Angiogenesis is a recent highlight in the medical field; the developmental process and pathological conditions for various diseases can be understood from the novel aspect of "angiogenesis". Many angiogenesis-related factors are involved in the development of vessels during embryogenesis (vasculogenesis), as well as the induction of new vessels in response to physiological or pathological stimuli. In particular, the appearance of hemangioblasts, precursor cells for vascular endothelial cells and blood cells, and blood islands are expected to play a "prelude" role hi tubulogenesis. Gene knock out mice of vascular endothelial growth factor (VEGF)/VEGF receptor, ephrin-B2, and angiopoietin-1 results in a failure of normal vessels production. Dormant factors derived from proteolytic cleavage of various physiological substrates are expected to balance a homeostasis of "angiogenic states" in the host. Furthermore, angiogenesis under various pathological conditions of malignant tumors, ocular diseases, psoriasis, rheumatoid arthritis, atherosclerosis and other diseases is associated with complex angiogenesis networks, suggesting pleiotropic mechanisms for angiogenesis.
(Internal Medicine 40: 565-572, 2001)

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End-stage renal disease (ESRD) comprises an enormous public health burden, with an incidence and prevalence that are increasingly on the rise. This escalating prevalence suggests that newer therapeutic interventions and strategies are needed to complement current therapeutic approaches. Although much evidence demonstrates conclusively that angiotensin II mediates progressive renal disease, recent evidence also implicates aldosterone as an important pathogenetic factor in progressive renal disease. Recently, several lines of experimental evidence demonstrate that selective blockade of aldosterone, independent of renin-angiotensin blockade, reduces proteinuria and nephrosclerosis in the spontaneously hypertensive stroke-prone rat (SHRSP) model and reduces proteinuria and glomerulosclerosis in the subtotally nephrectomized rat model (ie, remnant kidney). Whereas pharmacologic blockade with angiotensin II receptor blockers and angiotensin-converting enzyme (ACE) inhibitors reduces proteinuria and nephrosclerosis/glomerulosclerosis, selective reinfusion of aldosterone restores these abnormalities despite continued renin-angiotensin blockade. Aldosterone may promote fibrosis by several mechanisms, including plasminogen activator inhibitor-1 (PAI-1) expression and consequent alterations of vascular fibrinolysis, by stimulation of transforming growth factor-betal (TGF-βl), and by stimulation of reactive oxygen species (ROS). Based on this formulation, randomized clinical studies will be initiated to delineate the potential renal-protective effects of aldosterone receptor blockade.
(Internal Medicine 40: 573-583, 2001)

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Objective To investigate whether the increased homocysteine levels occur in the first 6 months postoperatively, when nutritional intake is the most inadequate and weight reduction is the most drastic.
Patients and Methods Fasting glucose, insulin, lipoprotein, homocysteine, folic acid and vitamin B12 levels and oral glucose tolerance test (OGTT) were determined in 12 morbidly obese subjects (3 men and 9 women with a mean age of 31±3 years, mean±SEM) before, 6 and 12 months after banded gastroplasty.
Results Gastroplasty resulted in significant weight loss, from 12±16 to 92±6 and 88±7 kgs, 6 and 12 months postoperatively (all p<0.001). Fasting plasma insulin and triglyceride concentrations, the ratio of total cholesterol to HDL cholesterol, glucose and insulin responses to OGTT, and the degree of insulin resistance as expressed by the Homeostasis model index decreased significantly (p<0.05-0.001) following gastroplasty. Fasting plasma homocysteine concentrations increased from 10.2±0.8 to 12.110.6 at 6 months (p=0.036) and 12.0±1.2 μmol/l at 12 months (p=0.040), respectively. Pooled plasma homocysteine levels were negatively correlated with serum folate concentrations (r=-0.42, p=0.013). However, serum folate and vitamin B12 levels did not change after gastroplasty, nor did the relation between the loss of body weight and increase in homocysteine levels.
Conclusion We observed that elevated circulating homocysteine levels occurred as early as 6 months after gastroplasty despite improvement in carbohydrate and lipoprotein metabolism in morbidly obese Chinese subjects.
(Internal Medicine 40: 584-588, 2001)

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Objective To assess the long-term prognosis after recovery from acute myocardial infarction (AMI) in the general population in Japan.
Patients and Methods Among the 575, 000 inhabitants of the Yamagata metropolitan area, a total of 117 patients suffered from first their AMI from April to December 1993. Thirteen patients (11%) died within four weeks after the onset. Of the remaining 104 patients, 101 (mean age, 69±12 years) were followed for an average of 65±5 months.
Results Twenty-seven of the 101 patients (27%) died during the follow-up period. Compared with survivors, the patients who died were significantly older at the onset of AMI (74±12 vs. 67±12 years, p<0.01). More diabetic patients than non-diabetic patients died (42 vs. 21%, p<0.05) because of the higher frequency of non-cardiac deaths (29 vs. 11%, p<0.05). The total number of deaths of cardiac origin, including sudden deaths, was 11 (40%) and was lower than the number of definite non-cardiac deaths (n=15). The time from the onset of AMI to death was significantly shorter in cases of cardiac death than in cases of non-cardiac death (median, 16 vs. 45 months, p<0.01). Among non-cardiac deaths, deaths due to lung cancer and cerebral infarction were notable in men (standardized mortality ratio 278) and women (571), respectively.
Conclusion Non-cardiac death during long-term follow-up after AMI was more frequent than death of cardiac origin. Thus, preventive measures, including early treatment of complicating diseases, must be implemented to improve the long-term prognosis of patients with myocardial infarction.
(Internal Medicine 40: 589-593, 2001)

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Objective Myocarditis has been described as a complication of influenza. Patients with influenza may have symptoms and abnormal laboratory data (including chest X-ray, electrocardiogram, etc.) suggestive of myocarditis, although few observations have been made regarding the prevalence of asymptomatic myocardial injury. We investigated whether influenza can produce myocardial injury without cardiac symptoms.
Methods During the epidemic of influenza A (H3N2) from 1998 to 1999 in Japan, we examined possible cardiac muscle damage associated with influenza in patients without apparent clinical myocardial injury by measuring serum myosin light chain concentrations.
Patients Ninety-six influenza-positive patients (46 males and 50 females, average age 43.4 years) without impaired renal function were studied.
Results Of these patients, 11 (11.4%) had elevated serum myosin light chain I concentrations.
Conclusion Asymptomatic myocardial injury may be present in patients with influenza even when they have no symptoms suggestive of myocardial injury.
(Internal Medicine 40: 594-597, 2001)

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Objective The activity of systemic lupus erythematosus (SLE) has been reported to decrease in patients who have developed end-stage renal disease (ESRD). However, extrarenal symptoms attributable to the disease activity are noted, especially during the first year of dialysis. We studied the clinical course and evaluate the disease activity of SLE in patients with ESRD on hemodialysis for more than 6 months.
Subject and Methods Fourteen patients with SLE who had been initiated on maintenance dialysis at our center between 1982 and 1999 were examined retrospectively. Their clinical details, organ system manifestations, serologic profiles and immunosuppressive treatment regimens were reviewed. Patients with and without postdialysis flaras of SLE were compared statistically.
Results Five patients exhibited 6 SLE flares under treatment with corticosteroids. Two flares occurred within the first year of the initiation of dialysis, and in 1 patient, aggravation of the disease activity was noted 98 months after the initiation of dialysis. Polyarthritis was noted in 5 cases and fever in 4 cases. The serum complement levels decreased in all 6 cases with relapse of SLE activity. Compared with the other 9 patients who did not exhibit SLE relapse, no significant differences were found in 5 patients who did with respect to the demographic and serologic features at the initiation of dialysis.
Conclusion We conclude that the disease activity does not always burn out in patients of SLE who show progression to ESRD. SLE flares can sometimes occur even after one year of the initiation of dialysis. SLE patients on dialysis should be carefully followed up by clinical and serological monitoring, and treated by appropriate immunosuppressive therapy.
(Internal Medicine 40: 598-602, 2001)

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Objective This dose escalation was conducted to evaluate the applicability of Chatelut's dosing, and to determine the efficacy and toxicity of carboplatin with etoposide in previously untreated elderly patients (>70 years) with small cell lung cancer.
Patients and Methods Seventeen patients were treated with etoposide for 3 days and carboplatin calculated dose using Chatelut's formula on day 1 intravenously. The starting doses of etoposide on days 1 to 3, and carboplatin using the area under the concentration versus time curve (AUC) were 90 mg/m2 and 4 mg/ml-min, respectively.
Results The median age was 77 years (range 71 to 87). Dose-limiting toxicity (DLT) was seen at level 4 (AUC 5 mg/nil min of carboplatin and etoposide 100 mg/m2). Hematologic toxicity was the primary DLT. Grade 4 thrombocytopenia and Grade 4 leukopenia were observed at level 4. Non-hematologic toxicity was insignificant. The overall response rate was 94%.
Conclusion Etoposide at 100 mg/m2 and AUC of carboplatin of 4.5 mg/ml-min as calculated using Chatelut's formula every four weeks is the recommended dose for further phase II trials for elderly patients with small cell lung cancer.
(Internal Medicine 40: 603-606, 2001)

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Objective Interferon-alpha (IFN-α) is one of the most effective therapeutic agents for a number of hematological malignancies, including chronic myelogenous leukemia (CML). Nevertheless, its efficacy is limited because of the development of resistance to IFN-α therapy. Previously, we established the novel human CML cell line KT-1, which is sensitive to the antiproliferative effects of IFN-α. Here, we report the establishment of an IFN-α-resistant subline, KTl/A3Rα 1000, by culturing KT-1/A3 cells (IFN-α-sensitive subline of KT-1) with increasing concentrations of IFN-α, in order to analyze the mechanism of acquisition of IFN-α resistance in CML cells after IFN-α therapy.
Subjects and Methods We developed an IFN-α-resistant tumor cell variant, KT-1/A3Rα 1000, from the KT-1/A3 cell line by culturing cells with increasing concentrations of IFNα. This subline was examined for its ability to proliferate and its resistance to apoptosis in high concentrations of IFNα. The induction of the ISGF3 complex in response to IFNα in KT-1/A3Rα 1000 was compared with that in the parental cell.
Results The levels of interferon-stimulated gene factor 3 components (STAT1, STAT2, and p48) proteins and STAT2 tyrosine phosphorylation induced after IFN-α treatment were unchanged, but formation of the ISGF3 complex was remarkably reduced in KT-1/A3Rα 1000 cells compared to parental cells.
Conclusion The KT-1/A3Rα 1000 subline is a useful model for studying the mechanism of IFN-α resistance after IFN-a therapy.
(Internal Medicine 40: 607-612, 2001)

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Objective To clarify the clinical features of myelitis associated with atopic disorders in Japanese patients.
Subjects and Methods We retrospectively studied the clinical, immunological and electrophysiological features of 68 consecutive patients with myelitis of acute or subacute onset diagnosed at Kyushu University Hospital during the past 20 years.
Results While only 2 of 28 (7%) patients with myelitis diagnosed between 1979 and 1993 had either atopic dermatitis (AD) or bronchial asthma (BA), 19 of 40 (48%) patients with myelitis diagnosed between 1994 and 1998 did. Among the 40 patients with myelitis diagnosed between 1994 and 1998, 19 patients with either AD or BA as well as 21 patients without either disease showed a significantly higher level of serum total IgE, higher frequency of hyperlgEaemia and higher frequency of mite antigen-specific IgE than 82 healthy controls. Myelitis patients with AD presenting as persistent paresthesia/dysesthesia in all four limbs showed cervical cord lesions on MRI and abnormalities in upper limb motor evoked potentials but no abnormalities in the cerebrospinal fluid (CSF), while myelitis patients with BA showed preferential involvement of the lower motor neurons clinically and electromyographically. In addition, 12 patients with myelitis who had hyperlgEaemia and mite antigen-specific IgE but neither AD nor BA showed incomplete transverse myelitis with mild motor disability and few CSF abnormalities.
Conclusion The clinical features of myelitis associated with atopic disorders were in part distinguished by the type of preceding atopic disorder, and also were different from those of hyperlgEaemic myelitis with no preceding atopic disorders.
(Internal Medicine 40: 613-619, 2001)

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Tracheoesophageal fistulas (TEF) in adults are most commonly neoplastic, and very rarely congenital in nature. We report a 45-year-old Hispanic male with TEF and initial presentation of minimal hemoptysis. The patient had radiographic evidence of unilateral upper lobe (RUL) bronchiectasis, massive esophageal dilatation, and dysmotility. However, there was no evidence of esophageal malignancy, achalasia, or Chagas' disease. Bronchoscopy revealed a large TEF in the posterior wall of trachea, which was not visualized on esophagram or esophagoscopy. Bronchoalveolar lavage (BAL) cultures grew Mycobacterium avium complex (MAC). Our report illustrates that idiopathic, or congenital, TEF can be associated with esophageal dysmotility, adulthood bronchiectasis, and atypical m¥ cobacterial superinfection.
(Internal Medicine 40: 620-623, 2001)

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A 68-year-old Japanese woman was admitted to our hospital in September 1995, because of a mass detected by ultrasonography during a follow-up examination for chronic hepatitis B. Hepatocellular carcinoma (HCC) in the right liver lobe was diagnosed based on imaging studies and elevated alpha-fetoprotein (AFP). Percutaneous ethanol injection therapy (PEIT) was performed. PEIT was repeated in November 1998, because the tumor had enlarged and serum AFP was re-elevated. Follow-up ultrasonography (US) demonstrated low echoic mass in the left liver lobe in August 1999; serum AFP was normal, but serum carbohydrate antigen 19-9 (CA19-9) was elevated to 420 U/ml. In October 1999, radiofrequency interstitial tissue ablation (RITA^R) was performed after tumor biopsy. Pathological findings revealed adenocarcinoma and pathological diagnosis was made as intrahepatic Cholangiocellular carcinoma (ICC). Three weeks later, her serum CA19-9 was remarkably decreased (180 U/ml). The patient has been well for 5 months. Her latest AFP and CA19-9 in the serum were 2 ng/ml and 89 U/ml, respectively. The incidence of double cancer in the liver is rare. This is also the first case report to discuss ICC treated with RITA^®.
(Internal Medicine 40: 624-630, 2001)

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A 55-year-old man was admitted to our hospital with fever and vomiting. Abdominal computed tomography (CT) revealed multiple low density masses in the liver. A diagnosis of primary adenosquamous carcinoma of the liver was confirmed by histological examination of a necropsy specimen. The present case showed leukocytosis and hypercalcemia with high levels of serum granulocyte-colony-stimulating factor (G-CSF) and parathyroid hormone related protein (PTHrP). Recent studies have shown that G-CSF and PTHrP are responsible for the paraneoplastic syndromes with leukocytosis and hypercalcemia. The tumor cells demonstrated positive cytoplasmic immunohistochemistry staining with anti-G-CSF and anti-PTHrP antibodies. This result suggested that the tumor produced G-CSF and PTHrP.
(Internal Medicine 40: 631-634, 2001)

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Hyperbaric oxygen was given to a patient with anorexia nervosa who had developed postoperative ileus, resulting in not only improvement in ileus, but also enhancement of intestinal movement, inducing the feeling of hunger, and thereby increasing food ingestion. Hyperbaric oxygen may be effective as an initial treatment for anorectic patients showing severe bloating and resistance to food ingestion.
(Internal Medicine 40: 635-637, 2001)

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The case was a 51-year-old man, who has been undergoing treatment with oral medication for hypertension for three years. The patient was admitted to the author's clinic for hemorrhage in the left putamen. He was diagnosed as having primary pheochromocytoma of the bladder from such symptoms as paroxysmal blood pressure elevation after urination, mild increase in catecholamine levels before and after urination, and from the results of 131I-MIBG scintigraphy, and cystoscopy, and underwent excision of the bladder tumor. Upon endocrinological examination, only mild increases in catecholamine levels were found. Therefore, constant monitoring of blood pressure and ¹³¹I-MIBG scintigraphy were useful for a definitive diagnose.
(Internal Medicine 40: 638-642, 2001)

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We report the case of a severe bronchial asthma attack 15 minutes after the ingestion of food containing small amounts of alcohol. Although an ethanol inhalation test was negative, an acetaldehyde inhalation test was positive. Furthermore, it was discovered that the patient was homozygous for a mutation of the aldehyde dehydrogenase-2 (ALDH-2) gene. We subsequently diagnosed his attack as acute severe alcohol-induced asthma. Since bronchial asthma patients who are homozygous for mutant ALDH-2 genes are susceptible to acute severe alcohol-induced asthma attacks, strict clinical attention is thought a necessity.
(Internal Medicine 40: 643-645, 2001)

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A 61-year-old man was started on hemodialysis in June 1998. Just after the commencement of dialysis, a chest X-ray film revealed bilateral pleural effusions. The effusions were hemorrhagic and exudative, and did not respond to dialysis. He was transferred to our university hospital on October 8, 1998. Repeated thoracentesis demonstrated hemorrhagic and exudative characteristics without any diagnostic evidence. Pleural biopsies showed fibrosis and lymphocyte infiltration. The effusions were massive and did not respond to treatments including hemodialysis, repeatedly performed pleurodesis and the administration of antituberculous drugs. He died of respiratory failure on December 30, 1998. The autopsy confirmed bilateral fibrinous pleuritis without any underlying infections or malignancy. We diagnosed this case as uremic pleuritis from this clinical course and the autopsy findings. The clinical entity of uremic pleuritis was recognized as a complication of patients with hemodialysis in 1969. Uremic pleuritis generally responds to continued hemodialysis and the prognosis is usually good. However, some case reports demonstrated that surgical decortication is only indicated in cases with a severe clinical course. The clinical course of the present case was progressive and fatal. Uremic pleuritis is a serious complication of hemodialysis, which may lead to death.
(Internal Medicine 40: 646-649, 2001)

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A 44-year-old woman was admitted to our hospital for repeated hemoptysis. Selective angiography of the bilateral bronchial arteries showed them to be enlarged and convoluted, and revealed shunts between the bronchial and pulmonary arteries. The patient was diagnosed as having racemose hemangioma of the bronchial artery. Although embolization of the bronchial artery with gelatin sponges was performed, hemoptysis emerged again about one year later. Finally, segmentectomy of the right lower lung was performed and primary racemose hemangioma of the bronchial artery was histopathologically confirmed.
(Internal Medicine 40: 650-653, 2001)

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Multiple brain and liver abscesses developed immediately after Bacillus cereus bacteremia in a neutropenic patient with acute lymphoblastic leukemia. After even 8 weeks of antimicrobial chemotherapy together with administration of granulocyte colony-stimulating factor, every infectious process disappeared but the patient's headache has still persisted. Because the wall of one brain abscess became thin and was in danger of rupturing into the ventricle, surgical drainage was performed, resulting in disappearance of headache and resolution of brain abscess. The present case indicates that a combined medical and surgical approach is mandatory to treat patients with brain abscesses.
(Internal Medicine 40: 654-657, 2001)

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We report here an autopsy case of massive pontine hemorrhagic infarction secondary to embolic basilar artery occlusion. A large embolus appeared to have traversed the vertebral artery into the basilar artery as a result of basilarization of the vertebral artery due to severe stenosis of the contralateral vertebral artery. Extensive ischemia due to embolic occlusion of the entire length of the basilar artery, and migration of the embolus are assumed to have resulted in a massive pontine hemorrhagic infarction.
(Internal Medicine 40: 658-661, 2001)

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A 25-year-old man developed a stroke-like episode. He suffered from renal failure and became dialysis-dependent. His mother was also dialysis-dependent. A3243G point mutation of the mitochondrial tRNA^leu gene was detected in both of them. The patient was diagnosed with mitochondrial encephalomyopathy with lactic acidosis and stroke-like episodes (MELAS), and died of a recurrence of stroke-like episodes at the age of 30. Autopsy revealed numerous abnormal mitochondria in the kidneys, but no renal vascular changes. This is the first report of a MELAS case in which the presence of numerous abnormal mitochondria in podocytes and tubules was confirmed by electron microscopy.
(Internal Medicine 40: 662-665, 2001)

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Wegener's granulomatosis (WG) has two different clinical phases: the initial phase and generalized phase. In patients with generalized WG, both steroids and cyclophosphamide have generally been used. We report a case of generalized WG that was temporarily, but successfully treated with sulfamethoxazole-trimethoprim (S/T) alone. S/T therapy reduced the elevated levels of soluble IL-2 receptor and IL-6 in parallel with improvement of the patient's symptoms and urinary protein excretion. In view of the high incidence of lethal adverse effects of cytotoxic drugs, S/T monotherapy may be worth trying not only for initial phase WG but also for generalized WG with careful follow-up when the patient is not acutely ill.
(Internal Medicine 40: 666-670, 2001)

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We report cases of amebiasis in 6 human immunodeficiency virus (HIV)-positive male patients. Five were confirmed homosexuals while one was suspected. Three patients had liver abscess and 5 had colitis with duration of 10 days to months. The patients with liver abscess showed a lower incidence of abdominal pain but a higher incidence of concomitant diarrhea. Drainage therapy was effective for rapid afebrile results. Two invasive colitis cases died from perforation. This may have been due to delayed diagnosis. Invasive amebiasis is not common even in HIV-infected individuals. Among Japanese homosexual men, however, it may cause symptomatic diseases.
(Internal Medicine 40: 671-675, 2001)

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