Yuya Yamada

Myogenic hyperuricemia. A common pathophysiologic feature of glycogenosis types III, V, and VII

To identify the mechanism of hyperuricemia in glycogen storage diseases (glycogenoses) that affect muscle, we studied the effects of exercise and prolonged rest on purine metabolism in two patients with glycogenosis type III (debrancher deficiency), one patient with type V (muscle phosphorylase deficiency), and one patient with type VII (muscle phosphofructokinase deficiency). All had hyperuricemia except for one patient with glycogenosis type III. Plasma concentrations of ammonia, inosine, and hypoxanthine increased markedly in all the patients after mild leg exercise on a bicycle ergometer. The plasma urate concentrations also increased, but with a delayed response. Urinary excretion of inosine, hypoxanthine, and urate increased greatly after exercise, consistently with the increases in plasma levels. Hypoxanthine and urate concentrations were extremely high in the plasma and urine of the patient with glycogenosis type VII. With bed rest, the plasma hypoxanthine level returned to normal within a few hours, and the plasma urate concentration decreased from 18.6 to 10.6 mg per deciliter (1106 to 630 mumol per liter) within 48 hours. Similarly, the urinary excretion of these purine metabolites was reduced by bed rest. These findings indicate that muscular exertion in patients with glycogenosis types III, V, and VII causes excessive increases in blood ammonia, inosine, and hypoxanthine due to accelerated degradation of muscle purine nucleotides. These purine metabolites subsequently serve as substrates for the synthesis of uric acid, leading to hyperuricemia.

A genomic analysis of adult T-cell leukemia

Adult T-cell leukemia (ATL) is an intractable malignancy of CD4+ T cells that is etiologically associated with infection by human T-cell leukemia virus-type I. Most individuals in the chronic stage of ATL eventually undergo progression to a highly aggressive acute stage. To clarify the mechanism responsible for this stage progression, we isolated CD4+ cells from individuals in the chronic (n=19) or acute (n=22) stages of ATL and subjected them to profiling of gene expression with DNA microarrays containing >44 000 probe sets. Changes in chromosome copy number were also examined for 24 cell specimens with the use of microarrays harboring ∼50 000 probe sets. Stage-dependent changes in gene expression profile and chromosome copy number were apparent. Furthermore, expression of the gene for MET, a receptor tyrosine kinase for hepatocyte growth factor (HGF), was shown to be specific to the acute stage of ATL, and the plasma concentration of HGF was increased in individuals in either the acute or chronic stage. HGF induced proliferation of a MET-positive ATL cell line, and this effect was blocked by antibodies to HGF. The HGF-MET signaling pathway is thus a potential therapeutic target for ATL.

Increased plasma uric acid after exercise in muscle phosphofructokinase deficiency

Type VII glycogenosis (muscle phosphofructokinase deficiency) is attended by hyperuricemia and hyperuricosuria. In one patient, we found that exercise on a bicycle ergometer increased plasma uric acid, inosine, and hypoxanthine levels. Forearm exercise also markedly increased venous inosine, hypoxanthine, and ammonia in the exercising arm of two patients. Exaggerated release of precursors for uric acid synthesis from exercising muscle may be related to the hyperuricemia.

Zinc deficiency exaggerates diabetic osteoporosis

Streptozotocin diabetic rats showed an increase of bone fragility (11.9 +/- 2.1 kg/cm2 vs. 16.8 +/- 2.0, P < 0.005) which was normalized by insulin treatment (18.3 +/- 4.2), indicating that osteoporosis was induced in diabetic rats. The rats were fed a zinc-deficient diet (0.16 mg/100 g) or a control diet (5.2 mg/100 g). This mild zinc-deficient diet did not lower the serum zinc level. The cortical bone of diabetic rats was shown to be markedly thinner by microscopic examination of ground cross-sections of the tibia. Zinc deficiency induced a reduction in the calcium content of diabetic bone when compared with the rats on a control diet. Urinary excretion of calcium and phosphorus was significantly increased in diabetic rats, and increased further when the rats were fed a zinc-deficient diet. Moreover. the bone calcium and phosphorus concentrations were significantly lower in these animals. These changes in the zinc-deficiency rats were not reversed by insulin treatment. Our findings suggest that osteoporosis in the diabetic rats was due to thinning of the bone cortex secondary to mineral loss and can be reversed by insulin treatment, and that these skeletal changes are greatly enhanced by mild zinc deficiency. In addition the effects of zinc deficiency cannot be completely reversed by insulin treatment.

Association of adiponectin with blood pressure in healthy people

With the increasing prevalence of diseases related to obesity, metabolic syndrome and its key player adiponectin are now attracting considerable attention. Hypoadiponectinaemia is reported to be a risk factor for hypertension and associated with endothelial dysfunction, which is closely related to complications of obesity such as hypertension. As there is limited information regarding serum adiponectin levels in normotensive people, we undertook the large‐scale study to determine the association of adiponectin with blood pressure (BP) in mainly normotensive people.

Relationship between serum adiponectin levels and age in healthy subjects and patients with type 2 diabetes

Serum adiponectin levels are affected by gender, body fat mass, several pathological factors or therapeutic interventions and it might be also affected by age. This study aimed to investigate the relationship between serum adiponectin levels and age in several physiological states.

Effect of eicosapentaenoic acid and docosahexaenoic acid on diabetic osteopenia

To evaluate the effect of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), which are polyunsaturated fatty acids, on diabetic osteopenia, we measured the bone fragility in streptozotocin-induced diabetic rats. The fragility of femur was increased in diabetic rats, which was prevented in part by EPA or DHA. Moreover, EPA prevented osteopenia even in diabetic rats fed a low zinc feed, which was a potent accelerator of diabetic osteopenia. Plasma alkaline phosphatase activity and parathyroid hormone level showed no difference between the two groups of diabetic rats with or without EPA. Urinary excretion of calcium and phosphate was increased and plasma inorganic phosphate level was high in diabetic rats, suggesting severe mineral loss. In diabetic rats fed EPA, although urinary and plasma calcium levels did not change significantly, urinary phosphate excretion and plasma inorganic phosphate concentration were slightly lowered, which suggested that EPA may have an effect in suppressing phosphate release from bones in diabetic rats. These data suggest that EPA and DHA could be effective on diabetic osteopenia, but to elucidate the precise mechanisms, further examinations will be needed.

Human Herpes virus 8-negative primary effusion lymphoma with BCL6 rearrangement in a patient with idiopathic CD4 positive T-lymphocytopenia

Primary effusion lymphoma (PEL) was initially designated as a body-cavity-based lymphoma and recognized as a distinct clinical entity without a contiguous tumor mass. PEL was first reported in patients with acquired immunodeficiency syndrome (AIDS) and the distinctive feature of PEL originally reported as a B-cell neoplasm characterized by infection of the tumor cells by human herpes virus 8 (HHV-8).1 However, there have recently been several reports of PEL in patients without human immunodeficiency virus (HIV) or HHV8 infection.2–4

Asymptomatic multiple lacunae in diabetics and non-diabetics detected by Brain magnetic resonance imaging

We investigated the relationship between asymptomatic multiple lacunae (ASML) and related risk factors by using brain MRI in 209 patients including 152 NIDDM patients. Patients with ASML (97 cases) were significantly older (68 +/- 9 vs. 63 +/- 10) and hypertension was more frequent (57/97 vs. 33/112) than in patients without ASML. In addition, by multivariate analysis, ASML showed significant association with aging and hypertension, but not with NIDDM. In the NIDDM patients, diabetics with ASML were significantly older, and showed a higher association with hypertension and triopathy than those without ASML, although the results were the same for the middle-aged (< 65 years old) diabetics. From multivariate analysis, the lesions in the penetrating branch area were highly associated with hypertension (F = 8.46) and nephropathy (F = 4.75), while those in the subcortex and white matter were associated with aging (F = 6.02) and retinopathy (F = 5.15). In the middle-aged diabetics, the former was associated with hypertension (F = 10.72) and retinopathy (F = 13.32), whereas the latter was associated with retinopathy (F = 20.76). In the elderly diabetics, no significant association was found in either lesions. These results suggest that control of hypertension and prevention of microangiopathy by keeping good control of blood glucose, is essential to prevent asymptomatic lacunae in NIDDM patients.

Asymptomatic Cerebral Small Infarcts (Lacunae), Their Risk Factors and Intellectual Disturbances

This study examines the relationship between cerebral small infarcts (lacunae) and the multiple risk factors of diabetes, age, hypertension, hyperlipidemia, and atherosclerosis in asymptomatic NIDDM patients and nondiabetic subjects by comparing brain magnetic resonance imaging (MRI) findings to these risk factors. Brain MRI was performed on 155 asymptomatic NIDDM and 39 asymptomatic nondiabetic patients, using a Shimazu SMT-150, 1.5-T instrument. Among the diabetic patients, 65 showed evidence of lacunae. The incidence of lacunae was significantly higher in older diabetic patients, but it did not significantly differ in those with or without the risk factors of atherosclerosis. We also correlated the results of a freehand cube-drawing test with the incidence of lacunae. Cube-drawing is a good indicator of spatial cognition ability supported by wide association areas of the brain. Drawing ability was tested in 56 diabetic and 39 nondiabetic subjects. Correlations of lacuna incidence with deformity in drawing and with age were high in the diabetic group. Correlation of lacunae with deformity in drawing was also significant in nondiabetic subjects. The incidence of lacunae was highly correlated with intellectual impairment.