Ieo Akaoka

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 μg/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 (ΔAG), assuming 0.3 μ/day to be the maximum increase rate in a day, we found a high correlation between βAG 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 × 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.

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 μg/ml (SD = 5.9 μg/ml, range 9.6–38.8 μg/ml). This distribution of AG concentration was significantly different from that in patients with impaired glucose tolerance (IGT) (13.3 ± 5.4 μg/ml) and definitely different from that in diabetic patients (2.1 ± 1 . 8 μg/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 HbA, 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.

Common characteristics of mutant adenine phosphoribosyltransferases from four separate Japanese families with 2,8-dihydroxyadenine urolithiasis associated with partial enzyme deficiencies

Summary2,8-Dihydroxyadenine urolithiasis associated with partial deficiencies of adenine phosphoribosyltransferase (APRT) has been found only among Japanese families. All Caucasian patients with the same lithiasis are completely deficient in this enzyme. Partially purified APRT from one of the Japanese families with the lithiasis associated with a partial deficiency of APRT had a reduced affinity for 5-phosphoribosyl-1-pyrophosphate (PRPP). In the present investigations, we have shown that this characteristic is common in mutant enzymes from all the four separate Japanese urolithiasis families associated with partial APRT deficiencies so far tested. The mutant enzymes also had several other characteristics in common including increased resistance to heat in the absence of PRPP and reduced sensitivity to the stabilizing effect of PRPP. These data suggest that these families have a common mutant allele (APRT*J) at the APRT gene locus.

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.

Renal Handling of Hypoxanthine and Xanthine in Normal Subjects and in Cases of Idiopathic Renal Hypouricemia

Pyrazinamide (PZA) was used to study the renal handling of hypoxanthine, xanthine and uric acid in 2 normal subjects and in 4 patients with idiopathic renal hypouricemia; one patient was classified as having a postsecretory reabsorption defect, whereas the others were classified as having a presecretory reabsorption defect. In normal subjects, PZA suppressed strongly the excretion of xanthine as well as uric acid; however, it showed a weak effect on that of hypoxanthine. PZA suppressed all excretion of these 3 compounds in the patient with postsecretory reabsorption defect. PZA showed almost no effect on the excretion of either hypoxanthine, xanthine or uric acid in the patients with presecretory reabsorption defect.

Direct Evidence for a Hot Spot of Germline Mutation at HPRT Locus

Hypoxanthine-guanine phosphoribosyltransferase (HPRT) is a well-studied purine metabolic enzyme which converts hypoxanthine or guanine into IMP or GMP in the presence of 5-phosphoribosyl-l-pyrophosphate. A genetic deficiency of this enzyme causes either Lesch-Nyhan syndrome characterized by neurological symptoms and self-mutilation behavior or severe overproduction-type gout, both of which show X-linked inheritance. The germline mutations causing this enzyme deficiency have been studied extensively at the molecular level (Sculley et al. 1992). Typically, germline mutations associated with HPRT deficiencies differ from family to family. These data imply that the defective mutant genes at this locus do not expand in human populations and that mutations in patients from different families are a reflection of different germline mutations. Although the mutations in a limited number of families with this disease have shown the same molecular alteration, conclusive evidence that these mutations reflected independent events has been lacking (Davidson et al.1991, Sculley et al.1991, Marcus et al. 1992, Peterson et al. 1993).

A germ line mutation within the coding sequence for the putative 5-phosphoribosyl-1-pyrophosphate binding site of hypoxanthine-guanine phosphoribosyltransferase (HPRT) in a Lesch-Nyhan patient : missense mutations within a functionally important region probably cause disease

Lesch-Nyhan syndrome caused by a complete deficiency of hypoxanthine guanine phosphoribosyltransferase (HPRT) is the result of a heterogeneous group of germ line mutations. Identification of each mutant gene provides valuable information as to the type of mutation that occurs spontaneously. We report here a newly identified HPRT mutation in a Japanese patient with Lesch-Nyhan syndrome. This gene, designated HPRT Tokyo, had a single nucleotide change from G to A, as identified by sequencing cDNA amplified by the polymerase chain reaction. Allele specific oligonucleotide hybridization analysis using amplified genomic DNA showed that the mutant gene was transmitted from the maternal germ line. This mutation would lead to an amino acid substitution of Asp for Gly at the amino acid position 140 located within the putative 5-phosphoribosyl-1-pyrophosphate (PRPP) binding region. Missense mutations in human HPRT deficient patients thus far reported tend to accumulate in this functionally active region. However, a comparison of the data suggested that both missense and synonymous mutations can occur at any coding sequence of the human germ line HPRT gene, but that a limited percentage of all the missense mutations cause disease. The probability that a mutation will cause disease tends to be higher when the missense mutation is within a functionally important sequence.

Changes caused by ethanol intake on metabolism of hypouricemic agents (combination of allopurinol and benzbromarone).

Several agents have been employed for treatment of hyperuricemia. Allopurinol, an inhibitor of xanthine oxidase (1) is often used as a hypouricemic agents. Benzbromarone, which is reported to have a uricosuric effect (2), has also been employed. It has been recently reported that combination of these two drugs has been favorable in gouty patients (3).

Microanalysis of Pathological Crystals and Urinary Calculi

Pathological crystals are known to cause crystal-induced arthritis (1). The identification of crystals is necessary on the diagnosis of the disease (2). The identification of crystals is usually carried out with a polarizing microscope. However, it is difficult to determine the composition of crystals with the microscope. X-ray analysis is recommended on the determination of crystals.

EFFECT OF HYPOURICEMIC AGENTS ON SERUM CARBOHYDRATE-DEFICIENT TRANSFERRIN IN GOUTY PATIENTS

Carbohydrate-deficient transferrin (CDT) was demonstrated to be a reliable biochemical marker of alcohol abuse by Stibler et al(1, 2). CDT is currently regarded as the most accurate biological indicator of recent, heavy alcohol consumption. Alcohol consumption has been reported to be closely related to hyperuricemia and gout(3). The measurement of CDT in gouty patients is considered to be helpful on their management of hyperuricemia.