(Vol.73. No.1 January 1998) <1> Kekkaku Vol.73, No.1: 1-3, 1998 THE DIAGNOSTIC VALUE OF THORACOSCOPIC EXAMlNATIONS IN TUBERCULOUS PLEURISY Shuichi YANO*, Shinji SHISHIDO, Takeaki TORITANl, Katstihiko YOSHIDA, Hiroko NAKANO and Tekeshi TOKUSHIMA We evaluated the diagnostic value of thoracoscopic examinations in eleven patients who had pleural effusion and were diagnosed as tuberculous pleurisy. The characteristic white or yellowish-white micronodules were observed by thoracoscopy in eight patients and all their biopsied tissue were compatible with tuberculosis. We had some cases which were not determined as tuberculous pleurisy from bacteriological examinations and were deter- mined only from the thoracoscopic findings. Key words : Tuberculous pleurisy, Adenosi-nedeaminase (ADA), Thoracoscopy, Tho - racoscopic findings *From the Department of Pulmonary Medicine, National Sanatorium Matsue Hospital 5-8-31, Agenogi, Matsue 690-0015 Japan. (Received 31 Jul. 1997/ Accepted 17 Oct. 1997) <2> Kekkaku Vol.73, No.1: 5-12, 1998 SUPPRESSIVE EFFECT OF GLYCOPEPTIDOLIPID FROM MYCOBACTERIUM A VIUM-INTRACELLULARE COMPLEX SEROVAR 4 AND 16 ON BLASTOGENESIS OF HUMAN PERIPFIERAL BLOOD MONONUCLEAR CELLS Jun-ichi FUKUl* Mycobacterium avium-intracellulare complex (MAC) consists of 28 serotypes. Co-infec- tion of several specific serotype strains with the advent of acquired immunodeficiency syndrome (AIDS) has been dramatically increasing in the past fifteen years, although the reason for this fact is not clearly understood. Since the cell surface lipid components of MAC impaired the capacity of human peripheral blood mononuclear cells (PBMC) to pro- liferate, some particular glycopeptidolipid (GPL) with serologically specific carbohydrate chains are supposed to inhibit blastogenesis and to affect the immune response in MAC infection. In this study, we have investigated the effect of serovar 4 and 16 GPLS on the human PBMC function and cell mediated immunity. As the result, it was demonstrated that the percentage of viable cells was decreased prominently after the incubation of PBMC with the serovar 4 GPL. Blastogenic responses of PBMC to stimulation with the purified protein derivatives (PPD) were inhibited by the presence of GPL dose - dependently. In the case of stimulation with anti-CD3 antibody (a-CD3 Ab), blastogenic response of PBMC was suppressed markedly by GPL at the concentration of 175 g/m. Flow-cytometric analysis demonstrated that the expression of interleukirh2 receptor alpha on a-CD3 Ab-stimulated T Iymphocyte was markedly inhibited in the presence of GPL. Enzyme-linked immunosorbent assay showed that the production of interleukin-2 by a- CD3 Ab-stimulated PBMC was reduced dose-dependently after the incubation of PBMC with GPL. In these results, there was no remarkable difference between serovar 4 and serovar 16 GPLs. These results indicate that serovar 4 and 16 GPLS inhibit the cell me- diated immunity and serovar 4 GPL can affect the viability of PBMC. Key words: Mycobacterium avium-intracellulare complex, Glycopeptidolipid, lymphoblastogenesis, IL-2,@IL-2 receptor *From the Department of Bacteriology and Urology, Osaka City University Medical School, 1-5-7 Asahimachi, Abeno-ku, Osaka 545-0051 Japan. (Received 7 Oct. 1997/ Accepted 31 Oct. 1997) <3> Kekkaku Vo.73, No.1: 13-15, 1998 DECREASE OF REMNANT LIKE PARTICLE (RLP) IN ACTIVE PULMONARY TUBERCULOSIS Tadayoshi IMAIZUMI* Remnant like particle (RLP) is a lipoprotein produced by decomposition of chylomicron or very low density lipoprotein (VLDL). PLP was observed on serum of cases with active pulmonary tuberculosis. Serum level of RLP was decreased in all of the patients with pulmonary tuberculosis ; below 2.5 mg/dl till O mg/dl. The level was gradually elevated with clinical improvement of the disease. It was suggested that denutrition of chronic infection would be reflected to serum RLP level in active tuberculosis Key words : RLP Pulmonary tuberculosrs Infection *From Landmark Clinic, Minatomirai 2-2-1-1, Nishi-ku, Yokohama 220-8107 Japan. (Received 18 Aug. 1997/ Accepted 6 Nov. 1997) <4> Kekkaku Vol.73, No.1: 17-35, 1998 The 72nd Annual Meeting Round Table Discussion EDUCATION AND TRAINING FOR TUBERCULOSIS IN MEDICAL SCHOOLS AND IN HOSPITALS Chairpersons : Masahiko YAMAMOTO* Mitsuo ASAKAWA** Discussers 1 . From Medical School Lacking Tuberculosis Ward Shigeki SATO (Second Department of Internal Medicine, Nagoya City University, Medical School) 2 . From Medical School Holding Tuberculosis Ward Yasuhito HONDA (Third Department of Internal Medicine, Sapporo Medical Uni- versity, School of Medicine, Present address : Department of Respiratory Medi- cine, NTT Sapporo Hospital) 3 . From General Hospital Lacking Tuberculosis Ward Takehito NAKABAYASHI (Department of Pulmonary Diseases, Sapporo National Hospital. Present address : Department of Pulmonary Diseases, Hakodate Na- tional Hospital) et al. 4 . From General Hospital Holding Tuberculosis Ward Kosho YOSHIKAWA (Respiratory Division, Daido Hospital) 5 . The Significance of Tuberculosis Training in the Training of the Respiratory Diseases Tadashi MATSUMURA (Internal Medicine, Maizuru, Municipal Hospital) 6 . The Training of Tuberculosis Control Personnel by Research Institute of Tuberculo- sis, Japan Anti-Tuberculosis Association Toru MORI et al. (Research Institute of Tuberculosis, Japan Anti-Tuberculosis Association) 7 . From the Training School for Nurse and Public Health Nurse Mitsuo ASAKAWA (Date Red Cross Hospital) The recent decrease of the number of tuberculosis patients in Japan, by the economi- cal development and the establishment of standard regimen with INH, RFP, SM/EB and PZA, have brought decrease of concern to tuberculosis not only in the masses but also in the medical personnels, and the worsing of the medical economy by the advancing of the ages in the nations is forcing to close the tuberculosis wards. On the other hand, the recent situation of tuberculosis in Japan, such as the increase of HIV infection, the additional inflow of the foreign tuberculosis patients, the increase of tuberculosis patients in the younger population by the increase of mass-infection, and recent progress of the maldistributions of the tuberculosis patients realized the efforts of the education and training for tuberculosis to the medical students and medical personnels, even in the increase of items that they must learn. The Japanese Society for Tuberculosis set a Symposium "How Tuberculosis be Taught in Medical Education" in 1986. It will be worth to have Round Table Discussion concern- ing to the education and training for the tuberculosis, after 11 years. Doctor Sato from Nagoya City University reported as follows. To survey the actual condition of tuberculosis education before graduation, a nationwide medical school ques- tionnaire survey was carried out. Answers were received from 80 institutions (100% ). It was found that 58 institutions (72% ) Iacked tuberculosis ward. When the results from this survey, in the area of medical school lecture, were compared to the previous survey of 11 years ago, it showed a decrease in the time and frequency that tuberculosis covered during lecture. This tendency was clearly seen, with the exception of internal medicine, in surgery, in plastic surgery, in urology and in public health. Furthermore, medical schools lacking tuberculosis ward were found to have a lesser percentage of clinical lectures and bed-side teaching when compared to ones with tuberculosis ward. He concluded that in the medical school without tuberculosis ward, the tuberculosis education is virtually im- possible, and it is necessary to carry out with hospitals that have tuberculosis ward. Doctor Honda from Sapporo Medical University reported that in the University Hos- pital, the Third Department of Internal Medicine holds 6 isolation sick-beds for tubercu- losis (3 for men and 3 for women) which containing an exclusive day room and bath room, in 52 beds alloted to their department. They always give 2 or 3 Iectures about tu- berculosis to medical students and also give bed-side teaching using these beds. He con- cluded education on tuberculosis is necessary for the protection of doctor's delay, and the tuberculosis ward in the university is very useful in the education of tuberculosis to medical students, even the economical efficiency of these beds are low. Doctor Nakabayashi from Sapporo National Hospital reported that his hospital is a general hospital with 513 beds but has no tuberculosis-bed, and that this hospital is com- bined with Hokkaido Cancer Center and 91.7% of in-patients of pulmonary division are lung cancer and one or two residents are trained in pulmonary division by 6 months ro- tation. He also reported that in his hospital, 18 mycobacteria positive cases were treated through 1996, however the training for tuberculosis to residents are mainly by the differ- ential diagnosis of tuberculosis with lung cancer through case conferences with staffdoc- tors. Doctor Yoshikawa from Daido Hospital reported as follows. In his hospital, tubercu- losis-beds and other respiratory-beds are in the same nursing unit managed with the same standard for nursing, although tuberculosis-beds are separated from other respira- tory-beds by door and have exclusive toilets and bath-room. The doctors could study gen- eral respiratory diseases and tuberculosis at the same time. Thirteen doctors have finished this training, and all of them could deepen their knowledge to tuberculosis through this training by actually treating tuberculosis patients. They also reported 6 journal articles and 138 conference proceedings related to tuberculosis and these studies were very valuable for training of tuberculosis. Doctor Matsumura from Maizuru Municipal Hospital, who has introduced an unique training system for resident, thinking much on common diseases, inviting foreign clini- cians as consultants, reported as follows. The significance of teaching of tuberculosis can- not be overemphasized. Mycobacterium tuberculosis invades not only lung and pleura but also pericardium, kidney, intestine, peritoneum, brain, bone and joint in our practice. The clinical pictures continue to be protean and misleading. In spite of the decreasing concern on the part of physicians, the incidence of the disease has not declined much for the past decade according to our statistics. He concluded that under the circumstances, the teach- ing of tuberculosis can be most effective when incorporated into postgraduate education as a whole, and that the additional learning of other pulmonary diseases, infectious dis- eases and general internal medicine is mandatory. Doctor Mori from Reseach Institute of Tuberculosis, Japan Anti-Tuberculosis Asso- ciation, presented the activities of the Research Institute of Tuberculosis that has been playing a role of a national center for the training since 1940s, in the discussion over the training of tuberculosis. He also reported that currently there are several types of train- ing programs for various categories of the personnel, i. e., doctors, public health nurses, X-ray and laboratory technicians, etc., mainly from health centers or local goverments. He also discussed as follows. Recently, the attendance of the training courses are increas- ing, but there is regional difference in number of the attendant. Because the undergradu- ate education of tuberculosis is very poor recently, the training here is becoming urgently necessary and important. In a new and popular program for doctor, a limited number of invited experts are given high level of training to technically support the health centers. Possibility of making the program still more effective was also considering, such as use of computer media. Finally, Doctor Asakawa from Date Red Cross Hospital, one of the chairpersons re- ported that he has lectures on tuberculosis at the training school for registered nurse at- tached to his hospital and at the training school for practical nurse sponsored by local Medical Association, and he also carried out questionnaire survey about the education for tuberculosis to the 90 training schools all over Hokkaido. He presented by the results of questionnaire, only 31.9% of the training schools for registered and practical nurse had practicing hospitals holding tuberculosis ward, and in 75.5% of the training schools for registered nurse and only 39.1% of the training schools for practical nurse the teachers for tuberculosis were specialist of respiratory diseases, and the many text books were in- adequate. In discussion, importance of tuberculosis ward in education and training for tubercu- losis are emphasised by all discussers. All members agreed to suport the efforts to open several beds for tuberculosis in all medical schools and central general hospitals, and to suport many attemptions to intensify the tuberculosis education by the Committee for Education of the Japanese Society for Tuberculosis. Key words : Tuberculosis, Education, School of medicine, Hospital, Training institute, School for nurse *From Nagoya Medical Examination Center, Postal Life Insurance Welfare Corporation, 1-21 Shumoku cho, Higashi-ku, Nagoya 461-0041 Japan **From Date Red Cross Hospital, 81 Suenaga-cho, Date, Hokkaido 052-0021 Japan. (Received 1 Oct. 1997) <5> Kekkaku Vol.73, No.1: 37-42, 1998 The 72nd Annual Meeting Education Lecture CORD FACTOR lkuya YANO* Mycobacterial cell wall contains various lipids (glycolipids and phospholipids) to con- tribute to its hydrophobic property or acid-fastness and these surface molecules contact with host cells in the early step of infection. Among them, cord factor (trehalose 6,6'- dimycolate, TDM or CF) is the most ubiquitous component, which may be a key molecule for pathogenesis and immunity. Initially, cord factor was isolated from a highly virulent strain of M. tuberculosis which grows in the form of serpentine cords, and showed a marked toxicity for mice when it was administrated intravenously. These observations led to the early hypothesis that cell wall components are related to virulence. However, later studies revealed that cord factors were also found in other non-cord-forming mycobacterial species and other mycolic acid-containing bacteria. Structural studies dem- onstrated that there were various mycoloyl glycolipids differing in carbohydrate moiety such as glucose mycolate, mannose mycolate, arabinose mycolate and fructose mycolate besides trehalose mycolate in acid-fast bacteria. Therefore, the interest has been focused to the structure-activity relationships of mycoloyl glycolipid and to the mechanism of virulence for host animals. So far, it has been demonstrated that cord factor showed le- thal toxicity, granuloma forming activity, adjuvant activity, tumor regressing activity and non-specific infection prevention activity in experimental animals. We have extended investigations further on the structure analysis and immunomodifying activities of cord factor and related mycoloyl glycolipids from various species of mycobacteria, nocardia, rhodococci and gordona, and demonstrated that the most activities were shown in trehalose or glucose esters, but not in mannose, arabinose or fructose esters. Futhermore, it was shown that the longer chain-mycoloyl glycolipids showed the higher toxicity and immunomodifying activities. In mice, in vivo, cytokine inducing activities such as IL-1, IFN- , TNF-, GM-CSF and chemotactic factor were observed and in vitro, TNF- , GM-CSF, chemotactic factor, complement, NO, PGE (2) inductions and protein kinase C activa- tion were demonstrated. Furthermore, recently, we have demonstrated that cord factor in- duced a marked thymic atrophy due to the cortical lymphocyte apoptosis befor granuloma formation in mice. It was also established that cord factor showed antigenicity in mice and rabbits and human tuberculous patient sera contained specific antibody (IgG) reactive against cord factor. From above results, cord factor seems to be one of the most potent immunomodulators in the mycobacterial cell wall components pathologically and benefi- cially. Key words : Cord factor, Tuberculous granuloma, Macrophage, Cell wall adjuvant, Mycoloyl glycolipids *From the Department of Bacteriology Osaka City University Medical School, Asahimachi 1-4-54, Abeno-ku, Osaka 545-0051 Japan. (Received 7 Nov. 1997)