Epidemiology of sarcoidosis in Japan.

The present study was designed to identify recent clinical phenotypes using the National Epidemiological Survey and to compare findings with those of previous surveys in Japan. Pathologically confirmed sarcoidosis cases newly diagnosed in 2004 were eligible for the present study. Disease parameters were recorded and compared. A total of 1,027 patients were enrolled from a cluster encompassing 79.4% of the entire Japanese population. The study participants consisted of 364 males and 663 females, providing an average incidence rate of 1.01 per 100,000 inhabitants (0.73 for males and 1.28 for females). The age-specific incidence rate displayed a biphasic pattern in the whole patient population and in the females. The male incidence rates peaked in the 20-34-yr-old group. A second peak for 50-60-yr-old females showed a higher incidence than the first younger peak. Patients with abnormalities in eyes, skin and cardiac laboratory findings accounted for 54.8, 35.4 and 23.0% of cases, respectively. The female/male incidence ratio was increased, and the frequency of eye and skin involvement and cardiac abnormality was higher than in previous surveys conducted in Japan. In conclusion, the data obtained in the present study differ from those of other countries and showed changes in sarcoidosis clinical phenotypes compared with previous studies in Japan.

[A case of sarcoidosis acutely aggravated with high fever and diffuse interstitial pulmonary infiltrates].

We present a case of sarcoidosis acutely aggravated with high fever and diffuse interstitial pulmonary infiltrates in a female patient at the age of 64. Sarcoidosis was diagnosed in another hospital as a result of iritis, chest radiography findings, and a negative reaction in a tuberculin skin test. She was admitted to our hospital because of dyspnea and a high temperature of 39 degrees C in February 1994. A marked hypoxemia (PaO2 46.5 torr) was found in arterial blood gas analysis. Chest radiography revealed a bilateral diffuse reticulo-nodular shadows, and chest CT showed ground glass opacity predominant posteriorly. Analysis of bronchoalveolar lavage fluid revealed an increase in lymphocytes and an increased ratio of CD4 to CD8 T lymphocyte. Transbronchial lung biopsy revealed lymphocytic alveolitis and proliferation of epithelioid cell granulomas in the alveolar septa and intraalveolar spaces. The patient was treated for deterioration of sarcoidosis with 40 mg of prednisolone and her respiratory status and the radiographic findings improved rapidly. With dose tapering of prednisolone, dyspnea and deterioration of the radiographic findings occurred, but with addition of a weekly low dose of methotrexate, dose reduction of prednisolone was achieved.

Pulmonary tuberculosis with unusual cystic change in an immunocompromised host.

We present a rare case of upper zone cystic change of the lung with disseminated tuberculosis of a non-smoking 30-year-old immunocompromised male. He suffered from repeated pneumothorax. The basic pathological feature of video-assisted thoracoscopic lung biopsy revealed granulomatous involvement in the respiratory bronchioles with poorly developed epithelioid cells and disruption of elastic fibers. Electron microscopy demonstrated a decrease in elastic fibers and disruption of the epithelial basement membrane of the respiratory bronchiole and no Langerhans cells in the lesion. Autopsy of the lung revealed centroacinar distribution of multiple cystic lesions in the bilateral upper lobe. Almost all cystic walls showed loss of elastic fibers and cysts frequently involved the respiratory and terminal bronchioles, alveolar ducts and, occasionally, alveoli. Some larger cystic lesions revealed communication to the bronchi. The cystic changes in this case of pulmonary tuberculosis may be caused by a check-valve mechanism due to granulomatous involvement of the bronchioles and also by excavation of caseous necrotic material by draining bronchi.

Telomerase activity significantly correlates with chromosome alterations, cell differentiation, and proliferation in lung adenocarcinomas.

Telomerase activity was examined by the telomeric repeat amplification protocol assay in 25 cases of lung adenocarcinoma, in relation to cancer cell differentiation, proliferation, and chromosome alterations. Telomerase activity, chromosome alterations, and cell proliferation assessed by Ki-67 labeling were significantly lower (P < .001 to .05) in well-differentiated (10 cases) than in moderately differentiated (8 cases) or poorly differentiated (7 cases) lesions. Telomerase activity by semiquantitative analysis with scoring of 0 to 3 was significantly correlated with similarly graded chromosome alterations (P < .05) and Ki-67 labeling indices (P < .002). Telomerase activity and chromosome alteration (T-C) indices generated by multiplication of telomerase activity and chromosome alteration scores also showed a significant correlation with cell differentiation. The Clara cell subtype, confirmed by electron microscopic analysis, significantly predominated in the well-differentiated group, showing a low grade of telomerase activity and chromosome alterations and low Ki-67 labeling indices, suggesting clinical relevance. No significant association of telomerase activity was found with p53 protein accumulation or Bcl-2 protein expression. The good correlation of telomerase activity with chromosome alterations, cell differentiation, and Ki-67 labeling indices suggests that this parameter might have potential application in estimation of prognosis.

Significant increase in prostaglandin E-main urinary metabolite by laxative administration: comparison with ulcerative colitis.

OBJECTIVE: To assess the production of prostaglandin E(2), an important chemical mediator in diarrhea induced by laxative administration, a prostaglandin E-main urinary metabolite (7alpha-hydroxy-5,11-diketotetranor-prosta-1,16-dioic acid, PGE-MUM) was measured in healthy volunteers and compared with the values of patients with ulcerative colitis. METHODS: PGE-MUM was determined by a simplified immunoassay of bicyclic PGE-MUM and analyzed for the influence of laxative administration and active/remission phases of ulcerative colitis. RESULTS: Administration of laxatives induced a significant increase in PGE-MUM in healthy volunteers. A significant elevation was also found in the active as compared with the remission phase of ulcerative colitis. The PGE-MUM levels were significantly correlated with our modified Talstad scores, clinical disease activity indices in ulcerative colitis. It was confirmed by time course studies of individual patients that changes in PGE-MUM correlated well with colitis activity. CONCLUSION: Laxative administration induces production of prostaglandin E(2) as one of the chemical mediators, although its production grade is relatively low as compared with ulcerative colitis in the active phase.

[A case of Wegener's granulomatosis which showed early spontaneous remission].

An 80-year-old woman presented at our hospital on October 1995 with fever, hemoptysis and a cavitary shadow on chest X-ray. Blood examination revealed an accelerated erythrocyte sedimentation ratio and elevated CRP. Pulmonary cryptococcosis was suspected, but serological tests and bronchoscopic examination for cryptococcus were both negative. There was also no evidence of the tuberculosis or malignancy. She was treated with the antibiotic cefpirome sulfate intravenously for thirteen days. Her chest X-ray and abnormal blood test findings became almost completely normal following the i.v. antibiotic treatment. In February 1996 (2 months after her first admission), she had severe right cheek pain, and Coldwell Luc's operation was performed after right maxillary sinusitis was diagnosed. A high fever (39 degrees C) continued after surgery, and multiple cavitary shadows were seen on chest X-ray. Blood examination revealed an accelerated ESR, elevated CRP and slightly elevated c-ANCA. She was treated with i.v. infusion of antibiotics and antifungal drug's, but did not improve. Wegener's granulomatosis was diagnosed after transcutaneous lung biopsy and histopathological examination of the maxillary sinus. Dramatic improvement was seen following treatment with oral cyclophosphamide and prednisolone. Whether her first remission was due to antibiotic treatment or spontaneous is an interesting question.

Vascular involvement in cutaneous sarcoidosis.

Sarcoidosis is a systemic granulomatous disease with systemic vascular involvement, that is, granulomatous angiitis and microangiopathy. To determine if there is vascular involvement in cutaneous sarcoidosis, we examined 42 skin specimens taken from 32 patients with cutaneous lesions of sarcoidosis. Cutaneous sarcoidosis was prevalent in older females with high serum angiotensin-converting enzyme (ACE) levels. Most skin lesions appeared during the following-up of sarcoidosis. Granulomatous angiitis was present in 12 specimens of sarcoid skin lesions (30.8%). Eight of the 12 specimens showed venous involvement in the dermis. There was no correlation between the incidence of granulomatous angiitis and the gross pattern of cutaneous sarcoidosis. Immunohistochemically, thrombomodulin was negative in the vascular endothelium close to the granuloma or a periphlebitis lesion. Electron microscopy revealed endothelial swelling, luminal narrowing, and basal lamina layering of the basement membrane in the capillaries and venules in the dermis. These findings demonstrated that granulomatous angiitis and microangiopathy coexist in cutaneous sarcoidosis.

Detection of antibodies to Borrelia species among patients with confirmed sarcoidosis in a region where Lyme disease is nonendemic.

BACKGROUND: Lyme disease is a multisystemic disorder caused by the spirochete Borrelia burgdorferi, while sarcoidosis is a multisystemic granulomatous disease of unknown etiology. The purpose of this study was to evaluate the relationship between Lyme disease and sarcoidosis. METHODS: We examined the seroprevalence of antibody to Borellia species in patients with sarcoidosis. We performed the enzyme-linked immunosorbent assay, using three Japanese Borrelia species in addition to B. burgdorferi, and dotblot analysis using purified Borrelia-specific proteins in 38 patients with histopathologically confirmed sarcoidosis and 80 healthy controls. RESULTS: Two patients (5.3%) were positive for antibodies to Borrelia species according to one or both assays, and one (1.2%) healthy control was positive. In both patients it was suspected that Borrelia infection had developed prior to the development of sarcoidosis. CONCLUSION: Borrelia species were thought not to be responsible for the development of sarcoidosis in a nonendemic region in Japan. Since clinical manifestations of Lyme disease share certain similarities with those seen in sarcoidosis, ophthalmologists should be aware of the need to differentiate between the two diseases and the need for prompt treatment in each case.

Ultrastructural features of alveolitis in sarcoidosis.

Seventy-nine specimens of lung parenchyma from 61 patients with sarcoidosis were examined ultrastructurally with a focus on alveolitis, and they were compared with specimens of hypersensitivity pneumonitis (HP) and the percentage of lymphocytes in bronchoalveolar lavage fluid (BALF). Lymphocytes and monocytes were frequently observed in the capillary lumina, and these cells and macrophages were found in the interstitium of the alveolar walls in the specimens with alveolitis of sarcoidosis and HP. Increases in the percentage of lymphocytes in BALF correlated with the degree of alveolitis. Swelling and bleb formation of the endothelium of alveolar capillaries and changes in the capillary basement membrane were commonly found and were significantly increased in the specimens with alveolitis. The frequency of bleb formation was significantly higher in alveolitis of sarcoidosis than in that of HP. However, the changes in alveolar epithelium were not significant in sarcoidosis. Microvascular changes in alveolitis are not specific for sarcoidosis, but they are observed in other interstitial lung diseases. These alterations may play an important role in the development of pulmonary sarcoidosis.

[Clinical usefulness of the combined empirical therapy with flomoxef and fosfomycin for intractable respiratory tract infections. With a background of increasing MRSA incidence].

We conducted a multicenter trial to determine the clinical usefulness of the combined therapy with flomoxef (FMOX) and fosfomycin (FOM) (FF therapy) as an empirical therapy in the treatment of intractable respiratory tract infections, because FF therapy has clinically been proved to be very useful for the treatment of severe infections including MRSA infections. The overall efficacy rate of FF therapy was 69.2%. The efficacy rate for "pneumonia/lung abscess," which occupy the largest portions of respiratory tract infections, was 70.0%, showing a statistically significant difference from the efficacy rate for FMOX alone (56.7%) found in a previous study (P = 0.09 by chi-squared test). Although MRSA was eradicated in only 3 cases (37.5%) including superinfection cases, of 8 patients, from whom MRSA had been isolated as causative organisms, none of our patients were superinfected with MRSA. Thus it has been concluded that FF therapy is clinically very useful when used as an empirical therapy in the treatment of respiratory tract infections.

[Steroid treatment of neurosarcoidosis].

In cases of simple cranial neuropathy, observation of the course of recovery is sufficient since the majority of cases heal spontaneously. However, in cases of multiple cranial neuropathy, symptoms are sometimes severe, and it may become necessary to administer steroids. This applies to spinal neurosarcoidosis. The symptoms of central nervous system sarcoidosis are usually severe and many cases are intractable, and steroid therapy is always indicated in such cases.

[A case of coccidioidomycosis with central nervous system involvement].

We report a 44-year-old Japanese man with chronic meningitis due to coccidoiodomycosis. He was admitted to our hospital because of pneumonia after the business trip to Phoenix, Arizona. Coccidioid immitis was cultured from periathric abscess on the sternoclavicular joint. He became asymptomatic by 5-FC administration. One year later, however, he complained of headache and fever. Coccidiodial meningitis was diagnosed by cerebrospinal fluid (CSF) examination. Both systemic and intrathecal administration of miconazole and oral itraconazole were ineffective. While meningitis was not cured for three years, normal pressure hydrocephalus (NPH) developed. CSF cell count fell into normal range after administration of fluconazole (800 mg/day) for thirteen months, but NPH continued. This is the first report of coccidiodimycosis with CNS involvement in Japan.

Pulmonary vascular involvement in sarcoidosis: granulomatous angiitis and microangiopathy in transbronchial lung biopsies.

To evaluate the occurrence of granulomatous angiitis and microangiopathy in the lung with sarcoidosis, transbronchial lung biopsy specimens were examined from 174 cases with sarcoidosis. Granulomatous angiitis was seen in 72 cases, which corresponded to 53% of the cases with granulomata. Granulomatous angiitis showed venous involvement (65%), both venous and arterial involvement (24%) or arterial involvement only (11%). There was no significant difference in occurrence of granulomatous angiitis between upper and lower lobes. The cases with granulomatous angiitis in the lung had a higher frequency of ophthalmic symptoms and elevated serum angiotensin converting enzyme level. Basal lamina layering in the microvasculature was more often observed in the bronchial mucosa than in the alveolar walls and is not exclusively related to granulomata. Endothelial proliferation and basal lamina alterations in granulomatous angiitis may be closely associated with granulomas. The present study revealed coexistence of granulomatous angiitis and microangiopathy in the lung with sarcoidosis and suggests that both may participate in the development of pulmonary sarcoidosis.

[Neurosarcoidosis].

It is easy to identify patients with neurosarcoidosis who have a lesion the neural lesion. However, it is be difficult if the patient has a preceding neural lesion or isolated CNS sarcoidosis in which the lesion is localized in CNS and the lesion in another organ hem regressed. The finding of generalized or localized cerebral edema and the shadow of tumor on CT, and the result of CSF examination which indicates an increase in cell count, protein or ACE activity (especially in meningitis type) are helpful for the diagnosis of the above disorder. Epidemiological studies on the basis of 21 patients with neurosarcoidosis in our center and 166 patients in our country indicated that this disorder was more common in females than in males (1.6/1). The age of patients showed predominance in the twenties in males, and the twenties, forties and fifties in females. Common pathological finding in our postmortem examinations (n = 2) and intracranial biopsy (n = 1) was lymphocytic phlebitis in central and peripheral neurons and in neurons with no clinical symptom.