Diabetic nephropathy is a major chronic complication of diabetes mellitus and an important cause of increased morbidity and mortality in diabetic patients. Although several lines of evidence have suggested that poor glycemic control undoubtedly plays a significant role, the metabolic events responsible for its development are not understood well. Possible mediators of untowards effects of hyperglycemia include the advanced glycation end products (AGEs). AGEs, carboxymethyllysine and pentosidine, whose formation is closely linked to oxidation, accumulate in the characteristic diabetic glomerular lesions, such as the expanded mesangial matrix and nodular lesions, in co-localization with other oxidation-specific protein adducts, such as malondialdehyde-lysine, 4-hydroxynonenal-protein adduct, and acrolein-protein adduct. These five biomarkers are formed under oxidative stress by carbonyl amine chemistry between protein amino group and carbonyl compounds derived from carbohydrates, lipids, and amino acids. This article focuses on new aspects of the pathology of diabetic nephropathy, implicating an increased oxidative stress and carbonyl modification of proteins by autoxidation products of carbohydrates, lipids, and amino acids in diabetic glomerular tissue damage ("carbonyl stress").
(Internal Medicine 38: 309-314, 1999)

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Over the last decade, gene targeting technologies have provided investigators with powerful new tools to study the physiology and pathophysiology of the kidney. In that, the renin-angiotensin system (RAS) has been a subject of intense investigation. Detailed analyses of mutant mice have not only confirmed notions already suggested by other studies, but also shed a new light on previously unrecognized functions of RAS. In this review, we will focus on what we have learned from these gene targeted animals in particular relevance to nephrology.
(Internal Medicine 38: 315-323, 1999)

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Object: This study was performed to compare the coronary microvascular response to adenosine 5'-triphosphate (ATP) with the response to adenosine in humans.
Methods: Coronary blood flow velocity was determined using a Doppler flow wire. After intracoronary nitroglycerin infusion, intracoronary bolus injections of adenosine (20 μg) and ATP (20 μg) were performed to induce reactive hyperemia.
Patients: Twenty-nine patients (23 men and 6 women, mean age: 63±9 years) with coronary artery disease and risk factors for coronary atherosclerosis were studied.
Results: Coronary flow reserve in response to ATP was similar to that for adenosine (2.7±0.7 vs. 2.7±0.7). However, the duration of ATP-induced vasodilation was longer than that of adenosine-induced dilation (39±25 seconds vs. 26±12 seconds, p<0.0001). The coronary flow reserve obtained with either ATP or adenosine was significantly reduced in the interventioned arteries compared with non-stenosed arteries. The coronary flow reserve obtained with ATP was similar to that obtained with adenosine in both artery groups. The duration of the vasodilator effect of ATP was significantly greater than that of adenosine in both artery groups.
Conclusion: These results suggest that ATP induces maximal dilation of coronary microvessels, most likely through an endothelium-independent mechanism. The degradation of ATP to adenosine S'-monophosphate (AMP) and adenosine, as well as the direct action of ATP on A₂-adenosine receptors may be responsible for the dilation. We conclude that coronary flow reserve can be determined safely with intracoronary ATP administration.
(Internal Medicine 38: 324-329, 1999)

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Object: T o assess the value of secondary prevention with lipid lowering therapy following either balloon angioplasty (PTCA) or bypass surgery (CABG) in familial hypercholesterolemia patients, the correlation of the new evolution of stenotic lesions and therapeutically achieved cholesterol levels was studied in 50 patients.
Methods: All surviving patients were followed angiographically after 5 years, and findings were correlated with the annually determined total serum cholesterol (TC) levels.
Results: New coronary atherosclerotic plaques were not observed in 18 patients in whom the TC was controlled to <220 mg/dl but in 19 of 32 patients in whom the TC was >220 mg/dl, a new evolution of stenotic lesions was observed angiographically.
Conclusion: The new evolution of stenotic lesions following revascularization in patients with FH can be controlled significantly by lipid lowering therapy to maintain a TC level of <220 mg/dl, and if diet alone can not achieve it, aggressive medication and even LDL apheresis might be justified.
(Internal Medicine 38: 330-335, 1999)

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Object: To examine the role of human leukocyte antigen (HLA) class II genes in the development of systemic sclerosis (SSc) as well as in the clinical and serologic expression of SSc in patients.
Methods: HLA-DRB1, DRB3, DRB4, DQB1, and DPB1 alleles were determined by genotyping; and serum antinuclear antibodies were identified using indirect immunofluorescence, double immunodiffusion and immunoprecipitation.
Patients: One hundred and five Japanese patients with SSc and 104 race-matched healthy controls.
Results: Frequencies of DRB1 and DQB1 alleles were not different between SSc patients and healthy controls, while DPB1*0901 was marginally increased in SSc patients. In contrast, SSc-related autoantibodies were closely associated with the clinical features. HLA class II genes were detected as follows: anti-DNA topoisomerase I antibody with diffuse cutaneous involvement, pulmonary fibrosis, and DRB1*1502-DQB1*0601-DPB1*0901; anti-U1RNP antibody with overlapping features of lupus and/or myositis and DRB1*0401/*0802-DQB1*0302; and anticentromere antibody with limited cutaneous involvement and DRB1*0101-DQB1*0501-DPB1*0402. In the analysis of the association of HLA class II and the clinical features in SSc patients significant differences were obtained only for the increased frequencies of arthritis and rheumatoid factor in patients with DRB1*0405 compared to those without.
Conclusion: HLA class II genes strongly influence the production of SSc-related autoantibodies rather than the development of SSc. In addition, SSc is a composite disease of distinctive subsets defined by serum autoantibodies, which have specific clinical and HLA class II associations.
(Internal Medicine 38: 336-344, 1999)

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We report a case of tuberous sclerosis associated with hepatic lipomatous tumors and renal angiomyolipomas. Abdominal ultrasonography revealed a high echoic large tumor in the left kidney. A provisional diagnosis of angiomyolipomas of the kidney was made based on computed tomography. Subsequent laparotomy revealed that the extracted tumor was renal angiomyolipoma. It was also revealed that there was an association with hepatic lipomatous tumors thought to be lipomas or angiomyolipomas by liver biopsy. Nearly half of all cases of angiomyolipoma in the kidney are reported as occasional association with tuberous sclerosis complex, but lipomatous tumors in the liver are rare.
(Internal Medicine 38: 345-348, 1999)

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A 62-year-old Japanese male developed multiple hepatic metastases two years after resection of pheochromocy toma of the right adrenal gland. Transcatheter arterial embolization (TAE) was performed for the purpose of the treatment of hepatic metastases resistant to 27 cycles of combined chemotherapy consisting of cyclophosphamide, vincristine, and dacarbazine. After TAE, the hepatic metastatic lesions decreased in size and hypertension passed its crisis. The present case suggests the utility of TAE for multiple hepatic metastases under careful blood pressure monitoring.
(Internal Medicine 38: 349-354, 1999)

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A 62-year-old man was admitted with increasing palpitations. Radiography of the chest demonstrated a calcified mass. Magnetic resonance imaging revealed compression of the right ventricle by a tumor. At the time of cardiac catheterization, the coronary arteries were found not to supply blood flow of the mass, and no dip-and-plateau pattern was seen in the right ventricular pressure measurements. At the time of surgery, the mass was found to be a focal calcified thickening of the pericardium containing only pus. The thickening resembled an oval pericardial tumor. Microbiologic examination of the pus revealed Propionibacterium acnes.
(Internal Medicine 38: 355-358, 1999)

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Idiopathic ventricular tachycardias (VTs) are generally divided into those arising from the right ventricle and those arising from the left ventricle. There has been few reports of two morphologically distinct VT occurring in patients with no apparent structural heart disease. We report a patient with verapamil-sensitive left VT with a right bundle branch block pattern that spontaneously changed to VT with a left bundle branch block pattern. Ventricular fibrillation was induced by the application of programmed stimulation. Although it is unclear if our patient with pleomorphic VT has ventricular vulnerability, it is necessary to investigate further and follow him carefully.
(Internal Medicine 38: 359-364, 1999)

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A 20-year-old Japanese female needed frequent hospitalization due to premenstrual exacerbation of hereditary coproporphyria (HCP). Intranasal buserelin acetate, a gonadotropin-releasing hormone analogue, was given to suppress her menstrual cycles. Her porphyric symptoms subsided dramatically as she became amenorrhoeic. Urinary excretion of porphyrin derivatives fell significantly. She has been free from recurrent attacks, but suffers a minor porphyric attack once in 5 years. However, borderline osteopenia secondary to hypoestrogenism has been noted. Although these analogues are potent in suppressing estrogen-induced porphyric symptoms, due precautions should be taken to avoid bone demineralization in the long-term use.
(Internal Medicine 38: 365-368, 1999)

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A 58-year-old woman was hospitalized because of progressive respiratory distress. She had a history of myasthenia gravis and invasive thymoma. After thymectomy, she had been administered oral prednisolone and intrathoracic anti-cancer drugs postoperatively. Her chest radiograph revealed bilateral pleural effusions. Legionella micdadei (L. micdadei) was isolated from the pleural effusions, and she was diagnosed as pleuritis caused by L. micdadei. She died despite intensive therapy with mechanical ventilation, drainage tube in the chest and intravenous erythromycin. Although only two cases of Legionellosis caused by L. micdadei have been reported in Japan, clinicians should be aware of L. micdadei as one of the candidates for infection in immunosuppressed hosts.
(Internal Medicine 38: 369-371, 1999)

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We describe the first report of intrabronchial Aspergillus nidulans infection in an immunocompetent patient, which fit the description of bronchocentric granulomatosis. The patient had a history of accidental aspiration of light grade oil. Fiberoptic bronchoscopy revealed that the right B⁴aiiα was obstructed. Endobronchial biopsy specimens contained fungal hyphae. The fungus was confirmed to be Aspergillus nidulans by culture. We suspected that aspiration of light grade oil had injured the bronchial mucosa, after which airborne Aspergillus nidulans had entered the lesion and multiplied. Intrabronchial fungal infection can occur in a healthy person without immunologic abnormalities, if a bronchial lesion provides an entry portal.
(Internal Medicine 38: 372-375, 1999)

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A 26-year-old woman was admitted for the evaluation of edema and massive proteinuria. She had a history of purpura of the lower extremities, abdominal pain and melena. Laboratory investigations showed hypoalbuminemia, hypercholesterolemia and proteinuria of over 10 g/day. Renal biopsy showed moderate proliferative glomerulonephritis with mesangial immunoglobulin A (IgA) deposition. She was diagnosed as having Henoch-Schönlein purpura nephritis. Oral prednisolone, dipyridamole and intravenous heparin treatment were not effective. Steroid pulse therapy induced a partial improvement of proteinuria to 2-3 g/day. High-dose intravenous immunoglobulin (IV-IG) treatment was introduced and a dramatic improvement of proteinuria was noted. IV-IG should be fully considered in patients with steroid-resistant Henoch-Schönlein purpura nephritis.
(Internal Medicine 38: 376-379, 1999)

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