Cardiovascular disease is the one of the most important causes of morbidity and mortality throughout the world. Despite the advances in technology in the surgical or interventional therapies, complete understanding of the causes and pathogenesis of the disease is imperative to develop specific therapeutic modalities tailored to those underlying abnormalities. Recent progress in molecular biology has markedly expanded our knowledge of the pathophysiology of many cardiovascular diseases. Such an evolution of the basic science of cardiovascular medicine will allow the physician to treat the primary dysfunction rather than treating secondary manifestations. This review is designed to illustrate the impact of molecular biology on cardiovascular medicine with an emphasis on the pathogenesis of cardiac hypertrophy, and identification of the genes responsible for familial hypertrophic cardiomyopathy, long QT syndrome, and inherited vasculopathies such as Marfan syndrome.
(Internal Medicine 35: 243-248, 1996)

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This work extends a recent observation that Otsuka Long-Evans Tokushima Fatty (OLETF) rats show a congenital defect of the cholecystokinin (CCK)-A receptor gene. Expression of CCK-A receptor mRNA in the pancreas, small intestine and brain were not detected in OLETF rats by the reverse transcriptase polymerase chain reaction. In vitro studies showed that the maximal effective concentrations of neuromedin C, acetylcholine and secretin for stimulation of amylase secretion were comparable in both strains, but that CCK-stimulated amylase secretion was observed only in Long-Evans Tokushima Otsuka (LETO) rats. Intracellular cytosolic Ca²⁺ movement stimulated by acetylcholine and neuromedin C was similar in both strains. In vivo studies showed that the pancreatic secretions in response to secretin and acetylcholine were not impaired in OLETF rats. However, protein responses to neuromedin C and 2-deoxy-D-glucose were impaired in OLETF rats. The findings suggest that pancreatic exocrine functions in OLETF rats are regulated by all neural and peptidergic agents except CCK.
(Internal Medicine 35: 249-256, 1996)

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We have previously shown that high altitude pulmonary edema-susceptible subjects (HAPE-S) have an accentuated pulmonary vascular response to hypoxia. In this study, we investigated the relationship between plasma endothelin-1 (ET-1) levels and the acute hypoxic pulmonary vascular response in HAPE-S and control subjects. In six HAPE-S and seven healthy subjects, we evaluated acceleration time/right ventricular ejection time (AcT/RVET) using Doppler echocardiography, and measured plasma ET-1 levels by radioimmunoassay (RIA) before and after 5 minutes of breathing 10% oxygen. The HAPE-S showed a significantly increased pulmonary vascular response to hypoxia compared with healthy subjects. However, no statistically significant changes of plasma ET-1 levels were observed before and after hypoxia in both groups. We conclude that the increased pulmonary vascular response to acute hypoxia in HAPE-S may not be related to ET-1 release.
(Internal Medicine 35: 257-260, 1996)

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In patients with a posteroinferior acute myocardial infarction and both ST depression (in lead VI or V2) and ST elevation in the inferior leads, it is difficult to differentiate a left circumflex artery occlusion from a right coronary artery occlusion. Furthermore, there is no useful method to identify the obstruction site in the left circumflex artery. In a study of 52 patients with single-vessel left circumflex artery disease, ST elevation in V6 was found to be a useful indicator for left circumflex artery occlusion in such patients. Furthermore, the sum of the ST changes in leads aVF and V2 is useful for identifying the occluded site in the left circumflex artery.
(Internal Medicine 35: 261-265, 1996)

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The incidence of complete thyroxine-binding globulin (TBG) deficiency (TBG-CD) was determined for a Japanese population from a comprehensive health examination, in which a T3 resin uptake test of the upper 5% (78 subjects from among 1, 589 men) was the screening line for TBG-CD. Further analysis of the known mutation in TBG-CD gene of the Japanese population (reported as TBG-CDJ with codon 352 deletion) was performed on 72 subjects, and three were found to have TBG-CDJ, two of whom were siblings. Only those three subjects had a serum TBG concentration of less than 5 mg/l. The six subjects for whom the DNA analysis was not performed, did not have a serum TBG level of less than 5 mg/l. From these findings, the gene frequency of TBG-CDJ was calculated to be 0.13%. The incidence of TBG-CDJ in the total Japanese population is suggested to be 0.09%.
(Internal Medicine 35: 266-269, 1996)

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We measured exhaled nitric oxide (NO) with a chemiluminescence method to elucidate the clinical significance of the increased concentration of exhaled NO in patients with bronchial asthma. Exhaled NO was measured in 25 patients with bronchial asthma and in 10 healthy control subjects. The concentration of exhaled NO in asthmatics was significantly higher than in the controls (250.4±30.4, 59.9±9.6 ppb, respectively, p<0.01). Symptomatic patients (unstable asthmatics) had a higher exhaled NO concentration than did the asymptomatic patients (stable asthmatics) (384.2±32.5, 143.6±18.8 ppb, respectively, p<0.01). The exhaled NO concentration was significantly correlated with the peak expiratory flow rate (r=0.671, p<0.01) and eosinophil ratio in induced sputum (r=0.772, p<0.05), but it was not correlated with the parameters of bronchial hyperreactivity (Dmin and PD35 Grs). We conclude that the increased concentration of exhaled NO in patients with bronchial asthma reflects the state of airway inflammation, and we suggest that measurement of exhaled NO is a useful, non-invasive and simple method for the management of bronchial asthma.
(Internal Medicine 35: 270-275, 1996)

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The prevalence of Parkinson's disease (PD) was investigated in Hokkaido, the northernmost island of Japan. A pilot case-finding study was carried out to estimate the prevalence in the entire island of Hokkaido (population = 5, 643, 647) initially, then we surveyed the prevalence at one of the smaller cities, Iwamizawa City (population = 80, 417). We ascertained 5, 342 cases with PD in Hokkaido and 77 cases in Iwamizawa City, estimating the crude prevalence of 94.7/100, 000 in Hokkaido (June 30, 1993) and 95.8/100, 000 in Iwamizawa City (April 1, 1994), respectively. We calculated that the crude prevalence rate of PD in Japan is currently close to 100/100, 000, but the age-adjusted prevalence is still low, compared with those in Europe and North America.
(Internal Medicine 35: 276-279, 1996)

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We describe a 73-year-old man with the syndrome of inappropriate antidiuretic hormone secretion (SIADH) due to an ectopic ADH-producing pancreatic adenocarcinoma. His laboratory findings showed marked hyponatremia, and the water load test showed uncontrolled ADH secretion. The imaging studies revealed pancreatic body cancer. Histological examination revealed an adenocarcinoma of the pancreas, which was positive for ADH immuno-staining. The ADH in the tumor extract was 53.3 pg/g wet weight. In attempt to diagnose ADH-production from the tumor, the ADH in his pancreatic juice was measured and found to be 2.1 pg/ml. We conclude that it is valid to measure the ADH in pancreatic juice to diagnose ectopic ADH production by tumors.
(Internal Medicine 35: 280-284, 1996)

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A 51-year-old man was hospitalized with a gait disturbance and hypoesthesia below the level of his chest. These symptoms were due to a spinal tumor which was surgically resected and identified as an ependymoma. Additionally, the patient had hypercalcemia and a family history of insulinoma. An endocrine evaluation revealed parathyroid hyperplasia and a pancreatic islet cell tumor. Magnetic resonance imaging disclosed a pituitary microadenoma. He was diagnosed with spinal ependymoma and multiple endocrine neoplasia type 1 (MEN 1). A review of the literature revealed that chromosome 11q13 abnormalities have been reported in both ependymoma and MEN 1. We discuss the pathogenesis of these diseases.
(Internal Medicine 35: 285-289, 1996)

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A case of malignant thymoma with pure red cell aplasia (PRCA) complicated by syndrome of inappropriate secretion of antidiuretic hormone (SIADH) following intrathoracic cisdichlorodiammine platinum (CDDP) administration is reported. A 59-year-old Japanese woman who presented with severe general fatigue was diagnosed with PRCA associated with a thymoma, based on the findings of a bone marrow biopsy, computed tomography of the chest, and the existence of anti-acetylcholine receptor antibodies. She underwent a thymectomy after frequent blood transfusions. This was followed by intrathoracic CDDP administration, because of pleural dissemination. Nine days following chemotherapy, her serum sodium concentration was found to be 104 mM, while her consciousness was drowsy with severe fatigue and vomiting. This hyponatremic state was diagnosed as SIADH induced by CDDP infusion into the thoracic space, based on the hypo-osmolality of her serum, the hyper-osmolality of her urine, and an inappropriate level of plasma vasopressin.
(Internal Medicine 35: 290-294, 1996)

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We describe a 31-year-old man. Although the plasma renin activity (PRA) and plasma aldosterone concentration (PAC) were elevated, computed tomography and rapid sequence pyelography disclosed no abnormality. However, based on the findings of the small tumor (8×8 mm) in the kidney visualized by magnetic resonance imaging (MRI) and excessive PRA in the right renal vein, tumor resection was performed. The positive immunohistochemical staining of renin and the visualization of renin mRNA by in situ hybridization provided evidence supporting the diagnosis of Juxtaglomerular cell tumor. Blood pressure, PRA, and PAC were normalized after the surgery. The observations suggest that MRI is a powerful diagnostic procedure in small Juxtaglomerular cell tumor.
(Internal Medicine 35: 295-300, 1996)

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A 42-year-old man experienced recurrent episodes of nonproductive cough, fever, and dyspnea on exertion. He had worked as a mushroom farmer for 10 years. The diagnosis of hypersensitivity pneumonitis was confirmed immunologically by detecting a precipitin to spores of Pholiota nameko but not to other antigens. After separation from the antigen along with an addition of corticosteroid therapy, the symptoms, inflammatory findings and a reduced level of PaO₂ quickly subsided.
(Internal Medicine 35: 301-304, 1996)

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A 45-year-old male was referred due to prolonged productive cough. Despite the fact that bronchoalveolar lavage fluid suggested lymphocytic and neutrophilic alveolitis, the histologic diagnosis of his biopsied lung was diffuse panbronchiolitis-like lesion with infiltration of lymphocytes and plasma cells into respiratory bronchioles but few foamy cells. Serologic examination revealed that he was a carrier of human T-cell lymphotropic virus type I (HTLV-I). Together with uveitis and ulcerative colitis in his past history, the persistent respiratory symptoms of this patient can be attributed to non-neoplastic inflammation due to the chronic HTLV-I infection.
(Internal Medicine 35: 305-309, 1996)

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Human brucellosis is an imported zoonosis extremely uncommon in Japan. Brucellosis was found in a 38-year-old surgeon who had never been abroad; he developed intrapulmonary infiltrates and pleural thickening indistinguishable from pulmonary tuberculosis. Despite extensive antibiotic therapy for tuberculosis he developed systemic serositis. A culture of resected lung tissues grew CO₂-required coccobacilli. Polymerase chain reaction test using a specific primer pair for Brucella abortus revealed that the isolated pathogen is highly homologous to B. abortus. We emphasize that undetermined cases of human brucellosis may be present in Japan.
(Internal Medicine 35: 310-314, 1996)

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We describe a case of varicella pneumonia in a 24-year-old healthy man presenting with severe respiratory failure. A chest radiograph showed diffuse, bilateral airspace consolidation; additional complications included liver dysfunction and thrombocytopenia. However, treatment with intravenous acyclovir and γ-globulin improved his clinical symptoms and signs. A greater than four-fold change in paired titers of the varicella-zoster virus antibody was observed. Bronchoalveolar lavage performed during the recovery phase revealed increased total cell and lymphocyte counts and a decreased CD4:CD8 ratio of T lymphocytes. Transbronchial lung biopsy findings were compatible with a diagnosis of interstitial pneumonia.
(Internal Medicine 35: 315-318, 1996)

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A 28-year-old severe hemophiliac with a factor VIII inhibitor was admitted to our hospital with a massive and serious intraperitoneal hematoma. He was a high-responder patient showing maximal serum inhibitor levels as high as 255 Bethesda Units/ml (BU/ml). He was successfully treated with "bypass therapy" using a prothrombin complex concentrate (PCC).
(Internal Medicine 35: 319-322, 1996)

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A 38-year-old man with pancytopenia due to myelodysplastic syndrome exhibited persistent pyrexia and mediastinal lymphadenopathy. A biopsy specimen of the lymph nodes showed diffuse infiltration of epitheloid cells, including acid-fast bacilli identified as Mycobacterium kansasii. Cultures from gastric lavage and stool yielded M. kansasii, and granulomas were found in the bone marrow. A diagnosis of disseminated nontuberculous mycobacteriosis (DNTM) was established. The patient's condition improved after treatment with isoniazid, rifampicin, ethambutol and granulocyte colony-stimulating factor. Although DNTM due to M. kansasii is rare in Japan, it should be recognized as a possible cause of opportunistic infections.
(Internal Medicine 35: 323-326, 1996)

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Pericentric inversion of chromosome 16 [inv(16)(p13q22)] is seen in patients with acute myelomonocytic leukemia with bone marrow eosinophilia. This inversion juxtaposes the MYH11 gene on p13 and the CBFB gene on q22, resulting in the formation of a chimeric mRNA transcript. We describe a patient with acute myelogenous leukemia (M1), with del(16)(q22), who expressed the chimeric transcript. Reverse transcriptase polymerase chain reaction and the sequencing of its product showed fusion of 5'CBFB at position 495 to 3'MYH11 at position 1201. To our knowledge, this is the first report of an AML (M1) case with del(16) and CBFB/MYH11 rearrangement.
(Internal Medicine 35: 327-330, 1996)

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A 50-year-old woman is presented here with natural killer (NK) cell type lymphoproliferative disorder of granular lymphocytes. She was admitted to the hospital because of dyspnea on exertion. Chest X-ray revealed bilateral reticular shadows. Open lung biopsy demonstrated usual interstitial pneumonia (UIP). Her white blood cell count was 3, 900/mm³, of which 55% was large granular lymphocytes (LGLs). The LGLs were CD3^- CD16⁺CD56⁺, and the clonality of them was not confirmed. Despite steroid therapy, she died from exacerbation of UIP complicated with opportunistic infection. The patient, her father and son had pancytopenia. Congenital immunological abnormality might cause both large granular lymphocytosis and UIP.
(Internal Medicine 35: 331-336, 1996)

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A 70-year-old woman with type lib therapy-refractory hyperlipidemia was diagnosed as having IgA kappa type multiple myeloma. She had neither a family history nor any other disease known to accompany hyperlipidemia. The serum IgA concentration fell from 3.42 g/dl to 1.24 g/dl following chemotherapy with melphalan and prednisolone, and a concomitant decrease in both the serum cholesterol and triglyceride levels was observed. These serum lipids were positively correlated with the serum IgA concentration (p<0.001) during the three cycles of chemotherapy. These findings suggest the involvement of the monoclonal protein of IgA in the development of hyperlipidemia in the present case.
(Internal Medicine 35: 337-340, 1996)

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Bronchiolitis obliterans organizing pneumonia (BOOP) is a pathologic entity characterized by the formation of fibrous tissue plugs within terminal bronchioles and alveolar ducts. Although BOOP has been associated with several connective tissue disorders, there are rare reports of BOOP in patients with systemic lupus erythematosus (SLE). We present a patient with SLE accompanying antiphospholipid antibody who developed recurrent respiratory symptoms and radiographic abnormalities. The diagnosis of BOOP was confirmed by transbronchial lung biopsy. This case suggests that not only SLE, but also the presence of antiphospholipid antibody, may be associated with the development of BOOP.
(Internal Medicine 35: 341-344, 1996)

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