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The prognostic significance of serial measurements of serum KL-6 levels in patients with idiopathic pulmonary fibrosis (IPF) is unclear; hence, it was assessed in this study.Medical records of 66 patients with IPF, who were not treated with pirfenidone prior to enrollment, were retrospectively reviewed for information on clinical progress, forced vital capacity (FVC), survival, and serum KL-6 levels. We assessed initial serum levels of KL-6, serial changes in serum KL-6 levels, yearly decline in FVC (ΔFVC), and the rate of decline (%ΔFVC).Patients with increased serum KL-6 levels during follow-up had a significantly steeper decline in ΔFVC than those with no KL-6 increase (-201 vs. -50.7ml/year; p=0.0001). Patients with both initial serum KL-6 ≥1000U/ml and serial increases in serum KL-6 had the steepest decline, while those with both initial serum KL-61000ml and no serial increases in KL-6 had the least decline in ΔFVC and %ΔFVC. Relative to the non-increased KL-6 group, survival in the increased KL-6 group tended to be poorer (p=0.0530). Patients with both initial serum KL-6 values1000U/ml and no serial increase in KL-6 had more favorable prognoses than those with serial increases in KL-6 or initial serum KL-6 values ≥1000U/ml (p0.0044). Prognosis was significantly poorer in patients with serial KL-6 changes51.8U/ml/year than in those with serial KL-6 changes51.8U/ml/year (p=0.0009).Thus, serial serum KL-6 measurements can be useful for assessing prognosis in patients with IPF.

Vaccination against Streptococcus pneumoniae is recommended for rheumatoid arthritis (RA) patients receiving immunosuppressive treatments. The objective of this study was to evaluate the humoral response to 23-valent pneumococcal polysaccharide vaccination (PPSV23) in RA patients receiving methotrexate (MTX) alone or in combination with a tumor necrosis factor inhibitor, golimumab (GOM). PPSV23 was given to 114 RA patients, who were classified into three groups: RA control (n = 35), MTX alone (n = 55), and GOM + MTX (n = 24). Before and 4 to 6 weeks after vaccination, concentrations of antibodies against pneumococcal serotypes 6B and 23F were measured using an enzyme-linked immunosorbent assay and antibody functionality was determined using a multiplexed opsonophagocytic killing assay, reported as the opsonization index (OI). The IgG concentrations and OIs were both significantly increased in all treatment groups in response to PPSV23 vaccination. In the GOM + MTX group, the IgG responses were lower than those in the MTX alone or control groups, whereas the OI responses were similar to those in the other 2 groups. Furthermore, discrepancies between the IgG and OI responses were found in GOM + MTX group. No severe adverse effect was observed in any treatment groups. OI responses indicate that antibody functionality rather than antibody quantity is important. The similarity of these measurements between all 3 groups suggests that RA patients receiving MTX + GOM still benefit from receiving the PPSV23 vaccination, even though they produce less IgG in response to it. These results can help clinicians to better schedule and evaluate pneumococcal vaccination for RA patients.

Malignant pleural effusion (PE) is one of the poor prognostic factors in non-small cell lung cancer (NSCLC), and the detailed mechanism of the malignant PE formation is not fully elucidated. Recently, CXCR4, a receptor for chemokine stromal-derived factor-1alpha (SDF-1alpha) that can induce chemotaxis of cells, was reported to be expressed on NSCLC. In this study, we hypothesized that the SDF-1alpha/CXCR4 axis may be involved in the dissemination of malignant cells into pleural space, and investigated its expression, function, and signaling pathway using NSCLC cell lines and clinical samples from 43 patients with NSCLC with malignant PE. We found functional expression of CXCR4 on NSCLC cell lines, and also found that SDF-1alpha could induce migration via phosphatidylinositol 3 (PI-3) kinase- and p44/42 mitogen-activated protein kinase-dependent manner. The SDF-1alpha levels in malignant PE were significantly higher than those in transudate PE and showed a significant positive correlation with PE volumes. The sensitivity and specificity for prediction of recurrence of malignant PE was 61.5% and 83.3%, respectively (cutoff SDF-1alpha = 2,500 ng/ml), and better than those using pH of PE. Cancer cells in malignant PE expressed CXCR4, and mesothelial cells of the pleura stained positive for SDF-1alpha. The SDF-1alpha/CXCR4 axis is involved in the dissemination of NSCLC cells into pleural space.

SUMMARYHuman T lymphotrophic virus type-I (HTLV-I), a human retrovirus, infects CD4+ lymphocytes and is thought to modify their function; a possible association with pulmonary diseases has also been suggested. However, little is known about the influence of HTLV-I on cryptogenic fibrosing alveolitis (CFA), a chronic inflammatory interstitial lung disease of unknown aetiology. In order to clarify the influence of HTLV-I infection on CFA, 72 CFA patients with and without HTLV-I infection were examined. HTLV-I positive CFA patients were likely to have larger affected areas and to show traction bronchiectasis with honeycombing change. An imbalance of matrix metalloproteinases and tissue inhibitor of metalloproteinases were also observed in the BALF of HTLV-I positive CFA patients. CD3+/CD25+ lymphocyte percentage was significantly higher in the BALF of HTLV-I positive patients compared to negative patients. MIP-1α, IP-10 and sICAM levels in BALF were also significantly higher in HTLV-I positive patients than in negative patients. The levels of MCP-1 and IL-8 were not significantly different. In HTLV-I positive patients, the MIP-1α and IP-10 levels showed a significant positive correlation with percentage of CD3+/CD25 lymphocytes. HTLV-I positive CFA patients showed a larger lesion than negative patients and exhibited increased levels of certain cytokines that correlated with activated T cells in the BALF. We suggest that HTLV-I infection may contribute to the development of CFA via activation of T cells. We also propose that these features should be taken into consideration in the treatment of CFA in HTLV-I infected individuals.

To evaluate the predictive value of vascular endothelial growth factor (VEGF) in the differential diagnosis of pleuritis and its association with other proinflammatory cytokines in pleural effusion, we measured VEGF together with interleukin-1beta (IL-1beta), tumor necrosis factor alpha (TNF-alpha) and soluble intercellular adhesion molecule-1 (sICAM-1) in pleural effusions. We investigated 127 patients with pleural effusion (congestive heart failure: 21; parapneumonic: 27; tuberculous: 41; malignant: 38). We examined standard parameters of pleural effusion and measured pleural effusion VEGF, IL-1beta, TNF-alpha and sICAM-1 using enzyme-linked immunosorbent assay. VEGF level was significantly higher in malignant effusion than in other groups. TNF-alpha level was significantly higher in tuberculous pleurisy than in other groups. In tuberculous pleurisy VEGF level showed significant positive correlations with mononuclear cell counts and all investigated cytokines. The sensitivity and specificity of VEGF in the diagnosis of malignancy was 100 and 84%, respectively (cutoff = 2000 pg/ml). The sensitivity and specificity of VEGF and TNF-alpha in the diagnosis of tuberculous pleurisy (VEGF titer2000 pg/ml and TNF-alpha titer55 pg/ml) was 88.9 and 77.1%, respectively. We propose that measurement of VEGF together with TNF-alpha is helpful in differentiating between tuberculous pleurisy and malignant pleural effusion and that VEGF correlates with proinflammatory cytokines especially in tuberculous pleurisy. We also propose that measurement of pleural VEGF is helpful for the diagnosis of malignant pleural effusion.

The purpose of this study was to investigate the cellular source and significance of vascular endothelial growth factor (VEGF) which, as reported previously, is elevated in the sera of pulmonary tuberculous patients. We obtained peripheral blood mononuclear cells (PBMCs) from 28 patients with active pulmonary tuberculosis, from 11 healthy controls who were positive for purified protein derivative of tuberculin (PPD), and from eight healthy individuals who were negative for PPD. We incubated the PBMCs with PPD in the presence or absence of major histocompatibility (MHC) class I or class II antibody in vitro, and measured the VEGF levels of culture supernatants. We also analysed the source of cells that secrete VEGF by using flow cytometry with intracellular staining. The T lymphocytes of active tuberculous patients secreted a higher level of VEGF than those of healthy controls. This production of VEGF was inhibited by adding MHC class II antibody. The addition of MHC class I antibody, however, did not inhibit. We propose that CD4+ T lymphocytes are almost certainly the cells that produce VEGF in response to PPD. VEGF production might be associated with an antigen-specific immune reaction via CD4+ T lymphocytes in tuberculosis.

The pathogenesis of tuberculous meningitis is still unclear. Recently, vascular endothelial growth factor (VEGF) was found to be associated with inflammatory diseases and we found the increased serum level of VEGF in pulmonary tuberculosis. We hypothesized that VEGF might be associated with the pathogenesis of tuberculous meningitis and measured serum and cerebrospinal fluid (CSF) levels of VEGF in 28 patients with tuberculous meningitis and 31 non-tuberculous infectious meningitis patients (13 bacterial meningitis patients, eight fungal meningitis patients and 10 patients with viral meningitis) before therapy. We examined the CSF VEGF levels 3 months after in 12 tuberculous meningitis patients. The serum and CSF levels of VEGF were significantly higher in tuberculous meningitis than in other meningitis. The decrease in titer of CSF VEGF paralleled the clinical improvement of tuberculous meningitis. Immunohistochemical staining of autopsied brains demonstrated the presence of VEGF in the inflammatory mononuclear cells of the dense fibroconnective tissue both in the subarachnoid space and surrounding the vasculitis lesion. We found the expression of VEGF in tuberculous meningitis and think that VEGF reflects its activity.

We report a case of Crow-Fukase (POEMS) syndrome associated with pulmonary hypertension (PH). In this case, the concentration of vascular endothelial growth factor (VEGF) was extremely high in the serum, and the levels of IL-1beta, IL-6, TNF-alpha, and thiamine, which were thought in past reports to be mediators of PH in Crow-Fukase syndrome, were normal. After prednisolone therapy, PH disappeared with a dramatic decrease in serum VEGF. Our results suggest that VEGF is closely correlated with PH in Crow-Fukase syndrome.

Background: Adhesion molecules may play an important role in eosinophilic activation as well as adherence of extracellular matrix (ECM) including fibronectin (FN) in the inflamed focus. Tissue eosinophils expressed inter-cellular adhesion molecule-1 (ICAM-1, CD54), whereas peripheral blood eosinophils did not. The molecular mechanisms of ICAM-1 expression on eosinophils are not clear. We immunologically examined the effect of adherence to FN on the expression of adhesion molecules in an eosinophilic cell line (EoL-1). Methods: EoL-1 cells, suspended at a concentration of 2 × 106 cells/ml, were cultured at 37°C in BSA or FN-coated 24-well plates. After 4 h, the cells were removed by pipetting, and the expression of adhesion molecules was evaluated by immunofluorescence. Results: Adherence of EoL-1 to FN enhanced ICAM-1 (CD54) expression on EoL-1 (FN vs. BSA: 84.76 ± 17.90 vs. 43.73 ± 7.60, mean fluorescent intensity). Regarding other adhesion molecules on EoL-1 (CD11a, CD18, CD49d), the expression was not significantly augmented by adherence to FN. Conclusions: We concluded that the signal via adhesion of FN regulates the expression of ICAM-1 on eosinophilic cells. This study suggests that eosinophilic adhesion to ECM via adhesion molecules plays an important role in the pathogenesis of allergic inflammation through eosinophilic functional changes, including regulation of expressive adhesion molecules such as ICAM-1.

We investigated five cases with cerebrotendinous xanthomatosis (CTX) with particular reference to biochemical and pathological pulmonary disorders. To date, few reports discuss the pathophysiology of pulmonary disorders of CTX patients. This study is the first investigation of such pulmonary disorders. All 5 patients had no pulmonary symptoms and no disturbances on radiological studies and pulmonary function tests. However, in bronchoalveolar lavage (BAL) fluids, many cells with cruciform reflexes, which is characteristic of intracellular sterol accumulation, were found under phase contrast microscopy. Biochemically, cholestanol was found to be increased in the BAL fluid as well as in serum. Pathological findings of transbronchial lung biopsy (TBLB) samples disclosed foamy macrophages and small granulomas in alveolar septa. In conclusion, the lung was apparently involved in CTX, and the lesions were characterized with the accumulation of foamy and giant cells with a high concentration of cholestanol, which likely results in the formation of foreign body granulomas.

A 23-year-old man was suffering from high fever and general fatigue 6 months before admission. The levels of serum Ca and intact-parathyroid hormone (PTH) were low. His brain computed tomography (CT) revealed marked calcifications of the basal ganglia, and pelvis magnetic resonance imaging (MRI) showed inflammation of his seminal vesicle. His candida antigen titer was high and antibiotic therapy was unsuccessful. High fever persisted despite fluconazole treatment, however he recovered after treatment with fluconazole and vitamin D (alfacalcitol). Idiopathic hypoparathyroidism hinders the activation of vitamin D via insufficient PTH secretion, and vitamin D has some immunological effects. His decreased natural killer (NK) cell activity improved after alfacalcitol treatment. We suggest the possible immunological effects of vitamin D in this fungal infection.

Background/Aims The Japanese National Hospital Organization evidence-based medicine (EBM) Study group for Adverse effects of Corticosteroid therapy (J-NHOSAC) is a Japanese hospital-based cohort study investigating the safety of the initial use of glucocorticoids (GCs) in patients with newly diagnosed autoimmune diseases. Using the J-NHOSAC registry, the purpose of this observational study is to analyse the rates, characteristics and associated risk factors of intracellular infections in patients with newly diagnosed autoimmune diseases who were initially treated with GCs. Methodology/Principal Findings A total 604 patients with newly diagnosed autoimmune diseases treated with GCs were enrolled in this registry between April 2007 and March 2009. Cox proportional-hazards regression was used to determine independent risk factors for serious intracellular infections with covariates including sex, age, co-morbidity, laboratory data, use of immunosuppressants and dose of GCs. Survival was analysed according to the Kaplan-Meier method and was assessed by the log-rank test. There were 127 serious infections, including 43 intracellular infections, during 1105.8 patient-years of follow-up. The 43 serious intracellular infections resulted in 8 deaths. After adjustment for covariates, diabetes (Odds ratio [OR]: 2.5, 95% confidence interval [95% CI] 1.1–5.9), lymphocytopenia (≦1000/μl, OR: 2.5, 95% CI 1.2–5.2) and use of high-dose (≧30 mg/day) GCs (OR: 2.4, 95% CI 1.1–5.3) increased the risk of intracellular infections. Survival curves showed lower intracellular infection-free survival rate in patients with diabetes, lymphocytopaenia and high-dose GCs treatments. Conclusions/Significance Patients with newly diagnosed autoimmune diseases were at high risk of developing intracellular infection during initial treatment with GCs. Our findings provide background data on the risk of intracellular infections of patients with autoimmune diseases. Clinicians showed remain vigilant for intracellular infections in patients with autoimmune diseases who are treated with GCs.

We report here the results of therapeutic trials in 200 patients with HTLV-I-associated myelopathy (HAM)/tropical spastic paraparesis (TSP) conducted in our department between 1986 and 1993. Motor disability grades were improved by more than one grade in 69.5% (91/131) of patients by oral administration of prednisolone, 50% (3/6) by eperisone hydrochloride only, 43.8% (7/16) by blood purification (lymphocytapheresis and plasmapheresis), 40.0% (2/5) by intrathecal injection of hydrocortisone, 30.0% (3/10) by intravenous injection of high-dose methylprednisolone, 23.3% (10/43) by interferon-alpha (intramuscular injection and inhalation), 22.2% (2/9) by azathioprine, 20.0% (4/20) by high-dose vitamin C, 16.0% (4/25) by erythromycin, 12.5% (3/24) by salazosulfapyridine, 11.8% (2/17) by mizoribine, 7.1% (1/14) by fosfomycin, and 6.3% (1/16) by thyrotropin releasing hormone. No critical side effects of these therapies were seen with the exceptions of one patient with adult respiratory distress syndrome due to cytomegalovirus infection and one patient with drug-induced hepatitis/hepatic failure. Selection of these treatments for patients with HAM/ TSP must be considered on the basis of age, sex, disease severity and complications to reduce adverse events and to improve quality of life. Although the results were a synopsis of different treatments given to 200 patients with HAM/ TSP as an open trial, we consider this the first report of a large-scale therapeutic trial in patients with HAM/TSP. The results of this study indicate that immunomodulatory therapies have some beneficial effects in HAM/TSP, and the functions of these agents are related to the pathophysiology of this disease.

Fibronectin is an extracellular matrix (ECM) that binds to very late antigen-4 (a beta 1 integrin molecule) expressed by eosinophils. To investigate the effect of adherence to fibronectin on regulation of eosinophil cell death, survival of eosinophils was examined by trypan blue exclusion and Fas antigen expression on the cell surface using an eosinophilic cell line (EoL-1). Adhesion to fibronectin resulted in prolongation of eosinophil survival (fibronectin vs. bovine serum albumin (BSA), 62.9 +/- 5.10 vs. 53.9 +/- 4.30% viability at 72 h) and the decreasement of Fas antigen expression on EoL-1 (fibronectin vs. BSA, 24.3 +/- 2.15 vs. 74.5 +/- 8.25% positive). These findings suggest that eosinophil adhesion to ECM via adhesion molecules plays an important role in the pathogenesis of allergic inflammation, which involves eosinophil accumulation at the inflammatory site, through regulation of eosinophil cell death.

Sinobronchial syndrome (SBS) is a clinical entity in which chronic sinusitis is accompanied by chronic inflammation of the lower airway.This paper describes the clinicopathological characteristics of a new SBS entity in patients with HTLV-1 associated bronchopneumopathy (HAB) accomponied frequently chronic sinusitis, or primary ciliary dyskinesia.We investigated the mechanism of clinical effectiveness of low-dose and long-term erythromycin (EM) or roxithromycin (RXM) treatment for SBS and HAB by studying the effects of these drugs on neutrophil function and on mucociliary transport function.These drugs inhibited neutrophil adhesion to surfaces of cultured vascular endothelial cells and active oxgen production in neutrophils taken from both venous blood and nasal discharge of patients after drug therapy.The effect of these drugs on ciliary function was studied in monolayer cultures of human respiratory cells with a differential interference microscope equipped with a high speed video system; however, no marked change of ciliary movement was observed in this experimental series.On the other hand, lectin histochemistry of nasal mucosa showed that the increased amounts of glycoconjugates, such as sialic acid and fucose, were returned to within the normal range by drug therapy of patients with chronic sinusitis.The improvement of chronic respiratory inflammation is probably dependent not only on the antimicrobial effect of macrolide antibiotics but also on their antiinflammatory effect, regulation of the hyperimmune response and normalization of glycoconjugate composition in airway secretion.

A 75-year-old man with diabetes mellitus visited our hospital because of a chest radiograph abnormality. He was asymptomatic, and no abnormality was detected by blood tests including QuantiFERON-TB Gold (QFT-2 G); hence we conducted a follow-up examination. In 8 months, his chest radiography and CT findings worsened despite remaining asymptomatic. He was admitted for further tests. Analysis of bronchoalveolar lavage fluid (BALF) showed normal results for total cell counts and lymphocytes, but the CD4/8 ratio increased, and bacterial examination yielded negative results. Surgical lung biopsy showed an epithelioid cell granuloma with fibrinoid necrosis and Langhans giant cells, and some bacilli were positive for acid-fast stain. At this point, we suspected sarcoidosis, necrotizing granulomatosis, and mycobacterosis. However, the mycobacterial culture from the lung tissue was positive, and it was identified as Mycobacterium tuberculosis. We diagnosed pulmonary tuberculosis. Even if QuantiFERON-TB Gold In-Tube (QFT-3 G) for active tuberculosis is negative, it may yield false negative results in individuals in an immunosuppressed state and low CD4 count. When we suspect pulmonary tuberculosis from radiographic and pathological findings, we should consider the results of QFT-2 G and QFT-3 G carefully as an adjunct to the diagnosis of tuberculosis.

A 33-year old man was admitted to our hospital because of an abnormal shadow on the chest radiograph, dry cough, and exertional dyspnea. Chest radiograph and high-resolution computed tomography (HRCT) on admission showed ground-glass opacities and bronchiectasis with volume loss in the bilateral dorsal areas. Thoracoscopic lung biopsy specimens showed mainly a pattern of NSIP (nonspecific interstitial pneumonia). We considered this case as hypersensitivity pneumonia or interstitial pneumonia (IP) associated with collagen disease. Oral prednisolone (PSL) was initiated at 55 mg/day (1 mg/kg). However he complained of proximal muscle weakness and pain and difficulty of breathing. He had heart failure due to the myocarditis. We established a diagnosis of IP associated with polymyositis and it was confirmed by his symptoms, muscle biopsy findings and elevation of serum CPK. We considered this case as the myocarditis due to polymyositis.

A 36-year-old man who often ate raw chicken meat had abnormal chest radiograph findings on a health check-up in July 2009, and visited our department. A chest computed tomographic scan revealed 6 nodular shadows in both lungs, and a hematologic examination revealed eosinophilia and elevation of IgE. Because of his history of eating raw chicken meat, antiparasite antibody testing was performed which revealed antibodies to Toxocara canis, leading to the diagnosis of pulmonary toxocariasis due to Toxocara canis. Although treatment with albendazole was performed, it was discontinued because of hepatic impairment. However, hematological examination showed that his eosinophil count and IgE increased again, and chest image findings were exacerbated. Therefore, ivermectin, reported as effective in cases outside Japan, was administered, resulting in decreased peripheral eosinophils, normalized IgE level, and disappearance of the shadows on chest images. In Japan, no cases of pulmonary toxocariasis responding well to ivermectin have previously been reported. Administration of ivermectin should be considered when albendazol cannot be used due to hepatic impairment or related problems.

Background It is difficult to predict survival in patients with idiopathic pulmonary fibrosis. Recently, several proteins, such as surfactant protein (SP) and KL-6, have been reported to be useful biologic markers for prediction of prognosis for interstitial pneumonias. It is not clear whether there is any relationship between expression of these proteins in regenerative/hyperplastic alveolar epithelial cells and prognosis of idiopathic interstitial pneumonias (IIPs). Objectives This study aimed to elucidate the clinical significance of the expression of such lung secretory proteins as SP-A and KL-6 in lung tissues of patients with IIPs. Methods We retrospectively investigated the immunohistochemical expression of SP-A, KL-6, cytokeratin (CK), and epithelial membrane antigen (EMA) in alveolar epithelial cells in lung tissues obtained from surgical lung biopsy in 43 patients with IIPs, and analyzed the correlation between expression of these markers and the prognosis of each IIP patient. CK and EMA were used as general markers for epithelial cells. Results In patients with usual interstitial pneumonia (UIP), the ratio of SP-A positive epithelial cells to all alveolar epithelial cells (SP-A positive ratio) in the collapsed and mural fibrosis areas varied, ranging from cases where almost all alveolar epithelial cells expressed SP-A to cases where only a few did. On the other hand, in many patients with nonspecific interstitial pneumonia (NSIP), many of the alveolar epithelial cells in the diseased areas expressed SP-A. The SP-A positive ratio was significantly lower in patients who died from progression of UIP than in patients with UIP who remained stable or deteriorated but did not die. In NSIP patients, a similar tendency was noted between the SP-A positive ratio and prognosis. Conclusions The results suggest that the paucity of immunohistochemical SP-A expression in alveolar epithelial cells in diseased areas (i.e. regenerative/hyperplastic alveolar epithelial cells) may predict a worse prognosis for patients with IIPs, especially patients with UIP. A prospective study is needed to confirm these results.

A 70-year-old man presented with a deteriorating fever and productive cough after the administration of drugs including L-carbocisteine against the common cold. Since chest radiograph revealed pulmonary infiltrates in the right lower lung field, he was admitted to our hospital, then L-carbocisteine was continued and antibiotics started. However, his symptoms, laboratory findings, and hypoxia worsened. Pulmonary infiltrates on his chest radiograph increased and chest CT demonstrated pulmonary consolidation with traction bronchiectasis and ground glass opacity with thickened of interlobular septae in the right lung field. Analysis of bronchoalveolar lavage fluid showed elevated numbers of total cells, neutrophils and eosinophils, and the CD4/CD8 ratio was 5.65. Under a suspected diagnosis of drug-induced pneumonia, we halted L-carbocisteine administration stopped and began corticosteroid therapy. Subsequently his symptoms and findings markedly improved. The drug lymphocyte stimulation test for L-carbocisteine using peripheral blood lymphocytes showed positive results. On the basis of the clinical course, laboratory and radiographic findings, we considered this case to possibly be drug-induced pneumonia due to L-carbocisteine. To our knowledge, this is possibly the first case of L-carbocisteine-induced pneumonia to be reported.

Background: A study was undertaken to investigate the pathogenesis of pulmonary involvement in human T lymphotropic virus type I (HTLV-I) carriers. Methods: The bronchoalveolar lavage (BAL) cell profile of 30 HTLV-I carriers (15 asymptomatic HTLV-I carriers (AHCs) and 15 symptomatic HTLV-I carriers (SHCs)) with chronic inflammatory diseases of respiratory tract and eight patients with HTLV-I associated myelopathy/tropical spastic paraparesis (HAM/TSP) was investigated. The HTLV-I proviral deoxyribonucleic acid (DNA) load in peripheral blood mononuclear cells (PBMCs) and BAL fluid from HTLV-I carriers was estimated using the quantitative polymerase chain reaction method and the correlation between the lymphocyte number in BAL fluid and the HTLV-I proviral DNA load in PBMCs and BAL fluid was examined. Results: The percentage of lymphocytes in BAL fluid was increased (>18%) in 11 of 30 HTLV-I carriers although there was no significant difference compared with control subjects. In HTLV-I carriers the lymphocyte number in BAL fluid correlated well with the copy number of HTLV-I proviral DNA in PBMCs. In addition, the copy number of HTLV-I proviral DNA in BAL fluid correlated well with the number of lymphocytes (both CD4+ and CD8+ cells) in BAL fluid. Conclusions: These findings suggest that pulmonary lymphocytosis can occur in a subset of HTLV-I carriers without HAM/TSP and that the increased HTLV-I proviral DNA load may be implicated in the pathogenesis of pulmonary involvement in HTLV-I carriers.

A 19-year-old man was admitted to our hospital because of chest pain. He was diagnosed as having pleural cryptococcosis by pleural biopsy. His CD4 positive T-lymphocyte count was low (300 microl) and there was no evidence of human immunodeficiency virus infection. He was successfully treated with fluconazole. However, his CD4 positive lymphocyte counts remained low after the recovery and he was diagnosed as idiopathic CD4 positive T-lymphocytopenia. Pleural cryptococcosis is rare and its predisposing condition is still controversial. To our knowledge, this is the first case of pleural cryptococcosis associated with idiopathic CD4 positive T lymphocytopenia.

An asymptomatic patient with a pulmonary coin lesion surgically diagnosed with pulmonary dirofilariasis caused by infection with Dirofilaria immitis (D. immitis) is presented. The preoperative stored serum of the patient was positive for D. immitis by enzyme-linked immunosorbent assay (ELISA). A family study showed that three of five family members were seropositive for D. immitis. These results suggest that family members of a patient with pulmonary dirofilariasis were frequently exposed to D. immitis and serodiagnostic methods are useful for detecting subclinical infection of D. immitis.

Neutropenia is a common laboratory finding in systemic lupus erythematosus (SLE). However, the molecular mechanism of SLE neutropenia has not been fully explained. In this study, we examined whether TNF-related apoptosis-inducing ligand (TRAIL) is involved in the pathogenesis of SLE neutropenia using samples from SLE patients. Serum TRAIL levels in SLE patients with neutropenia were significantly higher than those of SLE patients without neutropenia and healthy volunteers. Serum TRAIL levels showed a significant negative correlation with neutrophil counts in SLE patients. The expression of TRAIL receptor 3 was significantly lower in SLE patients with neutropenia than in patients without neutropenia or in healthy volunteers. Treatment with glucocorticoids negated the decrease of TRAIL receptor 3 expression on neutrophils of SLE patients. TRAIL may accelerate neutrophil apoptosis of neutrophils from SLE patients, and autologous T cells of SLE patients, which express TRAIL on surface, may kill autologous neutrophils. Interferon gamma and glucocorticoid modulated the expression of TRAIL on T cells of SLE patients and also modulated the expression of cellular Fas-associating protein with death domain–like interleukin-1β–converting enzyme (FLICE)–inhibitory protein (cFLIP), an inhibitor of death receptor signaling, in neutrophils. Thus, our results provide a novel insight into the molecular pathogenesis of SLE neutropenia.

A 62-year-old woman with diabetes mellitus and chronic hepatitis C was admitted to our hospital because of fever and productive cough. A thoracic CT scan demonstrated a cavity in the left upper lobe, thickening of the bronchial walls and multiple subpleural infiltrates. Fiberoptic bronchoscopy revealed aspergillus bronchitis. The patient was treated with 200 mg/day of oral itraconazole, but no effect was seen. Treatment with 300 mg/day of oral itraconazole, however, resulted in improvement of the symptoms and resolution of the radiographic abnormalities. We report a rare case of aspergillus bronchitis.

The optimal management of patients with non-small cell lung cancer (NSCLC) depends onthe accuracy of appropriate staging strategies. Thebest approach for clinical staging, especially theevaluation of lymph node metastasis, continuesto confound clinicians. A specific, less-invasivemethod to support preoperative stage evaluation isrequired. Recently, Fliss et al. [2000] reported a highfrequency of mitochondria DNA (mtDNA) mutationin NSCLC. MtDNA is preferentially modified bymany carcinogens and is repaired less efficientlycompared with that of nuclear DNA [Khrapko et al.,1997]. We speculated an association between mtDNAmutation and NSCLC exists and, therefore, se-quenced the mtDNA of tumor cells from NSCLCpatients.This study was reviewed and approved by theKagoshima University Faculty of Medicine Committeeon Human Research.We prospectively investigated 202 NSCLC patients(adenocarcinoma, 106; squamous cell carcinoma,86; bronchoalveolar carcinoma, 4; large cell carcino-ma, 6), including 119 men and 83 women whosemean age was 63.2

Objective:To evaluate the usefulness of an assay using two polymerase chain reaction-based genotyping methods in the practical surveillance of methicillin-resistantStaphylococcus aureus(MRSA).Methods:Nosocomial infection and colonization were surveyed monthly in a university hospital in Japan for 20 months. Genotyping withmec-HVR is based on the size of themec-associated hypervariable region amplified by polymerase chain reaction. Toxin genotyping uses a multiplex polymerase chain reaction method to amplify eight staphylococcal toxin genes.Results:Eight hundred nine MRSA isolates were classified into 49 genotypes. We observed differing prevalences of genotypes for different hospital wards, and could rapidly demonstrate the similarity of genotype for outbreak isolates. The incidence of genotype D: SEC/TSST1 was significantly higher in isolates causing nosocomial infections (49.5%; 48 of 97) than in nasal isolates (31.4%; 54 of 172) (P= .004), suggesting that this genotype may represent the nosocomial strains.Conclusion:The combined use of these two genotyping methods resulted in improved discriminatory ability and should be further investigated.

A 49-year-old woman with myasthenia gravis who underwent left panpleuropneumonectomy for an invasive thymoma that disseminated through the left thoracic cavity. After six year, radiotherapy was conducted on the recurrent tumor in the left anterior chest wall. Two years later, the recurrent tumors in the intrapelvic and intrathoracic cavities were resected. It was thought that long-term survival was obtained by combining radiotherapy and surgical treatment in view of the patient's general condition, and of the recurrent invasive thymoma present in this case.

Objective Vascular endothelial growth factor (VEGF), a cytokine associated with malignant neoplasms, is increased in a number of inflammatory and infectious disorders. But little is known about VEGF in pulmonary aspergilloma (PA). In order to clarify the predictive value of VEGF in PA, we examined serum VEGF levels in PA patients as well as expression of VEGF in the PA lesion. Patients Twenty-one patients with PA (6 with hemoptysis and the rest without hemoptysis) were investigated. Methods In all patients, serum VEGF levels were measured by enzyme-linked immunosorbent assay. We examined the statistical correlations of serum VEGF levels with the ratio of affected area to total lung volume and VEGF with PaO2 levels. In patients with hemoptysis, we measured the serum VEGF levels three months after the initiation of therapy. We examined the expression of VEGF in the resected lung tissue of 4 patients with PA using immunohistochemistry. Results Serum VEGF levels showed a significant positive correlation with the ratio of affected to total lung area and a significant negative correlation with PaO2 levels. Serum VEGF levels in patients with hemoptysis were significantly higher than in those without hemoptysis. The serum levels of VEGF in patients with hemoptysis decreased significantly in parallel with the alleviation of hemoptysis. Immunohistochemical staining demonstrated the expression of VEGF in alveolar macrophages in the lesion of PA patients. Conclusion We suggest that VEGF can be used as a serum marker to determine the extent of the lesion, hypoxia and hemoptysis in PA.(Internal Medicine 40: 1195-1199, 2001)

Interstitial lung disease (ILD) has a heterogeneous clinical presentation and establishing prognosis for these patients is challenging. We investigated the clinical characteristics and outcome of patients with idiopathic interstitial pneumonias (IIPs) and patients with connective tissue disease-associated interstitial lung disease (CTD-ILD). We conducted a multicenter prospective study on 104 patients diagnosed with IIPs and 29 patients diagnosed with CTD-ILD, which were newly diagnosed and treated with corticosteroids initially. We compared the clinical characteristics, high-resolution computed tomography (HRCT) imaging date, and outcomes. Cox proportional hazard regression analysis was used to identify variables with increased risk of death. Survival was analyzed according to the Kaplan–Meier method and was assessed with the log-rank test. Of 133 patients with IIPs (n = 104) or CTD-ILD (n = 29), 44 patients died during the follow-up period (mean: 1.6 ± 0.78 years). Patients with IIPs seemed to be associated with worse survival compared with those with CTD-ILD; however, this difference was not significant (log-rank test, P = 0.084). Significant predictors for mortality in patients with IIPs at baseline were lower for performance status and definite usual interstitial pattern (UIP) on HRCT. Patients with UIP experienced worse survival than those with non-UIP. A definite UIP on HRCT and lower baseline performance status have important prognostic implications in patients with IIPs.

BACKGROUND We have previously reported that disseminated pulmonary Mycobacterium avium complex (MAC) infection is more common in human T lymphotrophic virus type I (HTLV-I) carriers than in non-carriers. However, the reason for this remains unclear. It has been shown that glycopeptidelipid (GPL), one of the lipid components of the cell envelope of MAC, is able to reduce the lymphocyte blastogenic response to mitogens. The purpose of this study was to clarify whether or not the inhibitory effect of GPL differs between HTLV-I carriers and non-carriers. METHODS Peripheral blood lymphocytes were obtained from 29 patients who had recovered from pulmonary MAC infection (10 of whom also had HTLV-I infection) and the lymphocyte counts and T cell subpopulations of the peripheral blood lymphocytes in HTLV-I carriers and non-carriers were compared. The inhibitory effect of GPL on the lymphocyte blastogenic response to phytohaemagglutinin (PHA) was tested in these 29 cases and in 15 healthy controls who had never suffered from MAC (seven of whom also had HTLV-I infection). All HTLV-I positive cases were carriers. RESULTS There was no significant difference in the numbers or subset proportions of T cells between HTLV-I carriers and non-carriers. Lymphocyte activation by PHA was significantly inhibited by GPL in MAC positive and negative HTLV-I carriers compared with MAC negative non-carriers and MAC negative healthy controls (p

Pulmonary tuberculosis, one of the granulomatous diseases, has few serological markers for its activity. Recently, an increased serum level of vascular endothelial growth factor (VEGF) was detected in patients with Crohn's disease, also a granulomatous disease. We hypothesized that VEGF might be associated with the pathogenesis of pulmonary tuberculosis. We investigated the serum level of VEGF in 43 patients with active pulmonary tuberculosis, 29 patients with old tuberculosis, and 25 patients with acute bronchitis. We were able to examine the serum VEGF levels every 3 mo for a period of 6 mo in seven patients with active pulmonary tuberculosis. We examined the presence of VEGF in the resected lungs of three patients with active pulmonary tuberculosis by immunohistochemistry. The serum levels of VEGF were significantly higher in patients with active pulmonary tuberculosis than in patients with old tuberculosis and acute bronchitis. The decrease in titer of serum VEGF paralleled the clinical improvement of patients with pulmonary tuberculosis. Immunohistochemical staining of the resected lungs demonstrated the presence of VEGF in alveolar macrophages surrounding the lesion. Therefore, VEGF may be associated with the pathogenesis of pulmonary tuberculosis.

BACKGROUND—Little is known about pulmonary Mycobacterium avium complex (MAC) infection in human T lymphotrophic virus type I (HTLV-I) carriers. A study was undertaken to investigate and clarify the characteristics of pulmonary MAC infection in these subjects. METHODS—Twenty nine patients with pulmonary MAC infection without any underlying pulmonary disorder were investigated. The clinical features and radiographic appearance of HTLV-I carriers and non-carriers were compared and the bronchoalveolar lavage (BAL) fluid of these 29 patients and eight normal female control subjects was analysed. RESULTS—The prevalence of the HTLV-I carrier state in patients with pulmonary MAC infection was 34.5% (10/29) compared with 16.7% (529/3169) among all patients admitted to our department between 1994 and 1998 (odds ratio (OR) 2.63, 95% confidence interval (CI) 1.21 to 5.68). The HTLV-I carriers were all women and all had clinical symptoms, but they did not show systemic dissemination. Peripheral multifocal bronchiectasis with nodular shadowing was seen frequently on the chest computed tomographic (CT) scans of HTLV-I carriers. The area of the pulmonary lesions was more extensive than in non-carriers (p

A 56-year-old woman was hospitalized for recurrent hemoptysis. She had been suffering from bronchiectasis for 4 years. Pseudomonas aeruginosa was persistently detected in her sputum. Serum was positive for Myeloperoxidase antineutrophil cytoplasmic antibody (MPO-ANCA) and bactericidal/permeability-increasing protein antineutrophil cytoplasmic antibody (BPI-ANCA). She underwent lung resection. Histopathologically, the resected lung showed bronchiectasis with pulmonary fibrosis but did not show vasculitis. Her serum became negative for the ANCAs after the operation. To date, she has no recurrence of hemoptysis. We discuss this case of bronchiectasis with MPO-ANCA and BPI-ANCA and suggest a possible role for ANCAs in chronic airway infection.

A 48-year-old man was admitted to our hospital with cough, fever and dysphagia. He had a past history of bronchial asthma and surgery for nasal polyp. Chest radiograph and computed tomography showed atelectasis in the right lower field and infiltrative shadow in the left lower field and overall thickening of the esophageal wall. Transbronchial lung biopsy (TBLB) specimens revealed infiltration of eosinophils and lymphocytes under the bronchial mucosa. Gastrointestinal tract biopsy specimens showed submucosal infiltration of eosinophils. These findings led to a definite diagnosis of eosinophilic pneumonia associated with eosinophilic gastroenteritis, a disease which has been rarely reported.

Indoor cultivation of oyster mushroom Pleurotus osteatus lead to an outbreak of extrinsic allergic alveolitis in two workers. High titer of indirect fluorescent antibody and positive precipitins against basidiospores of P. osteatus were demonstrated in sera of the patients. Mushroom workers should protect themselves from the basidiospores, being aware of their pathogenicity.

We present 2 cases of idiopathic CD4+ T-lymphocytopenia (ICL) in elderly patients. Case 1, a 73-year-old man, with pneumonia had received several antibiotics with unsuccessful results at another hospital. On admission, his CD4+ T-lymphocyte count was 109/microl and Pneumocystis carinii was detected by bronchoalveolar lavage fluid staining. No evidence of human immunodeficiency virus (HIV) infection was found. Despite therapy, the patient died of respiratory failure. Case 2, a 72-year-old man, contracted severe pneumonia, and Hemophillus influenzae was believed to be the pathogen. On admission, his CD4+ T-lymphocyte count was 238/microl. No evidence of HIV infection was found. He received antibiotics and improved successfully. We suggest that ICL may currently be incubating in a number of elderly pneumonia patients.

An 18-year old male was admitted to our hospital complaining of back pain. His chest computed tomography showed a tumor in the posterior mediastinum. Open biopsy was performed, and a diagnosis of peripheral neuroepithelioma was made. No genetic abnormalities were detected in the DNA obtained from the biopsy specimen. He received chemotherapy and radiation several times. These treatment regimens were effective, but he relapsed 14 months later and died of respiratory failure due to tumor growth. Autopsy examination revealed a large tumor which occupied almost the entire right thoracic cavity, but there was no evidence of metastasis to other organs. Chromosomal translocation t(14;17) (q24;p12.2) and point mutation of exon 5 of the p53 gene were detected.

Fosfomycin has recently been reported as an antibiotic with immunomodulatory activities. To evaluate the possibility of clinical administration of fosfomycin in patients with human T lymphotropic virus type I (HTLV-I)-associated myelopathy/tropical spastic paraparesis (HAM/TSP), the effects of this agent on the HTLV-I-induced in vitro phenomenon were studied. The influence of fosfomycin on in vitro spontaneous proliferation (SP) of peripheral blood mononuclear cells (PBMCs) from four patients with HAM/TSP was measured by thymidine incorporation into the cells, and the concentration of several cytokines in the culture supernatants was examined in three HAM/TSP patients. Enzyme-linked immunosorbent assays (ELISAs) were employed to detect the concentrations of interleukin-4 (IL-4), IL-6, IL-10, interferon-gamma (IFN-gamma), transforming growth factor-beta1 (TGF-beta1), and macrophage inflammatory protein-1alpha (MIP-1alpha). The data were compared to the changes by prednisolone which is known to regulate the HTLV-I-associated in vitro phenomenon and to have a therapeutic benefit in patients with HAM/TSP. Production of IL-6, IFN-gamma and MIP-1alpha from the spontaneously proliferating cells were demonstrated. Fosfomycin could not suppress the HTLV-I-associated SP, but had the properties to decrease the levels of TGF-beta1 and MIP-1alpha. It was also demonstrated that the concentrations of IFN-gamma and MIP-1alpha in the cultures in the presence of prednisolone were apparently decreased, suggesting a possible involvement of these cytokines in the pathogenesis of HAM/TSP. These findings support the hypothesis that fosfomycin may have immunomodulatory potentials in HTLV-I-related cellular interactions in a different manner from ordinary immunomodulatory agents.

We studied the clinical features and laboratory findings in 213 patients with HTLV-I-associated myelopathy/tropical spastic paraparesis as diagnosed in Kagoshima University Hospital. Some aspects of clinical features in HTLV-I-associated myelopathy/tropical spastic paraparesis were characterized by mode of HTLV-I transmission and age of onset. The patients with onset after 15 years old and no history of blood transfusion before the onset of the disease (151 patients, group I) showed a shorter interval between the time of disease onset and that of inability to walk. The patients with onset before 15 years old and without history of blood transfusion (21 patients, group II) had short stature and slow progression of the disease. The interval time and the progression of the disease in patients with history of blood transfusion before onset of disease (41 patients, group III) were in between those of the above two groups. Patients whose ages of onset were older than 61 years old showed a faster progression than those with younger onset regardless of the mode of HTLV-I transmission. HTLV-I-associated myelopathy/tropical spastic paraparesis patients often also showed other organ disorders such as leukoencephalopathy (69%), abnormal findings on chest X-ray (50%), Sjogren syndrome (25%) and arthropathy (17%). The patients with low anti-HTLV-I antibody titers in the cerebrospinal fluid (2X-8X by PA method) had an older age of onset on average, milder clinical symptoms and lesser increase of neopterin in the cerebrospinal fluid than those in the high titer subgroup whose titers were higher than 1024X in cerebrospinal fluid regardless of the mode of HTLV-I transmission. We speculate that the clinical course of HTLV-I-associated myelopathy/tropical spastic paraparesis mainly shows a slow progression which consists of an initial progressive phase (probably an inflammatory phase) and a latter chronic phase, although some patients showed acute/subacute onset and rapid progression.