Hypoxia-inducible factor 1 (HIF-1) mediates transcriptional responses to hypoxia. HIF-1 is composed of an O₂-and growth factor-regulated HIF-1α subunit and a constitutively-expressed HIF-1β subunit. Four lines of evidence indicate that HIF-1 contributes to tumor progression. First, HIF-1 controls the expression of gene products that stimulate angiogenesis, such as vascular endothelial growth factor, and promote metabolic adaptation to hypoxia, such as glucose transporters and glycolytic enzymes, thus providing a molecular basis for involvement of HIF-1 in tumor growth and angiogenesis. Second, in mouse xenograft models, tumor growth and angiogenesis are inhibited by loss of HIF-1 activity and stimulated by HIF-1α overexpression. Third, immunohistochemical analyses of human tumor biopsies indicate that HIF-1α is overexpressed in common cancers and that the level of expression is correlated with tumor grade, angiogenesis, and mortality. Fourth, in addition to intratumoral hypoxia, genetic alterations in tumor suppressor genes and oncogenes induce HIF-1 activity.
(Internal Medicine 41: 79-83, 2002)

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ATP sensitive potassium (K_ATP) channels reside in the plasma membrane of many excitable cells such as pancreatic β-cells, heart, skeletal muscle and brain, where they link cellular metabolic energy to membrane electrical activity. They are composed of two subunits, K⁺ ion selective pore (Kir) and sulfonylurea receptor (SUR). In addition to the central role of pancreatic β-cell K_ATP channels in glucose-mediated insulin secretion, several lines of evidence support the hypothesis that K_ATP channels modulate glucose transport in the insulin target tissues. Inhibition of K_ATP channels by glibenclamide or gliclazide or an increase in intracellular ATP during hyperglycemia (glucose effect) or exercise facilitates glucose utilization, while activation of the channels by potassium channel openers, hypothermia (cardiac surgery), or ischemic damage (myocardial and brain infarction) reduces glucose uptake induced by insulin or hyperglycemia. Because insulin action has been known to depend on the energy level of the target cells, K_ATP channel may function as an effector in this respect. It is now evident that long chain acyl-CoA esters, metabolically active forms of fatty acids, are the most potent and physiologically important activator of K_ATP channels. Thus, I suppose that the sustained activation of K_ATP channels by long chain fatty acyl-CoA seems to be a missing link between lipotoxicity and insulin resistance in obesity and type 2 diabetes mellitus.
(Internal Medicine 41: 84-90, 2002)

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Objective The aim of this study was to clarify the prognosis of economy class syndrome (pulmonary thromboembolism following long distance flight) patients discharged from the intensive care unit.
Method Medications, daily activities, recurrence of pulmonary thromboembolism, and quality of life were investigated for an average of 471 days following discharge from the intensive care unit. The information from the patients was obtained by means of a mailed questionnaire or telephone interview.
Patients Ten patients with economy class syndrome were enrolled in this study. Nine were female and one was male (61±9 years).
Results In addition to appropriate acute care, additional management was given including the placement of an inferior vena cava filter in 3 patients and a course of oral anticoagulation therapy in 7 patients. None of them died or had recurrence of pulmonary thromboembolism. Four patients took subsequent air flights. No thromboembolic episodes were seen during the follow-up period.
Conclusion The long-term prognosis in these patients can be favorable with appropriate management of the acute episode in conjunction with adequate preventive measures.
(Internal Medicine 41: 91-94, 2002)

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Objective Primary lung cancer generally has a poor prognosis if not diagnosed at an early stage. But some lung cancers grow very slowly. In particular, adenocarcinoma is sometimes observed for years with no change of tumor size. In this study, we examined the reasons for the delays in reaching a definitive diagnosis of lung cancer.
Methods We retrospectively reviewed primary lung cancer cases between January 1995 and December 1999 and examined those whose definitive diagnoses were delayed for more than a year.
Results A total of 222 primary lung cancers were diagnosed. Of those, 19 patients (group A, 8.6%) were diagnosed after more than a year, and the other 203 (group B, 91.4%) were diagnosed within one year. The proportion of women in group A was significantly higher than that in group B (p<0.05). The mean age of group A was significantly younger than that of group B (p<0.05). The Brinkman Index of group A was significantly lower than that of group B (p<0.05). The histologic types were significantly different between the two groups (p<0.05). In group A, 18 patients (94.7%) had adenocarcinomas. Five primary reasons for the delays in group A were identified: 1) Four patients were tentatively diagnosed as inflammation or benign tumor on CT and were consequently not followed-up. 2) The chest CT shadows in 6 patients were suspected lung cancers but transbronchial lung biopsy findings did not show malignancy. 3) Four patients were tentatively diagnosed as inflammation or benign tumor on CT, but the tumors showed only very slow growth or no change at all. 4) The chest CT shadows of 2 patients were suspected lung cancer, but the patients refused to undergo video-assisted thoracic surgery (VATS) or closer examination. 5) Three patients did not consult medical facilities for a second examination.
Conclusions Many of the adenocarcinomas reviewed in our study grew slowly or remained unchanged for years. Doctors are mainly responsible for the delays in the definitive diagnosis and should aggressively perform VATS or closer examinations without hesitation.
(Internal Medicine 41: 95-102, 2002)

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Objectives We have often observed silent subcortical brain lesions on CT or MRI in first-ever ischemic stroke, but there is little published information on the relationship of these lesions to stroke subtypes. Here, we describe the incidence of MRI-detected silent subcortical brain lesions, including infarctions and white matter lesions, in a series of patients with first-ever ischemic stroke classified according to stroke subtypes. We also discuss the pathogenesis of these silent subcortical lesions.
Patients We evaluated 171 patients with acute first-ever ischemic stroke.
Methods The subjects were divided into three groups: lacunar, atherothrombotic and cardioembolic infarction groups. We evaluated silent subcortical brain infarction (SSBI), enlargement of perivascular space (EPS), and other white-matter lesions using MRI.
Results Hypertension was observed in 67.6% of lacunar infarction, 57.1% of atherosclerotic infarction, and 54.1% of cardioembolic infarction. SSBI was more frequently observed in lacunar infarction than the others (lacunar vs. atherothrombotic vs. cardiogenic infarction, 81.5% vs. 44.4% vs. 42.1%, p=0.006). High-grade EPS (grade 2 or higher) was also observed more frequently in lacunar infarction than in the others (lacunar vs. atherothrombotic vs. cardiogenic infarction, 63.3% vs. 24.2% vs. 0%, p<0.001). Scheltens' score of silent subcortical lesions was significantly higher in lacunar infarction than in the others.
Conclusions The frequency of silent subcortical ischemic brain lesions was significantly higher in lacunar infarction than in atherosclerotic or cardioembolic infarction. We suggest that the pathogenesis of silent subcortical ischemic brain lesions is common to that of lacunar infarction, that is, small-vessel vasculopathy.
(Internal Medicine 41:103-108, 2002)

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Pulmonary hypertension (PH) sometimes occurs in patients with systemic lupus erythematosus (SLE). We report a case of 51-year-old-woman with PH associated with SLE. She had been diagnosed as SLE on the basis of pericardial effusion, hematological disorder, positive antinuclear antibody, and hypocomplementemia. Despite minimal lupus activity, she had marked elevation of pulmonary arterial pressure (101/53 mmHg) and decreased cardiac index (1.5 /lmin/m²). Symptoms related to PH were progressive under treatment with oral corticosteroids, oxygen, calcium antagonists, and warfarin. After 17 months of epoprostenol treatment, she died of pulmonary infarction. SLE-associated PH is often severe and progressive even in association with minimal activity.
(Internal Medicine 41:109-112, 2002)

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A 27-year-old woman with short statue, sensorineural deafness, and renal dysfunction was hospitalized for evaluation. The serum lactate and pyruvate concentrations were elevated. The analysis of her mitochondrial DNA revealed an A-to-G mutation of the tRNA^Leu(UUR) gene at the 3243 position. Renal biopsy revealed many sclerotic glomeruli, advanced tubulointerstitial changes, and numerous swollen mitochondria of the tubular cells. It was concluded that the patient's mitochondrial gene mutation was etiologically related to her nephropathy. The clinicopathologic features of this patient, as contrasted to the previous reports, suggested that renal affection due to this mitochondrial gene mutation can be heterogeneous.
(Internal Medicine 41:113-118, 2002)

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A 47-year-old man presented with polydipsia, which had had since childhood, and recent onset of hypertension. Genetic analysis proved that he had nephrogenic diabetes insipidus caused by a novel mutation (deletion of 6 amino acids between G107 and C112) in the vasopressin V2 receptor gene. Results of 24-hour blood pressure monitoring disclosed a greater dipping pattern and greater blood pressure variability during waking hours than in male patients with only essential hypertension. This characteristic blood pressure profile may result from daily occurrence of free water depletion, as further observation indicated that water deprivation was associated with a reduction in blood pressure.
(Internal Medicine 41:119-123, 2002)

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Here, we report two rare female cases of Sjögren's syndrome with multiple bullae, involving a 66- and a 51-year-old. Neither had any obvious pulmonary complaint. Chest radiographs and high-resolution CT (HRCT) scans showed interstitial linear and nodular opacities and multiple bullae. In the first case spirometry indicated an obstructive change judged by FEV_1.0, and ?? ₅₀/ ?? ₂₅. In both cases, histologic examination of the lung revealed thickening of alveolar septa and interstitial mononuclear cell infiltration. In the first case the bullae decreased in size with corticosteroid treatment. Airway narrowing due to peribronchiolar mononuclear cell infiltration causes a check-valve mechanism, which may lead to bullae formation. Although a rare occurrence, it is important to recognize that cystic or bullous lung disease can accompany Sjögren's syndrome.
(Intenal Medicine 41:124-128, 2002)

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This is the first case report of acute sarcoidosis with increased serum thymidine kinase (TK) activity. A 43-year-old male presented fever, swelling of parotid glands, lymphadenopathy, and peripheral neuropathy. Sarcoidosis was pathologically diagnosed by lung and parotid gland biopsy. His serum TK, which was increased to 11.2 U/l at diagnosis (normal <5U/l), normalized after glucocorticoid therapy. Serum TK has been considered as a good marker of the proliferative activity of various types of neoplasms. Its rise in sarcoidosis has, however, not been described. Because acute sarcoidosis sometimes resembles malignant lymphoma, the possible rise of serum TK in sarcoidosis may be worthy of note.
(Internal Medicine 41:129-132, 2002)

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We describe two cases of lung abscess caused by Legionella pneumophila in immunocompromised patients. The first case had been treated initially with 60 mg prednisolone for ulcerative colitis, and L. pneumophila serogroup 1 was isolated from sputum samples after cavitation of the lung lesion. The second case was diagnosed as plasma cell lymphoma at post-mortem examination. L. pneumophila serogroup 5 was isolated from the contents of lung abscess, together with Enterococcus faecium and Prevotella intermedia in the post-mortem examination. Lung abscess caused by Legionella is unusual. Here, we discuss the difficulty of diagnosis of legionellosis in patients with unusual chest radiographic findings.
(Internal Medicine 41:133-137, 2002)

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A 39-year-old man was found to have hyperproteinemia after being treated with zonisamide for 10 years. Laboratory examination revealed a serum M-protein which consisted of IgG (λ) and an increased number of plasma cells in the bone marrow, resulting in a diagnosis of smoldering myeloma. Considering his age, zonisamide was suspected to play an etiologic role in the occurrence of smoldering myeloma. Zonisamide was changed to sodium valproate. Subsequently the M-protein did not increase over 13 months. When zonisamide is used, the monitoring of serum levels of M-protein and patterns of gammaglobulin is warranted.
(Internal Medicine 41:138-141, 2002)

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Most of the peripheral neuropathies in Sjögren's syndrome (SS) are sensory-or autonomic-dominant. In this report, we present two cases of a rare type of neuropathy, motor dominant neuropathy, in SS. One showed signs similar to those of Guillain-Barré syndrome, and the other showed signs characteristic of chronic inflammatory demyelinating polyradiculoneuropathy. These patients received i.v. immunoglobulin therapy. To our knowledge, this is the first report indicating that i.v. immunoglobulin has beneficial effects on motor dominant neuropathy in SS.
(Internal Medicine 41:142-146, 2002)

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A 46-year-old woman presented with rippling muscle phenomenon. She complained of uncomfortable muscular stiffness of extremities and abdominal wall. Muscle contraction was easily elicited by percussion, which was visible from the surface and propagated in a rolling manner. The mounding (or myoedema) phenomenon was also remarkable. Three years later, malignant lymphoma (histologically, lymphoplasmacytoid lymphoma) was found in the sacrum. The lymphoma subsided with treatment by vincristine, cyclophosphamide, doxorubicin and prednisolone. Serum IgG as well as creatine kinase values were normalized. The rippling phenomenon also responded to the treatment. The present rippling muscle syndrome might be of a paraneoplastic or autoimmune origin related to lymphoma, although the evidence seemed indirect. We discussed the role of the internal membrane system of the skeletal muscle in the pathogenesis of rippling muscle.
(Internal Medicine 41:147-150, 2002)

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Here, we report a case of systemic lupus erythematosus (SLE) complicated by cytomegalovirus (CMV)-induced hemophagocytic syndrome (HPS) and colitis. A 44-year-old woman with SLE was treated with corticosteroid and cyclophosphamide for lupus nephritis. Although her lupus nephritis improved, fever, progressive pancytopenia and intestinal bleeding were observed. A bone marrow aspiration showed an increase in mature histiocytes with hemophagocytosis. In addition, a colonoscopy showed hemorrhagic colitis with ulcer and the biopsy specimen from the colon revealed typical CMV cells with CMV inclusions confirmed by immunohistochemistry. Furthermore, a large number of CMV antigen-positive leukocytes was detected, suggesting an active CMV infection. CMV infection is serious in compromised hosts. Therefore clinicians should be aware of the clinical settings in which this infection can arise and the target organs potentially affected in order to initiate the appropriate intervention.
(Internal Medicine 41:151-155, 2002)

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Lupus-related transverse myelitis is a rare but serious complication. A 25-year-old Japanese woman with systemic lupus erythematosus (SLE) was admitted because of numbness of the face and left upper extremity, headache, and intermittent fever. Six days later, she developed tetraplegia. MRI of the spinal cord showed longitudinal high intensity signals from medulla oblongata to C5, and from Thl2 to conus medullaris on T2-weighted image. These MRI findings were consistent with acute catastrophic neurological abnormalities. Despite administration of the combination of methylprednisolone and cyclophosphamide pulse therapies, as well as plasmapheresis, her condition did not improve. Any vasculopathy in addition to the autoimmune pathogenesis, and narrow therapeutic window may relate to the present refractory case.
(Internal Medicine 41: 156-160, 2002)

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A case of systemic lupus erythematosus (SLE) associated with serositis presenting with disseminated intravascular coagulation (DIC) is reported. A 53-year-old woman was admitted because of a fever. Laboratory tests revealed increased plasma levels of fibrinogen degradation products (FDP) and FDP-D-dimer, high titers of anti-nuclear antibody, high serum levels of anti-DNA antibody, immune complexes, decreased serum complements, and persistent proteinuria. A CT scan showed massive ascites and pleural effusion, marked edema and swelling of the mesenterium. The patient's condition and immunological abnormalities improved after steroid therapy. The association of DIC and lupus serositis has never been described in the literature.
(Internal Medicine 41: 161-166, 2002)

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