Autoantibodies to a 68/48 kDa protein in chronic fatigue syndrome and primary fibromyalgia: a possible marker for hypersomnia and cognitive disorders.

OBJECTIVE: To identify antinuclear antibodies (ANA) specific for chronic fatigue syndrome (CFS), and in related conditions such as fibromyalgia (FM) or psychiatric disorders. METHODS: One hundred and fourteen CFS patients and 125 primary and secondary FM patients were selected based on criteria advocated by the Centers for Disease Control and Prevention and by the American College of Rheumatology, respectively. As controls, healthy subjects and patients with either various psychiatric disorders or diffuse connective tissue diseases were included. Autoantibodies were examined by immunoblot utilizing HeLa cell extracts as the antigen. RESULTS: Autoantibodies to a 68/48 kDa protein were present in 13.2 and 15.6% of patients with CFS and primary FM, respectively. In addition, autoantibodies to a 45 kDa protein were found in 37.1 and 21.6% of the patients with secondary FM and psychiatric disorders, respectively. Meanwhile, these two autoantibodies were not found at all in connective tissue disease patients without FM, nor in healthy subjects (P<0.05). As a group, the anti-68/48 kDa-positive CFS patients presented more frequently with hypersomnia (P<0.005), short-term amnesia (P<0.07) or difficulty in concentration (P<0.05) than those CFS patients without the antibodies. CONCLUSIONS: The presence of the anti-68/48 kDa protein antibodies in a portion of both CFS and primary FM patients suggests the existence of a common immunological background. These antibodies may find utility as possible markers for a clinicoserological subset of CFS/FM patients with hypersomnia and cognitive complaints.

Polymorphisms in the TNFA promoter region is not associated with palmoplantar pustulosis.

Polymorphisms of the 5'-flanking promoter/enhancer region of the TNAFA gene were determined in 80 Japanese patients with pulmoplantar pustulosis (PPP). The 5'-flanking region of the TNFA gene from -1107 to 66 was amplified by polymerase chain reaction (PCR) method. Nucleotide sequencing data from the PCR products revealed that 5 single nucleotide polymorphisms at position 1031, -863, -857, -307 and -237. None of the nucleotide substitutions were significantly increased in PPP patients when compared with those in controls. To clarify the linkage among the neighboring genetic marker, we analyzed the association between the polymorphisms in the TNFA promoter region and the NcoI polymorphism in the first intron of the TNFB gene as well as HLA-DR9. The genotype at 1031C is strongly associated with TNFB1 and negatively associated with TNFB2 which is reported to be associated with PPP. These data indicate that TNFA gene centromeric to TNFB is not associated with PPP and the susceptible gene of PPP is located between TNFB and HLA-B.

Idiopathic adrenal hemorrhage.

A case of idiopathic adrenal hemorrhage is reported. A 76-year-old woman exhibited a left adrenal tumor, 3 cm in diameter, on abdominal computed tomography. The patient was receiving aspirin medication for atrial fibrillation. There was no evidence of increased adrenal hormones. The mass enlarged to 6 cm in diameter within 18 months, and malignancy was suspected. The mass was diagnosed as adrenal hematoma by operative findings.

[Clinical significance of magnetic resonance imaging of skeletal muscles in idiopathic inflammatory myopathies of adults].

The purpose of this study was to evaluate the clinical significance of magnetic resonance imaging (MRI) of skeletal muscles in Japanese patients with idiopathic inflammatory myopathies (IIM). MRI was performed in 23 adult patients with IIM, including 10 with polymyositis, 12 with dermatomyositis, and 1 with focal myositis. Seven (73%) of 11 patients with active IIM and 2 (17%) of 12 patients with inactive IIM showed hyperintensity of T 2-weighted images and normal intensity of T 1-weighted images, indicating "edema-like abnormalities" (MRI findings for active myositis). Muscle lipomatosis and fibrosis were demonstrated in four patients and 1 patient, respectively. Considerable selectivity of muscles in developing inflammatory disorders was found. In quadriceps muscles, for example, vastus muscles seemed to be more often affected in DM patients, whereas adductors were more often affected in PM patients. Serial examination of muscle MRIs was carried out in 4 patients and the findings paralleled the disease activities. The muscle MRI findings did not necessarily correlate with other findings, such as the presence of muscle weakness, elevated serum creatine kinase levels, myogenic electromyogram, or muscle biopsy findings. The muscle MRI was considered to be an additional useful tool for the diagnosis, evaluation of disease activity, and planning treatment of IIM.

Polymorphism in the tumor necrosis factor B gene is associated with Palmoplantar pustulosis.

We investigated the allele and genotype distribution of a polymorphism of the tumor necrosis factor (TNF) B gene and the frequency of HLA-DR9 in 49 patients with Palmoplantar pustulosis (PPP) and 51 healthy controls. We found that the frequency of TNFB2 in the PPP patients was significantly higher than that in the controls. Furthermore, the DR9-TNFB2 haplotype was significantly more frequent in the PPP patients (P=0.0045). These results suggest that TNFB2 may confer susceptibility to PPP.

[Evaluation of restenosis after percutaneous transluminal coronary angioplasty using a Doppler index, the Tei index].

Cardiac function and restenosis were evaluated after percutaneous transluminal coronary angioplasty (PTCA) using a Doppler index (the Tei index). Thirty-eight patients, 31 men and 7 women (mean age 57 years) with ischemic heart disease were studied. The underlying heart diseases were angina pectoris without left ventricular asynergy in 16 patients and old myocardial infarction (OMI) with left ventricular asynergy in 22 . Ejection fraction was measured by M-mode echocardiography and deceleration time, and the interval between cessation and onset of the mitral inflow velocity (a), ejection time at aortic valve (b), and the Tei index [(a-b)/b] were measured by M-mode echocardiography performed before and 6 months after PTCA. The ejection fraction, deceleration time and Tei index showed no changes after PTCA in patients with angina pectoris with or without restenosis. In patients with OMI with restenosis, the Tei index increased slightly after PTCA, from 0.56 +/- 0.15 to 0.61 +/- 0.13. The deceleration time changed from 0.23 +/- 0.03 to 0.24 +/- 0.02 msec, and the ejection fraction from 0.46 +/- 0.11 to 0.51 +/- 0.17, neither significantly. However, in patients with OMI without restenosis (15 out of 22 patients), the Tei index significantly improved after PTCA, from 0.55 +/- 0.13 to 0.48 +/- 0.12 (p < 0.05). In patients with left ventricular asynergy due to old myocardial infarction, without restenosis, the Tei index significantly improved after PTCA. The Tei index is useful for evaluating restenosis after PTCA in patients with OMI.

[Cardiovascular complications of collagen diseases].

Recent progress in the field of clinical epidemiology and diagnosis of major cardiovascular complications of collagen diseases were reviewed including systemic lupus erythematosus, systemic sclerosis, polymyositis.dermatomyositis, polyarteritis and mixed connective tissue disease. Major cardiac complications comprise pericarditis, myocardial disease, cardiac conduction system disease, coronary artery disease and valvular disease. Vascular complications comprise necrotizing vasculitis as a major organic involvement and Raynaud's phenomenon as a major functional involvement. Due to the recent development of sensitive methods of evaluating cardiovascular abnormalities, clinical diagnosing rate of cardiovascular complications in the early stage has been considerably increasing in patients with collagen diseases. On the other hand, number of patients with atherosclerotic cardiovascular complications due to long-term corticosteroid therapy has been also gradually increasing.

[Echocardiographic observation of appearance and progression of mitral annular calcification in a patient with familial obstructive hypertrophic cardiomyopathy].

A 37-year-old man with familial hypertrophic obstructive cardiomyopathy (HOCM) developed mitral annular calcification (MAC) during the follow-up period. At the age of 23 years, a systolic murmur and electrocardiographic abnormality including giant T wave inversion were detected incidentally. His elder brother also had HOCM. Catheterization disclosed a left ventricular outflow pressure gradient of 25 mmHg and thickened interventricular septum. Echocardiography showed asymmetric septal hypertrophy and systolic anterior motion of the mitral valve. The patient was followed up by repeated echocardiography from age 37 years and the onset of MAC (2 mm in thickness) was found at age 48 years. One year later, the MAC had progressed markedly (5 mm) without other remarkable changes in the M-mode echocardiogram, except mitral regurgitation (at age 41 years), left ventricular apical as well as posterior wall hypertrophy (age 43 years) and left atrial enlargement (age 46 years). The left ventricular inflow velocity at the atrial contraction period decreased significantly concomitantly with MAC. MAC is a rare complication in young and middle aged patients. The onset and progression of MAC is still obscure in HOCM. This patient showed that sudden onset and rapid progression of MAC can occur in young patients with HOCM.

Anti-Jo-1 antibodies in polymyositis or dermatomyositis: evaluation by ELISA using recombinant fusion protein Jo-1 as antigen.

We evaluated an enzyme-linked immunosorbent assay (ELISA) for detecting anti-Jo-1 antibodies in patients with polymyositis (PM) or dermatomyositis (DM) by use of the recombinant fusion protein Jo-1. Sera from 64 patients with PM or DM, from 80 patients with other connective tissue diseases, and from 64 healthy subjects matched for age, sex and race, were studied by the ELISA and by the double immunodiffusion (DID) method. Eight patients with myositis (six PM, one DM and one DM with malignancy) with positive anti-Jo-1 by DID also showed positive results by the ELISA method, whereas five patients with positive anti-Jo-1 by this ELISA showed negative results on DID. One of the five had non-specific results. The incidence of positive results for anti-Jo-1 with the ELISA (18.8%) was greater than that for DID (12.5%), but the difference was not statistically significant. All patients with positive results for anti-Jo-1 by DID were also positive by the ELISA. The ELISA system with the recombinant Jo-1 antigen was useful in the detection of anti-Jo-1 antibodies in patients with PM/DM.

Tricuspid valve infectious endocarditis associated with dental treatment.

A 52-year-old man with neither congenital heart disease nor history of drug abuse had a spiking fever after dental treatment and was diagnosed with pneumonia at a local clinic. He was treated with antibiotics and his fever went down. Ten months later, he had again pyrexia and suffered from congestive heart failure. He admitted to our hospital and tricuspid valve endocarditis was proved by echocardiography. He was treated with penicillin. However, during the treatment, he developed a pulmonary embolism. So he underwent surgical treatment. We should take dental treatment into account one of predisposing causes of tricuspid endocarditis.

'Seronegative' Sjögren's syndrome manifested as a subset of chronic fatigue syndrome.

We determined the extent to which chronic fatigue syndrome (CFS) patients with sicca symptoms fulfil the diagnostic criteria for Sjögren's syndrome (SS). Three sets of diagnostic criteria for SS, formulated by the Japanese, Europeans and Fox, were used. One-third of the CFS patients with sicca symptoms fulfilled the diagnostic criteria for SS. However, they were 'seronegative', differing from the ordinary primary SS.

[Current status and problems in the treatment of patients with Sjögren's syndrome].

Current status of treatment of patients with Sjögren's syndrome in Japan was reviewed. Although the number of patients with the syndrome has been increasing due to the recent progress in diagnosing and understanding of the disease, treatment of patients still remains unsatisfactory. However a wide variety of methods have become available in the management of patients who have significant dryness of eye and mouth. This includes artificial tear, artificial saliva, moisture shields of glasses, and many other medical and nonmedical preparations. All patients with sicca complaints should receive therapy of tear replacement and intensive oral hygiene. New potential therapeutic approaches for treatment of Sjögren's Syndrome was also reviewed.

[Studies on clinical usefulness of new tumor markers of ovarian cancer, CA54/61 and CA602--III. Measurement of serum samples from patients with various benign or malignant diseases].

Serum samples from patients with benign or malignant diseases were measured for the newly developed tumor markers CA54/61 and CA602 with the respective EIA kits for assessment of their utility as tumor markers. A total of 5236 patients were entered into the study, consisting of ovarian cancer patients, those with other cancers, pregnant women, and healthy volunteers. The CA54/61-positive rate with a cut-off value of 12 U/ml was 61.2% for ovarian cancers (50.4% with a cut-off value of 20 U/ml). A positive rate of 75.0% (64.4%) was achieved for mucinous cystadenocarcinoma, which was high, compared with that for CA125. On the other hand, the false-positive rate was 12.2%(5.9%) for benign ovarian tumors, and as low as 18.5%(8.7%) for endometriosis. The CA602-positive rate with a cut-off value of 63 U/ml was as high as 76.0% for ovarian cancers (69.8% with a cut-off value of 90 U/ml). On the other hand, the false-positive rate was relatively high at 21.9% (12.6%) for benign ovarian tumors, and 56.7% (40.0%) for endometriosis. These positive rates were therefore similar to those for CA 125. The levels of both CA54/61 and CA602 antigens well reflected the postoperative prognosis. These results suggest the utility of CA54/61 and CA 602 as tumor markers of ovarian cancers.

[Studies of clinical usefulness of new tumor markers of ovarian cancer, CA 54/61 and CA 602--CA 602 assay reagent kit, performance its normal value and correlations with other tumor markers].

We made a preclinical study of a newly developed tumor maker, CA 602, and its clinical study using serum samples available from 58 institutions located throughout Japan. In the preclinical study, a CA 602 assay kit was investigated for the reproducibility and precision of assay results; and in the clinical study, the kit was investigated for the normal value of the marker, for variations in assay result with age, menstrual cycle and term of pregnancy, and for correlations of assay results with those of other tumor markers. The tests of the kit for simultaneous reproducibility and interval reproducibility of assay results, and the results of analytical recovery and dilution tests were all favorable; the kit proved to be reliable in both precision and reproducibility. For the study, 2 cutoff levels were set: mean + 2 SD of healthy subjects, i.e., 63 U/ml, and the level which permits the maximal efficiency of differential diagnosis of benign from malignant ovarian tumors, i.e., 90 U/ml. The assay results showed that CA 602 levels were low in women aged 50 and over; the levels were high in the first half of pregnancy, and also high in the menstrual period to the early follicular phase. The assay results of CA 602 also proved to be intimately correlated with those of CA 125, which suggested that the 2 markers might be analogous to each other. CA 602 proving to be of high reproducibility even in the range of concentrations below the cutoff value, the measurement with the marker appeared to be of high precision, capable of detecting even the slightest variations in the antigen. CA 602 therefore appears of great value in the early detection of recurrent ovarian cancers.

[A study of preclinical and clinical usefulness of new tumor markers of ovarian carcinoma, CA 54/61 and CA 602. 1. Evaluation of the diagnostic accuracy of CA 54/61, a study of the normal range of its values and its correlation with other tumor markers].

We made a preclinical study of CA 54/61, a recently developed marker of ovarian tumors, and also conducted a clinical study of it using serum samples collected from 58 institutions located throughout Japan. This paper describes the results of the preclinical study of the CA 54/61 marker that were obtained with a kit based on an enzyme immunoassay (EIA), and also the findings with the kit in the clinical study pertaining to the normal range of its values, its values relative to age, menstrual cycle, and pregnancy, and its correlations with other tumor markers. The tests for reproducibility of assay results, the analytical recovery test, and the dilution test all gave favorable results: the marker proved reliable in both precision and reproducibility. Two cut-off values were used: the mean + 2 S.D. of the mean for healthy subjects, or 20 U/ml; and the value for the maximum diagnostic efficacy, i.e., 12 U/ml. The assay results did not vary greatly with either age, menstrual cycle or pregnancy stage, which suggested that CA 54/61 might be a marker less liable to be affected by physiological conditions prevailing at the time of sample collection. The result correlated poorly with those of assays with other markers; thus CA 54/61 proved to differ in property from the previously recognized tumor markers.

Clinical effect of sizofiran combined with irradiation in cervical cancer patients: a randomized controlled study. Cooperative Study Group on SPG for Gynecological Cancer.

To evaluate the clinical effect of a biological response modifier (BRM), sizofiran (SPG), combined with irradiation, a randomized controlled study was performed in patients with stage II or III cervical cancer involving the collaboration of 52 institutes throughout Japan. Patients were randomly allocated to the control group (radiotherapy only) and the SPG group (radiotherapy + SPG). SPG was given intramuscularly, 40 mg once and 20 mg twice, a week concomitantly with radiotherapy. A total 315 patients were enrolled for the study but 23 were excluded from analysis. Of the remaining 292 patients, 121 were of stage II (43 controls and 78 SPG) and 171 of stage III (49 controls and 122 SPG). The results were as follows. (1) The complete response (CR) rate among stage II patients was higher in the SPG group (91.0%) than in the control group (79.1%); also the CR rate among stage III patients was significantly higher in the SPG group (77.9%) than in the control group (61.2%). (2) The SPG group showed a significantly rapid recovery from the decreased lymphocyte counts due to radiotherapy (P less than 0.05). (3) Side effects, probably associated with SPG administration, were observed in 11 cases (5.2%).

[A late phase II study of CPT-11 on uterine cervical cancer and ovarian cancer. Research Groups of CPT-11 in Gynecologic Cancers].

A late phase II study of CPT-11, a new derivative of camptothecin, in uterine cervical cancer and ovarian cancer was carried out by a cooperative study group at 26 institutions. Out of 144 patients enrolled, total cases were 110, involving 55 uterine cervical cancers and 55 ovarian cancers. In uterine cervical cancer, 5 cases of complete response (CR) and 8 cases of partial response (PR) were observed, with a response rate of 23.6% and a CR rate of 9.1%. In ovarian cancer, 13 cases of PR were observed, response rate was 23.6%. Both in uterine cervical cancer and ovarian cancer, the 95% confidence interval of response rate was 12.4-34.8%. In cases having undergone previous chemotherapy including platinum, derivatives, the response rate in ovarian cancer was 23.1% (12/52). In cases of uterine cervical cancer having previous radiotherapy, the response rate was 26.8% (11/41). In ovarian cancer of various histological types, a response was observed for not only serous cystadenocarcinoma but also mucinous cystadenocarcinoma, etc. A response was observed in distant metastatic lesions such as lung metastasis as well as primary lesion in uterine cervical cancer and ovarian cancer. Major adverse reactions were leukopenia, nausea and vomiting, diarrhea and anorexia, and these incidences (grade 2 or more) were 87.3, 60.3, 44.0 and 67.2%, respectively. Since some patients experienced severe adverse reactions, caution should be taken in treatment with CPT-11. Besides these reactions, alopecia was observed (33.1%), but severe adverse reactions such as nephropathy were not found. No significant difference in the efficacy and adverse reactions were observed between administration methods; A, 100 mg/m2 once weekly and B, 150 mg/m2 once every 2 weeks. Both were thought to be clinically useful. These results suggest that CPT-11 is clinically effective against uterine cervical cancer and ovarian cancer.