Endothelin-1 (ET-1), endothelin-2, and endothelin-3, a family of 21-aminoacid peptides, are potent, long-acting vasoconstrictors of mammalian blood vessels. Elevated levels of ET-1 have been found in the circulation of patients with various diseases, all of which have some degree of vascular involvement that is associated with endothelial cell activation. These diseases include systemic sclerosis, primary and secondary Raynaud's phenomenon, pulmonary hypertension, Buerger's disease, and Takayasu's arteritis. The role of circulating ET-1 in the pathogenesis of the vascular and fibrotic lesions in these conditions remains to be elucidated. This review focuses on the recent findings of the clinical significance and pathogenetic role of endothelin in collagen vascular diseases, especially in Raynaud's phenomenon and systemic sclerosis. Although the etiology of systemic sclerosis is unknown, a vascular pathogenesis is supported by a variety of clinical and laboratory observations. The fact that plasma levels of ET-1 are elevated in patients with systemic sclerosis and this elevation is more remarkable in patients with diffuse scleroderma compared with limited scleroderma patients might further support the vascular pathogenesis of systemic sclerosis.
(Internal Medicine 33: 579-582, 1994)

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In patients with POEMS syndrome, which often accompanies plasma cell dyscrasia, the roles of interleukin-6 (IL-6) and other acute phase cytokines are unknown. Serum IL-6, interleukin-1β; (IL-1β) and tumor necrosis factor-β (TNF-α) were measured by the enzyme-linked immunosorbent assay technique in 16 patients with POEMS syndrome and in patients with other neurological diseases (OND) as control. Serum IL-6 was more frequently detected and higher in active POEMS than in stable POEMS or in OND patients. No sample was positive for IL-1β. TNF-α; was positive in 3 out of 7 active POEMS patients, but its significance was not definite. Serum IL-6 levels in POEMS patients reflected the disease activity but not the severity of accompanying plasma cell dyscrasia.
(Internal Medicine 33: 583-587, 1994)

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To investigate the markers useful for evaluating the long-term efficacy of interferon (IFN) therapy, the quantity of hepatitis C virus (HCV) RNA and two anti-HCV antibody titers (anti-N14 and anti-C-100-3 antibody) in 21 chronic hepatitis C patients were determined. In all complete responders, a sustained clearance of the virus and reductions in the anti-HCV antibody titers were observed during and after therapy. In most of the temporary responders, reductions in the HCV RNA levels and in both anti-HCV antibody titers were observed temporarily during the therapy, and relapse followed. In nonresponders, although the HCV RNA levels and anti-N14 antibody titer tended to remain unchanged or increased during and after therapy, the anti-C-100-3 antibody titers showed no tendency. These results demonstrate that the monitoring of the HCV RNA level and anti-N14 antibody titer is clinically useful for following the patient's response to IFN therapy for chronic hepatitis C.
(Internal Medicine 33: 588-592, 1994)

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A somatostatin analogue (SMS-201-995, hereinafter "octreotide") was s.c. administered to 5 healthy subjects under consecutive dripping of CCK-PZ (cholecystokinin-pancreozymin) and secretin (0.01 CHR U/kg/minutes), after inserting a Dreiling double tube into Treitz's ligament. Bile acid concentration, and bicarbonate and lipase excretions in duodenal juice were determined every 10 minutes up to 120 minutes and compared with controls. Moreover, octreotide (100 μg) was s.c. administered to 5 healthy subjects 30 minutes before meals for 7 days. Fecal fat and bile acid excretions before and after administration were determined. Bile acid concentration, and bicarbonate and lipase excretions in the octreotide group decreased to 1/3 -1/4 that of controls. Bile acid concentration became 0 mM for 60 minutes. Fecal fat excretion increased; obvious Steatorrhea occurred in 2 cases. Fecal bile acid excretion decreased to about 1/4. These results suggest that decreases in bile acid secretion should be considered, as well as pancreatic lipase and bicarbonate secretions, when fatty stool occurs after octreotide administration.
(Internal Medicine 33: 593-596, 1994)

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Endoscopic biliary endoprosthesis was performed for 34 high-risk patients with common bile duct stones too large to be extracted by conventional endoscopic means. Bile duct drainage was established in all the patients without complications. Late complications developed in four patients and included cholangitis (three) and biliary pain (one). Twenty-five patients underwent a second endoscopic retrograde cholangiopancreatography between 4 and 30 months (mean, 15.1) during follow-up. Stone fragmentation was obtained in 76% (19/25) of the patients. Ten patients had complete stone clearance, and nine patients had disintegrated stones which could be readily removed endoscopically. The remaining nine patients were followed up with endoprostheses in situ for four to 60 months (mean, 24.8) without any symptoms. These results suggest that endoscopic endoprosthesis for difficult common bile duct stones is an effective method to clear the duct in selected cases, as well as an important definitive treatment in high-risk patients.
(Internal Medicine 33: 597-601, 1994)

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Patients with Addison's disease, newly diagnosed in the last five years were surveyed nationwide in conjunction with two past surveys. The decreasing incidence, i.e., 168 patients from 1977 to 1981 (survey 1), 108 from 1982 to 1986 (survey 2), and 74 from 1987 to 1991 (the present survey), reflects a decrease in the incidence (n=28) of tuberculous Addison's disease, but not that (n=36) of idiopathic Addison's, making the idiopathic form predominant for the first time in the history of the disease in Japan. Because the interval between the preceding tuberculosis and the onset of Addison's averages 32±15 years, tuberculous Addison's has a relatively late onset. Pigmentation is the most frequent symptom (90%). Other symptoms, abnormal laboratory data, and positive adrenal antibodies are observed less frequently in Japan than in North America or Europe. The types of associated disorders are also distributed differently. Adrenal CT and MRI scans have been the most useful means in differentiating between the two major types of the disease. This report focuses on features distinguishing Japanese sufferers from their western counterparts.
(Internal Medicine 33: 602-606, 1994)

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A 63-year-old female, who had been diagnosed with rheumatoid arthritis (RA) 3 years previously, was admitted due to progressive pancytopenia, lymphadenopathy, fever, and weight loss. The physical and laboratory findings fulfilled all of the American Rheumatism Association (ARA) revised criteria for RA. Her bone marrow aspirate revealed a decreased nuclear cell count (1.8×10⁴/μl) and megakaryocyte count (0/μl), and macrophages phagocytizing blood cells (4%), indicating the presence of hemophagocytic syndrome. The serological tests for several viruses revealed no obvious viral etiology. However, a slight Epstein-Barr virus (EBV) reactivation could not be excluded. Administration of 40 mg prednisolone daily improved her abnormal hematological findings and immunological laboratory parameters. This is a case of RA accompanied by hemophagocytic syndrome, which has not been reported previously as a complication of RA. (Internal Medicine 33: 607-611, 1994)

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We analyzed the HLA antigens in two patients with rheumatoid arthritis accompanied by diffuse panbronchiolitis in whom HLA typing could be done and found the presence of B54 and DR4 alleles. We previously reported that the frequency of HLA-B54 is significantly increased in patients with diffuse panbronchiolitis. This allele demonstrates a linkage disequilibrium with DR4 (or DR4.1) in Japanese individuals. The association of rheumatoid arthritis with HLA-DR4 is well established in various ethnic groups including Japanese people. Since both diseases show the same pattern of HLA correlation, more Japanese patients with these two diseases are likely to be encountered.
(Internal Medicine 33: 612-614, 1994)

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We report the successful management of cerebral vasculitis in a 46-year-old woman with longstanding rheumatoid arthritis with low-dose methotrexate. She suddenly developed dysarthria and left hemiparesis. Magnetic resonance imaging disclosed ischemia of the right pons, and angiography demonstrated cerebral vasculitis of vertebro-basilar arteries. The vasculitis was refractory with high-dose steroid therapy, which had only transient clinical benefit, and evolution to the pontine infarction followed. Her clinical status showed marked improvement in association with recovery of the vascular abnormalities after the initiation of the methotrexate therapy.
(Internal Medicine 33: 615-620, 1994)

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A rare case of duodenal schwannoma is reported. A 69-year-old man was admitted for evaluation of melena. Endoscopy and hypotonic duodenography showed a submucosal tumor in the third part of the duodenum. Biopsy findings were suggestive of leiomyosarcoma, therefore pancreatoduodenectomy was performed. Hematoxylin-eosin staining of the resected specimen showed interlacing bundles of spindle-shaped cells with palisading nuclei. Immunohistochemical staining showed positivity for S-100 protein and neuron-specific enolase, but desmin was negative, thus a diagnosis of schwannoma was made. Schwannoma is often difficult to distinguish from leiomyogenic tumors by standard staining, but immunohistochemical staining proved useful in this case.
(Internal Medicine 33: 621-623, 1994)

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A 65-year-old man with an occupational history of asbestos exposure developed dysphagia and vomiting. Clinical examinations at onset revealed a dilated esophagus with smooth narrowing at the gastroesophageal junction and no apparent tumor in and around the esophagus. Achalasia was suspected. Dysphagia progressed gradually and examinations performed three months after the onset disclosed a tumor in the pleural and the peritoneal cavitieis. At laparotomy, the tumor extended from the pleural cavity into the peritoneal cavity. Histological examination of the biopsied specimen demonstrated malignant mesothelioma. We report the first case of malignant pleural mesothelioma presenting as achalasia.
(Internal Medicine 33: 624-627, 1994)

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A case of infective endocarditis (IE) caused by a rare pathogen, Gemella morbillorum, is presented. Because of persistent low-grade fever after dental treatment, the patient was given oral antibiotics. Whereas he was diagnosed as having aortic regurgitation by a cardiologist, and IE was not suggested unfortunately. After long-term chemotherapy over five months, he was aware of nocturnal dyspnea and Gemella morbillorum was detected by blood culture. Then, he was treated with intravenous administration of Penicillin-G, and underwent surgical operation for valve replacement. No cases of IE due to this organism have been reported in Japan.
(Internal Medicine 33: 628-631, 1994)

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We describe a 52-year-old male manifesting severe insulin resistance associated with hypereosinophilic syndrome (HES). Diabetes mellitus was initially well-controlled by an oral hypoglycemic agent, and thereafter by human insulin. Due to the progression of hypereosinophilia, hepatosplenomegaly and peripheral lymphoadenopathy, severe insulin resistance associated with diabetic ketoacidosis occurred repeatedly, despite intravenous administration of over 1, 000 U per day of human insulin. A high plasma insulin-binding capacity as determined by Scatchard analysis was consistent with insulin antibody-mediated resistance. The diagnosis of HES was made due to the persistent elevation of eosinophil count and associated liver and cardiac damage. Glucocorticoid therapy successfully achieved both reducing clinical symptoms and improving glycemic control.
(Internal Medicine 33: 632-636, 1994)

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A 59-year-old woman with chronic active hepatitis C was treated with recombinant human interferon alpha-2a. After three days of administration, the patient complained of diplopia with dizziness and head heaviness. Ophthalmic examinations revealed a disturbance of the movement of left eye ball to the outer side without any other neurological signs. The diplopia, which was diagnosed as abducent nerve paralysis, improved rapidly and reversed at about 6 weeks after discontinuation of interferon and during infusion of hydrocortisone. To our knowledge, this is the first report of abducent nerve paralysis associated with alpha-2a interferon.
(Internal Medicine 33: 637-640, 1994)

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Two types of recombinant human granulocyte colony-stimulating factor (rhG-CSF) are available, and equally used for mitigation of neutropenia. One is a glv cos via ted natural product from mammalian cells, and the other a non-glycosylated form from Escherichia coli. Though only minimal adverse effects have been reported for both, we treated two patients with rhG-CSF-induced systemic eruption. Based on these patients, the following should be noted: 1) drug eruption may occur in both types of rhG-CSF without detectable antibodies, 2) intradermal test is useful for determination of the causal drug, and 3) if one rhG-CSF product causes eruption, the alternative one may possibly be safe and effective.
(Internal Medicine 33: 641-643, 1994)

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A patient with pigmentary retinopathy, nephrotic syndrome, Ménétrier's disease, and diabetes mellitus is presented. Other complications were congestive heart failure, hypothyroidism, hypertension, and hypertriglyceridemia. Hypogenitalism was also suspected. Pigmentary retinopathy is known to associate with many systemic diseases, which are classified into several syndromes. This case superficially resembles Alström's disease due to the common characteristics of pigmentary retinopathy, diabetes mellitus, renal disease, and hypogenitalism. But clinically and histologically, there are distinct differences. To our knowledge, this association has never been reported.
(Internal Medicine 33: 644-648, 1994)

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A 56-year-old man was admitted for the evaluation of recurrent pulmonary infections. Since the patient presented with the combination of diffuse cystic bronchiectasis, chronic sinusitis and obstructive azoospermia, the diagnosis of Young's syndrome was made. Because the sweat chloride value, pancreatic function and ciliary ultrastructure were normal, this case could be clearly differentiated from cystic fibrosis and primary ciliary dyskinesia. There have been only a few reported cases of Young's syndrome in Japan.
(Internal Medicine 33: 649-653, 1994)

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We report a rare case of complete remission for 32 months with continuous treatment with alltrans retinoic acid (ATRA) alone in a patient with acute promyelocytic leukemia which developed as a second malignancy after the treatment of osteosarcoma after failure of conventional chemotherapy. The adverse effects of ATRA were apparently tolerable.
(Internal Medicine 33: 654-657, 1994)

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