the recurrence of early gastric cancer. The expression of mutant p53 may be an indicator of recurrence in patients with n2 or above.

To examine whether losartan affects the plasma concentrations and urinary excretion of purine bases and oxypurinol.We administered allopurinol (300 mg) and then 9 h later losartan potassium (100 mg) to 5 healthy subjects.The urinary excretion of uric acid increased by 3.9- and 2.6-fold, and that of oxypurinol by 2- and 1.8-fold, at 1 to 2 h and at 2 to 3 h, respectively, after administration of losartan potassium. The fractional clearance of uric acid was increased by 4.3- and 3.2-fold, oxypurinol by 2.3- and 2.1-fold, and xanthine by 1.32- and 1.26-fold, at 1 to 2 h and at 2 to 3 h, respectively, after administration of losartan potassium. The plasma concentrations of uric acid decreased by 8% and 16%, oxypurinol by 7% and 11%, and xanthine by 42% and 45%, at 1.5 and 2.5 h, respectively, after oral administration.These results suggest that losartan potassium could increase urinary excretion of uric acid, xanthine, and oxypurinol by acting on their common renal transport pathways, since it was found that uric acid may share a renal transport pathway with oxypurinol and xanthine. It is also suggested that the effect of losartan potassium on oxypurinol and uric acid is clinically important, since the hypouricemic effect of a combination therapy using allopurinol and losartan potassium may be less than additive, while the uricosuric effect of losartan potassium may increase the frequency of calculi in the urinary tract.

We investigated the antiemetic effect, safety and usefulness of granisetron hydrochloride tablets on nausea and vomiting induced by oral anticancer drugs used in chemotherapy for gastric cancer and colorectal cancer. In the present trial, oral administration of granisetron hydrochloride was performed during 5 days after nausea or vomiting. 1) Clinically, the effective rate of granisetron hydrochloride (the percentage of cases in which the drug was assessed as "Remarkably effective" or "Effective") was more than 75% on each day of administration. There were no adverse events or abnormal laboratory tests. 2) In terms of usefulness, granisetron hydrochloride was rated "Extremely useful" or "Useful" in 17 out of 23 cases (78.2%). The above results have shown that granisetron hydrochloride tablets, administrated orally once daily at a dose of 2 mg, have an excellent antiemetic effect, and that this is a safe and useful drug.

The surgical results for stage IVb gastric cancer remain very poor. The purpose of the current study is to reveal indications for paraaortic lymph node dissection in stage IVb gastric cancer patients with paraaortic lymph node involvement by analyzing prognostic factors for 3-year survival of stage IVb gastric cancer patients followed by curative B resection.The 3-year survival in clinicopathologic variables were compared by univariate analysis. Using Cox proportional hazards regression model, independent prognostic factors were identified from 11 variables.Overall 5-year survival in stage IVb was 26.5%; mean survival was 19 months. Using univariate analysis, p53 expression significantly influenced 3-year survival. Using Cox proportional hazards regression model, the number of total positive lymph nodes, the number of positive paraaortic lymph nodes, and p53 expression were independent prognostic factors.In stage IVb, paraaortic lymph node dissection should be indicated in patients withor = 10 total positive lymph nodes, andor = 3 positive paraaortic lymph nodes or p53 expressionor = 50%. This indication can be applied according to the preoperative imaging, the staining of p53 by endoscopic biopsy specimens and the intraoperative microscopic evaluation of dissected lymph nodes.

Hyperlipidaemia is a common feature of nephrotic syndrome and this has been thought to involve increased assembly and secretion of very low density lipoprotein (VLDL) in the liver. An important pathway for an indirect modulation of VLDL. Synthesis is the reaction catalyzed by the acyl-coenzyme A:1-acyl-glycero-phosphcholine acyl transferase. We therefore investigated the activity of this enzyme in liver microsomes isolated from puromycin amino nucleoside induced nephrotic rats. When oleoyl-CoA was employed as the acyl-donor, our results indicated that both the total and detergent soluble enzyme activities (112.2 +/- 16.7; 116.1 +/- 17.5 units, respectively) were significantly higher than the corresponding control levels of 91.1 +/- 11.1 and 75.4 +/- 20.9 units respectively. The percentage stimulation by sodium cholate were 176.5 and 192.2 for the control and nephrotic rats, respectively. In absence of sodium cholate, when oleoyl CoA was replaced by arachidonoyl-CoA as acyl-donor, the measured total enzyme activity was only significantly reduced in the control rats (71.1 +/- 8.9 Vs 91.1 +/- 11.1 Units). Oleoyl-CoA as acyl-donor gave higher values for the soluble and residual enzyme activities (90.4 13.3; 99.5 34.5 unit) than the corresponding control levels (75.9 +/- 10.0; 50.5 +/- 34.0 units) as compared to arachidonoyl-CoA. In the control group the difference was only significant in the residual activity (92.9 20.5 Vs 64.7 24.1 units). The addition of monomethylethanomine (200 mM) had little or no effect, while both reduced glutathione (10 mM) and 1,2-diacylglycerol (1 mM) caused significant reduction in measured activity. These results indicated that in nephrotic rats new phospholipid synthesis is enhanced and this could contribute to the increased VLDL assembly and secretion usually associated with nephrotic syndrome.

The distribution of aldehyde oxidase activity was evaluated in unfixed cryostat sections from tissues of male Wistar rats using a tissue protectant, polyvinyl alcohol, with Tetranitro BT as a final electron acceptor. The distribution of aldehyde oxidase activity was compared with that of xanthine oxidoreductase. The enzyme histochemical method demonstrated aldehyde oxidase activity in the epithelium of the tongue, renal tubules and bronchioles, as well as in the cytoplasm of liver cells. Such activity was not detected in oesophagus, stomach, spleen, adrenal glands, small or large intestine or skeletal and heart muscle fibres. In contrast, xanthine oxidoreductase activity was demonstrated in the tongue, renal tubules, bronchioles, oesophageal, gastric, small and large intestinal epithelial cells, adrenal glands, spleen and liver cytoplasm but not in skeletal and heart muscle fibres. The significance of the ubiquitous distribution of aldehyde oxidase activity, especially in surface epithelial cells from various tissues, except for the gastrointestinal tract, is unclear. However, aldehyde oxidase may possess some physiological activity other than in the metabolism of N-heterocyclics or of certain drugs.

We describe an enzymatic histochemical localization of two allopurinol-oxidizing enzymes, xanthine oxidase and aldehyde oxidase in rat hepatic tissues. This method is based on the tetrazolium salt procedures by use of a tissue protectant, polyvinyl alcohol, with tetra-nitro BT as the final electron acceptor. The present study demonstrated that both oxidases are present in the cytoplasm of hepatic cells. However, the distribution of the enzymes was uneven, being seen mainly in the pericentral rather than the periportal area. When allopurinol was used as a substrate, the specific staining by xanthine oxidase was more prominent than that of aldehyde oxidase. The results suggested that xanthine oxidase is more effective in oxidizing allopurinol than aldehyde oxidase.

The effect of Tofu (bean curd) ingestion on uric acid metabolism was examined in 8 healthy and 10 gout subjects. Ingestion of Tofu increased plasma concentration of uric acid, together with increases in uric acid clearance and urinary excretion of uric acid. However, the increase in plasma concentration of uric acid was fairy small. Interestingly, no significant rise in the plasma, urinary and clearance of uric acid was observed in gout patients with uric acid clearance6.0 mL/min (lower normal limit). The results suggest that tofu is a preferable source of protein, especially in gout patients with uric acid clearance6.0 mL/min.

Changes in intraocular pressure were studied in 141 eyes following intraocular lens implant. The average observational time was twelve years. We tried to fix both loops of the implant in the ciliary sulcus. The intraocular pressure increased over the ten year interval at 0.19 mmHg per year. Twenty-seven of the 141 eyes developed glaucoma. We studied the intraocular pressure of the cases with or without complications. Thirty-eight eyes had complications, fifteen eyes (39%) developed secondary glaucoma, and three eyes (8%) developed glaucomatous visual field defect. In twenty-three cases without secondary glaucoma, the intraocular pressure increased over a three-year interval after surgery and remained constant thereafter. 103 eyes had no complications to influence the intraocular pressure, twelve eyes (12%) developed secondary glaucoma, and four eyes (4%) developed glaucomatous visual field defect. In 91 cases without secondary glaucoma, the intraocular pressure increased over a five-year interval after surgery at 0.28 mmHg per year and remained constant thereafter. We recommend regular examination, especially during the initial five-year period when the intraocular pressure is apt to increase even if complications are not evident.

To investigate whether glucagon increases the urinary excretion of oxypurinol and purine bases.We administered 1 mg glucagon intravenously to 5 healthy subjects taking 300 mg allopurinol orally, and determined plasma concentrations and urinary excretion of oxypurinol and purine bases.Glucagon increased the urinary excretion and fractional clearances of uric acid, xanthine, and oxypurinol, together with an increase in creatinine clearance, while it decreased plasma concentrations of xanthine and hypoxanthine.Glucagon-induced increases in urinary excretion of uric acid, xanthine, and oxypurinol were attributable to increases in the fractional clearances of uric acid, xanthine, and oxypurinol in addition to an increase in glomerular filtration rate. It is suggested that glucagon affects the renal common transport pathway of uric acid, xanthine, and oxypurinol by stimulating the release of a liver derived renal vasodilator.

The lipid components of very low density lipoproteins (VLDL) were significantly elevated in the nephrotic rats. Also the nephrotic VLDL particles had a significantly higher ratio of surface lipids (FC + PL) to core lipids (TG + CE) probably indicating production of smaller sized VLDL in the nephrotic rats. Electron microscopy showed VLDL particles with a reduced mean size in the nephrotic rats. The activities of VLDL core lipid synthesizing enzymes were evaluated in experimental nephrotic syndrome. In addition, the effects of exogeneous cholesterol, 25-OH-cholesterol and low density lipoprotein (LDL) on the acyl-coenzyme A: cholesterol acyltransferase (ACAT) activity were investigated as well. ACAT activity in nephrosis was normal, but stimulated to varying extents in the presence of these factors. On the other hand, the acylcoenzyme A:1,2-diacylglycerol acyltransferase (ADGAT) and phosphatidate phosphorylase-activities were significantly increased in the nephrotic rats. The microsomal cholesterol (free and ester) and phospholipid concentrations were normal but the triglyceride level was significantly reduced in the experimental group. We speculate that an excess production of smaller-sized VLDL particles due to altered activities of microsomal lipid synthesizing enzymes may occur in puromycin amino nucleoside induced-nephrotic rats.

To investigate how much the metabolism of allopurinol, oxypurinol, and purine bases during dietary intake (total calorie 2,083 kcal, total protein 107.5 g, total lipid 74.1 g, total carbohydrate 228.3 g, total purine 180.5 mg) differs from that during fast, allopurinol (300 mg) was administered to 5 normal subjects after a 6-hour fast and then breakfast was taken. Four and 10 hours after the administration of allopurinol lunch and dinner were taken, respectively. Two weeks later the same protocol was performed, except for the intake of only water instead of diet. The fractional clearances and urinary excretions of oxypurinol, uric acid, and the clearance of creatinine were increased by dietary intake, compared with the respective ones resulting from fasting. At the same time the plasma concentrations of hypoxanthine, xanthine, and oxypurinol were decreased in dietary intake, compared with the respective ones in fasting, while the urinary excretion of neither allopurinol, hypoxanthine, nor xanthine was affected. These results suggest that the administration of allopurinol at bed time (during the nocturnal fast) may be more effective than that after breakfast in order to decrease the plasma concentration of uric acid.

This study was undertaken to determine whether atrial natriuretic peptide (ANP)-, C-type natriuretic peptide (CNP)-, and nitric oxide (NO)-cyclic guanosine monophosphate (cGMP) pathways exist in the rat retina. Exposure of the retina to ANP (10(-7)M), CNP (10(-7)M), S-nitroso-N-acetylpenicillamine (10(-5)M, SNAP; a NO doner), A23187 (10(-5)M; a Ca2+ionophore), and carbachol (10(-5)M) caused 1.45-1.67 fold increases in cGMP content (p0.01). Carboxy-PTIO (10(-3)M; a NO scavanger) blocked the increase in cGMP induced by A23187. Both carboxy-PTIO (10(-3)M) and NG-nitro-L-arginine (10(-3)M, L-NNA; a NO inhibitor) blocked the increase in cGMP induced by carbachol. Atropine (10(-5)M; a muscarinic receptor antagonist) also blocked the cGMP increase induced by carbachol. These data demonstrate that ANP-, CNP- and NO-cGMP pathways exist in the retina and that the NO-cGMP pathway may be linked to the activation of the muscarinic receptor.

We investigated the effect of xylitol on the plasma concentration and the urinary excretion of purine bases, 5-hydroxypyrazinamide and 5-hydroxypyrazinoic acid in subjects who had ingested pyrazinamide (60 mg/kg weight). One liter of 10% xylitol was infused intravenously over 2 hours to 5 subjects to whom pyrazinamide had been administered 10 hours before. Xylitol increased the plasma concentration of uric acid, hypoxanthine and xanthine, the urinary excretion of hypoxanthine and a ratio of lactic acid/pyruvic acid in blood, while it decreased the plasma concentration and the urinary excretion of inorganic phosphate, 5-hydroxypyrazinamide and 5-hydroxypyrazinoic acid. These results suggested that in addition to an increase in purine degradation by xylitol, xylitol-induced increase in the cytosolic NADH inhibited xanthine dehydrogenase activity in the liver and the small intestine.

A case of thoracic empyema after artificial pneumothorax for lung tuberculosis was presented, which extended into the abdominal cavity. 65 years old man, who was operated on for lung tuberculosis about 30 years ago, took the routine physical examination and the abdominal mass was picked up on examination. Echogram and CT showed huge homogeneous mass in the right thorax and the right upper abdominal cavity. The operative finding showed that thoracic empyema extended into the abdominal cavity and formed a huge mass. Decortication and extirpation of thoracic empyema and abdominal mass was performed with a combined partial resection of the lung, diaphragma, and thoracic wall. The histopathology of the abdominal mass showed chronic empyema and hematoma.

Allopurinol or pyrazinamide was administered to rats treated with BOF-4272 (a potent xanthine oxidase inhibitor) to investigate to what degree xanthine dehydrogenase participates in the oxidation of these agents. BOF-4272 markedly decreased the plasma concentration and the urinary excretion of both oxypurinol and 5-hydroxypyrazinamide. It also decreased the sum of the urinary excretion of allopurinol and oxypurinol and that of pyrazinamide and its metabolites, although it did not affect the sum of the plasma concentrations of allopurinol and oxypurinol at 105 min after administration of allopurinol or the plasma concentration of pyrazinamide during the period after the administration of pyrazinamide. These results suggested that BOF-4272 almost completely inhibited the oxidation of allopurinol and pyrazinamide and had some effect on the excretion and/or the tissue incorporation of these two compounds. Since the in vitro study demonstrated that BOF-4272 did not inhibit the activity of aldehyde oxidase, which oxidized both allopurinol to oxypurinol and pyrazinamide to 5-hydroxypyrazinamide, the results suggested that xanthine dehydrogenase was the more important enzyme in converting allopurinol to oxypurinol and pyrazinamide to 5-hydroxypyrazinamide.

To evaluate the effect of surgical treatment for spontaneous pneumothorax, we examined eighty patients who underwent the surgical treatment. Out of these, thirty five patients (53.0%) were the recurrent episode of the disease, since we vigorously chose surgical treatment for the second attack of the disease. Operative complications were observed in 6 cases (7.1%) including 2 cases of lasting air leakage and 1 case of bleeding, pneumonia, wound infection and atelectasis. Postoperative recurrence was not seen. From a viewpoint of prevention of the postoperative recurrence, the surgical treatment is effective and safe method.

Ischemia and reperfusion experiments were carried out using rat small intestine. Intestinal segment and supplying vessels was occluded and released after following procedure: In group I, 60 minute occlusion. In group II, 30 minute occlusion-10 minute release-20 minute occlusion. In group III, superoxide dismutase (SOD) and catalase (CAT) were given during the period of intermittent release in the same time schedule as in group II. Tissue damage was evaluated histopathologically and lipid peroxide (LPO) of involved segment and chemiluminescence (CL) of draining venous blood was investigated. It was concluded as follows: 1. In these experiments, the tissue damage and the increment of LPO and CL were severer in group II than in group I. Then, the reactive oxygen species (ROS) derived from neutrophils was thought to play an important role in the tissue damage. 2. At the end of intermittent release, LPO and CL increased in group II, and these increments were suppressed by SOD and CAT treatment in group III. 3. After last release, the tissue damage in group II was diminished in group III. The severe tissue damage after intermittent occlusion is thought to be caused by reperfusion injury during the intermittent release.

We administered xylitol intravenously to normal subjects to investigate the mechanism of xylitol-induced increase in the purine degradation in humans. Xylitol increased the plasma concentrations of hypoxanthine, xanthine and uric acid but decreased the blood concentration of pyruvic acid. The erythrocyte concentrations of IMP, AMP, ADP, glyceraldehyde 3-phosphate and fructose 1,6-diphosphate as well as the urinary excretion of hypoxanthine and xanthine were increased, while the erythrocyte concentration of ATP was decreased. In addition, the in vitro incubation studies using erythrocytes demonstrated that both xylitol-induced purine degradation and xylitol-induced inhibition of the conversion of glyceraldehyde 3-phosphate to 1,3-bisphosphoglycerate were protected by pyruvic acid. These results indicate that xylitol-induced impairment of glycolysis in erythrocytes contributes to the observed xylitol-induced increase in the purine degradation in the body.

It has been reported that some of the topically-used antiglaucomatics have a central ocular hypotensive effect. In this study, the influence of topical and intracerebroventricular (i.c.v.) administration of phenylephrine, clonidine, guanfacine, prazosin, yohimbine on the intraocular pressure (IOP) was investigated in the rabbit. Male pigmented rabbits were used throughout the experiments. For measurement of IOP, an applanation pneumatonograph was used. By unilateral topical administration of phenylephrine, an increase in IOP in the eye in which instillation was performed was observed. On the other hand, a slight decrease in IOP was observed by similar treatment of prazosin and yohimbine. No significant change of IOP in the contralateral eye was observed with these drugs. On the contrary, unilateral topical administration of clonidine or guanfacine decreased the IOP of both eyes. Furthermore, the decrease of IOP was more remarkable in the contralateral eye compared to the eye which received instillation. The IOP of both eyes was decreased in a dose-related fashion by i.c.v. administration of clonidine or guanfacine. The ocular hypotensive effects of clonidine were diminished by the pretreatment by i.c.v. administration with yohimbine. These results suggest that the ocular hypotensive effect of clonidine and guanfacine is due to their alpha 2-adrenoceptor stimulation in the central nervous system.

The contribution of sympathetic cervical ganglion to the mechanism of action of clonidine for lowering intraocular pressure (IOP) was investigated. Pigmented rabbits were used. The animals were divided into 3 groups: normal control group (group 1), animals in which the bilateral cervical sympathetic trunks had been amputated presynaptically (group 2), animals in which the superior cervical ganglion (SCG) had been bilaterally dissected (group 3). Changes in IOP were measured after topical application of clonidine unilaterally. In group 1, IOP was significantly decreased in eye treated by clonidine and contralateral eyes compared to pretreatment values. Decrease of IOP in the contralateral eye was greater than that in the treated eye. In group 2, IOP was decreased in the contralateral eye but increased in the eye treated by clonidine. Pretreatment of yohimbine administered orally antagonized the ocular hypotensive effect of clonidine in a dose-related manner. In group 3, where SCGs were dissected, no changes in IOP were observed in both eyes by unilateral administration of clonidine. These results suggested that the bilateral ocular hypotensive effect of clonidine administered unilaterally is in part due to direct action on the SCG and that the alpha 2 receptor in the SCG plays some role in the regulation of IOP.

The effect of theophylline on the concentration of uric acid in plasma was investigated. Theophylline increased the plasma concentrations of purine bases (uric acid, hypoxanthine and xanthine) without a decreased urinary excretion of these purine bases in normal subjects. 1-methyl uric acid, a metabolite of theophylline, was not converted to uric acid in a detectable level by the hepatoma-derived cell line HuH-7 cells. Although theophylline affected neither the concentration of nucleotides nor the activities of the enzymes related to purine metabolism (hypoxanthine-guanine phosphoribosyl transferase, 5'-nucleotidase, adenosine deaminase and purine nucleoside phosphorylase) in erythrocytes, these results suggested that theophylline-induced purine degradation seems to be a cause of the increased concentration of uric acid in plasma.

The antibody was raised against purified human liver xanthine oxidase in a rabbit. In a xanthinuric patient, the double immunodiffusion method demonstrated the existence of an immunologically reactive duodenal mucosa xanthine oxidase which did not possess xanthine oxidase activity. These results indicated that xanthine oxidase protein is abnormal in structure and/or amino acid sequence.

Intake of completely purine-free foods of low sodium content increased the plasma concentrations of both hypoxanthine and inosine and the urinary excretion of hypoxanthine, while it decreased the urinary excretion of uric acid and the fractional clearance of uric acid. However, this diet affects neither nucleotides (inosine monophosphate, adenosine monophosphate, adenosine diphosphate and adenosine triphosphate) in red blood cells, enzymes (purine nucleoside phosphorylase, adenosine deaminase and hypoxanthine guanine phosphoribosyl transferase) in red blood cells nor the fractional clearance of oxypurines. These results suggest that the salvage of purines becomes more effective by limiting the conversion of hypoxanthine to xanthine and limiting the loss of uric acid during intake of completely purine-free foods of low sodium content; also that a decrease in the fractional clearance of uric acid due to completely purine-free foods of low sodium content may be an additional mechanism associated with the conservation of purines but is more likely to be a response to the low sodium diet on the renal handling of uric acid.

Both the benzbromarone loading test alone and the pyrazinamide suppression test combined with the benzbromarone loading test were performed in four healthy male volunteers to examine the renal handling of uric acid and to demonstrate whether benzbromarone selectively blocks postsecretory reabsorption. On the basis of the four-component theory, equations of four states of fractional uric acid clearance were constructed: 1) the control state, the states of 2) benzbromarone loading, 3) pyrazinamide suppression and 4) both pyrazinamide suppression and benzbromarone loading. As a result, presecretory reabsorption, tubular secretion and postsecretory reabsorption of uric acid were calculated to be about 93-98%, 30-44% and 79-92%, respectively. In addition, it was calculated that benzbromarone inhibited postsecretory reabsorption selectively. Because of the selectivity of the action site of benzbromarone in renal tubules, this loading test is considered to reflect uric acid transport more precisely than tests using probenecid.

Soluble interleukin-2 receptor (IL-2R) level and IL-2R positive (IL-2R+) cells were studied in twenty patients with carcinomatous pleural effusions. The mean value of soluble IL-2R level in carcinomatous pleural effusions was 2930 +/- 1722 U/ml and that in sera was 965 +/- 610 U/ml. Soluble IL-2R level in carcinomatous pleural effusions was found to be significantly higher (p less than 0.001) than that in sera of patients with carcinomatous pleural effusions and that in transudates. Serum soluble IL-2R level in patients with carcinomatous pleural effusions was found, to be significantly higher (p less than 0.001) than that in normal controls (264 +/- 70 U/ml). We also studied IL-2R+ cells in pleural fluids and peripheral blood of patients with carcinomatous pleural effusions. The mean percentage of IL-2R+ cells in carcinomatous pleural fluid lymphocytes was 22.8 +/- 17.8%, as compared with 3.0 +/- 2.2% in peripheral blood lymphocytes of normal controls (p less than 0.001). No significant differences were observed among the cell types of lung cancer examined (adenocarcinoma, squamous, small cell and large cell carcinoma) and no correlation among levels of soluble IL-2R and IL-2R+ cell in either pleural fluid or blood. Our results suggest that in patients with carcinomatous pleural effusions, T cell-mediated active immune mechanisms (IL-2/IL-2R system) against cancer cells are more active in pleural fluid than in peripheral blood.