Acute myocardial infarction in the Medicare population. Process of care and clinical outcomes. To describe the process of care and clinical outcomes associated with acute myocardial infarction (AMI) in the Medicare population, and to examine differences in process of care and outcome of care as a function of patient age, gender, and race. Retrospective cohort study using a longitudinal database created from Medicare utilization and administrative files. PATIENT POPULATIONS: A cohort of AMI patients covered by Medicare in 1987 and a random sample of Medicare patients without AMI. MAIN PROCESS AND OUTCOME MEASUREMENTS: (1) The use of coronary angiography, coronary artery bypass graft surgery, and percutaneous transluminal coronary angioplasty during the first 90 days after a new AMI; (2) mortality at 30 days, 1 year, and 2 years; (3) reinfarction rates; and (4) reoperation rates for coronary artery bypass graft surgery and percutaneous transluminal coronary angioplasty. Mortality rates were high: 26% at 30 days, 40% at 1 year, and 47% at 2 years. They varied greatly by age, less so by gender and race, and were high even among patients who survived the first 30 days. Compared with mortality, reinfarction was uncommon, occurring in 7.3% of patients. During the first 90 days, 23% of all patients underwent angiography and 13% underwent coronary revascularization (coronary artery bypass graft surgery, 8%; percutaneous transluminal coronary angioplasty, 5%). The use of all three procedures decreased with age and was less common among women and blacks than among men and whites. Differential use by age and race was greater for angiography than for revascularization procedures. The prognosis following AMI in patients aged 65 years and above is much worse than is commonly realized. Procedure use in these patients varies as a function of gender and race, even though mortality does not. Further research is needed to reduce the mortality of elderly patients with AMI and to understand the significance of differences in procedure use on the basis of sociodemographic characteristics.


Results of a second-opinion trial among patients recommended for coronary angiography. To assess the feasibility of carrying out a second-opinion trial for patients urged to undergo coronary angiography and to assess the long-range outcome of such patients denied that procedure, and the criteria evolved for reaching such a conclusion. A case series of patients referred for a second opinion as to the need for coronary angiography. Patients were followed up by questionnaire, telephone call, and center visits. Cardiovascular referral center and teaching hospital in Boston, Mass. One hundred seventy-one patients with coronary artery disease (144 men, average age 60 years; range, 36 to 88 years). Three patients became unavailable for follow-up during a mean of 46.5 months. Concordant-discordant outcome as to the second opinion, cardiac events, invasive interventions, quality of life questionnaire, and level of symptoms. One hundred thirty-four (80%) of the 168 patients were judged not to require angiography; it was recommended in six. In 28 (16%) recommendation was deferred pending further studies. At a mean follow-up of 46.5 months among the 168 patients, there were seven cardiac deaths (annualized cardiac mortality of 1.1%); 19 patients experienced a new myocardial infarction (2.7% annualized rate), while 27 patients (4.3%) were judged to have developed unstable angina. Twenty-six patients (15.4%) ultimately underwent either coronary bypass or angioplasty. In a large fraction of medically stable patients with coronary disease who are urged to undergo coronary angiography, the procedure can be safely deferred. While there may be a limitation in terms of generalizing this experience to all patients with coronary disease, we reasonably conclude that an estimated 50% of coronary angiography currently being undertaken in the United States is unnecessary, or at least could be postponed.


Evaluation and management of the patient with syncope. To review the studies on diagnostic evaluation of syncope and to provide an approach to the diagnostic testing and management of this condition. Published studies on the evaluation of syncope in the English language. Cohort studies and case series of patients presenting with syncope and focused studies of various diagnostic tests such as prolonged electrocardiographic monitoring, electrophysiologic studies, and upright tilt testing. Specific selection criteria were used in the case of prolonged electrocardiographic monitoring, in which all studies had to have performed at least 12 hours of monitoring. Studies reviewed by the author. Studies in the 1980s have shown that a cause of syncope is not diagnosed in as many as 47% of the patients presenting with this symptom. When a cause of syncope is established, a history and physical examination lead to the identification of 56% to 85% of the causes. In the remaining patients, arrhythmia detection is a central issue. A major problem with the use of ambulatory electrocardiographic (Holter) monitoring in the diagnosis of arrhythmias is that symptomatic correlation with arrhythmias is rarely found (only 4% of patients). Increasing the duration of monitoring from 24 to 72 hours does not lead to increased yield of symptomatic arrhythmias. Patient-activated intermittent loop recorders that can be worn for several weeks may occasionally show a symptomatic correlation, but they are most useful in patients with multiple recurrences of syncope. Electrophysiologic studies are more likely to be abnormal in patients with underlying heart disease or those who have abnormalities on surface electrocardiogram. The most common abnormality found on electrophysiologic studies is inducible ventricular tachycardia. Upright tilt testing has been used to induce vasovagal syncope in patients with syncope of unknown cause. A positive response has been found in 26% to 87% of patients undergoing this type of testing. The specificity of this test needs to be further investigated. In patients with recurrent syncope of unknown cause, psychiatric evaluation should also be pursued for illnesses such as generalized anxiety disorder, panic disorder, somatization, and major depression. A directed approach to the evaluation is possible using the studies on diagnostic testing of syncope.


Pattern of leucocyte acid phosphatase reaction in T-cell lymphoblastic leukaemia. Acid phosphatase (AP) reaction is a specific cytochemical marker for T-cell lymphoblastic leukaemia (T-ALL). Twenty six cases of ALL were diagnosed as T-ALL employing cytochemical profiles including AP and sheep red blood cell rosettes. Three district patterns of AP reaction were observed. On one end of the spectrum, 100% of the positive blasts showed the classical dot-like reaction while on the other 100% showed a scattered reaction. Between the two a mixed pattern was observed with 30-80% of the positive blasts showing the dot-like reaction while the rest showed scattered pattern. Dot-like pattern showed L1 morphology, high counts and low SRBC rosettes while scattered showed L2 morphology, low counts and high SRBC rosettes. The pattern observed in our series differs from the dot-like reaction observed in T-ALL in the western series. We recommend that this pattern must be borne in mind when employing AP reaction for T-ALL diagnosis (JPMA 42: 151, 1992).


Management of uric acid stone.

Management of uric acid stone. Uric acid stones are the most readily dissolvable of all types of urinary stones. By maintaining urinary pH between 6.2-6.8 with the use of sodium acid citrate or uralyt-U and reducing serum uric acid by allopurinol, we tried to dissolve 107 stones in 67 patients. Ninety three (86.9%) stones were dissolved and 6 (5.6%) passed spontaneously within a period of one year. Eight (7.5%) stones were removed surgically or with ESWL. Five (7.5%) patients had stone recurrence over a period of 3 years follow-up. Serum uric acid was raised in 19 (28.5%) and urinary uric acid in 12 (18%) patients while urinary pH was low in 46 (69%) patients. For uncomplicated uric acid stones oral chemolysis on an out-patient basis is the treatment of choice. It is simple, safe and inexpensive. However, it requires rigid compliance by the patient and strict follow-up by ultrasonography (JPMA 42: 153, 1992).


Anorectal melanoma in northern Pakistan. Melanoma of the anorectum is a rare malignancy. At Armed Forces Institute of Pathology (AFIP), 11 cases were diagnosed over a 10 year period (1981-1990) constituting 14.2% of all primary malignant melanomas. The anorectum was the commonest site for noncutaneous melanomas (45.8%). The age group commonly affected was the fifth to seventh decade (72.7%). Most of the tumours were extensive involving both anal canal and rectum. The proportion of anorectal melanoma is much higher in our study as compared to western reports (0.4-1.6%). The distribution of noncutaneous melanomas in our population also differs, with a relatively lower proportion of ocular melanomas (33.3%) which are the commonest (80%) in western studies (JPMA 42: 155, 1992).


Immunoglobulin classes G,A,M in brain tumours. Serum of 37 brain tumour patients was studied for, Total protein, Protein electrophoresis, IgG, IgA, and IgM in an attempt to ascertain humoral immune response. Findings were compared with 20 healthy subjects, matched for age, sex and socioeconomic status. There was significant rise in alpha-II globulin, while IgG was suppressed in tumour patients. Decrease of IgG was more marked in patients with malignant tumours. Immunoglobulin A was low in children when compared with adults. Immunoglobulin M remained unchanged (JPMA 42: 157, 1992).


Emergency coronary angioplasty for acute myocardial infarction--factors affecting acute restenosis in catheterization laboratory and reocclusion during hospitalization. A total of 107 consecutive patients with acute myocardial infarction underwent emergency coronary angioplasty (PTCA). Restoration of blood flow with TIMI grade III was established by emergency PTCA in 101 patients (94.4%). "Acute restenosis" was defined as a lesion that, when dilated to less than 50%, narrowed again to more than 75% luminar reduction 5 min after the balloon inflation. Acute restenosis occurred in 39 patients (39%). Multivariate analysis selected 3 factors associated significantly with an increased rate of acute restenosis: (1) dissection, (2) small balloon/artery diameter ratio and (3) low systolic blood pressure during PTCA. Reocclusion, which was defined as a total reobstruction of the lesion during hospitalization following emergency PTCA, was examined by predischarge coronary angiography. Acute restenosis correlated significantly with an increase in reocclusion rate. The incidence of documented reocclusion was 12%. Residual stenosis, multivessel disease and irregular dilation correlated significantly with an increased rate of reocclusion. The in-hospital and postdischarge mortalities were 5.6% and 2.1%, respectively. In summary, emergency PTCA produced a high angiographic success rate. Use of adequate balloon size and sufficient dilation correlated significantly with angiographic outcome in emergency PTCA. Patients with acute restenosis, high residual stenosis, irregular dilation, and multivessel disease would have a relatively high risk of reocclusion.


Screening of children with arrhythmias for arrhythmia development during diving and swimming--face immersion as a substitute for diving and exercise stress testing as a substitute for swimming. We compared face immersion and exercise stress testing by diving and swimming as screening methods for arrhythmias induced by immersion in water. The subjects were 64 children with various arrhythmias who were tested using 5 methods: diving, swimming, face immersion in 25 degrees C water, face immersion in 6 degrees C water, and a treadmill exercise test. Significant arrhythmias occurred during diving or swimming in 51 children, with 44 developing arrhythmias while diving. Both tachyarrhythmias and bradyarrhythmias were seen during diving, but 17 children who also showed significant arrhythmias while swimming mostly had tachyarrhythmias. A comparison with the incidence of arrhythmias produced by diving showed that face immersion in cold water had a sensitivity of 88.6%, a specificity of 85.0%, a predictive value of 92.9%, and an accuracy of 87.5%. Arrhythmias were alleviated in 12.5%, unchanged in 79.7%, and aggravated in 7.8% of the subjects. Face immersion thus appeared to be a useful and adequate screening substitute for diving. Exercise testing was also compared with swimming (sensitivity, 52.9%; specificity, 100%; predictive value, 100%; and accuracy, 87.5%). Arrhythmias were alleviated in 12.5% and unchanged in 87.5% of patients. Although exercise testing produced many false-negatives, all of the severe arrhythmias were reproduced.


Precordial ST segment elevation in acute ischemia caused by right coronary artery occlusion. The purpose of this study is to determine why precordial ST elevation (V1 lead) occurs during acute occlusion of the right coronary artery (RCA). Nineteen patients with vasospastic angina, in whom ergonovine administration into RCA provoked spasms, were divided into 2 groups by precordial ST change during spasms. Group I (n = 6) had precordial ST elevation; group II (n = 13) had no precordial ST elevation. A subgroup, IIA was comprised 6 patients in group II with spasms in the RCA proximal segment (segment number less than 2 of AHA coronary classification). None had left coronary dominancy. There was no difference in collateral flow during spasms. Location of spasms in group I was in the RCA proximal segment, and was significantly more proximal compared to group II. There was no difference in sigma ST in II, III, aVF between group I and II or IIA. Max ST elevation time by which duration of ischemia was estimated was significantly longer in group I than in group IIA. Three patients in group I displayed precordial ST depression before elevation, in all of whom in sigma ST in II, III, aVF was higher during precordial ST elevation than during depression. During acute occlusion in the RCA proximal segment, precordial ST elevation is caused by ischemia of the right ventricular anterior wall. Furthermore, precordial ST elevation can occur in a patient with RCA dominance, even if ischemic injury in the left ventricular infero-posterior wall increases progressively.


Collagen in dilated cardiomyopathy--scanning electron microscopic and immunohistochemical observations. The ultrastructural characteristics of collagen and the localization of collagen types were studied in formalin-fixed autopsied human hearts from patients who died in an advanced stage of dilated cardiomyopathy (DCM). The three-dimensional architecture of collagen fibers was studied by scanning electron microscopy by using the cell-maceration method. The localization of collagen type I-VI was demonstrated immunohistochemically using monoclonal antibodies specific to each collagen following the treatment of specimens with trypsin. In the hearts obtained from control subjects without heart disease, there were no significant differences in the ultrastructure and localization of collagens between the fresh and the formalin-fixed hearts. Therefore, formalin-fixation did not affect the ultrastructure of collagen or the immunoreactivity. In DCM, a dense endomysial weave network consisting of fine fibrils was associated predominantly with collagen type I and III, associated moderately with type VI collagen, but less associated with type IV collagen. Perimysial collagen bundles and collagen strands increased both in number and thickness. The outstanding finding was the presence of giant coiled perimysial fibers measuring about 20-30 microns in diameter. The prominent increase in perimysial fibrosis was closely associated with the accumulation of both type I and type III collagen, and associated moderately with type VI collagen. Interestingly, type V collagen increased in the intracellular matrix of the myocardium in DCM. Type II collagen was not present in either normal or diseased hearts. These structural and immunohistochemical characteristics of collagen may provide insights important to assessing the pathogenesis of the cardiac lesion of DCM.


Impairment of sarcolemmal permeability in the acute ischemic myocardium--a study with ionic lanthanum probe method. Impairment of sarcolemmal permeability after the initiation of acute ischemic myocardial injury was studied using an ionic lanthanum (La3+) probe in electron microscopy. Acute ischemic myocardium was induced by ligation of the left anterior descending coronary artery in dogs. In normal cardiac myocytes La is localized exclusively in the extracellular space. i.e. on the glycocalyx, in the T-system and in intercalated discs, with normal fine structures. In ischemic myocardial cells, La deposits were found in the cytosolic space in 22% of subendocardial cells with mild to moderate, but non-necrotic, fine structural changes as early as 30 min. The number of myocytes with La deposition increased with advancing ischemic injury, and necrotic fine structural changes were recognized following ischemia for 60 min. These results indicate that deposition of La occurs before the appearance of irreversible morphologic alterations in ischemic myocardial cells, and suggest an increased permeability of the sarcolemma for Ca2+ and the development of degradation of plasma membrane integrity.


Residual critical coronary stenosis during myocardial reperfusion is deleterious to myocardial salvage in dogs. Hyperemia, which occurs immediately after coronary reperfusion, injures the myocardium. Mild coronary stenosis may mitigate this hyperemia and thus may augment myocardial salvage. To test this hypothesis, left anterior descending coronary arteries of dogs were occluded for 3 h. Then, reperfusion was permitted without residual stenosis (group A, n = 17) or with 75% stenosis (group B, n = 10). Regional myocardial blood flow (RMBF) was determined using colored microspheres. Dogs were sacrificed 1 week later to measure myocardial creatine kinase activity (CK) and for staining with triphenyl tetrazolium chloride (TTC). The RMBF measured 5 min after reperfusion increased significantly (inner layer, 171 +/- 16; outer layer, 165 +/- 11% of control) in group A. This hyperemia disappeared in group B (inner, 106 +/- 8; outer, 117 +/- 10% of control). However, the myocardial CK was more preserved (group A: inner, 31 +/- 4; outer, 44 +/- 4%; and group B: inner, 21 +/- 6; outer, 29 +/- 5%), and the infarct size was smaller in group A than in group B (group A: inner, 44 +/- 6; outer, 33 +/- 5; and group B: inner, 53 +/- 10; outer, 58 +/- 7% of the area at risk). We concluded that a residual stenosis of 75% at reperfusion abolishes the hyperemia but does not improve myocardial salvage.


Role of sympathetic nerve inhibition in the vasodepressor effect of bromocriptine in normotensive and hypertensive rats. This study aimed to elucidate the mechanism of the hypotensive effect of bromocriptine (BRC), and to investigate whether or not the effects of BRC on the sympathetic nervous system are altered in hypertension. BRC was administered intravenously to normotensive and spontaneously hypertensive rats (SHR). It elicited hypotensive effects dose-dependently in urethane-anaesthetized normotensive rats, an effect which was antagonized with metoclopramide. Pretreatment with intravenous hexamethonium attenuated the hypotensive effect of BRC. BRC decreased plasma norepinephrine (NE) without inhibiting the sympathetic nerve spikes recorded from the postganglionic sympathetic nerve bundle. The hypotensive effect of BRC was significantly greater in SHR than in Wistar Kyoto Rats (WKY). Decrease in NE by BRC was also significantly greater in SHR than in WKY. These results suggest that the hypotensive effect of BRC is induced by suppression of NE release, not by inhibition of sympathetic nerve spikes, and that the dopaminergic presynaptic inhibition is attenuated in SHR.


Spontaneous coronary artery dissection after a natural course for 10 years--a case report. We encountered a patient with spontaneous coronary artery dissection complicated by acute inferior myocardial infarction. A 58-year-old male was admitted to our hospital due to acute inferior myocardial infarction in 1979. Coronary angiography performed 4 weeks after the onset showed a double lumen divided by a linear intimal flap in the right coronary artery, suggesting coronary artery dissection, but no apparent occlusion. Subsequently, he had been medicated with nitrates without any recurrent infarction. In February, 1989, 10 years after the first examination, coronary angiography was again performed and showed that the dissection had remained unchanged. Acetylcholine infusion into the right coronary artery induced coronary spasm. The prognosis of this condition seems to be better than has been generally considered, particularly in patients such as ours in whom the involvement of coronary spasm in the development of coronary artery dissection and myocardial infarction is suggested. When coronary spasm in controlled by treatment with nitrates or calcium antagonists, an uneventful course may be expected.


A right atrial thrombus, attached to the inferior limb of the fossa ovalis. A right thrombus was incidentally found in a 65-year-old male during mitral valve surgery. A mushroom-like thrombus was attached to the inferior limb of the fossa ovalis with broad based stalk. It developed in sinus rhythm and in the absence of evidence of blood stasis in the right atrium. The most likely pathogenesis of right atrial thrombus formation in this case is endocardial damage from right heart catheterization prior to surgery.


Pseudoaneurysm of the distal aortic arch in Behçet's disease--a case report. Behçet's disease, manifested as a triform of relapsing iritis, stomatitis and genital ulceration, is now recognized as a systemic vasculitis that affects both veins and arteries. However, aneurysms of the aortic arch associated with Behçet's disease are extremely rare. We report on a successfully resected pseudoaneurysm of the distal aortic arch in a patient with Behçet's disease. The aneurysm was evaluated preoperatively by computed tomography (CT), magnetic resonance imaging (MRI) and intravenous digital subtraction angiography (DSA). We found that these non-invasive methods were quite useful for diagnosing the aneurysm in the aortic arch. Aneurysms enlarge rapidly when coupled with infection and are prone to rupture, thus requiring extensive surgical repair. However, since false aneurysm formations often occur at the site of anastomosis, postoperative follow-up should be monitored very closely.


Fragmentation hemolysis in a patient with hypertrophic obstructive cardiomyopathy and mitral valve prolapse. We encountered a 65-year-old female with hypertrophic obstructive cardiomyopathy and mitral valve prolapse who had infective endocarditis and hemolytic anemia. The infecting organism of endocarditis was group A streptococci. With regard to the etiology of the hemolytic anemia, fragmentation hemolysis was considered because fragmented red cells and elevated lactic dehydrogenase were observed. Haptoglobin was markedly decreased. Coombs' test, Ham's test and abnormal hemoglobin were negative. She had not had a hemolytic attack in the past. Ultrasonic cardiography showed asymmetrical septal hypertrophy, mitral valve prolapse and 285 mmHg of calculated pressure gradient in the left ventricle. Cardiac catheterization showed 115 mmHg of left intraventricular pressure gradient and mitral regurgitation (grade 2). Hemolysis was slightly improved after treatment with propranolol. Thus, fragmentation of the normal red cells seemed to be due to shear stress.


[The prognosis of patients with multiple myeloma--the aspect of histological distribution to the renal tissue and serum level of beta 2-MG]. Beta-2-microglobulin (beta 2-MG) is a well-known tumor marker, particularly in patients with multiple myeloma (MM) in whom survival decrease in relation to high serum beta 2-MG concentrations. We investigated the level of serum beta 2-MG by radioimmunoassay (RIA) double antibody method in 14 cases of MM, 13 cases of benign monoclonal gammopathy, and 25 healthy controls. Beta-2-MG of the kidneys was stained by the MM by peroxidase-anti-peroxidase (PAP) method and clinical courses were compared. In controls, the serum beta 2-MG concentration increased with aging, and its concentration of MM was higher than that of controls. Most MM patients with positive beta 2-MG staining in glomeruli showed poor prognosis. Beta-2-MG staining of proximal and distal tubuli did not contribute to the prognosis of MM.


[Clinical analysis of 10 patients with chronic lymphoid leukemia]. Ten patients with chronic lymphoid leukemia were analyzed for clinical characteristics, morphology and phenotype of leukemic cells. There were 3 patients with T-chronic lymphocytic leukemia (CLL), 2 with T-prolymphocytic leukemia (PLL), 2 with B-CLL, 1 with B-PLL, 1 with non-T-non-B-CLL and 1 with Waldenström's macroglobulinemia. Although chronic lymphoid leukemia is usually characterized by proliferation of B-lymphocytes, our study revealed that 5 of 10 patients had T-cell phenotype. A peripheral blood specimen of T-CLL showed small lymphocytes with a mature appearance and an irregular nuclear margin. Most of the cells lacked large azurophilic granules in the cytoplasm and nucleoli were also inconspicuous in the nucleus by light and electron microscopic examinations. In PLL, a majority of the cells were large lymphocytes with a prominent nucleolus and abundant basophilic cytoplasm which were more clearly observed by transmitted electron microscopic examination. The patients were treated with cyclophosphamide and prednisolone, but response to treatment was transient. The median survival time was 7 months for all patients, while that of T-cell lineage cases was only 1 month. Therefore, new modalities of treatment must be investigated in the future.


[Acute lymphoblastic leukemia with extensive demyelinated lesion of the brain stem during complete remission]. A case of acute lymphoblastic leukemia (ALL) which showed extensive demyelinated lesion of the brain stem during complete remission is presented. A 13 year-old girl who was diagnosed as ALL in February, 1987 was treated according to the TCCSG L84-11 protocol, which induced complete remission in June, 1987. Her condition had been stable until April, 1988 when she abruptly complained of gait disturbance, vertigo and anorexia. She was subsequently admitted to our hospital. At the time of admission, she had ataxic gait, horizontal nystagmus towards right at dextroversion, bilateral exaggerated patellar tendon reflex, emotional incontinence, urinary incontinence and left 6th and 7th nerve palsy. In the middle of May, right spastic hemipalesia and hypesthesia became apparent. Left caudal pontine-basal lesion was suspected and was confirmed by MRI. Her synptoms progressed. Five months after admission, suffered repeated central apnea and died. Autopsy disclosed extensive cervical spinal cord. Cerebrum and cerebellum were intact. No evident findings suggesting the etiology were obtained. Whole skull radiation, intrathecal methotrexate, cytosine arabinoside and hydrocortisone might have contributed to the development of the demyelinated lesion.


[Overt leukemia from MDS associated with marked basophilia]. A 52-year-old woman was admitted to our hospital because of leukocytosis. She had been diagnosed with RAEB in another hospital in past time. At the admission, the white cell count was 30,900/microliter with blasts (14.0%) and marked basophilia (49.0%). Bone marrow aspiration revealed with 30.2% blasts and 21.1% basophils. Having obtained those results, diagnosis of RAEB in transformation was made. After admission, number of basophils in peripheral blood increased gradually, and level of histamine in serum was elevated significantly. Multiple peptic ulcers in stomach and bowel and high fever were induced due to histaminemia. Despite several therapy she died because of respiratory failure and septisemia. Although the mechanism of basophilia in this patient could not be clarified, there was a possibility that basophilia in this patient might be differentiated from leukemic clone because almost basophils in peripheral blood were mature and those had many granules including metachromasia by stained with toluidine blue.


[Phenacetin-induced hemolytic anemia misdiagnosed as unstable hemoglobinopathy]. A 30-year-old woman was admitted in August 1984 with anemia. She had an initial hemolytic attack in 1977. Unstable hemoglobinopathy was suspected. Despite splenectomy in 1979, hemolytic attacks continued. On admission, she was anemic and cyanotic. Hb heat denaturation test was positive. However, the first structure of amino acid of hemoglobin was normal. A large amount of white powder was found in her belongings, and was later identified as phenacetin. N-acetyl-P-aminophenol, a metabolite of phenacetin was demonstrated in her urine. Hemolytic attacks disappeared completely after she stopped taking phenacetin.


[Malignant lymphoma developing from the wall of chronic empyema following artificial pneumothorax]. A 60-year-old man who had had chronic empyema following an artificial pneumothorax for pulmonary tuberculosis when he was 26 years old developed malignant lymphoma of the chest wall. The patient was admitted because of right pyothorax as a result of pseudomonas aeruginosa infection and underwent right thoracotomy. During lavage of the right thoracic cavity a tumor was found arising from the empyematic wall. Pathologic examination revealed that it was malignant lymphoma (diffuse large, immunoblastic, B cell type). Treatment with VEAP-Bleomycin elicited a good response. Seven months after chemotherapy, the patient underwent thoracoplasty in addition to packing the cavity with the latissimus dorsi and the greater omentum. Following this, the patient received chemotherapy once a month for one and a half years, after which he was kept under close observation without treatment. Complete remission has now lasted for 49 months since the initial treatment. This is the first reported lymphoma case with closure of the empyematic wall and is remarkable since this patient has remained in complete remission for the last two years without any treatment.


[Multiple hepatosplenic abscesses: successful treatment by continuous intraportal administration of amphotericin B in a case with acute promyelocytic leukemia]. A 40-year-old female was admitted in August 1989 with a diagnosis of acute promyelocytic leukemia (AML; M3). One course of modified-DCMP regimen induced complete remission in September, but she developed spiking fever at a nadir period of WBC after induction chemotherapy. CT revealed multiple hepato-splenic abscesses presumably due to candida infection. She was treated with intravenous administration of amphotericin B (AMPH-B) and other antifungal agents. Despite the hematological remission and prolonged use of these antifungal agents, high fever persisted. A catheter was inserted into the portal vein under ultrasonic-guidance. AMPH-B was administered through the catheter: the initial dose was 3 mg/day and was soon increased to 20 mg/day. Her fever subsided in 1 week, and the sizes of liver abscesses on CT reduced markedly. Chill and hypokalemia were observed during this therapy. The catheter was removed from the portal vein after 29 days. Partial portal vein thrombosis was noted around the catheter tip. This case suggests the usefulness of intraportal administration of AMPH-B in patients with hematological malignancy developing multiple liver abscesses.


[Studies on pseudo-Chediak-Higashi granules formation in acute promyelocytic leukemia]. Leukemic cells from acute promyelocytic leukemia containing pseudo-Chediak-Higashi (P-CH) granules in a 38-year-woman were studied with ultrastructural and cytochemical techniques to evaluate the origin and nature of the granules. Wright-Giemsa stain revealed giant granules to be azurophilic. Cytochemical stain revealed p-CH granules ot the basic of their peroxidase and glycoprotein content. Electron microscopy revealed numerous giant granules formed by fusion of azurophilic granules these morphological, different type granules were classified into four types, 1) circular granule with homogeneous matrix, 2) circular granule with heterogeneous change by autolysis, 3) Auer body-like granule with crystalline arrangement, 4) vacuolar formation. The results demonstrate that the Auer body-like granule of P-CH granules in leukemic cells is a morphologically variant type of the classical Auer body observed in common acute myeloid leukemia.


[Non-Hodgkin's lymphoma in a patient with sarcoidosis (the sarcoidosis-lymphoma syndrome)]. A-31-year-old man with right cervical and supraclavicular lymphadenopathy was admitted in March, 1991. He was diagnosed as having muscular sarcoidosis at the age 8 year, and was treated with corticosteroids. Since age 18, his skin was erythematous and ulcerous, and later his skin became gradually atrophic. Lymph node biopsy revealed diffused large cell non-Hodgkin's lymphoma. Lymphoma cells showed TCR-beta gene rearrangement by Southern blot hybridization. His lymphoma was refractory to CHOP and CHOP-Bleo regimens. Complete remission was achieved with cisplatin and etoposide. However, early relapse occurred, and he died of pulmonary hemorrhage 4 months after the diagnosis of non-Hodgkin's T-cell lymphoma. The so called "sarcoidosis-lymphoma syndrome" is uncommon in Japan. In 9 of 10 cases previously reported, malignant lymphoma occurred during the course of sarcoidosis. Most of the sarcoidosis cases were chronic active type, and required systemic administration of corticosteroids. Hodgkin's disease coexistent with sarcoidosis as reported in other countries, was not found in Japan. These findings suggest that the low incidence of sarcoidosis-lymphoma syndrome in our country is due to the relative rareness of Hodgkin's disease. The sarcoidosis-lymphoma syndrome possibly appears as a consequence of immunological abnormalities observed in sarcoidosis.


[Evolution to megakaryoblastic leukemia observed in myelodysplastic syndrome with erythrolekemia-like features]. A 63-year-old man was admitted because of anemia and thrombocytopenia. The bone marrow was hypercellular with 66.6% erythroblasts with dysplasia and 19.8% blasts. Cytogenetically, MAKA (major karyotypic aberrations) containing 5q-, -7, -17, with karyotypic instability was observed. A diagnosis of erythroleukemia (FAB M6) was made. Six months later, immature neutrophils increased in the peripheral blood, and blasts and promyelocytes increased to 25.8% and 20.0% of marrow cells, respectively. Three months later, blasts asts increased to 33.0% in the peripheral blood. They were ultrastructually positive for platelet peroxidase. Phenotypically, 69% and 63% of blasts were positive for CD41b (GPIIb/IIIa) and CD42a (GPIb), respectively. Bone marrow biopsy showed marked proliferation of blasts and dysplastic megakaryocytes accompanied by reticulin fibrosis. These findings suggested evolution to megakaryoblastic leukemia (FAB M7). In most cases, M6 defined by the FAB criteria is stem cell disorder with multilineage involvement and major erythroid component. M6-like features may be observed in the evolutive phase to acute leukemia from myelodysplastic syndrome (MDS).


[Thrombotic thrombocytopenic purpura achieving complete remission by slow infusion of vincristine]. A case of thrombotic thrombocytopenic purpura (TTP) which was successfully treated by slow infusion of vincristine (VCR) is reported. A 40-year-old female was admitted to our hospital because of sudden onset of genital bleeding. Her blood cell count showed severe anemia and thrombocytopenia. Biochemistry disclosed high titers of serum LDH. Based upon these findings, the patient was initially diagnosed as having Evans syndrome and was treated with steroid-pulse therapy and high-dose immunoglobulin. However, no response was obtained. A diagnosis of TTP was established when mental disturbance and renal dysfunction developed later. Aspirin and plasmapheresis relieved the mental disturbance and decreased serum LDH level, but anemia and thrombocytopenia were not corrected. Slow infusion therapy of 1 to 2 mg VCR was performed for 4 to 8 hours once a week, which dramatically improved the hematological abnormalities and controlled the disease. In conclusion, slow infusion of VCR may indicated, if initial standard therapies such as PE would fail.


[A case of hemophagocytic syndrome with multiple myeloma]. A case with multiple myeloma complicated with hemophagocytic syndrome (HS) is presented. Because pancytopenia, liver dysfunction and increase of mature histiocytes in the bone marrow appeared rapidly a diagnosis of HS was made. The patient died of multiple organ failure, despite steroid therapy. Autopsy revealed marked invasion of hemophagocytic histiocytes not only into the bone marrow but also into many other organs such as the liver, lymph nodes and kidneys. HS is a histiocyte proliferative disorders, which is likely to be seen in immunocompromised hosts, but there is no previous report about HS and multiple myeloma.


[Chimerism monitoring by VNTRs polymorphism analysis in a patient who received allogenic bone marrow transplantation]. A 39-year-old female diagnosed as acute myelogenous leukemia received allogenic bone marrow transplantation (BMT) pre-conditioned with busulfan and cyclophosphamide regimen from her HLA identical sibling. To distinguish donor and recipient cells, we analyzed variable numbers of tandem repeats (VNTRs) polymorphisms using a YNH-24 probe by Southern blot hybridization. VNTRs polymorphism analysis documented the engraftment of donor cells, relapse of recipient cells, and mixed hematopoietic chimerism. Assessment of the chimerism state is important for determining the prognosis of patients undergoing BMT, and VNTRs polymorphisms analysis is very useful for identifying the chimerism state.


[Tracer kinetics of amino acid].

[Tracer kinetics of amino acid]. In vivo turnover of an amino acid can be determined either by analysing the disappearance curve of a labeled amino acid after a single dose of labeled amino acid or by measuring the dilution of a continuously infused labeled amino acid at a steady state. From ethical concerns stable isotopically labeled amino acids, such as 13C-leucine and 15N-glycine have been routinely used to study amino acid kinetics with subsequent estimation of whole body protein turnover. Recently, instead of these 2 methods, pulse labeling by taking a single oral dose of labeled amino acid is more practical for the study of whole body protein turnover. We observed plasma 15N-glycine kinetics and urinary 15N excretion by a single oral dose of 15N-glycine simultaneously in healthy subjects and cirrhosis patients, and the results are discussed.


[Phenylalanine transport in the living human brain by a dynamic PET of L-[2-18F]-fluorophenylalanine]. The transport kinetics of L-[2-18F]-Fluorophenylalanine in the human brain were studied in one normal subject and 6 patients with brain tumor using a dynamic positron emission tomography. The tracer kinetics from blood to brain were described by two compartment model with K1 (influx) and k2 (efflux). The rate constants in normal brain tissue and tumor tissue were K1 = 0.045 ml/g/min, k2 = 0.078 ml/g/min and K1 = 0.122 ml/g/min, k2 = 0.102 ml/g/min, respectively. The Michaelis-Menten constants (Kt and Tmax) for phenylalanine transport in the normal cortex were graphically estimated. The estimated Kt was 35 nmol/ml, whereas the Tmax varied with cerebral blood flow.


[Membrane transport system of amino acids in the small intestine]. The membrane transport system of amino acids in the small intestine is reviewed. Amino acids are transported by three processes: 1) simple diffusion, 2) facilitated diffusion and 3) active transport. In the brush border membrane, there are at least six Na(+)-dependent systems (NBB, PHE, IMINO, beta, X-G,A, Y+) and the Na(+)-independent systems (L, beta, Y+). On the other hand, the basolateral membrane has at least four Na(+)-dependent systems (A, ASC, X-G,A, N) and three Na(+)-independent systems (asc, L, y+). These systems are discussed.


[Mode of membrane transport of amino acids--the kidney]. In the kidney, more than 99% of filtered free amino acids are reabsorbed by the proximal tubule. The brush border membrane of this segment is known to possess at least 5 independent amino acid carriers; neutral alpha-amino, basic, acidic, neutral beta-amino and imino acid carriers. Ionic interactions have been shown to be markedly different among these carriers. Characteristics of the interaction were outlined for each carrier. Basolateral membrane carriers have not been investigated extensively, but existence of neutral amino acid carrier (s) devoid of ionic interaction has been established. In addition, a Na+ plus K+ gradient-dependent transport has been identified for acidic amino acids and a Na+ exchange carrier has been suggested for basic amino acids. Also, asymmetric ionic interactions are suggested for luminal and basolateral membrane carriers for beta-amino acids. Proton-dependent carrier (s) for di- and tri-peptides has also been identified in the proximal tubule.


[Mechanism of amino acid transport at the liver plasma membrane]. Several amino acid transport systems have been known in the liver: sodium-dependent systems A, ASC and N for neutral amino acids, a sodium-dependent system for glycine (system Gly), sodium independent systems L1 and L2 for neutral amino acids, and sodium dependent systems for anionic amino acids. Recent studies with isolated sinusoidal and canalicular membrane vesicles have revealed that sodium dependent transport of an anionic amino acid, glutamate, and glycine occurs at the canalicular membrane, not at the sinusoidal membrane. Furthermore, solubilization and reconstitution of systems A and N has been reported and a 100 kD protein responsible for system N transport has been identified in the rat liver.


[Molecular biological approach to mammalian amino acid transporters]. Several mammalian amino acid transporters have been purified from solubilized membranes to a single protein band with a molecular mass of 60-130 kDa. It has been demonstrated that the mammalian amino acid transporters are expressed in Xenopus oocytes following microinjection of mRNA from various cells and tissues. Using this expression system, a cDNA clone, encoding an amino acid transporter, has been isolated from a tissue cDNA library, and a topological model for the deduced protein is depicted. At present, the models for the structure of the three kinds of amino acid transporters are proposed, one of which is identical with an ecopropic retrovirus receptor.


[Molecular biological aspects of amino acid metabolizing enzymes]. This article briefly describes the molecular biological aspect of studies on some enzymes involved in amino acid metabolism. Aspartate aminotransferase is one most extensively studied enzyme. Together with its three dimensional structure, recent studies using site-directed mutagenesis have led to the understanding of its structure-function relationships. Successful cDNA cloning of other aminotransferase has enabled us to understand the degree of homology in amino acid sequence. cDNAs for several amino acid decarboxylases were also cloned. Genomic structures for the enzymes involved in urea cycle have been studied. These studies have provided a molecular basis for some hyperammonemias. Its is strongly anticipated that the understanding of other metabolic disorders may be promoted by further accumulation of molecular biological data on the relevant enzymes.


[Amino acids as a modulator of hormone secretion]. Amino acids stimulate or inhibit the releases of some pituitary, pancreatic and gastrointestinal hormones by oral or intravenous administration. These effects are clinically used as amino acid loading tests to examine the reserve of hormones, including growth hormone, insulin, glucagon, somatostatin, etc., and of use for the diagnosis of endocrine and gastrointestinal diseases. The mechanism of pituitary hormone release, induced by amino acids, has been explained by their actions on peptidergic and monoaminergic systems in the brain but it is still not known as for pancreatic and gastrointestinal hormones.


[Advances in automated amino acid analysis]. Recent progress in the field of amino-acid analysis, characterized by the development of fully automated chromatographic equipment, is described. For separation and quantitation of free amino acids from biological fluid, such as blood and urine, ion exchange column chromatography followed by colorimetric detection of ninhydrin reactive products is the most widely adopted methodology in the clinical field. Analytic procedures are fully automated. The computer controlled pumping mechanism guarantees a precise buffer supply for separation and peak identification and peak height or/and area detection of each amino acid in the effluent are highly reproducible. Complete analysis of more than 30 amino acids in biological fluids can be performed within 2 hours. Amino acid analysis is now easily adopted in the routine clinical laboratory and is expected to contribute to the clinical diagnosis of amino acidopathies.


[Inborn errors of amino acid metabolism--concepts and classification]. After the definition and the heredity of inborn errors of amino acid metabolism and a discussion of the incidence of these diseases, the four primary types of clinical features, namely 1) the prenatal, 2) neonatal (with acute onset), 3) mild, and 4) abortive types are described. The pathophysiology of brain damage is discussed. Based on recent findings, inborn errors of amino acid metabolism were classified according to their cause, 1) primary defect in catabolism, and 2) disturbances in the transport of amino acid. For each disease, the amino acids which can be detected in the plasma or in the urine are listed, along with the enzymes which are defective in each case.


[Biochemical diagnosis and mass screening for hereditary amino acid disorders]. During the past 50 years, the development of both organic and analytical chemistry has greatly contributed to the discovery of new hereditary amino acid disorders. As a result, more than 80 new amino acid disorders have been discovered. More recently, the development of protein chemistry has made it easily to investigate the biochemical basis of these disorders. In this paper we present the status of biochemical diagnosis as well as mass-screening for amino acid disorders. The result of neonatal mass-screening for 4 amino acid disorders (PKU, MSUD, homocystinuria and histidinemia) from 1977 to 1990 revealed that the incidence of PKU is extremely rare in Japan when compared to European Countries, and the incidence of MSUD and homocystinuria are also less common in Japan. On the other hand, the incidence of histidinemia is higher in Japan than in Europe, however, a follow up study of more than 1,500 patients showed almost all cases developed normally without any dietary treatment.


[Prenatal diagnosis of inborn error of amino acid metabolism]. Prenatal diagnosis of inborn errors of amino acid metabolism was discussed from the viewpoints of its purpose, ethical problems, analysis methods, and sampling methods of the fetal tissues. In addition to the general discussion, our results of the prenatal diagnosis of 20 cases with nonketotic hyperglycinemia (NKH) were also reported. Nineteen cases were diagnosed by the enzymatic method, while one Finnish case was successfully diagnosed by DNA analysis, which is based on our observation that a missense mutation we identified accounts for 70% of the mutant alleles in Finland. The DNA analysis would be a great help for the prenatal diagnosis in Finland where the incidence of NKH is unusually high (1: 12,000 births).


[Inherited metabolic disorders of the transsulfuration pathway]. Several inherited metabolic disorders of the transsulfuration pathway are discussed. They are hypermethioninemia, homocystinuria, cystathioninuria, beta-mercaptolactate cysteine disulfideuria and sulfite oxidase deficiency (SOD). Primary coverage is given to homocystinuria and SOD. In the case of homocystinuria, metabolic defects include cystathionine beta-synthase deficiency, methylenetetrahydroforate reductase deficiency, and mutations in cobalamin metabolism. Their main clinical pictures, metabolic abnormalities, and treatment are also described. SOD appears in two cases as an isolated enzyme defect and a combined deficiency of sulfite oxidase and xanthine dehydrogenase that share a common molybdenum cofactor. The clinical, biochemical and neurological features of the two disorders are reviewed.


[The dibasic amino acid metabolic disorders]. The ornithine transcarbamylase deficiency (OTCD), arginase deficiency (ARD), Hyperornithinemia-Hyperammonemia-Homocitrullinuria (H.H.H) syndrome and Lysinuric protein intolerance (LPI) are characterized by the accumulation of the precursors of urea, principally ammonia because of the abnormal metabolism of ornithine, arginine and lysine which are the dibasic amino acid. We mainly described the recent knowledge for these disease and introduced the great advancement of the molecular biology in this field which makes us to give an early diagnosis for these disease to have an early treatment.


[Metabolic disorders of amino acids due to enzyme mutation--branched-chain amino acids]. Three kinds of inborn error of branched-chain amino acids (valine, leucine isoleucine) are described with a focus on the findings in recent biochemistry and molecular genetics. Frequency of valinemia and leucinisoleucinemia is quite low but their significance is distinct because of our knowledge that at least two aminotransferases, one branched-chain keto acids dehydrogenase and two short-chain acyl-CoA dehydrogenases are present in human, is based on the observations of these limited cases. In MSUD, the sequential study of each subunit cDNA reveals a close relationship between the clinical phenotypes and the various sites of mutation.


[Inborn errors of imino acid metabolism]. Several conditions and disorders were caused by enzyme defects in metabolism of imino acids. Hyperprolinemia type I and type II, hyperhydroxyprolinemia, imidopeptiduria (prolidase deficiency) were related to proline and/or hydroxyproline metabolism. Sarcosinemia and abnormality in pipecolic acid metabolism were also classified as inborn errors of imino acid metabolism. In this brief review, the outline of these genetic conditions or disorders were described. Among the genetic enzyme defects, imidopeptiduria (prolidase deficiency) caused severe clinical problems. Other conditions were thought to be benign.


[Abnormal metabolism of substances related to glycine and beta-alanine]. Glycine and serine are interconverted by serine hydroxymethyltransferase and hence share their metabolic pathways. In the rat the carbon skeleton of choline is derived from the alpha and beta carbons of serine through phosphatidylserine and is further converted to that of glycine through N-methylated molecules of glycine i.e. betaine, N-dimethylglycine, and sarcosine (N-methylglycine). Thus far, the production of a folate derivative of the active one carbon that is an essential material for purine nucleotides and thymidylate biosynthesis is the notable feature of this metabolic process. In the major degradative pathway for pyrimidine nucleotides, beta-alanine, one of omega-amino acids, is produced and further catabolized by beta-alanine: oxoglutarate transaminase which is suggested to be identical to that for gamma-aminobutyrate, another omega-amino acid. Disorders included in these metabolic pathways are succinctly reviewed.


[Vitamin B6 dependency syndrome].

[Vitamin B6 dependency syndrome]. Many enzymes that require pyridoxal 5'-phosphate (PLP), a coenzyme from a vitamin B6, are involved in amino acid metabolism. B6 dependency syndromes are defined as a group of metabolic disorders which are prevented or alleviated by non-physiologically large doses of vitamin B6, and, hence, they are tacitly accounted for by some structural alteration in a responsible B6-dependent enzyme such as a decrease on the affinity for PLP as compared to the normal. In this article, the mode of binding the coenzyme is exemplified by the case of aspartate aminotransferase, a typical B6-dependent enzyme whose three-dimensional structure is known, and, several B6 dependency syndromes are briefly reviewed. Among these syndromes, the molecular basis of only gyrate atrophy has recently been defined by the identification of a mutation in the relevant enzyme, ornithine aminotransferase.


[Inherited amino acid transport disorders]. Disorders due to inherited amino acids transport defect are reviewed. The disorders were categorized into three types of transport defects, namely, brush-border membrane of epithelial cells of small intestine and kidney tubules (Hartnup disease, blue diaper syndrome, cystinuria, iminoglycinuria and lysine malabsorption syndrome), basolateral membrane (lysinuric protein intolerance) and membrane of intracellular organelles (cystinosis and hyperornitinemia-hyperammonemia-homocitrullinuria syndrome). Pathogenesis, clinical feature, laboratory findings, diagnosis, genetics and treatment of these disorders are described, briefly. There is not much data for the transport systems themselves, so that further investigation in molecular and gene levels for transport systems is necessary to clarify the characteristics of the transport and heterogeneity of phenotypes in inherited amino acids transport disorders.


[Cystinosis].

[Cystinosis]. Recent progress of the study of the pathogenesis, diagnosis, and treatment of a lysosomal transport disorder, cystinosis is reviewed. Cystinosis is an autosomal recessively inherited disease that is caused by the accumulation of cystine in lysosome due to lack of the cystine transport system in lysosome. Renal transplantation has been a successful treatment for the cystinosis patients who are in the end stage renal failure, and this therapy has markedly prolonged the life span of cystinosis patients. Recently, oral cysteamine therapy has been successful in the excretion of accumulated cystine in cystinosis patients, and in improving the symptoms. Studies are now under way to see if early (within a month of life) start of cysteamine therapy would achieve the most satisfactory therapeutic effect and maintain normal renal function.


[Imbalance of amino acid metabolism in fulminant hepatitis and its management]. Fulminant hepatitis shows characteristic imbalance of amino acid levels; increased aromatic amino acid (AAA) and methionine. Elevated plasma AAA may cause hepatic encephalopathy and BCAA-enriched amino acids solution (BCAAs). Glucagon-Insulin (G-I) therapy and artificial liver support system have been proposed to correct the imbalance of amino acids. BCAAs and G-I therapy correct the aberrant amino acid patterns and artificial liver support system, including plasma pheresis, and charcoal haemoperfusion has also been used to reduce plasma amino acids levels. While imbalance of amino acids level in fulminant hepatitis is a result of acute necrosis of a large proportion of hepatocytes, careful and sufficient management of the disease is essential to normalize amino acid profiles.


[Amino acid metabolism in liver cirrhosis]. In patients with liver cirrhosis the fasting plasma alpha-amino nitrogen concentration is high as the rule, due to reduced clearance of total alpha-amino nitrogen. The urea cycle is diminished of its capacity in cirrhotic patients than in the control subject, and to compensate for this, the extrahepatic glutamine cycle capacity is enlarged in the patients. The following important topics were taken up in this mini review: some problems concerning Fischer ratio, amino acids metabolism and pH regulation in the liver, and the supplementation therapy with branched chain amino acids under the condition of organ relationship.


[Amino acids metabolism and nutritional support in acute renal failure]. It has been claimed that conventional essential amino acid (EAA) solution may give rise to adverse effects such as hyperammonemia, in acute renal failure (ARF). On the other hand the majority the ARF treated recently have been complicated by multiple organ failure (MOF). These data indicate that a new regimen in nutritional support should be applied to those patients. A new amino acid solution for renal failure, containing not only EAA but also branched chain and non-essential amino acids, has been developed. We administered this solution as total parenteral nutrition (TPN) to ARF patients complicated by MOF. Continuous hemodiafiltration is simultaneously applied to remove excess water. The nutritional status and the deranged aminogram are improved by this treatment. We believe that an ARF patient complicated by MOF should be nutritionally supported with this new regimen.


[Impaired amino acid metabolism and its management in chronic renal failure]. The protein and amino acids (AAs) metabolism are known to be impaired in the uremic patients. The etiology of those abnormalities is multifactorial, such as inadequate nutritional intake, protein-restricted diet, decreased urinary excretion of AAs, impaired activity of AAs-synthetic and/or-degrading enzymes, disturbed absorption, loss of AAs during dialysis, and abnormal transcellular movement due to hormonal abnormalities. As the nutritional supplement for the uremic patient, essential amino acid has been proposed. It was, however, reported to cause the hyperammonemia with or without encephalopathy in addition to fatty liver. Further investigation concerning the optimal composition of AAs solution for uremic patients is required to solve these problems.


[Amino acid metabolism in surgical stress]. Amino acid metabolism under surgical stress, injury or infection was reviewed from the literature. The glucose-alanine cycle in coupling with branched chain amino acids (BCAA) metabolism plays a central role for gluconeogenesis, in such a catabolic state. Glutamine is as important as alanine for sparing glucose and furthermore for intestinal repair. Changes in plasma amino acid concentration and clearance following hepatectomy are described, and effects of BCAA solution are evaluated. It was suggested that BCAA improved the Fischer ratio by increasing, not only plasma BCAA level, but also AAA clearance.


[Abnormal amino acid metabolism in diabetes mellitus]. Abnormal amino acid metabolism is sometimes observed among patients with diabetes mellitus. Of many amino acids, alanine and branched-chain amino acids such as valine, leucine, isoleucine show characteristic changes. In diabetic ketoacidosis, plasma concentration of alanine decreases and that of branched-amino acid increases and the oxidation of branched-amino acids is enhanced. Splanchnic amino acid uptake is generally higher in diabetics and this level is partially restored by exercise. Some glycosylated proteins are used to estimate the condition of diabetes mellitus. Increment of urinary glycosylated amino acid excretion is reported in diabetics. Plasma homocysteine, reactive vascular-injuring amino acid, increases in diabetics with nephropathy. Those abnormal amino acid metabolism would be restored after good glycemic control is obtained.


[Eosinophilia-myalgia syndrome].

[Eosinophilia-myalgia syndrome]. Eosinophilia-myalgia syndrome (EMS) is a newly recognized disease, characterized by peripheral eosinophilia with scleroderma-like features. By July 1991, 1543 cases of EMS, including 31 fatal cases, have been reported. Although epidemiologic studies strongly suggest the association of EMS with ingestion of L-tryptophan (LT) containing a contaminant from a single manufacture, the pathogenesis of this disease is not well understood. The insight obtained from the study of EMS may be applicable to scleroderma or eosinophilic fasciitis. Recent advances in the understanding of clinical and pathologic features of EMS are reviewed.


[Immuno-hematopoietic cytokine receptor family--its structure and function]. Receptors for immuno-hematopoietic cytokines are multi-chain complexes of membrane proteins. Molecular cloning of these cytokine receptor genes revealed the existence of a here-to-fore unidentified receptor superfamily. They are primarily characterized by a shared extracellular structure that may be involved in the formation of multi-chain receptor complex. Inspite of the lack of any catalytic function, several members of the superfamily are known to act as the transmembrane transducers of cytokine signals. Such molecules may interact physiologically/functionally with multiple intracellular catalytic molecules to generate signals. In this regard, potential involvement of protein tyrosine kinase and protein serine/threonine kinase in the post-receptor signalling has been described. Dysregulated activation of the cytokine receptor gives rise to transformation of immuno-hematopoietic cells.


[Development and application of biosensors for medical field]. Methods for the selective determination of organic compounds in biological fluids, such as blood, are very important in clinical analyses. Most analyses of organic compounds can be performed by spectrophotometric methods, based on specific enzyme-catalyzed reactions. However, because of the complicated procedure, these methods cannot be applied directly to bed-side monitoring. Alternatively, biosensors based on enzymes and electrochemical transducers possess excellent sensitivity for biological substrates and can determine a single compound in a biological fluid directly without need for a prior separation step. Therefore, in the past several years, many kinds of biosensors have been developed, and implantable microbiosensors for a body organ have also been reported.


[A study of hepatocellular transplantation]. Clinical liver transplantation has been done for patients with irreversible hepatic diseases, but the shortage of donor livers from heart beating cadavers has become very serious. Hepatocyte transplantation requires no vascular anastomosis and donor hepatocytes are easy to obtain from living donors and easy to preserve for a long time. In the animal experiments, transplanted hepatocytes survived in the spleen for long periods of time, and cytochemical investigation revealed differentiated liver functions, such as gluconeogenesis, albumin synthesis, bilirubin conjugation. Intrasplenic transplantation of hepatocytes relieved congenital disorders of liver enzymes in rats. Moreover, transplanted hepatocytes re-composed normal cord structures with hepatic sinusoids in the spleen of rats. Hepatocytes could also be isolated from human cirrhotic livers by a multi-perfusion method, and the viability was almost 80%. After the success in transplantation of human hepatocytes into the spleen of athymic mice, 6 patients have undergone clinical trial of intrasplenic hepatocyte transplantation without any complications. In the future, the progress of gene manipulation techniques may make possible rapid growth of transplanted hepatocytes. Intrasplenic transplantation of isolated hepatocytes provides an in-vivo experimental model to study cellular growth and functions in detail.


[Present status and problems of the normal values (clinical reference range) of the laboratory tests--results of a questionnaire survey in university hospitals in Japan]. The normal values (clinical references range) of the laboratory tests differs among hospitals due to the differences in: (1) the kinds of instruments and reagents used, (2) how the population for study was selected and the size of the population was, (3) when the specimens were taken, (4) how they were stored until use, and (5) how the data obtained were calculated and (6) who evaluated the results. In this study, questionnaires regarding the above-mentioned points were sent to the heads of the clinical laboratories in 80 university hospitals in Japan. Answers were received from 71 laboratories (the rate of recovery was 88.8%). The normal range of potassium, uric acid, total cholesterol, enzyme activities [ALP, LDH, CHE, AST (GOT) and ALT (GPT)] in the university hospitals in Japan varied. It is not ideal to use different reference values in different hospitals. However, it is impossible to prepare a standard manual to obtain the normal range at present. When the inter-hospital differences become small enough to obtain one normal range for the Japanese peoples, a standard manual for normal values should be made.


[Evaluation and selection of normal range calculation methods]. There are many methods for normal range calculation, and they give different values even with the same normal data sample. I proposed three parameters, accuracy, precision and robustness, for evaluating the calculation methods. A complicated calculation method, the distribution selection method, seems to be theoretically correct, but it shows unstable precision and inadequate robustness when the normal data contain a small amount of abnormal data. A method called "Clinical reference range program (CRRP)" is a robust method, and is applicable to the data which contains abnormal data. I also proposed a condition which defines the sample size required for the calculation using the precision parameter.


[Factors that influence reference values]. The factors that influence reference values are briefly reviewed using our experimental data. The factors can be divided into the following 3 subfactors: analytical technology, selection of so called healthy person and statistical method. The most large effect came from a variety of physiological conditions in healthy persons, i.e., age, sex, diurnal and menstrual rhythms, drinking and smoking habits, diet, physical exercise, posture, tourniquet etc. A new concept of tow-step reference values "the basal value and the equivocal value" is postulated from the studies of the effect of these physiological conditions. The effects of the statistical methods for obtaining the distribution type of data of normal reference group and the 95% reference range were not so large. Then, we conclude that the reference values or the reference ranges should be made in your own laboratories using carefully selected healthy persons even if 30 or 50 small numbers are used.


[Methods and normal ranges for predicting diseases]. Predictions of diseases require suitable laboratory tests, mathematical methods for analyzing data and true normal ranges. Normal ranges are to be defined as 95% range of test results obtained on healthy subjects. "Healthy" subjects here refers to the persons who are free of the particular disease now and previously. However, to confirm the disease-free condition, laboratory test result must be evaluated on the basis of a normal range. This is a dilemma. The only way to overcome this problem is to follow a cohort for 10 or 20 years. Some of the "healthy" subjects will be suffering from diseases, while the others will still remain free of disease. That the latter persons would be the truly "healthy" subjects. Therefore, by their laboratory data and/or specimens such as serum every year we can determine the differences between the laboratory data of the patients and the true healthy subjects. In this respect, the development of laboratory database systems and serum banks are essential. We report a mathematical method for selecting significant data items for such a database and decision-making.


[Detection of mRNA in megakaryocytes using in situ hybridization]. The usefulness of in situ hybridization for detecting mRNA encoding various kinds of proteins in megakaryocytic cell lines (K562, HEL and CMK) was examined. Using in situ hybridization, glycoprotein (GP) IIIa mRNA was found to be present in K562, HEL and CMK cells. Both GPIb and GPIIb mRNA were also present in HEL and CMK cells, while only HEL cells expressed platelet factor 4 mRNA. These findings were identical to those obtained with Northern blotting. It should be emphasized that in situ hybridization was useful to clearly define each cell expressing platelet specific protein mRNA. The expression of interleukin-6 (IL-6) and IL-6 receptor mRNA in mononuclear cells prepared from bone marrow aspirates was examined. In situ hybridization study demonstrated the presence of IL-6 receptor mRNA in the recognized megakaryocytes only, while IL-6 mRNA was found to be present in the megakaryocytes and a few mononuclear cells. These findings suggest that differentiation and proliferation of normal megakaryocytes might be controlled by an IL-6 autocrine loop, and detection of IL-6 receptor mRNA might be useful to identify megakaryocytes.


[Evaluation of clinical features, cytopathological findings and prognosis of histiocyte proliferative disorders]. Clinicopathological analysis was performed in 19 patients diagnosed clinically with malignant histiocytosis. Ultimately, 9 patients died and 10 are still alive. All 19 had fever of unknown origin. Among the 10 surviving patients, 6 recovered with only supportive therapy such as antibiotic treatment. One recovered with steroid therapy and 2 with VP (vincristine and prednisolone) therapy. Complications due to immunodeficiency were detected in one surviving patient and 2 who died. All 9 patients who died had anemia, and 8 had thrombocytopenia. However, among survivors, only one had anemia and only 2 had thrombocytopenia. Chromosomal abnormality was detected in one patient who died. Histiocytic cells were classified morphologically into 3 types: immature, intermediate and mature. In 4 patients who died, histiocytic cells were immature, but in 4 others mature histiocytic cells were detected. In 5 of the 10 surviving patients, histiocytic cells were of the immature type. Immuno-histochemical analysis of the origin of histiocytic cells in 8 deceased patients showed T-zone histiocytes in one, T cells in one, monocyte phagocytic system (MPS) in 5, and histiocytes of unknown origin in one. Thus, malignant histiocytosis is a heterogenous entity including reactive histiocytic disorder, lymphocytic neoplasm and true histiocytic neoplasm. In histiocyte proliferative disorders, red blood cell counts and platelet counts are useful for assessing prognosis, while cytological findings only confuse this evaluation.


[Evaluation of platelet aggregation test by grading curve]. In order to standardize the platelet aggregation test, we used the grading curve (GC) produced by plotting four concentrations (0.5, 1.0, 2.0 and 4.0 microM) of ADP and four concentrations (0.25, 0.5, 1.0 and 2.0 micrograms/ml) of collagen, which are aggregation inducers, along the horizontal axis and plotting their individual rates (%) of aggregation 5 minutes after administration, along the longitudinal axis. The degree of platelet aggregation was classified in 6 stages (Types III, II, I, 0, -I and -II), ranging from marked increase to marked decrease, according to the GC of ADP aggregation in healthy subjects. Type I or 0 ADP aggregation was observed in 78% of the subjects, and Type I collagen aggregation was observed in about 50% of the subjects, whereas patients with cerebral infarction showed distinct increases in Type III and II aggregations of both ADP and collagen. In most patients who were treated with antiplatelet drugs, the aggregation were Type 0, -I or -II. The concentration of inducer, which corresponded to the maximum 50% value of the GC (Max 50) was significantly correlated with the minimum concentration (threshold concentration) in ADP aggregation, at which secondary aggregation was induced even if it was reversible, and with the minimum concentration (threshold concentration) in collagen aggregation, at which the aggregation rate 5 minutes after administration increased to 50% or higher. The GC of platelet aggregation seemed to enable easy determination of the degree of aggregation, and was also considered to be useful for monitoring platelet aggregation during the administration of antiplatelet drugs.


[Negative interference with peroxidase-coupled enzymatic serum creatinine assay by a hemostatic drug containing a hydroquinone structure]. We report a discrepancy between serum creatinine levels obtained by the method based on alkaline picric acid (Jaffé reaction) and that by automated analyzer employing enzymatic assay based on peroxidase-coupled reaction in a patient with renal dysfunction taking Ethamsylate, a capillary vessel stabilizer. Serum creatinine level obtained by the Jaffé reaction was 83 mg/l, and that by the enzymatic method was 22 mg/l. Recovery test of creatinine using the patient's serum showed 101 to 102% recovery by the Jaffé reaction and 77 to 89% by the enzymatic method. The same results were observed both in an in vitro test and in serum obtained from a healthy volunteer who had been given Ethamsylate previously. As the chemical structure of Ethamsylate includes a hydroquinone unit, it was thought that the compound may consume hydrogen peroxide produced by the reaction of peroxidase as the hydrogen donor and compete with the substrate used as the hydrogen donor for the color development. Thus evaluation of test results obtained by peroxidase coupled methods should be carefully interpreted in a patient who is consuming drugs which hydrogen peroxide such as hydroquinone.


[Clinical assessment of urinary free L-fucose levels]. We measured urinary levels of free L-fucose in healthy subjects, patients with benign diseases, and patients with cancer using an automated analyzer and a newly isolated L-fucose dehydrogenase, and evaluated the clinical usefulness of the results. The values obtained were corrected for urinary creatinine as micromoles per gram of creatinine. The cutoff value, set at the mean + 2SD for the healthy subjects, was 250 mumol/g.Cr. Patients with gallbladder cancer, bile-duct cancer, liver cancer, pancreatic cancer, or cirrhosis of the liver had significantly higher levels of L-fucose than the healthy subjects. The diagnostic sensitivity for these five diseases, taken together, was 68% (144/213). Specificity for the detection of cancer was calculated by use of false positives for patients with cholelithiasis, hepatitis, and pancreatitis: it was 73% (76/104). Diagnostic accuracy for these seven diseases taken together was therefore 69% (220/317). We compared the positive ratio of the L-fucose level with that of the tumor markers AFD and CA19-9. The positive ratio of an L-fucose value above the cutoff was higher than the positive ratio of either marker in bile-duct cancer, gallbladder cancer, liver cancer, and pancreatic cancer. The results suggested that the urinary levels of free L-fucose reflected the metabolism of sugar chains of glycoconjugates, and may be usefully clinically as a tumor marker.


[Creatine kinase activity and its isozyme levels in cord blood]. We measured creatine kinase (CK) levels of cord blood and evaluated them in relation to the degree of maturity and distress. The reference value of CK of cord blood in normal neonates was 209 +/- 99 U/l (mean +/- SD) and the percent values of the isoenzymes, CK-MM, CK-MB and CK-BB, were 86.7 +/- 6.2%, 5.1 +/- 2.6%, and 8.1 +/- 5.4%, respectively. There was a positive correlation between the birth weight and CK, CK-MM, CK-MB and CK-BB levels of cord blood. The CK and CK-MM levels of cord blood in the neonates who were prematurely delivered and small-for-date were significantly lower than those in normal controls. The CK and CK-MM levels of cord blood in the neonates with low Apgar scores, 6-4 and 3-0, were 172 +/- 74, 145 +/- 73 and 104 +/- 63, 92 +/- 55 U/l, respectively, which were significantly lower than those in the neonates with the high scores (10-7), 208 +/- 104, 183 +/- 92 U/l. The neonates with distress showed the low CK and CK-MM values, 76 +/- 12 and 61 +/- 8 U/l. The CK and CK-MM levels of cord blood tended to decrease with prolongation of labor, but did not differ from each other among the neonates delivered by different modes. These results suggest that the CK and its isoenzyme levels are good indicators for the degree of maturity of neonates and the severity of neonatal distress.


[Plasma lipid peroxides in the operation of esophageal cancer]. Lipid peroxides are formed by autooxidation of polyunsaturated fatty acids found primarily in cell membranes. An increase level of lipid peroxides in the tissue therefore reflects membrane damage. We reported that water immersion restraint rats caused significant increase of gastric mucosal lipid peroxide which reflected on gastric mucosal injury. The gastric mucosal injury is also known as the post-operative complication due to physical stress. So we studied plasma lipid peroxide and its related substances in the operation of esophageal cancer. Lipid peroxide levels increased significantly in pre- and post-operation but temporal decrease was found during the operation. Vitamin E is thought to be an important structural component of biologic membranes and is believed to act as a free radical scavenger in lipid peroxidation. Vitamin E also increased in the patients of esophageal cancer and decreased significantly during the operation. Superoxide dismutase changed frequently during the operation but there was no deficit tendency in its changes. Catalase levels also changes frequently and showed temporal but statistical elevation after the operation. These results indicated that lipid peroxidation may contribute to the development of organic damage in the operation of esophageal cancer.


[Endoscopic brushing cytology of esophageal lesions]. Endoscopic esophageal biopsy and brushing cytology were performed simultaneously in 121 cases, 25 of which were diagnosed as esophageal cancer by histologic examination of surgically resected material or at autopsy. Correct diagnosis was made in 88% of the cancer cases by endoscopic biopsy, and the same diagnostic rate was obtained by brushing cytology. Combination of the two methods revealed the cancer in 96% of the cases. There were no cases diagnosed as false-positive or false-negative by cytology. Three cancer cases were diagnosed as suspicious by cytology. Definite diagnosis was not made because of paucity of cells on the slide or of cellular atypism. For the improvement of accuracy in cytologic diagnosis it is important to sample adequate amount of cells, and in situ carcinoma cells should be differentiated from benign atypical cells in esophagitis.


[Rapid diagnosis of tuberculous lymphadenitis by amplification of mycobacterial DNA]. In patients with cervical lymph node swelling, prompt differential diagnosis of tuberculosis leads to an appropriate treatment. A method based on DNA amplification and hybridization for the rapid detection of Mycobacterium tuberculosis was used for demonstrating its specific DNA in cervical lymph nodes biopsied from seven patients. The DNA specific for Mycobacterium tuberculosis was detected in 5 patients. Four of them were histologically diagnosed as tuberculous lymphadenitis. In another case with necrotizing lesions but without granulomatous reactions, culture method subsequently revealed a positive result. In other 2 cases, the diagnosis of tuberculosis was promptly excluded by both this method and conventional methods (histologic diagnosis/direct microscopy). The rapid detection of Mycobacterium tuberculosis by amplification of mycobacterial DNA is helpful particularly in differential diagnosis of cervical lymphadenopathy.


[Event-related potential in patients with diabetes mellitus]. The event-related potential (ERP) was recorded for 24 patients with diabetes mellitus (age 67.5 +/- 8.5 years, mean +/- SD) and 28 healthy controls (age 61.0 +/- 10.6 years) to elucidate the involvement of the central nervous system (CNS) in diabetes mellitus. ERP was recorded during auditory discriminative tasks. The latencies of N100, P200, N200 and P300 from the Pz region were measured. Patients with diabetes mellitus showed significant prolongation of N200 and P300 latencies compared with the normal subjects, while no significant differences in N100 and P200 latencies were found between the two groups. In six of 24 patients, the P300 latency delayed beyond the 2SD of the appropriate age-related value estimated from the normal regression line. The delay of the P300 latency was not related to either the duration of illness, therapeutic methods, or metabolic control. From the present results, it would appear that higher brain function is impaired even in diabetic patients not manifesting overt CNS signs and symptoms.


[Effect of long-term administration of antisecretary drugs on rat gastric histamine synthesis and acid secretion--compare with omeprazole and cimetidine]. To investigate the effect of 6 weeks administration of proton pump inhibitor (omeprazole) and H2-receptor antagonist (cimetidine) on gastric histamine synthesis and acid secretion, we studied experimentally in the rat stomach. Then gastric mucosal histamine concentration, histidine decarboxylase (HDC) activity and serum gastrin concentration, and HDC positive cell number were examined in time-course. The 6 weeks administration of omeprazole caused more increase of HDC positive cells than cimetidine. After cessation of administration with omeprazole, high plasma gastrin level immediately reduced. However the increase of gastric mucosal HDC activity and histamine concentration were prolonged, compared with cimetidine. These findings suggest to affect differently between omeprazole and cimetidine on gastric acid secretion after cessation of long-term treatment.


[Morphological changes of extrahepatic bile ductal epithelia in hamsters feeded with lithogenic diet]. Experimental cholelithiasis was established by feeding hamsters with lithogenic diet. Morphological changes of extrahepatic bile ductal epithelia were observed under light and electron microscopes at weeks 1, 2, 4 and 6 after the treatment. Moreover, the changes of mucus composition in goblet cells, which were located among the epithelia, were particularly evaluated using High iron diamin-Alcian blue pH 2.5 (HID-AB) stain. Compared with the controls, goblet cells of both superior bile duct (S-BD) and inferior bile duct (I-BD) increased in number, but more prominently in I-BD than in S-BD. Furthermore, goblet cells of the controls mainly contained sulfomucin positive for the HID in their cytoplasm. On the other hand, goblet cells of the lithogenic diet group mainly contained sialomucin negative for the HID in their cytoplasm. Electron microscopy demonstrated the extensive accumulation of secretory granules in the cytoplasm of the epithelial cells of both S-BD and I-BD. These results suggest that cholelithiasis may enhance the mucus secretion from extrahepatic bile ductal epithelia, and that the mucus oversecretion results in the protective effect on biliary epithelia. On the other hand, it is suggested that the mucus oversecretion may cause the bile retention in extrahepatic bile ducts, and also may have relation to the choledochitis or pancreatitis associated with cholelithiasis.


[Effects of urso-deoxycholic acid (UDCA) on alpha-naphthyl-isothiocyanate (ANIT) induced intrahepatic cholestasis in rats]. Using the ANIT induced model of cholestasis in rats, the therapeutic effects of UDCA to the intrahepatic cholestasis were evaluated by changes of serum chemistry and liver histology. ANIT was administered once at a dosage of 40 mg/kg b.w. per os and UDCA was given ad libitum for 7 days by a drinking water containing UDCA at 0.5 and 5.0% solution. In the period of bile duct epithelial degeneration and necrosis, effects of UDCA for jaundice was not detected, but hepato-cellular disturbances were appeared histologically. Moreover, the elevation of serum levels of chenodeoxy-cholic acid, deoxycholic acid and lithocholic acid was accompanied. On the other hand, in the recovery stage of the bile duct epithelium, serum bilirubin was decreased significantly in the UDCA group which seemed to be related with the potent choleretic effect of UDCA. These results may indicate that UDCA is effective for the intrahepatic cholestasis in the case with no bile duct epithelial damage but in the presence of it hepato-cellular injury is introduced by the accumulated toxic bile acids in the blood.


[Calcium-dependent signaling of acid secretion in isolated parietal cells from guinea pigs and its modification by ethanol]. Treatment of isolated parietal cells from guinea pig gastric mucosa with ethanol caused a rapid increase in [Ca2+]i and concomitant decrease in the capacity for carbachol-stimulated acid secretion in a dose dependent manner. Carbachol rapidly increased the [Ca2+]i from trimethoxybenzoic acid 8-(diethylamino)-octyl ester sensitive intracellular pool. In contrast, the increase with ethanol was through La3+ sensitive Ca2+ channel from external source, which suppressed the Ca2+ response subsequently stimulated with carbachol. Pretreatment of the cells with EGTA or La3+ completely prevented the elevation of [Ca2+]i with ethanol and preserved the Ca2+ response to carbachol. These findings indicate that ethanol-induced elevation of [Ca2+]i may desensitize the stimulation of carbachol. Furthermore, treatment of the parietal cells with ethanol increased the activity of protein kinase C in both cytosolic and membrane fractions of the cells. Activation of protein kinase C with phorbol diester suppressed the capacity for acid secretion. These results suggest that ethanol may inhibit the carbachol-stimulated acid secretion through the desensitization of Ca2+ response and the activation of protein kinase C.


[An experimental pathologic study of acute small intestinal ischaemic in mongrel dogs--occluded proximal site of anterior mesenteric artery by balloon catheter]. We prepared experimental of small intestinal ischemia by occluding the inlet of the anterior mesenteric artery of adult mongrel dogs with balloon catheters. With these experimental models, the degree of tissue damage of the small intestinal mucosa, which became ischemic, was studied according to the different occlusion times of the anterior mesenteric artery (3, 5, 7, 10, 15 and 30 hours). As a result, ischemic mucosal lesions in the small intestine at an initial stage occurred on the antimesenteric side. In the gross findings of the mucosa when the occlusion time was within 5 hours, linear and spotted lesions appeared in a zone on the antimesenteric side. When the occlusion time was 7 hours or more, these lesions fused and the entire intestinal mucosa became a hemorrhagic lesion. By occluding the anterior mesenteric artery for 22-30 hours, all 6 experimental ischemic animals died.


[Extraction efficacy on uptake of intraportally injected monoclonal antibody by human colorectal metastases in nude mice]. Route of administration is an important determinant in tumor uptake of monoclonal antibody (mAb). We studied the extraction efficacy of intraportal injection (IP) on tumor uptake over time in hepatic metastases of human colon carcinoma (HT-29LMM) in nude mice. H-15, a murine IgG1 mAb reactive with HT-29LMM was labeled with I-125, and injected at dose of 0.1 microgram and 1.0 microgram intraportally (IP) or intravenously (IV). More than 3 animals per group were sacrificed immediately, 1 h, 24 h, 72 h, and 120 h following injection. Hepatic metastases, normal liver tissue, and blood were weighted and counted for radioactivity. Compared to IV, IP injection resulted in higher (P less than 0.01) percent injection dose per gram (%ID/g) in metastases at all time points for both doses. Metastases: blood and metastases: liver uptake ratios were higher (P less than 0.05) on day 3 and 5 for both IP doses compared to IV doses. Significant improvement in tumor uptake was seen following IP injection of specific mAb; this has important implications on the design of clinical trials using mAb.


[Extracorporeal shock wave lithotripsy (ESWL) for common bile duct stones]. We treated twenty-three patients with common bile duct stones (12 female, 11 male, mean age: 67.1 years) by Extracorporeal Shock Wave Lithotripsy (ESWL). The stones were focused by ultrasonic or choledochographic localization. The twenty-three patients received 53 ESWL treatments consisting of mean 2357 shocks per treatment at mean 18 kV. We performed ESWL in five cases with endoscopically unextractable common bile duct stones after endoscopic sphincterotomy (EST). In these cases, ESWL permitted stone disintegration and successful endoscopic extraction of the fragments. We performed ESWL in eighteen cases with common bile duct stones without EST. In fifteen of the eighteen cases (83%), fragmentation was achieved. The stone fragments were spontaneously discharged in ten cases (56%) after a median of 4 days following ESWL. In five cases, adjutant endoscopic procedures were performed. The complete fragmentation and the clearance rate for stones of diameter of less than 10 mm were higher than that for stones of diameter of more than 11 mm. In the cases with the stones of diameter of more than 10 mm, there is a very strong possibility that complete clearance is achieved by ESWL alone. No correlation was obtained for the effective results according to pretreatment number of stones. In eight of thirteen cases (62%) with gall bladder stones, complete clearance was achieved without EST. ESWL without EST can be thought as a rational treatment for preserving the function of papilla of Vater in the case of cholecysto-choledocholithiasis.


[Imaging diagnosis of the insulinoma--the clinical usefulness of intraductal ultrasonography of the pancreas and color Doppler sonography]. 5 cases of small-sized insulinoma of the pancreas were studied to evaluate the ability of diagnostic imaging techniques to determine tumor location. Techniques used were extracorporeal ultrasonography, endoscopic ultrasonography (EUS), angiography, percutaneous transhepatic portal catheterization and CT. EUS was superior to the other modalities in diagnosing the location of insulinomas. We employed Color Doppler (CD) ultrasonography in one case and obtained color expression in the tumor and a pulsatile wave in the FFT analysis. Intraductal sonography of the pancreas (IDSP) was also performed in this case resulting peripheral echo-lucent, central echogenic mass. From these results, we expect that CD and IDSP will be useful in clinical application for diagnosing various tumors.


[Epidemiology of non-ulcer dyspepsia (NUD) in Japan]. The purpose of this study is to investigate the incidence of NUD in Japan and to describe the clinical presentation of NUD. The population of this study consisted of the patients initially visited to our gastroenterology clinic during the period of one year from Feb. 1990 to Jan. 1991. Out of the total population, 106 patients with dyspepsia were suspected of NUD according to the definition of AGA, and have received the endoscopy and ultrasonography to find the existence of organic disease. While 50 cases presented organic diseases (19 peptic ulcers, 16 gastritis, 7 carcinoma, 4 gall stone, 4 esophageal disease), 56 cases were with no organic diseases and were regarded as NUD. NUD was more common in younger generation and was especially so in women under 40 years old. There was no significant difference in symptoms between NUD and organic diseases. On the other hand, peptic ulcer disease was frequently associated with sever epigastralgia, and smoking habit as a external factor, while abdominal fullness was predominant feature observed in NUD.


[Endothelin levels under water-immersion stress in rats]. Rats with water-immersion stress-induced ulcer were prepared to determine the levels of ET in blood and gastric tissues, and their relationship with the gastric mucosal blood flow, PGs and pathogenesis in the gastric mucosa were evaluated. Pathology in the gastric mucosa appeared an hour after stress loading, while blood flow rate decreased significantly 30 minutes later. PGE2 increased 30 minutes later, then decreased. PGI2 decreased significantly. Blood ET level was 1.22 +/- 0.50 pg/ml for the controls, but this increased remarkably after one hour and significantly peaked after two hours of water immersion. The level of ET in the gastric tissues was 25.87 +/- 1.63 pg/g tissue for the controls, and this increased markedly after two hours of immersion, reaching a significant peak. In the present study, increased in endogenic ET due to stress were confirmed, and the results suggested the possibility of ET being involved in the pathogenesis of ulcer.


[Hypergastrinemia and type A gastritis in Basedow's disease]. Hypergastrinemia is a very important clinical condition for the reason that a growing body of evidence obtained from animal and human experiments has revealed gastric carcinoids induced by hypergastrinemia. We investigated 35 patients with Basedow's disease (BD) to elucidate the mechanism of hypergastrinemia associated with BD as well as the relationship between type A gastritis and BD. Fasting serum gastrin levels in BD (296.1 +/- 251.4 pg/ml; mean +/- S.D.) were significantly (p less than 0.001) higher than those in age-matched 27 healthy subjects (106.1 +/- 69.2), and in the BD group, significant positive correlation was detected between fasting serum gastrin levels and thyroid hormones (i.e. T3 and free T4). In the hyperchlorhydria group in BD with hypergastrinemia, the levels of fasting serum gastrin were normalized after euthyroidism was attained due to antithyroidal drugs. On the other hand, in the achlorhydria group in BD significant hypergastrinemia was persisted in spite of normalization of thyroid function. Twenty % of the BD patients had histologically proved type A gastritis with achlorhydria, and all patients with type A gastritis were older than 60 years old. Endoscopic examination revealed that one patient with type A gastritis had an early gastric cancer. However, no gastric carcinoids were demonstrated in this study. In conclusion, the results described as above suggested, 1) hypergastrinemia observed in patients with BD may be induced by gastrin hypersecretion due to hyperthyroidism as well as type A gastritis, 2) BD patients with type A gastritis were recommended to undertake regular endoscopic examination for detecting gastric cancers as well as gastric carcinoids.


[Intracellular pH of surface epithelial cells and the movement of bicarbonate ions under acid-base imbalance in gastric mucosa]. To investigate the effect of the acid-base imbalance on the gastric mucosal defense mechanism, the intracellular pH of gastric surface epithelial cells were measured with double-barreled H+ selective microelectrodes in the isolated antral mucosa of bullfrog stomach. By knowing the intracellular pH and the PCO2 of the serosal perfusate, the intracellular HCO3- concentration was estimated, and the rate of HCO3- secretion was directly measured with the pH-stat method in mounted preparations on a Ussing's chamber. Both the calculated intracellular HCO3- concentration and the rate of HCO3- secretion were dependent on the exogenous HCO3- supplied from the serosal perfusate. The alkaline tide raised the intracellular HCO3- concentration, thus increasing the mucosal buffering power against acid. Under mild respiratory acidosis, the production of endogenous HCO3- from the serosal CO2 was enhanced, and both the intracellular HCO3- concentration and the rate of HCO3- secretion were increased. As a result, the intracellular pH was maintained at a physiologically optimal level, and the ability of gastric mucosal protection was strengthened by enrichment of cellular bicarbonate supply. It is confirmed in this study that the maintenance of acid-base status in the cell is indispensable in the protection of gastric mucosa against acid invasion.


[Clinical significance of measurement of PIIIP, laminin P1, type IV-C and 7S in patients with chronic liver diseases--with special reference to histological findings]. Four markers for hepatic fibrosis--N-terminal peptide of Type III procollagen (PIIIP), Laminin P1 (laminin), Type IV collagen (Type IV-C), and 7S domain (7S)--were measured in the sera of 90 patients with various chronic liver diseases diagnosed by liver biopsy--fatty liver (FL), chronic inactive hepatitis (CIH), chronic active hepatitis (CAH), and liver cirrhosis (LC)--and in the sera of 20 healthy controls. The values of markers were compared with the grade of histologic findings of the liver. Four markers were significantly raised in the CAH group and the LC group, and they were considered to be indicators of hepatic fibrosis. PIIIP reflected necrosis and inflammation as well as fibrosis of the liver. Laminin, Type IV-C, and 7S reflected severe fibrosis. 7S was considered to be useful marker for liver cirrhosis.


[Clinical evaluation of serum levels of monomeric dimeric and tetrameric pseudocholinesterases in patients with various liver diseases]. Serum levels of monomeric, dimeric and tetrameric pseudocholinesterases were measured by means of enzyme-linked immunosorbent assay in patients with various liver diseases and normal controls in order to evaluate their clinical significance. In patients with liver cirrhosis, serum levels of monomeric, dimeric and tetrameric were significantly lower than those in normal controls, patients with fatty liver and chronic hepatitis. The ratio of monomeric and dimeric to tetrameric in patients with liver cirrhosis was also significantly lower than that in normal controls, patients with fatty liver and chronic hepatitis. Serum levels of tetrameric, dimeric and monomeric were not significantly higher in the patients with fatty liver than in normal controls, but the ratio of monomeric and dimeric to tetrameric was significantly higher in patients with fatty liver than that in normal controls, patients with chronic hepatitis and liver cirrhosis. These findings suggest that the selective determinations of serum levels of monomeric, dimeric and tetrameric pseudocholinesterases are useful to estimate the metabolism of fat and protein in various liver diseases.