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Summary In vitro treatment of thymocytes and splenocytes with rabbit complement (C′) alone induced significant reductions in the proportion of NK-T cells in murine system. The reduction appeared to be prominent in the thymic NK-T cells compared to that in splenic NK-T cells. No reductions were detected in other populations, such as T, B and NK cells. Thus, NK-T cells lineage-specifically showed the enhanced C′ sensitivity. However, NK-T cells in T cell receptor (TCR) transgenic mice of RAG–/– background that lack B cells and antibodies exhibited no C′ sensitivity. On the other hand those from the same TCR transgenic mice of RAG intact background that have a normal population of B cells and antibodies showed the C′ sensitivity similar to that in normal mice. These findings suggest that the enhanced C′ sensitivity observed in the NK-T cell population is associated with the NK-T specific autoantibodies. Indeed, we found that a subset of NK-T cells in the thymus bound mouse immunoglobulins. Similar observations were obtained with several strains of lupus model mice, some of which show a decrease of NK-T cells with aging. Possible roles of the enhanced C′ sensitivity of NK-T cells in pathophysiological conditions in various mouse strains including lupus models are discussed.

Objectives: Few genetic markers for the prognosis of sarcoidosis have been found. Tumor necrosis factor (TNF)-a has been implicated in the pathogenesis of sarcoidosis. Induced TNF-a or TNF-b levels have been shown to be associated with the polymorphisms of the TNF genes. We investigated the roles of such polymorphisms in the development and prolongation of sarcoidosis. Subjects and measurements: One hundred ten Japanese patients with sarcoidosis and 161 control subjects were genotyped for three biallelic polymorphisms in the promoter region of TNF-a gene by direct sequencing of polymerase chain reaction (PCR) products. A polymorphism of the TNF-b gene (TNFB * 1/TNFB * 2) was detected by Nco I restriction fragment length polymorphism analysis of PCR products spanning intron 1 and exon 2 of the TNF-b gene. Results: None of the polymorphisms conferred susceptibility to sarcoidosis. However, our study identified the allele TNFB * 1, detected by the presence of a Nco I restriction site, as a marker of prolonged clinical course, with the resolution of sarcoidosis being defined as the disappearance of all clinical symptoms, physical signs of active lesions, abnormal chest radiograph findings, and abnormal results of pulmonary function and biochemical tests. When the probability of remission in patients homozygous for TNFB * 2 was defined as 1.00, it was 0.48 (95% confidence interval, 0.26 to 0.88; p < 0.05) in patients with TNFB * 1 (genotypes TNFB * 1/1 and TNFB * 1/2). Conclusions: The TNFB * 1 allele is a marker for prolonged clinical course in patients with sarcoidosis. Our study is the first to link a cytokine gene polymorphism to the prognosis of sarcoidosis. (CHEST 2001; 119:753‐761)

Ex-chromate workers are frequently afflicted with lung cancers, especially central-type squamous cell carcinomas (SCCs) of the lung. However, little is known about the molecular and cellular biologic characteristics of chromate-induced lung cancers. We investigated expression of cyclin D1, bcl-2, and p53 proteins in chromate-induced lung cancers by immunohistochemistry, compared with those in lung cancers from nonexposed individuals and those in individuals with pneumoconiosis. Of 19 chromate-induced lung cancers, 16 tumors were SCCs, including 11 central and 5 peripheral types. Eleven (69%) of 16 chromate SCCs showed cyclin D1 expression. In contrast, cyclin D1 expression was observed in only 3 (12%) of 26 SCCs from nonexposed individuals and 6 (16%) of 37 SCCs that developed in patients with pneumoconiosis, respectively. The frequency of cyclin D1 expression proved to be significantly higher in chromate-induced SCCs than in SCCs from nonexposed individuals and from those with pneumoconiosis (P < .001). When comparisons were extended to all histologic types of lung cancer, cyclin D1 expression was observed significantly more often in chromate-induced lung cancers than in lung cancers from nonexposed subjects and those from patients with pneumoconiosis (11 [58%] of 19 v 5 [10%] of 52, P < .001, and 7 [11%] of 63, P < .001, respectively). Frequencies of bcl-2 and p53 expression were not significantly different among lung cancers from ex-chromate workers, nonexposed individuals and those with pneumoconiosis. The current study suggests that cyclin D1 expression may be involved in the development of chromate-induced lung cancers, although its underlying mechanism remains to be determined.

Study objectives: Serum KL-6 (Krebs von den Lungen-6) has been recognized to be a marker for the activity of diffuse interstitial lung diseases. The purpose of the study is to evaluate serum KL-6 measurement as a marker for farmer’s lung disease (FLD). Design: A cross-sectional survey of a cohort of dairy farmers. Retrospective measurement of KL-6 stored serum samples from those dairy farmers previously screened for FLD. Setting: University hospital screening project for FLD within a dairy-farming community in Japan. Participants: Four hundred seventy-two dairy farmers were invited to attend a local clinic. Measurements and results: We examined serum KL-6 concentrations in 272 farmers. Subjects were classified into three groups: (1) 5 farmers with FLD, (2) 30 farmers with positive serum precipitating antibodies to Saccharopolyspora rectivirgula and/or Thermoactinomyces vulgaris without FLD (Ab 1 ), and (3) 237 farmers without these antibodies (Ab 2 ). Serum KL-6 concentrations in the FLD group were significantly higher than those in the Ab 1 and the Ab 2 groups (1,263 6 288 [SEM], 328 6 57, and 207 6 6 U/mL, respectively, p < 0.001). Serum KL-6 concentrations in those with FLD were significantly higher than KL-6 concentrations from stored screening samples from the same individual when FLD was not diagnosed (1,263 6 288 and 419 6 209 U/mL, respectively, p < 0.05). Serum KL-6 concentrations of the Ab 1 group were significantly higher than those of the Ab 2 group (p < 0.001). In the Ab 1 group, farmers with high serum KL-6 concentrations had lower permeability coefficients than farmers with normal serum KL-6 concentrations (p < 0.05). These results may suggest that subclinical FLD can be detected in farmers with high KL-6 concentrations and precipitating antibodies. Conclusion: Serum KL-6 concentration can be a useful marker for assessing the activity of FLD and may be able to be used to detect subclinical disease. (CHEST 2000; 118:445‐ 450)

Macrophage migration inhibitory factor (MIF) has been rediscovered as a proinflammatory cytokine, pituitary hormone, and glucocorticoid-induced immunoregulator. A survey of tissue distribution revealed that MIF expression is not limited to T lymphocytes, but exists in several other tissues; however, its presence in adipose tissue has never been investigated. In this study, we examined the expression of MIF in adipose tissue using the rat epididymal fat pad and murine 3T3-L1 adipocytes. Northern and Western blot analyses revealed the expression of MIF mRNA and MIF protein, respectively, in both the fat pad and the adipocyte cell line. In immunohistochemistry, a positive staining reaction with an anti-rat MIF antibody was detected largely in the cytosol of adipocytes of the epididymal fat pad. To examine the production and release of MIF by adipocytes, we examined its content in the culture medium of the 3T3-L1 adipocytes. The results showed that MIF content was 1.6 +/- 0.48 ng/ml (mean +/- SD) after 24 hr culture, and the content was increased up to 9.7 +/- 2.8 ng/ml by stimulation with TNF-alpha (50 nM). Since TNF-alpha produced in adipocytes is known to induce insulin resistance, the results suggest the possibility that MIF plays an important role in the mechanism of insulin resistance often observed in obesity and diabetes via regulation of TNF-alpha expression.

Little is known about the role of circulating platelets in PMA-induced lung injury in vivo. We investigated the effects of platelet depletion (PD) on the injury using seven unanesthetized sheep with lung lymph fistulas and eight other sheep for morphological study. PD diminished a decrease in the lymph to plasma concentration ratio (L/P) after 1 microgram/kg PMA treatment (n = 4) and caused more increases in lung lymph flow, L/P and lung lymph clearance after 5 micrograms/kg PMA treatment (n = 3) than in control sheep. The high dose was lethal to platelet-depleted sheep. However, PD had no effects on pulmonary hemodynamics. Morphologically, alveolar hemorrhages and exudate, and bleb formation of type I epithelial cells were more prominent in the platelet-depleted sheep than in the control sheep. We conclude that circulating platelets have protective effects against PMA-induced lung injury but have little involvement in PMA-induced pulmonary hypertension.

It is known that smoking affects the development and maintenance of certain types of granulomatous lung diseases. To explore this mechanism(s), we measured tumor necrosis factor (TNF)-alpha concentrations in the culture supernatants of lipopolysaccharide (LPS)-stimulated alveolar macrophages (AMs) in 13 healthy nonsmokers, 13 healthy smokers, 13 nonsmoking sarcoid patients, and 16 smoking sarcoid patients. We found that the capacity of smokers' AMs to release TNF-alpha was significantly decreased both in the normal and sarcoid groups. We also confirmed the previous observation that there was an exaggerated TNF release in patients with pulmonary sarcoidosis. These results indicate a significant role of TNF-alpha in the pathogenetic mechanisms of pulmonary sarcoidosis and suggest the possible involvement of TNF in the mechanisms by which smoking modulates local immune phenomena.

804 GASTROINTESTINAL ENDOSCOPY VOLUME 53, NO. 7, 2001 From the First Department of Medicine, Second Department of Surgery, and Department of Surgical Pathology, School of Medicine, Hokkaido University, Japan. Reprint requests: Toshiyuki Harada, MD, First Department of Medicine, School of Medicine, Hokkaido University, North 15, West 7, Kita-ku, Sapporo, 060-8638, Japan. Copyright © 2001 by the American Society for Gastrointestinal Endoscopy 0016-5107/2001/$35.00 + 0 37/4/114960 doi:10.1067/mge.2001.114960 Carcinoid tumor detected in gastric adenoma during long-term follow-up

The defense system of aortic endothelial cells against oxidative stress was studied in alloxan-induced diabetic rabbits, and the effect of insulin on the antioxidant activities was estimated. Endothelial cells were prepared from 10 diabetic rabbits, 18 diabetic rabbits treated with insulin, and 10 age-matched controls after 17 days of diabetes. These cells were used for the estimation of glutathione (GSH) levels and its related enzyme activities. The antioxidant activities in these endothelial cells from diabetic rabbits were compared with those from control subjects. The concentration of GSH decreased in diabetic rabbits (1.6 +/- 0.2 nmol/mg protein [mean +/- SD] v 3.7 +/- 0.6 nmol/mg protein). Decreases in the activities of Cu, Zn-superoxide dismutase (Cu,Zn-SOD) (62.7 +/- 11.0 U/mg protein v 172.9 +/- 20.2 U/mg protein), catalase (7.6 +/- 2.1 U/mg protein v 12.3 +/- 3.2 U/mg protein), and GSH peroxidase (134.0 +/- 27.0 mU/mg protein v 179.1 +/- 26.2 mU/mg protein) were observed. The activities of other GSH-related enzymes such as GSH S-transferase or GSH reductase did not change in endothelial cells from diabetic rabbits. Most of these antioxidant activities were prevented when diabetic rabbits were treated with insulin (1 to 2 U/kg/d). These antioxidant activities were also determined in the diabetic liver and kidney. Similar decreases in the cellular defense activities and prevention of the decrease in activities by insulin were observed in the diabetic liver, while these antioxidant enzyme activities in the kidney were resistant to diabetic conditions.(ABSTRACT TRUNCATED AT 250 WORDS)

We present the findings in a patient with liver cirrhosis who showed oppositional pulmonary vascular responses to various alveolar oxygen tensions. In this case the pulmonary artery constricted on exposure to hyperoxia and then gradually dilated during progressive hypoxic inhalation. Such a paradoxic response must result in severe arterial hypoxemia because of severe V/Q mismatching.

We describe a patient with pulmonary emphysema who developed paradoxical cardiodeceleration not only during incremental exercise associated with hypoxemia but also during progressive hypoxic challenge. Since coronary angiogram revealed no abnormality, this unique phenomenon seemed to be due to the direct effect of hypoxia on the sinus node activity.

Glycosylated form of carbonic anhydrase isozyme I was found in human erythrocytes. The percent of glycosylated enzyme of the total erythrocyte carbonic anhydrase I of patients with diabetes mellitus was significantly higher than that from normal controls. Characterization of the glycosylated carbonic anhydrase I was studied using an enzyme purified from diabetic patients. The glycosylated enzyme showed a slightly acidic isoelectric point in comparison with that of a nonglycosylated enzyme. The specific activity of the glycosylated enzyme was approximately 40% of that of the normal enzyme, and the immunological activity decreased to 52% of that of the normal enzyme. Estimation of carbohydrates which may form a ketoamine linkage with the enzyme was studied using [ 3 H]-labelled glycosylated enzyme synthesized by incubation of the enzyme with [ 3 H]- d -glucose in vitro, and it was found that one mol of glucose binds to one mol of enzyme. Exposure of red cells to a higher concentration of glucose in diabetics brought about glycosylation of carbonic anhydrase, which is associated with its low activity enzymatically and immunologically.

Whether genetic factors influence small airway function and lung volume was examined in 20 adolescent (mean age, 16.2 +/- SD 1.1 years) monozygotic twin pairs, 11 adolescent (mean age, 16.7 +/- 0.7 years) dizygotic twin pairs, and 20 adult (mean age, 38.7 +/- 9.3 years) monozygotic twin pairs. Within-pair variances of adolescent dizygotic twins for height, FVC, FEV1/FVC, V50, V25, V50/FVC, FRC, and delta N2 were significantly larger than those of adolescent monozygotic twins, indicating that these pulmonary function variables are influenced predominantly by genetic factors in adolescence. Within-pair variances of adult monozygotic twins were similar to those of adolescent monozygotic twins in terms of V50 and V25, indicating that these pulmonary function variables are influenced predominantly by genetic factors in adulthood. These results indicate that small airway dynamics, in terms of V50 and V25, are influenced in larger part by genetic factors in adolescence as well as adulthood, whereas lung volumes in terms of FRC and FVC are controlled by genetics only in adolescence.

We describe a case of eosinophilic pneumonia in which plasma cells appeared in bronchoalveolar lavage fluid (BALF). A 49-year-old man presented with wheezing, lung infiltrates, peripheral eosinophilia, and extremely high IgE levels in serum and BALF. A differential count of BALF revealed 56.6 percent lymphocytes and 1.3 percent plasma cells. The appearance of plasma cells suggests local maturation of B cells and represents a morphologic proof of local production of immunoglobulins. The increased number of lymphocytes suggests their role in B cell differentiation via the lymphokine network.

We examined the relationship between prognosis and arterial blood gases daring exercise and 100 percent oxygen inhalation in 54 patients randomly selected from 119 background patients with chronic obstructive pulmonary disease (COPD). Light exercise was performed and 100 percent oxygen was inhaled during clinically stable stages. By four years after these tests, 19/54 patients had died from respiratory failure. All subjects had similar physical and clinical features. Survivors had significantly higher PaO 2 during air breathing than nonsurvivors; in nonsurvivors, FEV 1 and MVV were significantly lower, and heart rate and RV/TLC were significantly higher. Exercise PaO 2 of nonsurvivors decreased by 6.7 mm Hg, whereas that of survivors did not change. The P(A–a)O 2 did not change in survivors and nonsurvivors during exercise, but in survivors it was significantly smaller. Mean PaO 2 after 100 percent oxygen was significantly lower, and PaCO 2 was significantly higher in nonsurvivors than in survivors, and in nonsurvivors the increase in PaO 2 during 100 percent oxygen correlated positively with the time between first admission and death. These results indicate that patients with combination of resting arterial hypoxemia, worsened hypoxemia during stepped-up exercise, and lesser degree of arterial oxygenation and increased PaCO 2 during 100 percent oxygen inhalation may have a poor prognosis.

Whether reversibility in airway obstruction with β-adrenergic stimulant is a significant determinant for the outcome was tested in 59 patients with pulmonary emphysema and chronic bronchitis. During four years of follow-up, 43 (73 percent) patients survived and 16 (27 percent) died. Initial VC, FVC, FEV 1 , and PaO 2 were significantly smaller, and PaCO 2 was significantly larger in nonsurvivors than those in survivors. After orciprenaline sulfate (10 mg in 0.5 ml solution) inhalation, VC and FEV 1 increased in comparable amount between the two groups. Airway reversibility as estimated by percentage changes in FEV 1 before and after the bronchodilator (reversibility index) was similar between the two groups. In the 16 nonsurvivors, hypoxemic patients had similar FEV 1 , FEV 1 /FVC, and reversibility indices as normoxemic patients. These results indicate that not airway reversibility per se but a fixed or irreversible component of airway obstruction is one of the determinants of the prognosis in pulmonary emphysema and chronic bronchitis. Chronic hypoxemia is related to neither airway obstruction nor its reversibility, while it does influence the prognosis.

A 55-year-old woman had bilateral hilar lymphadenopathy and retinouveitis. Microscopic examination of a biopsy specimen from a mediastinal lymph node revealed noncaseating epithelioid cell granulomas. Since granulomatous diseases of infectious origin and sarcoid reaction were reasonably excluded, she was diagnosed as having pulmonary sarcoidosis. Bronchoalveolar lavage findings were atypical in that the ratio of helper T cells to suppressor T cells (CD4/8 ratio) was 0.5 in two separate examinations, despite a moderately increased proportion of lymphocytes. Immunohistochemical examination of the lymph node also showed a predominancy of suppressor T cells. The inversion of the CD4/8 ratio suggests the presence of heterogeneity in the immunoregulatory mechanism in pulmonary sarcoidosis and may have a prognostic significance. (Chest 1989; 95:228-31)

The intensity of gallium-67 scintiscans, lymphocyte counts in bronchoalveolar lavage fluid, and pathologic changes were studied in 26 patients with untreated pulmonary sarcoidosis. Noncaseating granulomas were recognized with significantly greater frequency in stage 2 (80 percent; 8/10 cases) than in stage 1 (43 percent; 6/14 cases). Alveolitis showed little relation to the roentgenographic stage. There was a strong correlation between the intensity of gallium uptake in pulmonary parenchyma and the detection rate of granuloma; however, the detection rate of alveolitis was not statistically different from the intensity of gallium uptake. A highly significant correlation was revealed between the lymphocyte counts in bronchoalveolar lavage fluid and the intensity of alveolitis. These observations suggest that the gallium uptake reflects mainly the presence of granuloma, and the lymphocyte count in bronchoalveolar lavage fluid reflects the intensity of alveolitis in patients with pulmonary sarcoidosis.

HLA-DR typing was performed in 58 Japanese patients with sarcoidosis. We found a significantly increased frequency of HLA-DRw52 (p