Recent experimental and clinical studies have suggested that oxidative stress is enhanced in heart failure. The production of oxygen radicals is increased in the failing heart whereas antioxidant enzyme activities are preserved. Mitochondrial electron transport is an enzymatic source of oxygen radical generation and also a target against oxidantinduced damage. Chronic increases in oxygen radical production in the mitochondria can lead to a catastrophic cycle of mitochondrial DNA damage as well as functional decline, further radical generation, and cellular injury. These cellular events might play an important role in the development and progression of myocardial remodeling and failure.
(Internal Medicine 40: 1177-1182, 2001)

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Objective To determine optimal intensity of international normalized ratio (INR) of warfarin therapy for the prevention of ischemic events in patients with non-valvular atrial fibrillation (NVAF), we evaluated the risk of severe recurrent stroke, systemic embolism and major hemorrhagic complications according to INR and age.
Methods We carried out the National Cardiovascular Center (NCVC) NVAF Secondary Prevention Study and analyzed data with those of Japanese Nonvaluvular Atrial Fibrillation-embolism Secondary Prevention Cooperative Study to elucidate relationships of major stroke and hemorrhage with INR and age. In both studies, all patients with cardioembolic stroke were given warfarin, monitored with INR every month, and followed up for primary endpoints of stroke and embolism to other parts of the body, and for secondary endpoints of major hemorrhagic complications requiring blood transfusion or hospitalization. We regarded ischemic stroke with NIH stroke scale (NIHSS) score >10 or systemic embolism as a major ischemic event and ischemic stroke with NIHSS score <10 as a minor ischemic event. There were 203 patients enrolled in total (152 men and 51 women). We investigated the relationship of occurrence of the events with INR and age, and calculated the incidence rates of major and minor ischemic events and major hemorrhagic events.
Results During the mean follow-up of 653 days, major ischemic stroke and systemic embolism occurred in only 4 patients with INR <1.6, minor ischemic stroke in 10 patients with INR 1.50-2.66, and major hemorrhage in 9 patients with INR 2.30-3.56. Patients with major ischemic or hemorrhagic events were significantly older than those without any events (75±4 years vs. 67±7 years, p<0.001 unpaired t test). Incidence rates of any events at INR ≤1.59, 1.60-1.99, 2.00-2.59 and ≥2.60 were 8.6%, 3.8%, 4.9%, and 25.7%/year, respectively.
Conclusions Major ischemic or hemorrhagic events occur often in the elderly NVAF patients, in whom an INR value of between 1.6 and 2.6 seems optimal to prevent such events.
(Internal Medicine 40:1183-1188, 2001)

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Objective Homocysteine (Hey) is a sulfhydryl amino acid. Its precursor, the essential amino acid methionine, is derived from dietary protein; recently a number of studies have suggested its relation to atherosclerosis. The present study was performed to clarify the relation between the plasma Hey concentration and sclerotic lesions of the common carotid arteries.
Methods and Patients We evaluated sclerotic lesions of common carotid arteries by ultrasonography in 120 elderly in-patients (77±9 years), and studied the relationship of the known risk factors for atherosclerosis including plasma Hey. An ultrasonograph and 7.5 MHz linear type B-mode probe were used by a specialist to evaluate sclerotic lesions of the common carotid arteries. Blood was drawn from the patients while fasting for determination of plasma Hey. Plasma Hey concentrations were determined using a high-performance liquid chromatography assay.
Results Logistic regression analysis using IMT as an object variable, adjusted by various risk factors including the plasma Hey concentration, revealed that the relative risk in the group combining the second and the third highest Hey groups was 6.49 (95% confidence interval (CI): 1.95-21.9) compared with the first group and the plaque presence showed a relative risk of 4.45 (95% CI: 1.53-12.9).
Conclusion The findings of this study confirmed that observations of an association between plasma Hey concentration and common carotid atherosclerosis in Western populations is also present among the elderly Japanese.
(Internal Medicine 40: 1189-1194, 2001)

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Objective Vascular endothelial growth factor (VEGF), a cytokine associated with malignant neoplasms, is increased in a number of inflammatory and infectious disorders. But little is known about VEGF in pulmonary aspergilloma (PA). In order to clarify the predictive value of VEGF in PA, we examined serum VEGF levels in PA patients as well as expression of VEGF in the PA lesion.
Patients Twenty-one patients with PA (6 with hemoptysis and the rest without hemoptysis) were investigated.
Methods In all patients, serum VEGF levels were measured by enzyme-linked immunosorbent assay. We examined the statistical correlations of serum VEGF levels with the ratio of affected area to total lung volume and VEGF with PaO2 levels. In patients with hemoptysis, we measured the serum VEGF levels three months after the initiation of therapy. We examined the expression of VEGF in the resected lung tissue of 4 patients with PA using immunohistochemistry.
Results Serum VEGF levels showed a significant positive correlation with the ratio of affected to total lung area and a significant negative correlation with PaO2 levels. Serum VEGF levels in patients with hemoptysis were significantly higher than in those without hemoptysis. The serum levels of VEGF in patients with hemoptysis decreased significantly in parallel with the alleviation of hemoptysis. Immunohistochemical staining demonstrated the expression of VEGF in alveolar macrophages in the lesion of PA patients.
Conclusion We suggest that VEGF can be used as a serum marker to determine the extent of the lesion, hypoxia and hemoptysis in PA.
(Internal Medicine 40: 1195-1199, 2001)

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A 43-year-old woman with a huge portal-systemic shunt accompanied by myxedema showed slow speech and behavior. Several imaging studies revealed a bold portal-systemic shunt from the splenic vein to the left renal vein. In addition, hypothy roidism caused by chronic thyroiditis was diagnosed, and synthesized thyroxine replacement was effective for the symptoms. However, the serum ammonia and indocyanin green retention remained in the abnormal range, nevertheless the portal vein pressure was normal and findings of liver cirrohsis were not recognized histologically. Surgical shunt closure was performed, resulting in normalized serum ammonia levels and serum branched chain amino acids /aromatic amino acids ratio, and improvement of the ammonia tolerance test.
(Internal Medicine 40: 1200-1204, 2001)

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Pancreatitis is believed to be one of the uncommon extraintestinal manifestations of ulcerative colitis (UC). A 66-year-old woman who had been treated for UC for eight months was admitted to our hospital because of epigastralgia. Laboratory examinations revealed elevated pancreatic enzymes. Because differentiation of pseudotumorous pancreatitis from pancreatic cancer was difficult by the imaging findings, she underwent a distal pancreatectomy. Histologically, the tumorous lesion was composed of fibrosis with lymphocytic infiltration. We concluded that this case was pseudotumorous pancreatitis as an extraintestinal manifestation of UC.
(Internal Medicine 40: 1205-1208, 2001)

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We present a 66-year-old woman with primary sclerosing cholangitis (PSC) complicated with idiopathic thronibocytopenic purpura (ITP). Both PSC and ITP are considered to reflect an immunological disturbance. However, their coexistence is very rare and to the best of our knowledge this is only the second reported case. In Japan, PSC patients are rarely treated with liver transplantation. Fortunately, the present patient underwent successful hepatic transplantation from a brain-dead donor and simultaneous splenectomy. This case emphasizes the importance of liver transplantation as an effective treatment for primary sclerosing cholangitis.
(Internal Medicine 40: 1209-1214, 2001)

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A 36-year-old Japanese man was hospitalized with coughing and exertional dyspnea (NYHA class I). He was diagnosed as having congestive heart failure, and was treated with diuretics and a β-adrenergic blocking agent. He responded well to the treatment and his symptoms completely disappeared within a few days. Based on his clinical, laboratory, and molecular genetic findings, he was diagnosed as having X-linked dilated cardiomyopathy (XLDCM). He was found to have a large deletion in the dystrophin gene, involving exons 45-55. This is the first report on a Japanese XLDCM patient with a mutation in the central hot-spot region of this gene.
(Intenal Medicine 40: 1215-1221, 2001)

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A rare case of cardiac malignant fibrous histiocytoma (MFH) is reported. A 55-year-old woman complained of palpitation due to atrial fibrillation. Echocardiography, magnetic resonance imaging, and angiography demonstrated a tumor arising from the posterior wall of the left atrium. At surgery, the tumor was almost entirely resected and histologically defined as MFH. Neither chemotherapy nor irradiation was administered. Echocardiography revealed a local recurrence two months after the surgery and the patient died of advanced cachexy and heart failure 2 years later. The details of this case are presented with a review of the literature.
(Internal Medicine 40: 1222-1226, 2001)

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Acute fatty liver of pregnancy complicated with anterior pituitary insufficiency in a 24-year-old nullipara woman who presented fever and progressing liver damage after the delivery by Cesarean section is described. The liver biopsy revealed severe fatty changes with microvesicular fat drops in the hepatocytes. Serum growth hormone and adrenocorticotropic hormone levels were low, and did not respond to the stimulation. The daily urinary excretion of 17-hydroxycorticosteroid was also low. Acute fatty liver of pregnancy and antehypophyseal insufficiency were diagnosed. Secondary adrenal failure was also suspected. The co-existing hypercoagulable state could cause an ischemic attack on the pituitary gland.
(Internal Medicine 40: 1227-1231, 2001)

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A patient with end stage renal disease secondary to systemic lupus erythematosus (SLE) ultimately required amputation of the four extremities and developed mesenteric ischemia. The patient presented with widespread medial calcification involving various small to medium sized arteries, although no noticeable secondary hyperparathyroidism was observed. We speculated that SLE associated with systemic vasculitis and uremic milieu over a number of years may represent the perfect preexisting condition for calcific arteriolopathy to occur following which several factors including chronic administration of corticosteroids, photosensitivity in lupus, and significant weight loss may have contributed to acral gangrene and mesenteric ischemia.
(Internal Medicine 40: 1232-1237, 2001)

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Pulmonary infection with cavitation causes severe respiratory symptoms if the cavity has a communication with main bronchus, through which fluid flows out into trachea. In this report a young male with lung cancer invading an adjacent pre-existent fungus cavitary lesion is presented. Cancer invasion led to broncho-cavitary communication and caused massive intrabronchial aspiration. Subsequently, the cancer destroyed the thoracic wall, and a cavitary-cutaneous fistula developed which relieved symptoms as if treated with open drainage.
(Internal Medicine 40: 1238-1240, 2001)

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Cryptococcus neoformans (C. neoformans) var. gattii infection usually occurs in tropical and subtropical areas, and rarely in the northern hemisphere. We report the first Japanese with cryptococcal meningoencephalitis caused by C. neoformans var. gattii infection that occurred during a trip to Australia. This agent was identified in a cerebellar biopsy specimen by immunohistochemical technique with serotype-specific anti-sera. Because the meningitis caused by it did not respond well to conventional therapy, we used an aggressive therapeutic regimen to successfully treat the patient. Even in areas where C. neoformans var. gattii does not exist, this infection should be considered possible as a travel-related infection.
(Internal Medicine 40: 1241-1244, 2001)

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We report a 48-year-old man with thrombosis of the portal and superior mesenteric vein and inferior vena cava associated with primary antiphospholipid syndrome (APS). Primary APS was diagnosed by a positive reaction with anticardiolipin antibody (aCL) and the absence of any evidence suggesting the presence of other disease states known to be associated with aCL. A coeliac angiography showed obstruction of the portal and superior mesenteric vein with prominent collaterals and cavernous transformation. Femoral vein angiography showed total obstruction of the external iliac vein and inferior vena cava, and dilation of the pelvic veins, with contrast medium in the lumbar vein. This case is noteworthy as a report of primary APS accompanied by extensive abdominal and pelvic venous thrombosis.
(Internal Medicine 40: 1245-1249, 2001)

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We report the case of a young female patient with mixed connective tissue disease (MCTD). She had marked pulmonary hypertension (PH) without lung fibrosis. She developed renal crisis after delivery by caesarean section. Renal biopsy revealed severe renal intimal hyperplasia with mild glomerular changes. The combination of intravenous pulse high-dose corticosteroid and cyclophosphamide (CPA) infusion and subsequent corticosteroid oral administration rescued her from renal crisis. This suggests that the possibility of co-incident renal intimal hyperplasia should be considered in patients with MCTD accompanied by PH. In addition, there might be some clinical benefit in combining high-dose corticosteroid with CPA infusion in the treatment of renal crisis due to intimal hyperplasia in MCTD.
(Internal Medicine 40: 1250-1253, 2001)

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We report two sisters with hereditary deficiency of the third complement component (C3) and a homozygous mutation at C3303G (Tyr1081Stop) of the gene. They developed systemic lupus erythematosus-like symptoms during adolescence. Their C3 were not detected in serum immunochemically. Their mother and a brother had half of the normal C3 levels and a heterozygous mutation in the same position. Western blot analysis of murine L-cells transfected with the mutant C3 cDNA showed no C3 protein, however mRNA was detectable using reverse-transcriptase polymerase chain reaction. To the best of our knowledge, this is the first report of C3 deficiency due to a stop codon in the gene.
(Internal Medicine 40: 1254-1258, 2001)

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