Dendritic cell maturation overrules H-2D-mediated natural killer T (NKT) cell inhibition: critical role for B7 in CD1d-dependent NKT cell interferon gamma production.

Given the broad expression of H-2 class Ib molecules on hematopoietic cells, antigen presentation pathways among CD1d expressing cells might tightly regulate CD1d-restricted natural killer T (NKT) cells. Bone marrow-derived dendritic cells (BM-DCs) and not adherent splenocytes become capable of triggering NK1.1(+)/T cell receptor (TCR)(int) hepatic NKT cell activation when (a) immature BM-DCs lack H-2D(b)-/- molecules or (b) BM-DCs undergo a stress signal of activation. In such conditions, BM-DCs promote T helper type 1 predominant CD1d-restricted NKT cell stimulation. H-2 class Ia-mediated inhibition involves more the direct H-2D(b) presentation than the indirect Qa-1(b) pathway. Such inhibition can be overruled by B7/CD28 interactions and marginally by CD40/CD40L or interleukin 12. These data point to a unique regulatory role of DCs in NKT cell innate immune responses and suggest that H-2 class Ia and Ib pathways differentially control NKT cell recognition of DC antigens.

Patients with severe emphysema have a low risk of radiation pneumonitis following stereotactic body radiotherapy.

OBJECTIVE: To evaluate the risk of radiation pneumonitis (RP) after stereotactic radiotherapy (SBRT) for patients presenting with severe pulmonary emphysema. METHODS: This study included 40 patients with Stage I non-small-cell lung cancer who underwent SBRT, 75 Gy given in 30 fractions, at the Tokyo Medical University, Tokyo, Japan, between February 2010 and February 2013. The median age of the patients was 79 years (range, 49-90 years), and the male:female ratio was 24:16. There were 20 T1 and 20 T2 tumours. 17 patients had emphysema, 6 had slight interstitial changes on CT images and the remaining 17 had no underlying lung disease. The level of emphysema was classified into three groups according to the modified Goddard's criteria (severe: three patients, moderate: eight patients and mild: six patients). Changes in the irradiated lung following SBRT were evaluated by CT. RESULTS: On CT images, RP was detected in 34 (85%) patients, and not in 6 (15%) patients, during a median observation period of 313 days. Of the six patients, three had severe emphysema and three had no underlying lung disease. Patients with severe emphysema had lower risk of RP than those with moderate emphysema (p = 0.01), mild emphysema (p = 0.04) and no underlying lung disease (p = 0.01). CONCLUSION: Patients with severe emphysema had a low risk of RP following SBRT. ADVANCES IN KNOWLEDGE: Little is known about the association between RP and pulmonary emphysema. Patients with severe emphysema had lower risk of RP than those with no underlying lung disease.

Dosimetric evaluation of compensator intensity modulation-based stereotactic body radiotherapy for Stage I non-small-cell lung cancer.

OBJECTIVE: To evaluate the dosimetry of compensator intensity modulation-based stereotactic body radiotherapy (SBRT) [non-coplanar intensity-modulated radiotherapy (ncIMRT)], its use was compared with that of three-dimensional conformation-based SBRT, for patients with Stage I non-small-cell lung cancer (NSCLC). METHODS: 21 consecutive patients with Stage I NSCLC were treated with ncIMRT or SBRT at Tokyo Medical University. To compare the two techniques, ncIMRT and SBRT plans for each patient were generated, where the planning target volume (PTV) coverages were adjusted to be equivalent to each other. The prescribed dose was set as 75 Gy in 30 fractions. PTV coverage, conformity index, conformation number (CN) and homogeneity index (HI) were used to compare the two strategies. RESULTS: There was no statistically significant difference between PTV coverage for the 100%, 95% and 90% dose levels in the SBRT plan and those in the ncIMRT plan. The CN values were 0.53 ± 0.13 in the SBRT plan and 0.72 ± 0.10 in the ncIMRT plan. These values were significantly better than those of the SBRT plan (p < 0.001). The HI in the ncIMRT plan was 1.04 ± 0.03%, which was also significantly better than that of SBRT. CONCLUSION: The ncIMRT plan provided superior conformity and reduced the doses to the lung for patients with Stage I NSCLC. ADVANCES IN KNOWLEDGE: The delivery technique with compensator intensity modulation-based SBRT was evaluated. Concerning target motion, this is thought to be more robust and safer than SBRT for early-stage NSCLC.

Suppression of rat deoxycorticosterone-salt hypertension by kallikrein-kinin system.

Brown Norway kininogen-deficient rats had very low levels of plasma kininogens and lower levels of plasma prekallikrein, compared with those of normal rats of the same strain. Systolic blood pressure, determined by the tail-cuff method, of 5-week-old kininogen-deficient rats (106 +/- 0.4 mm Hg, n = 7) and the rate of systolic blood pressure increase with age were not different from those in normal rats. Weekly injections of deoxycorticosterone acetate (5 mg/kg s.c.) with 1% sodium chloride solution in drinking water after uninephrectomy at 7 weeks of age caused a gradual increase in the blood pressure of normal rats, reaching a plateau at 18 weeks of age, whereas that of deficient rats rose rapidly to 158 +/- 6 mm Hg 2 weeks after the start of treatment and continued to increase slightly, becoming significantly higher than normal rats at 8, 9, 10, 11, and 12 weeks of age (p less than 0.05 or 0.01). The levels of urinary prokallikrein and active kallikrein were slightly higher in deficient rats before deoxycorticosterone acetate-salt treatment but were not significantly increased after this treatment, whereas these levels in normal rats were increased 3.6- and 4.7-fold by this treatment. Urinary free kinin, collected from the ureter in untreated deficient rats, was below the detection limit. The plasma level of low molecular weight kininogen, the substrate of glandular kallikrein, was decreased in normal rats during the treatment. Continuous subcutaneous injection of aprotinin by an osmotic pump to normal rats induced significant increase in blood pressure. These results indicate that glandular kallikrein may play a suppressive role in deoxycorticosterone acetate-salt hypertension.

Establishment and usefulness of an anti-human CD57 IgG1 monoclonal antibody.

In the present study we established a new monoclonal antibody, JNK-1, which recognizes all cells recognized by CD57/HNK-1 mAb. JNK-1 and CD57 mAbs inhibited the binding of each other, suggesting that the molecules they recognize are either identical or sufficiently close to cause steric hindrance in the binding assay. JNK-1 mAb detected the 110-kDa protein, which is identical to the protein recognized by CD57/HNK-1 mAb in Western immunoblot analysis combined with immunoprecipitation. Therefore, JNK-1 mAb appears to recognize homogeneous molecules identified by the currently available CD57 mAb. Notably, JNK-1 mAb is composed of mouse IgG1 heavy chains, and thus can be used easily in immunoprecipitation, which cannot easily be performed with the available CD57 mAb because it is an IgM isotype. Thus, JNK-1, which is an IgG isotype, may present a useful tool to elucidate the CD57 protein.

Carcinogenic effect of N-bis(2-hydroxypropyl)nitrosamine by a single administration in rats.

The carcinogenic effect of a single intraperitoneal injection of N-bis)2-hydroxypropyl)nitrosamine (BHP) was studied in male Wistar rats. Lung tumors (adenomas and adenocarcinomas) had the highest incidence (100%). Fewer neoplasms were induced in the thyroid (adenomas and adenocarcinomas, 36%), kidney (renal cell carcinomas, 8%), and the sigmoid colon (adenomas and adenocarcinomas, 9%). No pancreatic neoplasms were found.

Effects of chrysotile asbestos on lung and pleural carcinogenesis of N-bis(2-hydroxypropyl)nitrosamine in rats.

The effects of chrysotile asbestos on lung and pleural carcinogenesis by N-bis(2-hydroxypropyl)nitrosamine (DHPN) in male Wistar rats were studied. Chrysotile, 30 mg per rat, was injected into the left pleural cavity and 3 g/kg body wt. DHPN was injected once into the abdominal cavity. Lung tumors (adenoma, adenocarcinoma, squamous cell carcinoma, and combined carcinoma) occurred at the highest incidence (100%). Adenocarcinoma was seen in 4 of 11 (36%) rats killed at 35 weeks and in 6 of 12 (50%) rats killed at 52 weeks, squamous cell carcinoma occurred in 1 of 11 (9%) rats killed at 35 weeks and 3 of 12 (25%) rats killed at 52 weeks, and mixed carcinoma was seen in 1 of 12 (8%) rats killed at 52 weeks, which received chrysotile and DHPN. Adenocarcinoma was seen in 9 of 11 (82%) rats which received DHPN only and killed at 52 weeks. Mesotheliomas were seen in 2 of 11 (18%) rats, killed at 35 weeks, and 3 of 12 (25%) rats, killed at 52 weeks, which received chrysotile and DHPN. Hyaline thickening of the pleura was seen in 100% of rats receiving chrysotile. Mesothelial cell hyperplasia and adenomatous and/or fibromatous growth of the mesothelium were seen in the pleura on both sides, ranging from 36% to 50% and 31% to 64% in rats receiving chrysotile and DHPN, respectively. Asbestos bodies were seen in the pleura on both sides and in the lung.

Pulmonary vascular involvement in sarcoidosis: a report of 40 autopsy cases.

We examined pulmonary vascular involvement in 40 autopsy cases of sarcoidosis. In these cases granulomatous involvement was observed at all levels from large elastic pulmonary arteries to venules, and venous involvement was more prominent than arterial involvement. The extent of granulomatous vascular involvement was related to that of parenchymal granuloma. No significant difference was found between upper and lower lobes in the incidence of granulomatous vascular involvement. The distribution of granulomata in the blood vessels was segmental and adventitial, and medial involvement was prominent in the larger vessels. Healed lesions of granulomatous vascular involvement also were observed at various levels in blood vessels. Prominent granulomatous involvement was found in the lymphatic capillaries and collecting lymphatic vessels in lungs with sarcoidosis. Serial sections of the lungs demonstrated interstitial granuloma directly connecting the lymphatic capillaries around small blood vessels. Granulomatous involvement in vasa vasorum and lymphatic capillaries is likely to be an important factor in the pathogenesis of granulomatous vascular involvement in lungs with sarcoidosis. The present study suggests that granulomatous vascular involvement and its sequelae may contribute to the development of pulmonary sarcoidosis.

Clinicopathological study of fatal myocardial sarcoidosis.

Presented here was an outline of fatal myocardial sarcoidosis in Japan based on 42 autopsy cases. The incidence, clinical features, pathological findings (particularly the distribution of sarcoid lesions in various organs, and gross as well as histological patterns have been reviewed. The ratio of fatal myocardial sarcoidosis to the total number of sarcoidosis deaths is higher than that of other countries and it appears characteristic of Japanese sarcoidosis that the disease occurs here predominantly after the fourth decade in females. Only 12% of myocardial sarcoidosis cases are diagnosed exactly. Conduction disturbances and dysrhythmias due to myocardial damage are its most common manifestations. The modes of presentation or cardiac death are sudden death, 16 cases (41%); congestive heart failure, 9 cases (23.1%); Adams-Stokes syndrome, except sudden death, 7 cases (17.9%); death due to dysrhythmia, 6 cases (15.4%); and 2 pacemaker deaths among the application of pacemakers, 7 cases. As for the ECG findings, A-V block and bundle-branch block was observed in most cases and ectopic beats were also frequently observed. The difficulty in exact diagnosis of myocardial sarcoidosis appears to be due to the frequency of lack of manifestation of systemic sarcoidosis as well as insidious cardiac involvement. The gross findings on myocardial lesions showed 3 patterns and each of the localized patterns corresponded to the histological extension. The conglomerate-band-like pattern corresponded to expansive invasion, the dendrite pattern to interstitial extension. The histological findings on the myocardial lesions were classified into four types: 1) exudative type, 2) granuloma type, 3) combined type of granuloma and fibrosis, 4) fibrotic type. Two extreme cases showed the exudative and fibrotic type, respectively, and were discussed.

A cooperative study of sarcoidosis in Asia and Africa: descriptive epidemiology.

An eight-nation cooperative epidemiological study revealed the Asian and African features of sarcoidosis. Almost every country reported from several to less than 30 cases, except for Japan which had already collected over 3,000 cases. Not a single case was found in the mass x-ray surveys conducted by several countries on a large scale (Tables 1 and 2). Although the number of the cases included in this study were small, this information is the first of this kind for Asia and Africa.

Clinical study on bacteria detected in the upper and lower respiratory tracts in patients with sinobronchial syndrome.

The authors examined bacteria to confirm the pathogenesis of sinobronchial syndrome (SBS). There were several theories such as the pus-descending, the pus-ascending, the coinciding theory and so on. Detection of bacteria was performed in SBS patients, empyema patients with no lower respiratory disease, and healthy adults. Considering SBS bacteriologically from the obtained results, the authors consider that internal infections of aerobic gram-negative bacteria of the normal flora mainly including Haemophilus influenzae possibly develop in two directions, downward and upward (into nasal cavities) from the pharynx, and so the pathogenesis of SBS might not be explained satisfactorily by either the ascending or the descending theory alone.

[Role of immune skin reactions in progressive lung cancer during the administration of OK-432--relation to reactions to DNCB, PPD and Su-PS].

In order to study the role of immune skin reactions (DNCB, PPD, Su-PS reaction) in progressive lung cancer, various investigations were conducted, in particular during the administration of OK-432, and the following results were obtained. Before and after chemotherapy, only a slight decrease in the skin reactions was noted. Su-PS reaction was intensified by the administration of OK-432, but other skin reactions were not changed after 3 months, being only slightly intensified by long-term administration. At the time of remission achieved through radiochemotherapy during administration of OK-432, Su-PS reaction was intensified compared to the level before treatment, and a lowering tendency was noted at the time of recurrence. PPD reaction presented a similar tendency, but DNCB reaction did not show this trend. Concerning the relationship between skin reaction and survival period, the positive DNCB reaction group before treatment had a significantly extended survival period compared to that of the negative group. During administration of OK-432, Su-PS reaction was most useful at all timings, while PPD reaction occurred during the intermediate period. Upon observing the Su-PS reaction after 3 months of treatment, the prognosis was excellent in cases with erythema of 10 mm or more. However, no such tendency was noted for the PPD reaction. Thus, for understanding the pathologic state and prognosis of patients with progressive lung cancer, the Su-PS reaction was most useful during intra dermal administration of OK-432, the PPD reaction was moderately useful, but the DNCB reaction produced different results. Therefore, for the evaluation of prognosis, it was considered essential to select and combine the skin reactions according to the examination timing and treatment schedule.

[A case of bronchogenic cyst which developed from negative findings to a thin-walled cavity for about 6 years].

A 56-year-old man whose chest radiograph in 1993 was normal was referred to our hospital because of a productive cough in 1997. Chest radiographs showed a thin-walled cavity filled with air. We followed his condition radiographically for three years and observed enlargement of the diameter of the lesion and appearance of an air fluid level, and we therefore decided to perform thoracoscopic middle lobe resection in 1999. Histological examination showed a communication between the cavity and a bronchus. As far as we know, there are no previous reports about intrapulmonary bronchogenic cysts which on radiographic observation developed from negative findings to a thin-walled cavity filled with air over a 6-year period.

[Spinal cord sarcoidosis without abnormal shadows on chest radiography or chest CT diagnosed by transbronchial lung biopsy].

The patient was a woman aged 56 years. In February 1998, she complained of fatigability of the right upper limb and disturbed extension of the right fourth finger. Because her condition deteriorated gradually and myelopathic signs such as difficulty in walking developed, she was hospitalized in May 1999 for close examination and appropriate treatment; and she was a few days later transferred to our hospital because of progressive myelopathy. In T2-weighted MR images of the cervical spine, the high-intensity area ranged between C2 and Th1, and in Gd-DTPA enhanced MRI the high-intensity area was seen between C3 and C7. Although chest radiographs and chest CT scans were normal, spinal cord sarcoidosis could not be ruled out, and therefore, bronchoscopic examination was performed. Specimens obtained from transbronchial lung biopsy (TBLB) revealed non-caseating epithelioid cell granulomas, and so and the disease was diagnosed as spinal cord sarcoidosis. Both symptoms and MRI findings were improved by treatment with corticosteroids. It is suggested that, in patients suspected of spinal cord sarcoidosis from MRI findings. TBLB should be aggressively attempted, even if chest radiographs and chest CT scans are normal.

[Proposal of a new classification of adult bronchial asthma--child onset asthma, adult onset asthma and adult relapse asthma. Project Team for Research into Adult Bronchial Asthma in Japan].

The first nationwide research into adult bronchial asthma in Japan proposed a new classification of adult asthma. Adult asthma was categorized into child onset asthma, adult onset asthma and adult relapse asthma. The frequency of child onset asthma, adult onset asthma and adult relapse asthma in adult asthma was 11.2%, 77.3% and 3.7%, respectively. The frequency of child onset asthma decreased markedly in the older age group. On the other hand, the frequency of adult onset asthma increased, and reached more than 90%, in the older age group. The frequency of the following factors: atopic asthma, complications with other atopic diseases, mild asthma, male patients, experience of mechanical ventilation, visits to night clinics and oxygen therapy on acute attack, was significantly higher in the child onset asthma group than in the adult onset asthma group. The frequency of infectious type, aspirin intolerance, steroid dependent asthma, severe asthma and regular medication was significantly higher in the adult onset asthma group. Adult relapse asthma seemed to fall between these two groups. Based on the above observations, we proposed a new classification of adult asthma which includes child onset asthma, adult onset asthma and adult relapse asthma.

[Pulmonary actinomycosis with "balls-in-a hole" appearance diagnosed by examination of bronchial lavage fluid].

A 49-year-old man was referred to our hospital because of abnormal chest X-ray findings. Chest X-ray films showed infiltrative opacities in the right lung, and histological findings of a transbronchial biopsy specimen showed non-specific inflammation. The patient was treated with Ofloxacin for one month. After the treatment, chest X-ray films showed that the infiltrative opacities in the right upper lobe had decreased, but that opacities in the right lower lobe had increased, with an air meniscus sign. A chest computed tomography scan at the same time revealed that the remaining opacities contained multiple mass-like lesions within a cavity in the right S6, appearing as "balls in a hole". One year after the first visit, the patient visited the hospital again because of cough and sputum. A chest X-ray film showed that the size of the cavity in the right lower lobe had increased. The histological findings from a fresh transbronchial biopsy specimen revealed a non-specific inflammation again; however, black clots obtained from bronchial lavage fluid after biopsy were histologically identified as sulfur granules, a classic pathological indication of actinomycosis. This confirmed the diagnosis of pulmonary actinomycosis. The patient was treated with penicillin, and the opacities in the right lower lobe subsided.

[Pneumonia caused by granulomatous Pneumocystis carinii in a patient with the acquired immunodeficiency syndrome].

A 54-year-old man was admitted to the hospital because of fever and general fatigue. A chest roentgenogram on admission showed lobular opacities and ill-defined opacities in both lower lobes. The pneumonia was successfully treated with antibiotics. The acquired immunodeficiency syndrome was diagnosed because ELISA and PCR tests for antibodies to the human immunodeficiency virus were positive and the CD 4+ lymphocyte count was 39 per cubic millimeter. Examination of bronchoalveolar lavage fluid revealed no Pneumocystis carinii. Trimethoprim and sulfamethoxazole were given prophylactically, but were withdrawn because of a rash. The patient began to receive aerosolized pentamindine and was discharged. On the next day, he was readmitted to the hospital because of a high fever. A chest roentgenogram showed diffuse miliary opacities. Chest CT scan also showed diffuse small nodular opacities in both lungs. Examination of a transbronchial biopsy specimen revealed well-defined, noncaseating granulomas with pneumocystis organisms in their centers. Cultures for tuberculosis and fungi were all negative. We diagnosed granulomatous pneumonia caused by Pneumocystis carinii, which is an atypical manifestation of Pneumocystis carinii pneumonia. The patient died of sepsis and cardiac tamponade. Microscopically, the lung tissue was found to have foamy intra-alveolar exdates, which is a typical histological feature of Pneumocystis carinii pneumonia.