Intravenous thrombolysis with tissue plasminogen activator is currently the most effective treatment of acute ischemic stroke if administerd within 3 hours after symptom onset. Intraarterial thrombolysis by prourokinase is the another choise if the middle cerebral artery is occluded and within less than 6 hours after onset. Although heparin especially a moderate dose is not proved to be effective, a randomized, placebo-controlled trial to determine the safety and efficacy of argatroban (a selective thrombin inhibitor) in patients with acute ischemic stroke was started in USA. Aspirin provides some benefit to patients with acute stroke. However, its effect is not fully satisfactory. Although reports of numerous trials for neuroprotective drugs have been disappointing, edaravone (free radical scavenger) was approved for the treatment of acute ischemic stroke in Japan. In the future, thrombolytic and neuroprotective drugs will be used in combination.
(Internal Medicine 41: 337-344, 2002)

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Objective The benefits of 5-year tamoxifen administration for patients with estrogen receptor-positive breast cancer undoubtedly outweigh the risk of any adverse effects. Massive hepatic steatosis is an example of its side effects. Here we show risk factors for the development of massive hepatic steatosis and describe a representative clinical course of these patients treated with fibrates for the first time.
Methods Computed tomography (CT) numbers of the liver and spleen were measured and correlated to body mass index (BMI) and pregnanetriol/pregnanediol ratio in urine (P₃/P2 ratio).
Patients We enrolled 56 premenopausal women treated with breast conservation treatment. They received oral tamoxifen (40 mg/day for 2 to 3 years) as adjuvant endocrine therapy with systemic chemotherapy.
Results Serum estradiol level in 48 of 56 patients treated with tamoxifen was less than 10 pg/ml. The ratio of hepatic CT number to splenic CT number<0.9 was related to increased BMI (>23.6 kg/sqm) and reduced P₃/P2 ratio (<1). Fibrates are potent enough to improve hepatic steatosis in tamoxifen-induced hepatic steatosis.
Conclusion P₃/P₂ ratio<1 was related to sufficient blockade of estrogen receptor proven by the development of massive hepatic steatosis. Therefore, we propose that tamoxifen is not a mere antagonist of estrogen, but it may also suppress estrogen synthesis when estrogen receptor is blocked sufficiently. The undetectable level of serum estrogen in tamoxifen-treated premenopausal women may partially explain why tamoxifen was so effective in estrogen receptor-positive early breast cancer.
(Internal Medicine 41: 345-350, 2002)

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Objective The purpose of this study is to clarify whether type 2 diabetes (DM) is a risk factor for asymptomatic (silent) ischemic brain lesion, which is controversial at present.
Subjects and Methods The subjects (n=187), who showed normal results on both neurological and neuropsychological examinations, underwent a 75-g OGTT and were examined by brain MRI on Tl-weighted, T2-weighted, and FLAIR (fluid-attenuated inversion recovery) images. Their brain MRIs were evaluated quantitatively with the ischemia rating scale defined here. The subjects were grouped based on their glucose tolerance: normal glucose tolerance (NGT) (n=48), impaired glucose tolerance (IGT) (n=62), and DM (n=65). The subjects with DM were further divided based on their duration of illness: 20 with short duration (short DM: 1.3+0.8 years) and 45 with long duration (long DM; 8.9±5.4 years). Ages were matched among the groups.
Results The percentages of individuals with asymptomatic ischemic brain lesion were 81% in NGT, 74% in IGT, 65% in short DM, and 78% in long DM. No significant difference was observed among the groups in terms of the percentage. Namely, even in individuals with a long history of DM without clinical stroke, the prevalence of asymptomatic ischemic brain lesion was not different from that of the other groups. Multiple regression and multiple logistic regression analyses showed that age and hypertension were significant independent risk factors for asymptomatic ischemic brain lesion, whereas hypercholesterolemia, smoking, and glucose intolerance, including IGT, short DM and long DM, were not.
Conclusion DM is not a risk factor for asymptomatic ischemic brain lesion.
(Internal Medicine 41: 351-356, 2002)

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Objective Hyper-high density lipoprotein (HDL)-cholesterolemia has been considered to be anti-atherogenic and is referred to as longevity syndrome. However, hyper-HDL-cholesterolemia induced by a cholesteryl ester transfer protein (CETP) deficiency may not be athero-protective, rather being atherogenic in nature. In a rural area in central Japan, the incidence of hyper-HDL-cholesterolemia has been found to be rather high (3.1% of healthy people). We studied healthy Japanese people in this area with hyper-HDL-cholesterolemia, particularly in relation to CETP.
Methods Serum lipids were analyzed, and CETP mass was determined with an enzyme immunoassay method.
Materials Blood was drawn after an overnight fast from 17 Japanese (5 males and 12 females) with serum HDL-cholesterol (C) ≥100 mg/dl.
Results Serum CETP mass in hyper-HDL-cholesterolemic subjects was distributed in a wide range. Serum CETP mass was positively correlated with low-density lipoprotein (LDL)-C, apolipoprotein (Apo) B, and LDL-C/HDL-C, with statistical significance. CETP was also positively correlated with LDL-C/Apo B.
Conclusion These results suggest that hyper-HDL-cholesterolemia may not be a single clinical entity, but a mixture of various pathophysiological conditions, and that the ratio of LDL-C to HDL-C and the size of LDL may be important factors in classifying these conditions.
(Internal Medicine 41: 357-359, 2002)

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Objective To investigate whether glycemic control is associated with reversible changes in axonal excitability in human diabetic nerves. It is known that voluntary contraction or compression ischemia alters nerve Na⁺/K⁺) pump activity, and axonal excitability changes due to the pump activity can be estimated by threshold tracking.
Methods Threshold, the current required to produce a compound muscle action potential 50% of maximum, was determined from the stimulus-response curve, and threshold changes produced by maximal voluntary contraction or ischemia were measured before and after insulin treatment in 10 diabetic patients.
Results Within 3 weeks of the start of treatment, the threshold changes became greater following voluntary contractions (+13±4% versus +23±5%; mean±SEM; p=0.04) and during ischemia (-5±2% versus -11±2%; p=0.04).
Conclusions The extent of threshold fluctuation depends on multiple metabolic factors associated with diabetes such as decreased Na⁺/K⁺) ATPase activity, increased anaerobic glycolysis, and tissue acidosis, and nerve excitability can respond quickly to glycemic control in diabetic patients.
(Internal Medicine 41: 360-365, 2002)

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Objective Influenza outbreaks have revealed that elderly persons are a great risk of death and serious complications after infection. The administration of oseltamivir, a neuramidase inhibitor, is effective for prophylaxis of influenza and to reduce disease duration and severity in healthy adults with naturally acquired febrile influenza. To clarify the usefulness of oseltamivir in the elderly we administered oseltamivir to all residents when an influenza A outbreak occurred in a nursing home.
Patients Sixty-eight residents in the nursing home were investigated in which the influenza A outbreak occurred; 32 residents had fever and 28 residents were positive for influenza A with direct enzyme immunoassay.
Methods Oseltamivir was administered at 75 nig twice daily for 5 days to all residents.
Results Oseltamivir almost inhibited symptom onset in the influenza A-positive afebrile group. Initiation at 0 hour (22 cases), 1-12 hours (4 cases), 13-24 hours (5 cases) or 72 hours (1 case) from onset of symptoms was associated with mean fever durations of 26±18 hours, 38±21 hours, 54±12 hours and 120 hours, respectively, indicating that earlier initiation of therapy was associated with faster resolution of fever in elderly patients. Oseltamivir may be effective for household prophylaxis in the elderly persons. Oseltamivir administration was well tolerated in elderly persons.
Conclusion Oseltamivir is effective for the reduction or prophylaxis of influenza A infection in elderly persons.
(Internal Medicine 41: 366-370, 2002)

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A 77-year-old man was admitted to our hospital showing symptoms of general fatigue and appetite loss. He had leukocytosis, thrombocytosis and hypercalcemia with elevated serum levels of parathyroid hormone related peptide (PTHrP) and interIeukin-6 (IL-6). An increase in tumor markers SCC and CYFURA21-1 was observed. The liver contained a huge tumor, which was proved to be PTHrP producing squamous cell carcinoma by immuno-histochemical analysis. Since the tumor did not express IL-6, it was assumed to be induced by PTHrP in osteoblasts. This is the first report of PTHrP producing squamous cell carcinoma of the liver.
(Internal Medicine 41: 371-376, 2002)

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A patient with duodenal ulcer and primary hyperparathyroidism was found to have an abnormally high intragastric pH. The pH level returned to normal after surgical removal of the parathyroid adenoma followed by normalization of parathyroid hormone (PTH) and serum calcium concentrations. The patient was positive for Helicobacter pylori (H. pylori) infection. Although the exact mechanism by which chronic hypercalcemia or high PTH level inhibited gastric acid secretion in this case remains unclear, our findings suggest that hypercalcemia may play some role in H. pylori associated gastroduodenal diseases through induction of proinflammatory cytokines or by enhancing the attachment of H. pylori to gastric epithelial cells.
(Intenal Medicine 41: 377-380, 2002)

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A 48-year-old man diagnosed as pulmonary alveolar proteinosis (PAP) received a whole-lung lavage by the conventional lavage technique, but he failed to show any clinical or functional improvement. Therefore, we applied a modified lavage technique of Bingisser resulting in the impressive clinical and functional improvement. We measured the levels of KL-6 in bronchoalveolar lavage fluid (BALF) at selected time intervals. KL-6 levels in BALF were higher during the lavage by the modified lavage technique of Bingisser than the conventional lavage technique. We were able to verify the usefulness of the modified lavage technique of Bingisser by monitoring the levels of KL-6 in BALF. The modified lavage technique of Bingisser may be useful for PAP treatment.
(Internal Medicine 41: 381-385, 2002)

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We report a 59-year-old man who was found to have plasma cell dyscrasia and amyloid A protein (AA) amyloidosis during the follow-up period of chronic inactive hepatitis C. Clinical manifestations such as swallowing disturbance, proteinuria and leg edema were associated with AA amyloid deposits in his tongue and kidneys. Although the relationship between these two diseases remains to be determined, the ability of peripheral blood mononuclear cells to degradate serum amyloid A protein was apparently reduced in this patient, compared with normal volunteers. This would, in part, account for the AA amyloid deposition in this patient.
(Internal Medicine 41: 386-391, 2002)

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A formerly healthy 32-year-old woman was hospitalized for a closer examination of undiagnosed fever with mild headache. Despite lack of distinct findings on physical and laboratory examinations at admission, she suddenly developed anuresis due to acontractile neurogenic bladder. On the basis of her symptoms and the faint nuchal rigidity revealed later, as well as the results of cerebrospinal fluid analyses, a diagnosis of aseptic meningitis was eventually reached. While aseptic meningitis subsided within 3 weeks, about 10 weeks, including a 26-day period of anuria, was necessary for complete restoration of normal voiding function, necessitating intermittent self-catheterization. Acute urinary retention should be considered an uncommon but critical manifestation of aseptic meningitis.
(Internal Medicine41: 392-394, 2002)

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We report an autopsy-confirmed case of amyotrophic lateral sclerosis (ALS) accompanied by syndrome of inappropriate secretion of antidiuretic hormone (SIADH). A 67-year-old man was admitted to our hospital with muscle weakness, dysarthria and dysphagia. During hospitalization, respiratory insufficiency was ingravescent, and hyponatremia, hypo-osmolarity, elevated osmotic pressure of urine, and elevated urinary sodium excretion were noted. Based on these findings we diagnosed ALS with SIADH, and treatment with infusion of concentrated NaCl was started. However, the patient died of respiratory failure on day 50. We assumed that severely restrictive ventilatory impairment was the cause of SIADH in this case.
(Intrenal Medicine 41: 395-397, 2002)

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A 51-year-old man with recurrent episodes of angioedema was diagnosed as having autoimmune acquired angioedema, based on adult onset, lack of apparent family history, decreased activity of C1 esterase inhibitor (C1 INH) and CH50, decreased levels of serum C4 and C1q and the presence of autoantibodies to C1 INH. The danazol treatment relieved the symptoms of angioedema and increased the C1 INH activity and concentration with the normalization of CH50, C1q and C4 levels. To our knowledge, this is the first case of autoimmune acquired angioedema in Japan.
(Internal Medicine 41: 398-402, 2002)

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Reactive AA amyloidosis frequently develops in patients with a long history of rheumatoid arthritis (RA), usually resulting in an unfavorable outcome due to dysfunction of the vital organs. We report a 56-year-old woman with this form of amyloidosis secondary to RA who has been successfully treated with intermediate-dose prednisolone for two and a half years since diagnosis. Because prednisolone is superior to other drugs used for amyloidosis with respect to possible harmful effects on vital organs, we can safely try this drug as an alternative therapy to improve the prognosis even in patients with severe organ dysfunction.
(Internal Medicine 41: 403-407, 2002)

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We treated a case of Tsutsugamushi disease diagnosed by polymerase chain reaction (PCR) using a scab specimen at the bite site of trombiculid mites. Otherwise the diagnosis could not be confirmed by serum antibody test nor the PCR test of blood. The genome of Rickettsia tsutsugamushi was detected and identified as the Kawasaki serotype strain. An attempt to extract the genome from the scab has not been reported, thus our data suggest that the scab is a useful specimen to confirm the diagnosis of Tsutsugamushi disease.
(Internal Medicine 41: 408-411, 2002)

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