Kohei Hara

Interleukin 1β, Tumor Necrosis Factor Alpha, and Interleukin 8 in Bronchoalveolar Lavage Fluid of Patients with Diffuse Panbronchiolitis: A Potential Mechanism of Macrolide Therapy

We measured the levels of interleukin (IL) 1 beta, tumor necrosis factor alpha, and IL-8 in bronchoalveolar lavage fluid (BALF) and sera of patients with diffuse panbronchiolitis (DPB) before and after administration of erythromycin or roxithromycin. The pretreatment levels of IL-1 beta and IL-8 were significantly higher in the BALF of patients with DPB than in the BALF of patients with sarcoidosis and controls. The tumor necrosis factor alpha level was also higher than in controls, but not statistically significant. There was a significant correlation between percentage of neutrophils and IL-8 level in the BALF of DPB patients (r = 0.509; p < 0.05) on the one hand and between IL-1 beta and IL-8 on the other (r = 0.476; p < 0.04). Treatment for 1-24 months significantly reduced BALF levels of IL-1 beta and IL-8 of DPB patients in parallel with a reduction in BALF neutrophils. The serum level of IL-8 of DPB patients was higher, albeit insignificant, than that of controls and significantly lower than that in the BALF of the same patients (p = 0.0088). Serum IL-1 beta was below the detection limit. In addition, the concentration of IL-8 in alveolar macrophages obtained from 2 volunteers before and after oral erythromycin administration also decreased ex vivo. Our results indicate that IL-8 induces the migration of neutrophils to inflammatory sites. It is possible that the macrolides impair production and/or secretion of these cytokines, ultimately reducing neutrophil accumulation in the airway.

A newly developed immunoliposome — an egg phosphatidylcholine liposome coated with pullulan bearing both a cholesterol moiety and an IgMs fragment

An improved methodology for providing a more stable and targetable drug carrier has been developed. This method involves the synthesis of a newly designed immunoliposome by coating the outermost surface of large oligolamellar vesicles of egg phosphatidylcholine with the polysaccharide pullulan, modified to carry both cholesterol, as the hydrophobic anchor, and the monoclonal antibody fragment (anti-sialosyl Lewis X, IgMs) as the sensory device. Compared with the binding of pullulan-coated liposomes, that of this immunoliposome to specific cells in vitro was significantly increased by factors of 447 to PC-9 and 295 to KATO-III, but only by a factor of 148 to the less specific cell, 3LL. This strong and specific binding of the immunoliposome to the cell surface of PC-9 was also confirmed by a fluorescence-microscopic investigation using the immunoliposome, which bore the hydrophobic fluorescent probe, terbium trisacetylacetonate, in the liposomal membrane.

Investigation of the mechanism of alcohol-induced bronchial asthma

BACKGROUND Many Japanese patients with asthma experience episodes or exacerbation of asthma after alcohol consumption. This phenomenon is not seen in Caucasians and is specific to Asians. This has been thought to be attributable to a difference in alcohol metabolism, in particular the metabolism of acetaldehyde, between Asians and Caucasians. METHODS An oral ethanol challenge test, a leukocyte histamine release test, and an ELISA for detection of IgE specific to acetaldehyde-human serum albumin conjugate were carried out in 42 adults with bronchial asthma and nine healthy adults. RESULTS Fifty-five percent of the patients with asthma responded to the ethanol challenge and showed a 20% or greater reduction in forced expiratory volume in 1 second. Blood acetaldehyde and plasma histamine levels were significantly higher in responders than in nonresponders. The leukocyte histamine release test revealed no ethanol-induced histamine release. Acetaldehyde, on the other hand, was found to induce histamine release in a volume-dependent manner. The histamine release was significantly higher in the asthma group (both responders and nonresponders) than in the healthy control group. ELISA did not detect any IgE specific to acetaldehyde-human serum albumin conjugate. CONCLUSION Alcohol-induced bronchial asthma seems to develop as follows. Alcohol elevates blood acetaldehyde levels, which leads to degranulation of mast cells (or basophils). The resultant release of chemical mediators, such as histamine, induces asthma.

Phase II study of (glycolate-O,O′) diammineplatinum(II), a novel platinum complex, in the treatment of non-small-cell lung cancer

SummaryA total of 68 patients with non-small-cell lung cancer who either had not previously been treated (38) or had undergone prior therapy (30) were treated in a phase II study of (glycolate-O,O′) diammineplatinum(II) (NSC 375 101D; 254-S), a new platinum complex. The drug was given as a single intravenous infusion at a dose of 100 mg/m2 every 4 weeks. All 68 patients could be evaluated for response and 62, for toxicity. Objective responses were seen in 10 of 68 cases (14.7%; 95% confidence interval, 7.3%–25.4%), and the median duration of response was 15 weeks (range, 8–23 weeks). The response rates were similar for previously untreated and treated patients (13% and 17%, respectively), including three previously treated with cisplatin. Myelosuppression was the dose-limiting toxicity. Thrombocytopenia (<100,000 platelets/mm3) and leukocytopenia (<3,000 WBC/mm3) were observed in 22 (35%) and 18 (29%) patients, respectively. Mild to moderate nausea and vomiting occurred in 45 cases (73%). No significant renal or neurotoxicity was observed. We conclude that as a single agent, 254-S is well tolerated but appears to have marginal activity against non-small-cell lung cancer.

An evaluation of serodiagnostic tests in patients with candidemia : Beta-glucan, mannan, candida antigen by Cand-Tec and D-arabinitol

The serodiagnostic tests, beta‐glucan, mannan, candida antigen by Cand‐Tec, and D‐arabinitol were evaluated in 10 patients with candidemia, 14 patients with suspected fungemia, and 10 healthy persons. By blood culture or lysis centrifugation, C. albicans was isolated from 5 patients, C. parapsilosis from 4, and C. tropicalis from 1 patient; no organisms were isolated from the 14 patients with suspected fungemia or the 10 healthy subjects. Beta‐glucan was measured by the difference between two chromogenic limulus tests (Endotoxin test‐D® and Endospecy®), which was more than 60 pg/ml in 7 of 9 (78%) candidemic patients and 1 of 12 (8%) patients with suspected fungemia. Mannan was positive in 6 of 10 (60%) candidemic patients and 1 of 13 (8%) patients with suspected fungemia. Both antigens were very sensitive and highly specific for candidemia. However, the Cand‐Tec assay was less specific, because titers of more than 4 were observed in 5 of 14 (34%) patients with suspected fungemia. D‐Arabinitol was the least sensitive, because a D‐arabinitol/creatinine ratio greater than 2.0 μmol/mg was observed in only 2 of 7 (29%) candidemic patients. The titers of serodiagnostic tests decreased after successful treatment with an anti‐fungal agent. Our results show that the combined use of the assays in necessary for accurate serological diagnosis of candidemia.

T Cell-Dependent Activation of Macrophages and Enhancement of Their Phagocytic Activity in the Lungs of Mice Inoculated with Heat-Killed Cryptococcus neoformans: Involvement of IFN-γ and Its Protective Effect against Cryptococcal Infection

Previous investigations have demonstrated that macrophages play a critical role in the first‐line cellular defense mechanism against infection with Cryptococcus neoformans. In the present study, to elucidate the way in which anticryptococcal activity of macrophages is regulated at the site of infection, pulmonary intraparenchymal macrophages were directly analyzed for expression of their surface molecules and their phagocytic activities against the organism, and the effects of depletion of T cells and endogenous IFN‐γ in vivo on these parameters were examined. In the lungs of mice intratracheally inoculated with heat‐killed C. neoformans, macrophages were activated, as indicated by augmented expression of MHC class II, intercellular adhesion molecule‐1 (ICAM‐1) and Fc receptor (FcR), and about two‐thirds of macrophages were found to have ingested an average of 3.77 ± 0.12 yeast cells per macrophage. In mice depleted of both CD4+ and CD8+ T cells by injecting the specific monoclonal antibodies (mAbs) or anti‐IFN‐γ mAb, not only augmentation of the expression of macrophage activation markers but also phagocytosis of C. neoformans was significantly reduced. These results suggest that anticryptococcal activity of macrophages is regulated by IFN‐γ endogenously produced by T cells. Additionally, treatment with IFN‐γ were shown to significantly prolong the survival time of mice infected with viable C. neoformans. Additionally, preimmunization with heat‐killed C. neoformans significantly prolonged the survival time of mice which received the following infection.

Activation of macrophages and expansion of specific T lymphocytes in the lungs of mice intratracheally inoculated with Cryptococcus neoformans

A quantitative and qualitative change in inflammatory cells in the lungs of mice after intratracheal inoculation of heat‐killed Cryptococcus neoformans was examined by direct analysis of the pulmonary intraparenchymal leucocytes. Macrophages and T and B lymphocytes increased, peaked at day 7, and then gradually decreased to the basal level, Macrophages were activated 7 days after the inoculation, as indicated by the enhanced expression of MHC class II, intercellular adhesion molecule‐1 (ICAM‐I)and Fc receptor (FcR), which have been known as their activation markers. T cells were also activated, as indicated by the induction of IL‐2 receptor (IL‐2R) and the enhanced expression of leucocyte function‐associated molecule‐1 (LFA‐1) and ICAM‐1, a pair of adhesion molecules which have also been regarded as T cell activation markers. CD4+ T cells preferentially accumulated in lungs, and proliferated in vitro by stimulation with heat‐killed whole yeast cells, suggesting that at least some of the infiltrated T cells expand locally in response to the organisms. These results demonstrate that the activation of macrophages and T cells reactive to C. neoformans is induced in lungs after intratracheal inoculation of heat‐killed organisms, and suggest that these cells interact to eliminate organisms more efficiently from the host.

Splenic metastasis from lung cancer

Splenic metastasis from lung cancer is a rare clinical event, most often diagnosed at the time of autopsy. We report 2 cases of splenic metastasis with a primary lung cancer. The first case was a 76-year-old man presenting with a recurrent solitary splenic metastasis 14 months after surgical removal of a squamous cell carcinoma of the lung. The second patient was a 72-year-old woman who had a poorly differentiated carcinoma of the lung and multiple abdominal metastasis. We also investigated 267 autopsy cases of lung cancer from 1975 to 1992. Histologically, there were 73 cases of squamous cell carcinoma, 123 adenocarcinoma, 29 large cell carcinoma, 36 small cell carcinoma, and 7 other miscellaneous tumours. The number of splenic metastasis from lung cancer in these cases was 15 (5.6%). Splenic metastasis from a primary cancer of the left lung was more frequent than that from the right lung. Nine of 15 splenic metastases were smaller than 1 cm in size. Splenic metastasis was associated with liver and pancreas metastasis. All 15 autopsy cases with splenic metastasis from lung cancer had other abdominal organ metastasis. Our analysis indicates that a solitary splenic metastasis is rare. Selection of a suitable therapeutic approach is important.

Clinical features, risk factors and treatment of fulminant Mycoplasma pneumoniae pneumonia: A review of the Japanese literature

Mycoplasma pneumoniae (MP) is one of the most common causes of community-acquired pneumonia in children and young adults. Although MP sometimes causes self-limiting pneumonia, severe and fulminant cases with hypoxia occur, but their clinical features have rarely been reported. This study aimed to reveal the clinical manifestations, risk factors, and treatment of fulminant MP pneumonia (MPP). Using PubMed and abstracts from the proceedings of several domestic Japanese academic societies, we reviewed the Japanese and English literature for cases of fulminant or severe MPP reported in Japan. All clinical information such as sex, age, underlying diseases, clinical symptoms, clinical course, laboratory and radiological findings, and treatment was collected and analyzed. In total, 52 fulminant MPP cases were reported between September, 1979 and February, 2010. The dominant population of fulminant MPP was young adults without severe underlying diseases. Cough (97.3%), fever (100.0%), and dyspnea (83.3%) with diffuse abnormal findings in radiological examinations were noted. Antibiotics without anti-mycoplasmal activity were used in 32 cases (61.5%) as initial treatment prior to the onset of hypoxia. Anti-mycoplasmal drugs were appropriately used in 41 cases (78.8%) after onset of respiratory failure with steroids (23 cases, 45.1%) and effective. The majority of patients improved within 3-5 days after steroid administration. There were only 2 fatal cases. Although this small retrospective study did not reveal the apparent risk factors of fulminant MPP, initial inappropriate use of antibiotics may be a risk factor, and early administration of appropriate anti-mycoplasmal drugs with steroids as a cellular immune suppressor is required.

Expression of human T lymphotropic virus type 1 (HTLV-1) tax/rex gene in fresh bronchoalveolar lavage cells of HTLV-1-infected individuals.

Accumulating evidence has suggested the involvement of HTLV‐1 in the inflammatory lesions of various organs, including the lung. However, the causal relationship between HTLV‐1 and inflammatory responses in the organs remains to be elucidated. In order to evaluate the expression of HTLV‐1 and its effects in the lung, we examined the expression of mRNA for the HTLV‐1 tax/rex gene in fresh bronchoalveolar lavage cells (BALC) and peripheral blood mononuclear cells (PBMC) of 23 seropositive individuals, including six patients with HTLV‐1‐associated myelopathy/tropical spastic paraparesis (HAM/TSP), by use of an improved method of reverse transcription‐polymerase chain reaction (RT‐PCR). The tax/rex mRNA was more frequently detected in BALC than in PBMC. All the HAM/TSP patients and eight of 17 carriers without neurological symptoms showed the expression of tax/rex mRNA in the BALC. IgM class antibodies to HTLV‐1 were preferentially detected in sera of the tax/rex mRNA‐positive individuals. The detection of tax/rex mRNA correlated closely with the presence of lymphocytosis accompanied by an elevated proportion of IL‐2 receptor‐bearing T cells in the BALC. Our findings indicate the crucial role of viral expression in the inflammatory response in the lung in HTLV‐1‐infected individuals.