A male patient who developed late-onset primary biliary cirrhosis presenting with antinuclear envelope antibodies.

Abstract An 81-year-old man who had previously shown high levels of alkaline phosphatase (ALP), γ-glutamyltransferase (GTP), and total bilirubin presented with acute liver damage. He was positive for serum anti-gp210 and anti-p62 antibodies, but negative for serum antimitochondrial antibody. A liver biopsy revealed massive interstitial fibrosis and pseudolobulus, which were compatible with a diagnosis of primary biliary cirrhosis (PBC) at Scheuer's stage 4. He was given ursodeoxycolic acid at 600 mg/day. However, his condition deteriorated, and he eventually died of hepatic insufficiency in a state of malnutrition. We hypothesize that the presence of anti-gp210 and anti-p62 complex protein antibodies, rather than that of antimitochondrial antibodies, was correlated with the progression of PBC in this particular case.

[A case of systemic lupus erythematosus with interstitial myocarditis leading to sudden death].

A 29-year-old female with systemic lupus erythematosus (SLE) was admitted because of exertional dyspnea in January, 1996. The diagnosis of SLE was made on the basis of malar rash, discoid rash, polyarthritis, leukopenia, positive antinuclear antibody and focal glomerulonephritis in 1991. She did not have any cardiac symptoms in 1994, when the electrocardiogram (ECG) abnormalities, such as poor R wave progression and right axis deviation, were present. On admission, she developed congestive heart failure without any signs of active SLE. Laboratory findings were unremarkable. There were new ECG abnormalities, such as left atrial overload and low voltage in limb leads. Chest roentgenogram showed mild pulmonary congestion and marked cardiomegaly. Echocardiography showed enlargement and diffuse hypokinesis of the left ventricle. Cardiac catheterization confirmed that the coronary arteries were normal and that the left ventricular function was poor (ejection fraction, 21%). Myocardial biopsy obtained from left ventricle revealed interstitial fibrosis. After furosemide, digoxin and captril were administered with predonisolone (PSL), her symptoms gradually improved. Since the Holter monitoring showed nonsustained ventricular tachycardia, the doses of PSL and mexiletine were increased up to 20 mg and 300 mg daily, respectively. Unexpectedly, she was found dead in her hospital room in May, 1996. The postmortem findings of the heart revealed mild infiltration of inflammatory cells, predominantly lymphocytes, and plasma cells, and interstitial fibrosis, which were consistent with interstitial myocarditis. In this case ECG abnormalities preceded cardiac symptoms, which may suggest that myocarditis subclinically developed. Serum creatinine kinase levels had not been elevated throughout the entire course. While several cases of acute myocarditis associated with a flare of SLE have been reported, there were few cases regarding interstitial myocarditis that chronically progress and can be fatal. This case is thought to be suggestive of elucidating the pathogenesis of lupus myocarditis.

[A case of bacillary dysentery caused by new quinolone-resistant Shigella flexneri 2a].

A 73-year-old male was admitted to our hospital because of detection of Shigella flexneri 2a from his stool. Antimicrobial treatment with levofloxacin (LVFX) was started, but could not eliminate the organism in the stool. In the examination of drug susceptibility, this strain was highly resistant to all new quinolones. The minimal inhibitory concentration of norfloxacin, ofloxacin and ciprofloxacin to this strain was 12.5 micrograms/ml, 6.25 micrograms/ml and 6.25 micrograms/ml, respectively. The dual mutations were detected in the codon 83 and 87 of the gyrA gene by sequencing the quinolone-resistance determining region (QRDR). There was, however, no significant difference between the intracellular uptake of ciprofloxacin in this strain and in the ciprofloxacin-sensitive strain. The amount of ciprofloxacin in this strain unchanged when carbonyl cyanide m-chlorophenyl hydrazone (CCCP) was added. These results suggest that the advanced resistance in Shigella flexneri against new quinolones could be acquired by only this dual mutations without the change of the active efflux mechanism.

[Two cases of polymyositis associated with interstitial pneumonia with anti-OJ (isoleucyl tRNA synthetase) antibodies].

We present two cases of polymyositis (PM) associated with interstitial pneumonia (IP) whose sera contain autoantibodies to OJ (isoleucyl tRNA synthetase). The first patient is a 51 year-old female who was diagnosed as rheumatoid arthritis (RA) and treated with gold and corticosteroid at another hospital. She was admitted to Keio University Hospital due to worsening of dyspnea on exertion and polyarthritis. Laboratory findings revealed elevation of serum CK and LDH. A diagnosis of PM was made based on the myogenic pattern of EMG and pathological feature by muscle biopsy. Chest radiography and CT showed interstitial fibrosis. Because of clinical deterioration, the dose of corticosteroid was increased (prednisolone 50 mg/day) and her symptom was stabilized. The second patient, a 62 year-old male, was admitted to Kawasaki Municipal Hospital because of dyspnea on exertion, polyarthritis, and fever. He was diagnosed as PM associated with IP on the basis of his clinical and laboratory findings, and chest radiography. He was treated with methylprednisolone pulse therapy (800 mg/day for three days) and his symptoms were improved. Both patients were found to have autoantibodies to OJ. Autoantibodies to aminoacyl tRNA synthetase have been described to be associated with myositis and/or IP. In North American, it was reported that all patients with anti-OJ had either myositis or IP or both. This suggests that anti-OJ was commonly associated with the anti-synthetase syndrome observed with other anti-synthetases. This is the first report of Japanese patients with anti-OJ antibody. The clinical features of these patients were likely to be similar to those observed in North American patients. However, further studies are necessary to clarify the precise clinical significance of this antibody.

Anti-transfer RNA antibodies in two patients with pulmonary fibrosis, Raynaud's phenomenon and polyarthritis.

Patient W.S. (a 61-year-old woman) and patient T.M. (a 41-year-old man) developed recurrent fevers, polyarthritis, Raynaud's phenomenon and interstitial pulmonary fibrosis without apparent polymyositis. From HeLa cell extracts, sera from both patients immunoprecipitated all species of intact and deproteinised tRNAs. To identify the antibody binding site more precisely, tRNAs transcribed in vitro from cloned Escherichia coli tRNA genes and various mutants were prepared and used as antigens for immunoprecipitation. When the TpsiC loop, or the D loop were deleted, such mutants were not bound by both sera, suggesting that the D and TpsiC loops were required for antibody binding. Abrogation of tRNA binding occurred when 18G of tRNATrp was replaced with 18A to break the tertiary L-shape structure of tRNA. These results strongly suggest that sera from W.S. and T.M. recognise the tertiary conformation of L-shaped tRNA which is constructed with both D and TpsiC loops. These autoantibodies may also serve as a marker for a new subset of patients with connective tissue diseases that is distinct from anti-aminoacyl-tRNA synthetase syndrome.

[A case of brain abscess accompanied with sudden-onset hemiplegia as initial manifestation].

A 58-year-old male experienced a sudden stroke-like onset of right hemiplegia and numbness of his right upper limb while engaged in his desk-work on April 7, 1997. He had a past history of diabetes mellitus and hyperlipidemia. On admission, he had no fever and the blood pressure was 140/70 mmHg. General physical examination was unremarkable. Neurological examination showed 4/5 strength of his right unilateral extremities and numbness of his right upper limb. Clinical features and computed tomography (CT) without contrast medium at the onset of hemiplegia suggested a stroke. Seven days after admission, his consciousness worsened and body temperature fluctuated between 37 and 38 degrees C. Subsequent Gd-enhanced magnetic resonance (MR) which demonstrated an irregular shaped ring-enhancement lesion and lumbar puncture 9 days after admission was compatible with the diagnosis of brain abscess. Surgical drainage confirmed the presence of brain abscess due to alpha-streptococcus. It improved following surgical drainage and antibiotic therapy with PAPM.BP 2 g/day and PIPC 4 g/day. An afebrile patient of sudden stroke-like onset may be a rarity to be added to the differential diagnosis of brain abscess.

[Toxic shock-like syndrome after acupuncturation].

A 80-year-olkd male was admitted to our hospital because of severe pain and swelling on his left lower leg on January 23, 1996. He had received an acupuncture to both legs because of intermittent claudication once a week from July, 1995 to January 18, 1996. On the next day of the last acupuncture, pain and swelling on his left leg appeared. On admission, his left leg showed diffuse swelling and redness with blisters. We diagnosed this patient as toxic shock-like syndrome (TSLS), based on the rapid exacerbation of the skin changes, necrotizing superficial fasciitis, multiple organ failure with shock, and the detection of group A streptococcus from culture samples obtained from both skin blister and necrotic fascia. He recovered from the disease by amputation of the involved leg and antibiotic therapy. Acupuncture could have been the cause of streptococcal infection.

[A case report--typhoid fever complicated with liver and gallbladder abscess, treated for long-time as fever of unknown origin].

A 25-year-old male admitted to Kawasaki municipal hospital with the diagnosis of typhoid fever. He had noticed high fever since one month ago, and had been treated with prednisolone with the diagnosis of fever of unknown origin in a hospital. Then he had admitted to St. Marianna University Hospital, and Salmonella Typhi had been detected from his blood and stool. On admission, multiple liver abscess were detected by abdominal ultrasonography. S. Typhi in bile was not eliminated with CP and AMPC, but he was successfully treated with cholecystectomy and the chemotherapy of LVFX. Abscess formation was found in the resected gall bladder wall. Typhoid nodule in the lymph node, liver or other organs is a well known pathological change in the typhoid fever. But abscess formation in the liver or other organs is rare. In this case, multiple abscess is characteristic and this cause is thought to be induced by the factors that the period from onset of typhoid fever to beginning of effective therapy was too long, and that steroid therapy was done without antibiotic therapy.

Fever of unknown origin responding to steroid therapy.

It is not uncommon to find cases of fever of unknown origin (FUO) in which no final diagnosis is made ever after various examinations. We investigated such cases of undiagnosed FUO, with fever persisting for a long periods and responding to steroid therapy. Among 4,596 patients who were hospitalized over 3-year period from September 1991, 25 met Petersdorf's definition of FUO. Among these 25 patient, six cases were steroid-responsive undiagnosed FUO (SR-FUO). Patients with SR-FUO had the following characteristics: marked inflammatory findings and severe illness; without a definite underlying disease being found despite various examinations; no findings which indicated any known diseases such as adult-onset Still's disease, polymyalgia rheumatica, or other collagen diseases; elderly onset, at 58 to 77 years of age (mean age: 67 years); no improvement with antibiotics, antituberculous agents, or antimycotic drugs; significant improvement of symptoms and signs with steroid therapy; and a relatively good prognosis. SR-FUO, which is not caused by any known disease and is highly responsive to steroids, is included among the FUO cases which we have difficulty in diagnosing and treating.

Sertoli-Leydig cell tumour complicated by X chromosomal mosaicism.

We describe a case of well-differentiated Sertoli-Leydig cell tumour (SLCT) of the ovary. A 48-year-old Japanese woman had had symptoms of virilization, i.e. alopecia and facial hair, for 8 years. Although the patient had given birth to three normal children, laboratory investigations revealed an elevated serum level of free testosterone and tripartite mosaicism (45X/46XX/47XXX). Computed tomography and magnetic resonance imaging revealed a tumour of the left ovary. After oophorectomy, the serum level of free testosterone returned to the normal range and symptoms of virilization resolved. To our knowledge, this is the first reported case of a patient with SLCT who had tripartite mosaicism and had given birth to normal children. Although the aetiology of SLCT is not known, we believe that SLCT is associated with sex chromosomal abnormalities at least in some cases.

[Studies of serum markers in patients with interstitial pneumonia/pulmonary fibrosis complicated with collagen diseases: clinical evaluation of CYFRA21-1].

The serum concentration of several markers in patients with collagen disease was studied to evaluate the useful indices for the diagnosis of interstitial pneumonia/pulmonary fibroses (pneumonitis). Procollagen N-terminal type III peptides, type IV collagen and monoamine oxidase were measured as the fibrosing markers. Squamous cell related antigen (SCC) and soluble cytokeratin 19 fragments (CYFRA21-1) were measured as the tumor markers. Hyaluronic acid, ESR and CRP were measured as the inflammation markers. The 119 patients with collagen disease (71 patients with RA, 16 with SSc, 9 with SLE, 8 with PM/DM, 6 with MCTI) and 9 with other collagen diseases) who have been followed in our hospital were studied. Of 119 patients, 23 patients (RA14, SSc7, PM/DM2) were complicated with pneumonitis. The results were as follows. 1. All the serum markers except CYFRA21-1 had no significantly difference between with and without pneumonitis. The serum CYFRA21-1 level in the pneumonitis group was higher than that of the non pneumonitis group (1.38 vs 0.66 ng/ml, P < 0.001). 2. The cut-off value was set at 2.0 ng/ml, corresponding to 26.1% sensitivity and 97.9% specificity for pneumonitis complicated with collagen disease. 3. The CYFRA21-1 level in early stage of pneumonitis group (from onset to measurement < 1 year) was significantly higher than that of late stage group (from onset to measurement > 1 year). And there are 75.0% sensitivity in early stage of pneumonitis group. 4. Case study was suggested that CYFRA21-1 had a potential as a diagnostic and monitoring marker for pneumonitis.

Novel autoantibodies directed against the common tertiary configuration of transfer RNA in a patient with interstitial lung disease.

OBJECTIVE: To identify and characterize a novel autoantibody, anti-WS, that binds total transfer RNA (tRNA). METHODS: Serum from patient WS, who had polyarthritis, Sjögren's syndrome, Raynaud's phenomenon, and interstitial pulmonary fibrosis, was used in this study. Characteristics of anti-WS and antibody-reactive determinants of tRNA were investigated by 32P immunoprecipitation using HeLa cell RNA and deletion mutants of tRNA transcribed in vitro. RESULTS: WS serum produced nucleolar and cytoplasmic staining on indirect immunofluorescence. 32P immunoprecipitation assays demonstrated that this serum immunoprecipitated total tRNAs and 5.8S and 5S ribosomal RNAs from 32P-labeled HeLa cell extract. When deproteinized RNA was used as antigen source, total tRNAs were still precipitated by WS serum. An immunoprecipitation study, using various deletion mutants of Escherichia coli tRNA, demonstrated that both D and T psi C loops were needed for antibody binding. Substitution of nucleotide 18G with 18A of E coli tRNA(Trp), which is essential in the formation of the tertiary "L" shape of tRNA, inhibited binding by anti-WS antibodies. CONCLUSION: Anti-WS antibodies are novel autoantibodies directed against tRNAs. The antibody binding site is the common L-shaped tertiary structure conformed by the D loop and T psi C loop of tRNA, suggesting that the antibodies are induced by a conserved sequence among all species. Furthermore, these antibodies could be a marker for a newly recognized subset of connective tissue disease.

[Clinical study of prulifloxacin on infectious enteritis. Japan Research Committee of Prulifloxacin, Research Group on Infectious Enteritis].

Prulifloxacin (PUFX), a new quinolone antimicrobial agent, was administered to a total of 122 patients and carriers to investigate its clinical efficacy, safety and usefulness in infectious enteritis (bacillary dysentery, enteritis caused by Salmonella spp. and enteropathogenic E. coli, cholera and so on). In addition, the minimum inhibitory concentration (MIC) of UFX (active compound) was determined against each clinical isolate, and compared with that of ciprofloxacin (CPFX), ofloxacin (OFLX), tosufloxacin (TFLX) and nalidixic acid (NA). The correlation between the concentration of UFX in feces and the change of the fecal microflora were also investigated when PUFX was administered to the patients with acute infectious enteritis. A daily dose of 400 mg of PUFX was administered orally in two divided doses (morning and evening) for 5 days, with the exception of 7 days administration against salmonella enteritis and 3 days administration against cholera. 84 cases were adapted for evaluating the usefulness. The clinical efficacy was 100% in all the enteritis except salmonella enteritis, in which it was 88.9% (8/9 cases). On the bacteriological efficacy, the elimination rate was 100% in all isolates except Salmonella spp., in which it was 75.0% (12/16 cases). As for the adverse effect, uriticaria in moderate degree was observed in 1 (0.9%) of 109 cases. Abnormal changes in laboratory findings were seen in 3 (3.0%) of 100 cases, consisting of 1 with eosinophilia and 2 with elevated S-GPT, although they were all slight in degree. The usefulness rate was 65.5% (55/84 cases) for "very useful" and 95.2% (80/84 cases) for "very useful" and "useful". MIC90 of UFX against Shigella spp., Salmonella spp., E. coli and V. cholerae, was 0.025, 0.05, 0.025 and 0.05 microgram/ml, respectively. These values were the same as those of CPFX and TFLX, and superior to OFLX and NA. UFX concentrations in feces followed by administration of PUFX in 3 cases with acute infectious enteritis were higher than that of MIC90 of UFX against Shigella spp., Salmonella spp., E. coli and V. cholerae. The changes of the fecal microflora, which influence the efficacy and safety of PUFX, were not observed.