Masaharu Kawabata

HTLV-I-associated myelopathy: analysis of 213 patients based on clinical features and laboratory findings

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%), Sjögren 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.

Therapeutic trials in 200 patients with HTLV-Iassociated myelopathy/tropical spastic paraparesis

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.

Expression of vascular endothelial growth factor in tuberculous meningitis.

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.

Bronchoalveolar lymphocytosis correlates with human T lymphotropic virus type I (HTLV-I) proviral DNA load in HTLV-I carriers

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.

Regulation of Eosinophil Cell Death by Adhesion to Fibronectin

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.

An epidemiologic survey of methicillin-resistant Staphylococcus aureus by combined use of mec-HVR genotyping and toxin genotyping in a university hospital in Japan.

OBJECTIVE To evaluate the usefulness of an assay using two polymerase chain reaction-based genotyping methods in the practical surveillance of methicillin-resistant Staphylococcus aureus (MRSA). METHODS Nosocomial infection and colonization were surveyed monthly in a university hospital in Japan for 20 months. Genotyping with mec-HVR is based on the size of the mec-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.

Purified protein derivative of tuberculin upregulates the expression of vascular endothelial growth factor in T lymphocytes in vitro.

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.

Outbreak of Bronchiolitis obliterans Associated with Consumption of Sauropus androgynus in Japan – Alert of Food-Associated Pulmonary Disorders from Japan

Outbreak of Bronchiolitis obliterans Associated with Consumption of Sauropus androgynus in Japan – Alert of Food-Associated Pulmonary Disorders from Japan Kenichi Oonakahara a, Wataru Matsuyama a, Ikkou Higashimoto a, Kentarou Machida a, Masaharu Kawabata a, Kimiyoshi Arimura a, Mitsuhiro Osame a, Miho Hayashib, Takashi Ogura b, Kazuyoshi Imaizumi c, Yoshinori Hasegawa c aThird Department of Internal Medicine, Kagoshima University Faculty of Medicine, Kagoshima, bDepartment of Respiratory Medicine, Kanagawa Cardiovascular and Respiratory Center, Yokohama, and c Department of Medicine, Division of Respiratory Diseases, Nagoya University Graduate School of Medicine, Nagoya, Japan

Influence of human T lymphotrophic virus type I on cryptogenic fibrosing alveolitis — HTLV-I associated fibrosing alveolitis: proposal of a new clinical entity

Human 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.

Adhesion to Fibronectin Regulates Expression of Intercellular Adhesion Molecule-1 on Eosinophilic Cells

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.