5'-Methylthioadenosine in urine from normal subjects and cancer patients.

In an attempt to study, in human body, the metabolism of 5'-methylthioadenosine, a byproduct of the polyamine biosynthesis, we examined whether this nucleoside is excreted into urine, and, if so, whether the amount increases when the synthesis of polyamines increases. We found that 5'-methylthioadenosine is a natural nucleoside in human urine as evidenced by two separate chromatography systems as well as the analysis of the acetylated compound by gas chromatography-mass spectrometry. Preliminary study did not show the elevation of urinary 5'-methylthioadenosine level in malignant patients, suggesting that the cleaving enzyme, 5'-methylthioadenosine phosphorylase, very efficiently removes this nucleoside in vivo.

Common reabsorption system of 1,5-anhydro-D-glucitol, fructose, and mannose in rat renal tubule.

1,5-Anhydro-D-glucitol (AG) is a major polyol, 99.9% of which is reabsorbed by the kidney. However, such reabsorption is inhibited by competition with glucose excreted in excess, i.e., glucosuria. Under such conditions, AG is excreted into the urine. We administered various types of sugars to rats by continuous intravenous infusion for two hours to evaluate the competition between AG and these sugars for renal reabsorption in vivo. The reabsorption of AG was significantly inhibited by competition with fructose and mannose. The excretion of AG in the 120 min after a load of 3.64 mmol of fructose was 1.99 +/- 0.33 mumol, that after 3.64 mmol of mannose loading was 2.34 +/- 0.43 mumol. These levels were comparable to the AG excretion observed after the administration of the same amount of glucose (3.87 +/- 0.61 mumol). No competition was observed with sucrose, xylose, myoinositol or galactose. The reabsorption of fructose and mannose was significantly inhibited by the presence of AG (P < 0.001) after a mixed load. Results suggest that AG is reabsorbed in the renal tubule by an AG/fructose/mannose-common transport system that is distinct from the major glucose reabsorption system. These findings may help to clarify the specific transport systems for various sugars in the renal tubule, as well as their physiological importance.

Reduction and recovery of plasma 1,5-anhydro-D-glucitol level in diabetes mellitus.

The plasma concentration of 1,5-anhydro-D-glucitol (AG) was measured in 135 newly diagnosed patients who were referred for oral glucose tolerance tests. AG concentrations in the nondiabetic patients indicated that the mean value of normal AG concentration was 21.8 micrograms/ml (SD = 5.9 micrograms/ml, range 9.6-38.8 micrograms/ml). This distribution of AG concentration was significantly different from that in patients with impaired glucose tolerance (IGT) (13.3 +/- 5.4 micrograms/ml) and definitely different from that in diabetic patients (2.1 +/- 1.8 micrograms/ml). In a standard glucagon test, it was suggested that the decrease of plasma AG was affected not only by glycemic control of the patients but also by pancreatic cell secretory activity. The reduction of AG concentration was more marked in IDDM patients than in NIDDM patients. In longitudinal studies, AG concentration was shown to be sensitive to glycemic control. However, its recovery showed a tendency toward much delay after the improvement of fasting blood glucose or HbA1 concentrations. On the other hand, AG concentration showed negligible diurnal change and no immediate change as a result of diet, oral glucose load, or acute shift of the insulin level in both normal and diabetic subjects.

Plasma 1,5-anhydro-D-glucitol as new clinical marker of glycemic control in NIDDM patients.

To elucidate the value of using plasma 1,5-anhydro-D-glucitol (AG) as a marker of glycemic control in diabetic patients, the relationship between the plasma concentration of AG and glucosuria was examined in 152 patients with non-insulin-dependent diabetes mellitus (NIDDM). After recovery from the deterioration of glycemic control in NIDDM patients had started, AG began to increase day by day. The recovery of plasma AG showed a constant linear increase curve when excellent glycemic control was attained. The ordinary daily recovery rate of plasma AG was estimated to be 0.3 microgram/ml, which was independent of body weight, sex, age, the difference in treatment, the duration of diabetes, or the level of plasma AG among NIDDM patients. This rate decreased according to the increase in urinary glucose. When we calculated the decrease rate of plasma AG (delta AG), assuming 0.3 microgram/day to be the maximum increase rate in a day, we found a high correlation between delta AG and urinary glucose at almost all AG levels except the normal range and observed that plasma AG (A) times urinary glucose (G) was relatively constant. The formula A x G = 16 is a simple equation for rough estimation of urinary glucose from the plasma AG concentration in a stable glycemic-controlled NIDDM patient, and we call it the A.G index. The plasma AG also correlated significantly with fasting plasma glucose (r = -.810) and glycosylated hemoglobin (r = -.856) in the same stable glycemic-controlled NIDDM patients. Based on these observations, we propose that plasma AG can serve as a new marker that may provide sensitive and analytical information about glycemic control.

Relationship between serum 1,5-anhydroglucitol and urinary excretion of N-acetylglucosaminidase and albumin determined at onset of NIDDM with 3-year follow-up.

OBJECTIVE: This prospective study was designed to elucidate the relationship between the serum level of 1,5-anhydroglucitol (1,5AG) and the urinary excretion of N-acetylglucosaminidase (NAG) and albumin in patients who were in the early stages of diabetes. RESEARCH DESIGN AND METHODS: A total of 1,062 male nondiabetic subjects with impaired glucose tolerance were monitored for blood glucose level once every 2-3 months, and the values were evaluated. Of these 1,062 subjects, 112 showed a worsening of glycemia during the observation period to the level seen in diabetes. We began to monitor the glycemia and parameters of renal damage in the 112 patients from the onset of diabetes. RESULTS: The urinary excretion of NAG and albumin were elevated even at the onset of diabetes. The abnormal excretion of NAG and albumin was associated with a change in serum 1,5AG and was quickly reversible when the serum 1,5AG improved. In the 3 years after the onset of diabetes, we obtained at least 18 measurements of one parameter for each patient and calculated the mean. Urinary NAG was found to be significantly correlated with the fasting plasma level of glucose (FPG; r = 0.512, P < 0.0001), the level of HbA1 (r = 0.351, P = 0.001), and the level of 1,5AG (r = -0.790, P < 0.0001). The urinary excretion of albumin was weakly but significantly correlated with levels of FPG (r = 0.383, P < 0.0001) and HbA1 (r = 0.337, P < 0.0001), but it was more strongly correlated with 1,5AG (r = -0.632, P < 0.0001). The level of 1,5AG was significantly correlated with FPG (r = -0.681, P < 0.0001) and HbA1 (r = -0.609, P < 0.0001). CONCLUSIONS: When the renal damage is not severe, the serum level of 1,5AG appeared to be an indicator of the reversible renal damage caused by hyperglycemia, as well as of the severity of the glycemia itself.

The differences in purine metabolism between T and B lymphocytes.

In this study enzyme activities involved in purine metabolism were measured in T and B lymphocytes separated by E and EAC rosetting methods. Adenosine deaminase, purine nucleoside phosphorylase and HGPRTase activities were significantly elevated in T cells, compared to the activities in B cells. There were no significant differences in adenosine kinase and APRTase activities between T and B lymphocytes. In contrast, PRPPsynthetase activities were higher in B cells than in T cells. The uptake of various radiolabeled precursors by mitogen stimulated lymphocytes was studied. The uptake of 14C-formate by the mitogen stimulated lymphocytes was markedly lower, compared to that of 14C-adenosine and or 14C-purine bases. The uptake of 14C-adenosine by PHA stimulated lymphocytes was considerably higher than that of Con A or PWM stimulated lymphocytes. However, the uptake of 14C-hypoxanthine into lymphocytes stimulated with PWM was increased by comparison with unstimulated lymphocytes. From these results it seems that adenosine plays a central role in the metabolism of T cells, and that purine bases are preferentially utilized in B cells.

Concentrations of adenine nucleotides in erythrocytes of patients with gout.

Gout has long been known as a disease of the high social class or of those with achieved social status. Brooks and Mueller (1966) studied the relationships between behavior and serum uric acid levels among university professors. They indicated that personal characteristics of drive, achievement, and leadership are positively associated with the uric acid levels in plasma. Hansen and Dimitrakondi (1974) reported a marked decrease in ATP levels in psychotic depression and significant correlation between ATP concentration and mood scores. We estimated the adenine nucleotides in erythrocytes of gouty patients.

Some factors related to obesity in the Japanese sumo wrestler.

Sumo is an ancient sport in Japan and there are at present over 800 professional sumo wrestlers (rikishis). After entrance into the wrestler society a wrestler takes strenuous daily training together with a very high calorie diet (more than 5,000 cal). Frequency of food intake is twice a day. The average diet of Japanese people contains of 2,279 calories and the meal frequency is generally three times a day. In 96 wrestlers average actual body weight and modified Broca index was 100.4 kg and 143.5%, respectively. In this group the prevalence of overweight with obesity, overweight without obesity, nonoverweight with obesity, and nonoverweight without obesity was 53.4, 39.1, 1.0, and 6.5%, respectively. Also mean serum levels of triglyceride, phospholipid, uric acid, and total protein were significantly higher than those obtained in 89 age-matched healthy males. The incidence of diabetes mellitus, gout, and hypertension in wrestlers was 5.2, 6.3, and 8.3%, respectively, all values being considerably higher than in controls. Weight correlated significantly with skinfold thickness, diastolic blood pressure, total cholesterol, and uric acid in each group. Multiple regression analyses were made treating weight or uric acid as dependent variables in both groups. Obesity, hyperlipidemia, and hyperuricemia in wrestlers were presumed to be caused chiefly by the high calorie diet and partially by the infrequent meal intake.

Hyperlipidaemia in patients with Down's syndrome.

Plasma lipid levels were measured in 20 mongoloid and 16 non-mongoloid mentally retarded subjects. Significant elevations of plasma triglyceride levels were found in patients with Down's syndrome compared with mentally retarded controls. However, no significant difference was found in plasma cholesterol, phospholipid and free fatty acid levels between the mongoloids and control subjects.

Disturbance in the metabolism of 5'-methylthioadenosine and adenine in patients with neoplastic diseases, and in those with a deficiency in adenine phosphoribosyltransferase.

5'-Methylthioadenosine (MTA) produced during the synthesis of polyamines is degraded to adenine by MTA phosphorylase. This pathway is considered to be the main source of endogenous adenine. We determined the concentrations of MTA and adenine in control subjects and in those with a pathological disorder. In patients with active leukemias, as well as with other types of malignancies, the concentrations of MTA and adenine in the urine were elevated. These changes seemed to be the result of an accelerated production of MTA due to an accelerated biosynthesis of polyamine. In patients with adenine phosphoribosyltransferase (APRT) deficiency, the concentrations of adenine in the urine were elevated, presumably due to a disturbance in the catabolism of adenine. Although adenine is a potent inhibitor of MTA phosphorylase, APRT-deficient patients did not excrete MTA into urine in concentrations significantly larger than noted for control subjects. However, the amount of MTA excreted positively correlated with that of adenine in these patients, hence that accumulated adenine probably had a slight, but positive, inhibitory effect on the degradation of MTA.

Estimation of plasma glucose fluctuation with a combination test of hemoglobin A1c and 1,5-anhydroglucitol.

We investigated the effect of plasma glucose fluctuation on hemoglobin A1c (HbA1c) and plasma 1,5-anhydroglucitol (AG) levels, especially in insulin-dependent diabetes mellitus (IDDM). Plasma AG is a new marker that provides sensitive and analytical information on glycemic control. The basic mechanisms underlying both the reduction and recovery of the plasma AG level, ie, the excretion into urine with glucosuria and the amount supplied to the body, were presumed to be similar in IDDM and non-insulin-dependent diabetes mellitus (NIDDM) patients. The correlation coefficient for mean plasma glucose and AG was -.591, and it was .578 for mean plasma glucose and HbA1c in IDDM patients. In NIDDM, the correlation between mean plasma glucose and AG was -.869, and between mean plasma glucose and HbA1c, .875. The plasma AG levels in the IDDM group showed a lower range than in the NIDDM group, even with similar HbA1c levels. All the cases showing lower plasma AG levels among those with similar HbA1c levels manifested greater fluctuation of plasma glucose and a larger amount of urinary glucose. The lower AG level in IDDM patients was reversible to the level in NIDDM patients when the greater fluctuation of plasma glucose was corrected. Thus, it was suggested that because urinary glucose excretion is intermittently high in IDDM patients, plasma AG is frequently low, even though the mean plasma glucose and HbA1c levels suggest good control.(ABSTRACT TRUNCATED AT 250 WORDS)

Altered kinetic properties of a mutant adenine phosphoribosyltransferase.

Three siblings in a Japanese family experienced recurrent 2,8-dihydroxyadenine urolithiasis despite the presence of adenine phosphoribosyltransferase (APRT) activities in the hemolysates (19.9% to 28.2% of normal value). However, studies on viable T cells from these patients indicated that APRT was not functional in viable cells. Further analysis of the partially purified enzymes from hemolysates disclosed that patient's APRT had a reduced affinity to 5-phosphoribosyl-1-pyrophosphate (PRPP). Seven healthy members of this family whose APRT functioned normally in viable T cells had the erythrocyte enzyme levels between the patients and normal individuals (38.2% to 65.6%), suggesting that they are carriers of the defective gene. These results indicate that the defective gene code a unique mutant APRT with a reduced affinity to PRPP, and the patients are homozygotes. The mutant enzyme was also shown to be more heat-stable than normal enzyme. However, since mutant enzyme, unlike normal enzyme, was insensitive to the stabilization effect of PRPP, the latter became more heat-stable than the former when the heat treatment was performed in the presence of PRPP. This type of defect with alterations in the kinetic and physical properties of APRT as described here is likely to be a common type of APRT deficiency in Japan.

Severe impairment in adenine metabolism with a partial deficiency of adenine phosphoribosyltransferase.

Among three unrelated patients with recurrent 2,8-dihydroxyadenine urolithiasis, two completely lacked adenine phosphoribosyltransferase (APRT) in both erythrocytes and proliferative T cells. The third patient possessed significant enzyme activities in both hemolysates and T-cell extracts at levels comparable to heterozygotes for complete APRT deficiency. Despite significant APRT activities in cell extracts, cultured T cells from the third patient were at least 100-fold more resistant than normal T cells to an adenine analog, 6-methylpurine, whose cytotoxicity is dependent on APRT. These data indicate that APRT activity in T cells from the third patient is positive in cell extracts, but apparently not operating in viable cells. Although the cells from the patients with complete APRT deficiency were as resistant to 6-methylpurine as the cells from the third patient, the cells from the heterozygotes for complete APRT deficiency were almost as sensitive as normal T cells. Therefore, adenine metabolism in the third patient but not in the heterozygotes seems to be as severely impaired as in the patients with complete APRT deficiency, which is quite consistent with the clinical manifestations in these individuals.

Prevention of diabetes by thymic hormone in alloxan-treated rats.

We investigated the effects of facteur thymique sérique (FTS), a thymic peptide hormone, on alloxan- and streptozotocin-induced diabetes in rats. Pretreatment with intravenous injection of FTS significantly suppressed both alloxan- and streptozotocin-induced hyperglycemia. The effects of FTS were time dependent. FTS suppressed hyperglycemia in a dose range of 1-6600 micrograms/kg. Alloxan-induced hyperglycemia was completely prevented when FTS was injected in doses of 40-50 micrograms/kg 1 min before injection of alloxan. Histological examination of islet areas showed that alloxan-induced destruction of beta-cells was inhibited by FTS. FTS had no significant effects on lymphocyte subsets and immunity-related cells or on plasma superoxide dismutase activity and total glutathione level. The blood half-life time of exogenously injected FTS was short (2-3 min), indicating acute internalization of FTS into pancreatic beta-cells. Our results suggested that FTS acutely and directly blocks some initial effect of alloxan, preventing the destruction of beta-cells.

Systemic lupus erythematosus with multiple perivascular spongy changes in the cerebral deep structures, midbrain and cerebellar white matter: a case report.

A 42-year-old woman with systemic lupus erythematosus developed an episode of tonic seizures and progressive disturbance of consciousness at the terminal stage. Neuropathological examination of the brain revealed a nearly symmetrical distribution of multiple spongy foci in the internal capsules, thalami, globus pallidus, mesencephalic tegmentum, cerebral peduncles and hilus of the dentate nuclei. The spongy lesions were obviously distributed along apparently intact medium-sized veins, and contained large numbers of macrophages, and axonal spheroids and a few reactive astrocytes, without inflammatory cell infiltration. In addition, the perivenous spongy lesions exhibited IgG immunoreactivity, so it is surmised that some neurotoxic factor(s) that exuded from the veins in the center of the perivenous lesions may have brought about such a unique pathology.

A case of appendiceal cancer metastatic to the stomach with pseudomyxoma peritonei.

Appendiceal cancer associated with pseudomyxoma peritonei is a low grade malignancy and its extraperitoneal metastasis is extremely rare. We report a case of gastric metastasis of this tumor in a 76-year-old man. Two metastatic gastric tumors, which appeared after a 1-year interval, were successfully resected endoscopically. The patient was well for more than 3 years after the onset of the disease. To our knowledge, gastric metastasis from appendiceal cancer with pseudomyxoma peritonei has not been previously reported.

Erythrocyte adenosine kinase activity in gout.

Erythrocyte adenosine kinase (AK) (EC 2.7.1.20) and guanosine monophosphate (GMP) reductase (EC 1.6.6.8) were measured in healthy male controls and primary gout subjects. Adenosine kinase activity in 19 controls and 26 gouty subjects was 0.717 +/- 0.176 and 0.615 +/- 0.128 nmol/mg protein/h, respectively. The difference was statistically significant (p less than 0.05). GMP reductase activity in 39 controls and 46 gouty subjects was 30.90 +/- 6.28 and 33.43 +/- 7.97 mumol/mg protein/h, respectively, without statistically significant difference.

Erythrocyte adenosine deaminase and purine nucleoside phosphorylase activity in gout.

1. Erythrocyte adenosine deaminase (EC 3.5.4.4) and purine nucleoside (inosine) phosphorylase (EC 2.4.1.1) were measured in 33 healthy controls and 43 primary gouty subjects. Adenosine deaminase activity in controls and gouty subjects was 0.373 plus or minus 0.108 and 0.457 plus or minus 0.140 A unit per 5-10-3 ml packed red cells per h, respectively. The difference was statistically significant (P less than 0.01). Mean adenosine deaminase: inosine phosphorylase (X10) in primary gout was also significantly higher than in controls (P less than 0.05). Inosine phosphorylase activities in the two groups were not significantly different. 2. When gouty patients were divided into two groups according to weight, normal weight gouty subjects had a higher adenosine deaminase activity and an increased ration of adenosine deaminase to inosine phosphorylase when compared with overweight patients (P less than 0.10). In two control groups divided according to the percentage overweight, such differences were not found. In the case of two gouty groups divided according to the existence of gouty heredity, tophi or renal impairment, adenosine deaminase and inosine phosphorylase activity in the two groups were not significantly different. The possible biochemical role of adenosine deaminase activity in primary gout is discussed.

Hyperlipidaemia in gout.

Significant elevations of plasma triglyceride and free fatty acids levels were shown in 107 gouty patients, but no significant difference was found in plasma cholesterol and phospholipid levels as compared with control subjects. A positive correlation was found between plasma triglyceride and free fatty acids levels (r = 0.249, P less than 0.05) in gouty patients. The heavy drinkers with gout (15.9% of the patients) had significantly higher plasma triglyceride, free fatty acids and gamma-glutamyltranspeptidase levels than the moderate or non-drinking gouty subjects. These results suggested that excessive intake of alcohol may play an important role in inducing hyperlipidaemia in gout.

[A case of pneumococcal arthritis in a patient with gout].

A 62 year-old man had suffered from gout and mild renal insufficiency since he was 40 years old. He was admitted to our hospital complicated by a productive cough, high fever and a right swollen knee joint. The chest radiographs demonstrated a left upper lobe infiltration shadow. Streptococci pneumoniae were found in the sputum, arterial blood and synovial fluid of the right knee joint, suggesting a severe pneumonia followed by pneumococcal septicemia which led to purulent arthritis. He was treated with cefamandole (CMD) and penicillin G (PC-G) for one week, but the chest X-ray findings were not improved. After treatment with cefbuperazone (CBPZ) and latamoxef (LMOX), his fever and other symptoms gradually resolved. Streptococcus pneumoniae is an uncommon organism of septic arthritis. Pneumococcal arthritis in a patient without immunodeficiency such as this case is very rare, and has not been reported in Japan.