Over the past decade, our understanding of apoptosis, or programmed cell death, has increased greatly, with the identification of some of the major components of the apoptotic program and the processes regulating their activation. Although apoptosis is an intrinsic process present in all cells, it can be regulated by extrinsic factors, including growth factors, cell surface receptors, cellular stress and hormones. Apoptotis plays an important role in autoimmune diseases. Normal thyrocytes could induce apoptosis of infiltrating activated T cells and protect against attack by such cells, i.e., the normal thyroid tissues act as an immune privileged site. In Hashimoto's thyroiditis (HT), Fas-mediated apoptosis of thyrocytes in a section of tissues is due to at least two separate mechanisms, the first by infiltrating activated T cells, and the other by FasL-possitive thyrocytes in a suicidal or fratricidal fashion. A common feature of autoimmune diseases such as systemic lupus erythematosus (SLE) is the breakdown of tolerance of self antigens, a consequence of which is the production of autoantibodies reactive with multiple self proteins. Evidence is accumulating that modifications of autoantigens during apoptosis lead to the development of autoantibodies by bypassing the normal mechanisms of tolerance. Tissue homeostasis is maintained through a balance between cell proliferation and apoptotic cell death. Rheumatoid arthritis (RA) is characterized by pronounced hyperplasia of the synovial tissue, cell infiltration and periarticular osteoporosis. Enhanced Bcl-2 expression and NF-κB nuclear translocation of synovial cells are induced by inflammatory cytokines and/or growth factors. These synovial cells become resistant toward apoptosis triggered by various stimuli. The infiltrated cells which are defect in activation-induced cell death can cause autoimmunity by allowing the survival of autoreactive T and B cells. These data suggest that apoptosis might be implicated with the pathogenesis of autoimmunity, whereas the mechanisms might be distinct in each autoimmune disease.
(Internal Medicine 40: 275-284, 2001)

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The pathogenetic mechanisms leading to progression of renal failure are only partly understood. Several studies in immune- and non-immune-mediated models of renal damage have recently implicated the endothelin (ET) system as a major player in these processes. In animal models, ET receptor antagonists have been shown to be highly effective in abrogating the progression of renal failure. Furthermore, cardiac structural alterations seen in hypertension and/or renal insufficiency, e.g. left ventricular hypertrophy, thickening of intramyocardial arterioles, and the increase in non-vascular interstitial tissue, are largely prevented by ET receptor antagonists. In this context it is of interest that these beneficial renal and cardiac effects are, at least in most studies, independent of systemic blood pressure. In addition to the specific pharmacological blockade of the renin-angiotensin system [ACE inhibitors, angiotensin II receptor (AT₁) antagonists], blockade of ET receptors or ET converting enzyme (ECE) may be a new tool to interfere with progression of renal failure and cardiovascular remodeling in humans.
(Internal Medicine 40: 285-291, 2001)

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Objective The incidence of subacute thyroiditis (SAT) is low and there are a few reports of recurrence of subacute thyroiditis. Current treatment protocols for SAT are not uniform. Prednisolone (PSL) is chosen more often for treatment than nonsteroidal anti-inflammatory drugs. This study was undertaken to confirm the recurrence rate of SAT managed by PSL, and to compare the initial laboratory data between the recurrent and the non-recurrent groups.
Methods After diagnosis, all patients were treated with PSL (starting at 30 mg or 25 mg per day, tapered by 5 mg per week) for 5 or 6 weeks. We evaluated data and symptoms at the first visit and during the therapy.
Patients Thirty-six patients who received only PSL for SAT at our hospital between January 1997 and December 1998 were referred. These patients asked to visit every 2 weeks for the monitoring of symptoms and laboratory data.
Results SAT symptoms recurred in eight patients (22 %), most upon cessation of PSL. There was no difference in initial serum sialic acid, erythrocyte sedimentation rate, C-reactive protein, thyroglobulin, serum free thyroxine and free triiodothyronine before PSL treatment between the recurrent and non-recurrent patient populations.
Conclusions The recurrence rate of SAT with treated PSL is about 20%. There was no difference in the laboratory data before starting the therapy between recurrent and non-recurrent groups. Therefore, a modified protocol of PSL administration may be needed to decrease the early recurrent rate of SAT.
(Internal Medicine 40: 292-295, 2001)

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Objective The purpose of this article was to study and clarify the features of Chinese herb nephropathy (CHN) in Japan.
Patients and Methods The subjects consisted of patients diagnosed as having CHN in Saiseikai Nakatsu Hospital and of those reported in the literature in Japan. We investigated the clinical and histological features of CHN patients in Japan and compared them with the Belgian cases.
Results The remarkable differences were as follows: (1) high prevalence in males compared with Belgian cases, (2) Fanconi syndrome was found in most cases, (3) no patients had malignant tumors in the urinary tract. In addition, the ascribed Chinese medicines in Japan were divided into three groups: 'Tenshin-toki-shigyaku-ka-gosyuyu-syokyo-to', 'Boui-ougi-to', and others.
Conclusion CHN in Japan has some characteristics distinguished from Belgian nephropathy. One hypothesis is a susceptibility to aristolochic acids (AAs), which is considered to be a causative agent, may be different among races. Another is that there could be some other toxic substances affecting the clinical findings although they are not identified at present. Further studies must be undertaken to clarify these differences.
(Internal Medicine 40: 296-300, 2001)

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The majority of human gastrointestinal mesenchymal tumors are gastrointestinal stromal tumors (GISTs). Recent reports have shown the existence of gain-of-function mutations in the juxta-membrane domain of receptor tyrosine kinase (KIT) in GISTs. We present a 77-year-old woman with GIST diagnosed by positive immunostaining of cluster designation (CD) 34 and KIT. This case had a novel mutation at codon 576 located in the juxta-membrane domain of KIT. Our results indicate the importance of mutations in this KIT region and suggest the possibility of the existence of other types of mutations in this region in GISTs.
(Internal Medicine 40: 301-303, 2001)

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A 41-year-old woman with long-standing anorexia nervosa showed paralytic ileus and serum creatine kinase elevation. Surgical treatment showed necrosis of the segmental ileum and cecum with perforation. She died of septic shock 3 days after the operation. Postmortem examination revealed no occlusion of the superior mesenteric artery or its main branches, and no arteriosclerotic changes. Histological examinations confirmed non-occlusive mesenteric infarction. This case suggested that necrosis of bowels might have been caused by poor blood supply due to severe malnutrition and dehydration for many years, which could be one of the fatal complications of anorexia nervosa.
(Internal Medicine 40: 304-307, 2001)

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Sjögren's syndrome occurs as an occasional complication of autoimmune hepatitis, and purpura or thrombocytopenia develops in some patients with this syndrome. This report describes a 62-year-old woman with a 6-year history of autoimmune hepatitis who concurrently had hypergammaglobulinemic purpura, immune thrombocytopenia and Sjögren's syndrome. Treatment with prednisolone resulted in marked improvement of biochemical, hematological and dermatological abnormalities. This case emphasizes the manifestation of purpura or thrombocytopenia as an associated disorder during the course of autoimmune hepatitis concomitant with Sjögren's syndrome.
(Internal Medicine 40: 308-311, 2001)

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A 69-year-old woman was admitted to the hospital with palpitations. Although left ventriculography showed extensive akinesis except in the basal hyperkinetic segment, coronary angiography showed normal coronary arteries. 123I-metaiodobenzylguanidine (MIBG) accumulation was obviously reduced in the anteroseptal, apical and inferior areas. Inverted T waves developed on day 3 and disappeared on day 104 after transient regression. Echocardiography showed normal left ventricular motion two weeks later. Ergonovine provocation test showed no vasospasm and thallium-201 showed no perfusion defect on day 46. Electrocardiography and MIBG returned to normal on day 216. These findings suggest prolonged sympathetic nerve injury in extensive myocardial stunning.
(Internal Medicine 40: 312-319, 2001)

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A 72-year-old man with diabetic triopathy was hospitalized with methicillin resistant staphylococcus aureus pneumonia. Six hours after the admission, his abdomen was fully expanded. An abdominal X-ray showed gastric dilatation. After insertion of a gastric tube to extract gastric air, his abdomen was flat and gastric dilatation improved. A positive Schellong test and decreased coefficient of RR interval in electrocardiogram variation indicated autonomic neuropathy, which may explain the reason for gastric hypomotility. Acute gastric dilatation in this patient may have occurred due to gastric hypomotility as a result of diabetic autonomic neuropathy in addition to gastric motility inhibition resulting from gastric autonomic nerve stimulation by bacterial toxin.
(Internal Medicine 40: 320-323, 2001)

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We report a hypoglycemic case with normal insulin levels, which was caused by an islet cell tumor that was releasing insulin and somatostatin. A fasting test suggested the over secretion of insulin. Moreover, this hypoglycemia was enhanced by the inhibitory effect of somatostatin on the secretion of insulin counter-regulatory hormones, such as glucagon, in addition to the autonomous secretion of insulin from the tumor. In cases of hypoglycemia with apparently normal insulin levels, the measurement of somatostatin and various provocative tests are recommended. Arterial stimulation venous sampling (ASVS) was useful to detect the location of this functioning islet cell tumor.
(Internal Medicine 40: 324-330, 2001)

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A 43-year-old man developed fever, skin rash, eosinophillia, and severe renal and liver dysfunction following treatment with allopurinol. The patient died after 3 months of hospitalization. Autopsy revealed systemic cytomegalovirus infection and bacteremia.
(Internal Medicine 40: 331-335, 2001)

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Alpha-1-antitrypsin (α1AT) deficiency is extremely rare among Orientals. We treated a 37-year-old man with severe pulmonary emphysema associated with a low serum concentration of α1AT. Mutation analysis of the α1AT gene was performed using a reverse transcription-polymerase chain reaction followed by sequencing. The patient proved to be a compound heterozygote carrying a S_iiyama deficient allele and a QO_clayton null allele. This is the first Japanese case of α1AT deficiency to arise from such compound heterozygosity in a family with no apparent consanguineous marriage, suggesting that the gene frequency for deficient alleles might be somewhat higher than previously estimated.
(Internal Medicine 40: 336-340, 2001)

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A 49-year-old woman with a malignant solitary fibrous tumor of the pleura presented with hypoglycemia. Most of the serum insulin-like growth factor II (IGF-II) existed as high molecular weight IGF-II. Furthermore, there were larger amounts of high molecular weight IGF-II found in the tumor cystic fluid than in the serum. After surgical resection of the tumor, high molecular weight IGF-II was not detected in the serum and the hypoglycemia resolved. Immunohistochemically, IGF-II was localized in the so-called Golgi area of the tumor cell. These findings suggest that hypoglycemia in this patient was caused by the high molecular weight IGF-II produced by the tumor.
(Internal Medicine 40: 341-344, 2001)

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A 64-year-old woman who was previously in good health was admitted because of progressive respiratory distress. Her chest radiograph revealed bilateral widespread alveolar infiltrates. She was given a diagnosis of pneumonia caused by Mycoplasma pneumoniae serologically, acute respiratory distress syndrome, and disseminated intravascular coagulation. She died of multiple organ failure despite intensive therapy with mechanical ventilation, intravenous erythromycin and corticosteroids, continuous hemodiafiltration, and plasma exchange. Although Mycoplasma pneumoniae infection is usually a benign self-limited disease, this case emphasizes its potentially serious nature even in normal healthy individuals.
(Internal Medicine 40: 345-348, 2001)

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A 49-year-old woman with diabetes mellitus developed progressive weakness and atrophy of both thighs rendering her wheelchair-bound within two months. The neurological findings and electrophysiological test results were compatible with diabetic amyotrophy (DA). Immediately after intravenous immunoglobulin (IVIg) therapy (20 g×3 days), she became able to walk with a cane. After the next course of the therapy, she could walk without assistance. This dramatic effect of IVIg therapy together with the recent observation of vasculitic neuropathy in DA indicates an inflammatory process in this condition, and gives support to this treatment for DA.
(Internal Medicine 40: 349-352, 2001)

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A 26-year-old woman suffered from acute myelitis at Th 6 level associated with systemic lupus erythematosus. Methyl-prednisolone pulse therapy, intravenous high-dose immunoglobulin administration and plasmapheresis were not effective. Her neurological signs had persisted in spite of subsequent administration of oral prednisolone and azathiopurine. Magnetic resonance imaging (MRI) of spinal cord at the onset showed a marked swelling with intramedullary high intensity signals on T2WI along the whole thoracic cord. Three years later, MRI demonstrated a severe longitudinal and segmental atrophy of the mid to low thoracic cord which resulted in transverse spinal signs.
(Internal Medicine 40: 353-357, 2001)

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A 31-year-old woman displayed sleepiness and impairment of recent memory. T2-weighted MRI revealed high signal intensity lesions in the bilateral basal ganglia, thalamus, and brainstem. Although remission was achieved with corticosteroid therapy, she again displayed memory dysfunction and emotional disturbance one year later, at which time MRI disclosed new lesions in the right caudate nucleus and left frontal white matter. Corticosteroid therapy lead to improvement, and she suffered no recurrence on maintenance steroid therapy. These findings suggest that caudate lesions do occur in multiple sclerosis, the manifestations of which can be abulia and memory dysfunction, as in the present case.
(Internal Medicine 40: 358-362, 2001)

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We report a 42-year-old Japanese woman with Recklinghausen's neurofibromatosis 1 (NF1) who developed mixed connective tissue disease (MCTD). Previously experiencing good health without an increase in subcutaneous nodules, she presented with Raynaud's phenomenon, swollen hands and polyarthralgia. Clinical examination revealed a high titer of anti-RNP antibody, and she was thus diagnosed as having MCTD. She was treated with oral prednisolone (10 mg/day) and her symptoms improved rapidly. Since the association of MCTD and NF1 has not been reported previously, we concluded that this association is rare. We also discussed the association of NF1 and autoimmune diseases including MCTD.
(Internal Medicine 40: 363-364, 2001)

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