Recent Advances of Diagnoses and Therapeutics in ...3. Discovery of KL-6 and its clinical application We discovered KL-6 in 1984 [1]. KL-6 is used widely used as a serum disease marker

Recent Advances of Diagnoses and Therapeutics in Practical Medicine

Nobuoki Kohno, MD, PhD

Department of Molecular and Internal Medicine, Graduate School of Biomedical Sciences,

Hiroshima University

1. Introduction In the biomedical science, a large quantity of

research budget and researchers’ efforts has been served to improve health and quality of life of people. I would like to show, during the course of this international workshop, some recent progress made in practical medicine which has been directly or indirectly influenced by myself; a medical doctor of internal medicine, respirologist, and clinical biologist. These may give the members of the 21st century COE program “Nanoelectronics for Terra-Bit Information Processing” some idea on how to apply nanotechnology in the field of practical medicine.

There are five major strategies in developing practical medicine. First, the discovery and development of new medical drugs have dramatically improved medical care, such as penicillin for bacterial infection, digitalis for heart failure, and corticosteroids for allergic diseases. These are mostly carried out by pharmacologists. Second, the discovery of unknown molecules and novel functions of known and unknown molecules in human cells is a quite important new area for medical scientists. Successful results produce the establishment of new diagnostic procedures and new drugs. Third, development of new procedures by inspired thinking, such as new operation methods, are also very important. Fourth, the application of recently developed industrial technologies will make a great improvement in experimental biology and medical devices. Fifth, the establishment of clinical evidences, such as epidemiologic study and translational research, is the final gateway to success for scientific efforts to be applied in practical medicine. 2. Discovery of unknown molecules and their clinical application

There are three effective methods in finding unknown molecules from human cells that may be crucial in the cause of root diseases. For example; in finding unknown molecules crucial for the occurrence of malignant formation, three major strategies are used. Namely, monoclonal antibody production, DNA microarray and proteomics. Using these methods, the differences of expression levels and functions between normal and malignant cells can be found. According to the results, many diagnostic and

therapeutic tools have been made. A lot of new molecules have been discovered by the monoclonal antibody research dating from 1974, when the method was invented. DNA microarray is a prevailing method that is strongly expected for the progress in medicine. Proteomics is promising, but the method of use is controversial at present. 3. Discovery of KL-6 and its clinical application

We discovered KL-6 in 1984 [1]. KL-6 is used widely used as a serum disease marker for interstitial pneumonia and pulmonary fibrosis in the national medical security system authorized by the Ministry of Health, Labour and Welfare, Japan, at present. Though interstitial pneumonia is a disease that is difficult for most medical doctors to diagnose, the popularization of KL-6 made the disease be diagnosed much easier than before; i.e., most interstitial pneumonia might have been diagnosed as bacterial and viral pneumonias previously and such erroneous diagnosed diseases became to be diagnosed correctly. KL-6 is measured in more than 40000 serum samples per month in Japan. Though some research reports on the usefulness of KL-6 in European and American people has been published, they are not able to share the up-to date benefits of KL-6, because the clinical measure is limited only to Japan. Serum KL-6 level is less than 500 U/ml in healthy individuals and most patients with respiratory diseases other than interstitial pneumonia, but the level is more than 500/ml in most patients with active interstitial pneumonia, as shown in Fig.2. The mechanism for the increase of KL-6 in serum might be supposed as the enhanced epithelial-capillary permeability caused by pulmonary alveolar epithelial damage (Fig. 3). 4. Three-dimensional culture of the cartilage and transplantation

This study and clinical application has been made by Dr. Mitsuo Ochi, Professor of Orthopedics, Hiroshima University Hospital, who has been my classmate from junior-high through the Medical course of Hiroshima University School of Medicine for twelve years. He is the first doctor in the world who began to develop the three-dimensional culture of chondrocytes making regenerating cartilage for the

therapy of cartilage defects in elbow and knee joints. The originality exists in the three-dimensional culture and its clinical application as shown in Fig. 4 [2]. 5. Visualization of the peripheral lung structure with synchrotron radiation computed tomography

This study is made using the synchrotron of Spring-8 in Hyogo, Japan, by Dr. Hirohiko Ikura and his colleagues, at the Department of Radiology, Ehime University Hospital, who was a student of the post-graduate course in my laboratory when I worked in Ehime University. Since synchrotron radiation has ultra brightness (1x108-fold higher than medically used X-ray), a monochromated beam can be used in CT. The detectability of high resolution CT in medical use is 200 µm, but the synchrotron CT (SRCT)10 µm. Using SRCT, Therefore, we can see the second lobule in the lung tissue and alveolar septa as shown in Fig. 5. 6. Discovery of new serum tumor markers by DNA microarray

ADAM8 was recently found to be a promising serum tumor marker for lung cancer detection as shown in Fig. 6 using the method of DNA microarray by Dr. Ishikawa N. and Prof. Nakamura Y, et al [3]. at the Institute of Medical Science, the University of Tokyo. They used highly elaborate devices to find differences in mRNA expression level between normal and cancer cells. By their methods, 23040 genes are able to be examined simultaneously. 7. Medical Research Center for Environmental Effects on Japanese Emigrants, Hiroshima University (Director: Nobuoki Kohno, M.D.)

We have been conducting the Hawaii-Los Angeles-Hiroshima Study since 1970, mainly to determine the effects of environmental changes on various diseases by comparing Japanese-Americans with native Japanese subjects. Japanese-Americans living in Hawaii and Los Angeles who originated mainly from Hiroshima, Japan, and are genetically identical with native Japanese (Fig. 7). Through this study, we made several clear observations about Japanese-Americans. First, Japanese-Americans were highly exposed to a westernized lifestyle; in other words, a relatively high fat and simple carbohydrate diet with low physical activity as compared to native Japanese. Second, the prevalence of type 2 diabetes among Japanese-Americans and death from ischemic heart disease among Japanese-American diabetes patients was higher. Third, the serum fasting insulin level as well as the insulin level after a glucose load, was higher among Japanese-Americans, even when the serum glucose levels were not statistically different as compared to native Japanese. Accordingly,

Japanese-Americans were thought to have a high insulin resistance status. Fourth, the intima-media wall thickness of the cartoid artery is apparently worse in Japanese- Americans than native Japanese as shown in Fig.8 [3]. In conclusion, it appears that for genetically pure Japanese people environmental factors are important for the development of metabolic diseases such as diabetes mellitus and cardiovascular disease. 8. Conclusion

Recent progresses in practical medicine which have been witnessed by the author have been shown here today. The author is hoping that this presentation will possibly make the researchers attending this workshop have some worthwhile research ideas in the field of application of nanotechnology in regards to practical medicine. References [1] Kohno N, et al., New serum indicator of interstitial pneumonitis activity: sialylated carbohydrate antigen KL-6. Chest 96: 68-73, 1989. [2] Ochi M, et al., Transplantation of cartilage-like tissue made by tissue engineering in the treatment of cartilage defects of the knee. J Bone Joint Surg Br. 84: 571-8, 2002.[3] Ishikawa N. et al., ADAM8 as a novel serological and histochemical marker for lung cancer. Clin Cancer Res, 2004 (in press) [4] Watanabe H, et al., Westernization of lifestyle markedly increases carotid intima-media wall thickness (IMT) in Japanese people. Atherosclerosis 166:67-72, 2003.

1. Monoclonal antibody production:

2. Genomics (DNA microarray):

3. Proteomics:

Antigenic Determinant of Protein, Peptide, & Carbohydrate

mRNA, DNA

Protein, Peptide

Finding differencesof

expression level & functions

Normal cells Cancer cellsDifferences

Diagnostic use Therapeutic use

1. Monoclonal antibody production:

2. Genomics (DNA microarray):

3. Proteomics:

Antigenic Determinant of Protein, Peptide, & Carbohydrate

mRNA, DNA

Protein, Peptide

Finding differencesof

expression level & functions

Normal cells Cancer cellsDifferences

Diagnostic use Therapeutic use

Fig. 1: Strategies to find unknown molecules and known molecules which are important for cancer development.

Jpn J Thorac Dis 34: 639-645, 1996

KL-6 (U/ml)

0

7000

6000

5000

4000

3000

2000

1000500

(n) 185 137 67 30 43□□□□□□□□□□□□□□□□□□□□□□□□□□□□□□□□□□□□□□□□□□□□□□□□□□□□□□□□□□□□□□□□□□□□□□□□□□□□□□□□□□□□□□□□□□□□□□□□□□□□□□□□□□□□□□□□□□□□□□□□□□□□□□□□□□□□□□□□□□□□□□□□□□□□□□ □□□□□□□□□□□□□□□ □□□□□

□□□□□□□□□□

□□□□□

□□□□□□□□□□□□□□□□□□□□□□□□□□□□□□□□□□□□□□□□□□□□□□□□□□□□□□□□□□□□□□□□□□□□□□□□□□□□□□□□□□□□□□□□□□□□□□□□□□□□□□□□□□□□□□□□□□□□□□□□

□□□□

□□□□□

□□□□□□□□□□□□□□□□□□□□□□□□□□□□□□□□□□□□□□□□□□□□□□□□□□□□□□□□□□

□

□□□

□□□□□

□□□□□□□□

□□□□□□□□□□□□□□□□□□□□□□□□□□□□□□□

□

□□□□□

□□□□

□□□□□□□□□□□□□□□□□

□□□□□□□□□□□□□□□□

Healthy

Bacteria

l

pneumonia

Emphysema

Bronchiectasis

Pulmonary

tuberculosis

●● ● ●○○○○○○ ○○○○○

●

●

●●

●

○○

○

○○

○○○

○○○○ ○○○ ○

○○○○○○○ ○○○○

●● ●●●

● ●● ●●●● ●

●● ●●

●● ●

●● ●●●●●●

● ● ●● ●● ●

○○●○○

○○

●

●

●●●●●●

●●

●

●●●●●

●

●

●●●

●●

● ●●

●

●●●●●●

●●●

●●

●

●●

●

●

○○○ ○○ ○

○○○ ○○○ ○○

○○○

○○○

○○○ ○○○○ ○○○

○○

○

● ●●●

●

●●● ●

●

○○○

○○

91 30 66

●

○

Active IPInactive IP

IIP EAA

CVD-IP

Jpn J Thorac Dis 34: 639-645, 1996

KL-6 (U/ml)

0

7000

6000

5000

4000

3000

2000

1000500

0

7000

6000

5000

4000

3000

2000

1000500

(n) 185 137 67 30 43□□□□□□□□□□□□□□□□□□□□□□□□□□□□□□□□□□□□□□□□□□□□□□□□□□□□□□□□□□□□□□□□□□□□□□□□□□□□□□□□□□□□□□□□□□□□□□□□□□□□□□□□□□□□□□□□□□□□□□□□□□□□□□□□□□□□□□□□□□□□□□□□□□□□□□ □□□□□□□□□□□□□□□ □□□□□

□□□□□□□□□□

□□□□□

□□□□□□□□□□□□□□□□□□□□□□□□□□□□□□□□□□□□□□□□□□□□□□□□□□□□□□□□□□□□□□□□□□□□□□□□□□□□□□□□□□□□□□□□□□□□□□□□□□□□□□□□□□□□□□□□□□□□□□□□

□□□□

□□□□□

□□□□□□□□□□□□□□□□□□□□□□□□□□□□□□□□□□□□□□□□□□□□□□□□□□□□□□□□□□

□

□□□

□□□□□

□□□□□□□□

□□□□□□□□□□□□□□□□□□□□□□□□□□□□□□□

□

□□□□□

□□□□

□□□□□□□□□□□□□□□□□

□□□□□□□□□□□□□□□□

Healthy

Bacteria

l

pneumonia

Emphysema

Bronchiectasis

Pulmonary

tuberculosis

●● ● ●○○○○○○ ○○○○○

●

●

●●

●

○○

○

○○

○○○

○○○○ ○○○ ○

○○○○○○○ ○○○○

●● ●●●

● ●● ●●●● ●

●● ●●

●● ●

●● ●●●●●●

● ● ●● ●● ●

○○●○○

○○

●

●

●●●●●●

●●

●

●●●●●

●

●

●●●

●●

● ●●

●

●●●●●●

●●●

●●

●

●●

●

●

○○○ ○○ ○

○○○ ○○○ ○○

○○○

○○○

○○○ ○○○○ ○○○

○○

○

● ●●●

●

●●● ●

●

○○○

○○

91 30 66

●

○

Active IPInactive IP

IIP EAA

CVD-IP

Fig. 2 : Serum KL-6 levels in Respiratory Diseases.

Alveolus

KL-6

Skin

Air

way

Vessel

Epithelial damageAlveolus

KL-6KL-6

Skin

Air

way

Vessel

Epithelial damageCartilageCartilage

Cartilage defectCartilage defect

chondrocyteschondrocytes

Subchondral bone

CartilageCartilage

Preformed cultured

3D-cartilage

Prof. M. Ochi, et al, Dept. of Orthopedics, Hiroshima University

CartilageCartilageCartilage defectCartilage defect

chondrocyteschondrocytes

Subchondral bone

CartilageCartilage

Preformed cultured

3D-cartilage

Prof. M. Ochi, et al, Dept. of Orthopedics, Hiroshima University

Fig. 3: KL-6 is absorbed into circulation, and the absorption levels are co-related with the alveolar-capillary permeability maybe reflecting epithelial injury.

Fig.4: Three-dimensional culture and transplantation.

0.2 mm

HistopathologyHistologic image

with pulmonary hemorrhage

μm

Detectablewithin

2nd Lobule

SRCT10 μm

CTChest Radiograph

High Resolution CT(HRCT)

HRCT image of the inflated lungwith pulmonary hemorrhage

mm

Hirohiko Ikura, MD, Dept. of Radiology, Ehime University

0.2 mm

HistopathologyHistologic image

with pulmonary hemorrhage

μm

Detectablewithin

2nd Lobule

SRCT10 μm

CTChest Radiograph

High Resolution CT(HRCT)

HRCT image of the inflated lungwith pulmonary hemorrhage

mm

Hirohiko Ikura, MD, Dept. of Radiology, Ehime University

Fig.5: Detectability of Lung Lesions with Various Modalities.

Fig.6: ADAM8 as a serum tumor marker for lung cancer.

Fig.7: Medical Research Center for Environmental Effects on Japanese Emigrants, Hiroshima University (Director: NobuokiKohno, MD,PhD).

Hawaii Island

Los Angeles

HiroshimaHilo

Kona

U.S. MainlandJapan

We have been conducting the Hawaii–Los Angeles–Hiroshima Study since 1970, mainly to determine the effects of environmental changes on various diseases by comparing Japanese-Americans with native Japanese subjects.

Hawaii Island

Los Angeles

HiroshimaHilo

Kona

U.S. MainlandJapan

We have been conducting the Hawaii–Los Angeles–Hiroshima Study since 1970, mainly to determine the effects of environmental changes on various diseases by comparing Japanese-Americans with native Japanese subjects.

ADCSCCSCLC

(N=72), 267 +/- 56 pg/ml

(N=25), 467 +/- 210 pg/ml(N=62), 427 +/- 286 pg/ml

(N=18), 400 +/- 112 pg/mlNormal

ADC NormalSCC SCLC

P < 0.001

P < 0.001

P < 0.001

0

200

400

600

800

1000

1200

1400

1600

1800

AD

AM

8 (p

g/m

l)

Ishikawa N, Kohno N, Nakamura Y, et al. Clin Cancer Res (in press).

ADCSCCSCLC

(N=72), 267 +/- 56 pg/ml

(N=25), 467 +/- 210 pg/ml(N=62), 427 +/- 286 pg/ml

(N=18), 400 +/- 112 pg/mlNormal

ADCSCCSCLC

(N=72), 267 +/- 56 pg/ml

(N=25), 467 +/- 210 pg/ml(N=62), 427 +/- 286 pg/ml

(N=18), 400 +/- 112 pg/mlNormal

ADC NormalSCC SCLCADC NormalSCC SCLC

P < 0.001

P < 0.001

P < 0.001

0

200

400

600

800

1000

1200

1400

1600

1800

AD

AM

8 (p

g/m

l)

Ishikawa N, Kohno N, Nakamura Y, et al. Clin Cancer Res (in press).

Age （years）Age （years）

1.01.0

1.51.5

1010 2020 3030 4040 5050 6060 7070 8080 9090

2.02.0

Japanese-AmericansJapaneseJapanese--AmericansAmericans

JapaneseJapaneseJapanese

00

1.1mm1.1mm

Watanabe H et al: Atherosclerosis, 2003

Cutoff

Age （years）Age （years）

1.01.0

1.51.5

1010 2020 3030 4040 5050 6060 7070 8080 9090

2.02.0

Japanese-AmericansJapaneseJapanese--AmericansAmericans

JapaneseJapaneseJapanese

00

1.1mm1.1mm

Watanabe H et al: Atherosclerosis, 2003

Cutoff

Fig.8: Comparison of carotid intima-media wall thickness (IMT) between Japanese-Americans and Japanese.

Recent advances of diagnoses and therapeutics in practical medicine

Nobuoki Kohno, MD, PhD Professor

Department of Molecular and Internal MedicineGraduate School of Biomedical Sciences

Hiroshima University

The ｔhird Hiroshima International Workshop on Nanoelectronics for Tera-Bit Information Processing Strategies to develop practical medicine

1) Discovery and development of new drugs　(mainly by pharmacologists)

2) Discovery of unknown molecules and novel functions of known molecules

3) Development of new procedures

4) Application of recently developed technologies

5) Establishment of clinical evidence

Diagnostic useTherapeutic use

Epidemiologic studyTranslational research

4

Discovery of unknown molecules and their clinical

application

1

2

3

Strategies to find unknown molecules and known molecules which might be important for cancer development

1. Monoclonal antibody production:

2. Genomics (cDNA microarray):

3. Proteomics:

Antigenic Determinant of Protein, Peptide, & Carbohydrate

mRNA, DNA

Protein, Peptide

Finding differencesof

expression level & functions

Normal cells Cancer cellsDifferences

Diagnostic use Therapeutic use

Monoclonal antibody production

Nobuoki Kohno, et al.Hiroshima University

The discovery of KLThe discovery of KL--6 as a serum marker for interstitial pneumonia6 as a serum marker for interstitial pneumonia

The production of monoclonal antibodies by hybridoma is theoretically infinite

Antigen 1

Cancer-associated molecule

Antigen 3

Monoclonal antibody secreting hybridoma

Cancer-associated antigenic determinant

We established KL-6 monoclonal antibodyAutopsied lung, died of acute exacerbation of IPF (UIP). 72 y, male

KL-6 antigens existed also in human serum.

KL-6

Serum KL-6 levels in interstitial pneumonia (IP)　Jpn J Thorac Dis 34: 639-645, 1996

KL-6 (U/ml)

0

7000

6000

5000

4000

3000

2000

1000500

(n) 185 137 67 30 43□□□□□□□□□□□□□□□□□□□□□□□□□□□□□□□□□□□□□□□□□□□□□□□□□□□□□□□□□□□□□□□□□□□□□□□□□□□□□□□□□□□□□□□□□□□□□□□□□□□□□□□□□□□□□□□□□□□□□□□□□□□□□□□□□□□□□□□□□□□□

□□□□□□□□□□ □□□□□□□□□□□□□□□ □□□□□

□□□□□□□□□□

□□□□□

□□□□□□□□□□□□□□□□□□□□□□□□□□□□□□□□□□□□□□□□□□□□□□□□□□□□□□□□□□□□□□□□□□□□□□□□□□□□□□□□□□□□□□□□□□□□□□□□□□□□□□□□□□□□□□□□□□□□□□□□

□□□□

□□□□□

□□□□□□□□□□□□□□□□□□□□□□□□□□□□□□□□□□□□□□□□□□□□□□□□□□□□□□□□□□

□

□□□

□□□□□

□□□□□□□□

□□□□□□□□□□□□□□□□□□□□□

□□□□□□□□□□

□

□□□□□

□□□□

□□□□□□□□□□□□□□□□□

□□□□□□□□□□□□□□□□

Healthy

Bacteria

l

pneumonia

Emphysema

Bronchiectasis

Pulmonary

tuberculosis

●● ● ●○○○ ○○○ ○

○○○○

●

●

●●

●

○○

○

○○

○○○

○○○○ ○○○ ○

○○○○○○○ ○○○○

●● ●●

●● ●● ●

● ●● ●

●● ●●

●● ●

●● ●●●●●●

● ● ●● ●● ●

○○●○○

○○

●

●

●●●●●

●

●●

●

●●●●●

●

●

●●●

●●

● ●●

●

● ●●●●●

●●●

●●

●

●●

●

●

○○○ ○○ ○

○○○ ○○○ ○○

○○○

○○○

○○○ ○○○○ ○○○

○○

○

● ●●●

●

●●● ●

●

○○

○○

○

91 30 66

●

○

Active IPInactive IP

IIP EAACVD-IP

Cut-off

7/27/95 9/29/95

61 y, man: IPF, died of acute exacerbationHigh resolution computed tomograpy (HRCT) image

73 76 75 66 59 85 40

0500

2,000

4,000

6,000

Apr Aug Spt 199529 7 14 21 28 410 10

10,000

8,000

Steroid-pulse

Oct

Cut-off

KL-6 (U/ml)

KL-6

PaO2 (mmHg) 55

O2 inspiration1 L/min 2 L/min 4 L/min 15 L/min

61 y, M: idiopathic pulmonary fibrosis, died of acute exacerbation

Drugs possibly causing drug-induced pneumonia (Drug-induced interstitial pneumonia)

　As adverse effects　　　　 　 ・・・　１２３２ drugs　　Pharmaceuticals and Medical Devices Agency, Japan, Apr. 2004

KL-6 is at present used as a diagnostic serum marker for interstitial pneumonia in the national health security system authorized by the Ministry of Health, Labour and Welfare, Japan, from 2000.

Chinese herb medicine “Sho-sai-ko-to”　　

Interferons α，α-２ａ，α‐２ｂ，β，β-１ｂ,　γ-１ａ，γ-ｎ１Gefitinib (Anti-cancer molecular targetting drug)Amiodarone (Anti-arrhythmia)Some anti-cancer cytotoxic drugsLeflunomide (Disease-modifying anti-rheumatic drug)

　As severe adverse effects 　 ・・・　５０　drugs　

KL-6 was evaluated as one of honorable discoveries achieved by Japanese researchers

Four Japanese researchers were presented in the preface of the 100 year commemorative book of the Japanese Respiratory Society.　（written by the late Prof. Hiomi Honma）

1. 1966　Invention of flexible fiber bronchoscope by Dr. M. Ikeda, et al.

2. 1967 Discovery of immunoglobulin E (IgE) by Dr. K. Ishizaka

3. 1982　Invention of high resolution computed tomography by Dr. Y. Tohdo

4. 1985 Discovery of KL-6 by Dr. N. Kohno, et al.

cDNA microarray

Ishikawa N, Nakamura Y, et al.The Institute of Medical Science,

The University of Tokyo

Seeing expression levels of 23,040 different Seeing expression levels of 23,040 different genes (messenger genes (messenger RNAsRNAs) in one lot) in one lot

RNAA = UG = C

cDNAcDNA and mRNA hybridizationand mRNA hybridization

DNAA = TG = C

cDNA --------A-T-G-C-A-T-G-C-A-T-G-C---

mRNAU-A-C-G-U-A-C-G-U-A-C-G---AAAAAAA

ADAM8 as a serum tumor marker for lung cancer

Ishikawa N, Kohno N, Nakamura Y, et al. Clin Cancer Res (in press)The Institute of Medical Science, The University of Tokyo

ADCSCCSCLC

(N=72), 267 +/- 56 pg/ml

(N=25), 467 +/- 210 pg/ml(N=62), 427 +/- 286 pg/ml

(N=18), 400 +/- 112 pg/mlNormal

ADC NormalSCC SCLC

P < 0.001

P < 0.001

P < 0.001

0

200

400

600

800

1000

1200

1400

1600

1800

AD

AM

8 (p

g/m

l)

Cut-off

Lung cancer

4

2

3

Development of new procedures for clinical

application

Cartilage repair with tissue-engineered cartilage created under three dimensional culture

Developed by Prof. M. Ochi, M.D., Dept. of Orthopedics, Hiroshima University

　　Autologous Autologous ChondrocyteChondrocyte Implantation (ACI)Implantation (ACI)

((BrittbergBrittberg, Peterson, et al, New Eng J Med, 1994), Peterson, et al, New Eng J Med, 1994)

Cartilage

ThreeThree--dimensional culture and transplantationdimensional culture and transplantation

Cartilage defectCartilage defect

chondrocyteschondrocytes

Cartilage

Preformed cultured

3D-cartilage

Prof. M. Ochi, et al, Dept. of Orthopedics, Hiroshima University

Subchondral boneSubchondral bone

(3) (3) TripsinTripsin digestiondigestion

(4) (4) Collagenase digestionCollagenase digestion (5) (5) Cultivation in Cultivation in AtelocollagenAtelocollagenfor 3 weeksfor 3 weeks

(2) (2) Mince of cartilage pieceMince of cartilage piece(1) (1) Harvest of cartilageHarvest of cartilage

Ochi M, et al ( Ochi M, et al ( ArtifArtif Organs, 2001) : tOrgans, 2001) : the first report in the world

(6) For clinical use

1) Curettage2) Resection of 　the periosteum

4) Implantation 5) Suture of the 　　　remaining periosteum

3) Pull out suture of the periosteum

DefectDefect

PreoperationPreoperation

Case 1: 13 yearCase 1: 13 year--old boy, OCD of the med. femoral condyleold boy, OCD of the med. femoral condyle

2 2 years postyears post--operation.operation.

Prof. M. Ochi, et al, Dept. of Orthopedics, Hiroshima University

4

3

Clinical application of recently developed

technologies

Virtual bronchoscopyby the reconstitution of

high resolution computed tomography (HRCT) images of the lung

Visualization of the Peripheral Lung Structure with Synchrotron Radiation CT

Hirohiko Ikura, MD, et al.Hirohiko Ikura, MD, et al.　　Department of Radiology, Department of Radiology, Ehime University Ehime University School of MedicalSchool of Medical

circumference 1,400 mdiameter 450 m

SPring-8 （Hyogo, Japan）

What is Synchrotron Radiation?electron

acceleration

SynchrotronRadiation

(SR)

• White beam (from infrared to hard X-ray)

• Ultra brightness (×108 to medically used X-ray)

Monochromated beam

• High directionality• Negligible geometrical blur

Hirohiko Ikura, MD, Dept. of Radiology, Ehime University

0.2 mm

Histopathologyμm

SRCT10 μm

CTChest Radiograph

High Resolution CT(HRCT)

mm

Detectability of Lung Lesions with Various Modalities

Hirohiko Ikura, MD, Dept. of Radiology, Ehime University

4

Establishment of clinical evidence

The project for health promotion「Ken-minn　Genki－Baizou　Project]

by Hiroshima University co-operated with theCorporations of Hiroshima Prefecture, Hiroshima City and Higashi-

Hiroshima City (2002-2004)

Director: Nobuoki Kohno, M.D., Ph.D.

As the special enterprise for social contribution granted by theMinistry of Education, Culture, Sports, Science and Technology,

Japan

The instructed groupEducation & exercise

with the instruction

The control groupEducation & examinations

without the instruction

Subjects:Well-controlled diabeticsat the out-patient clinics A

B

The project for health promotion

Entry 3rd 6th 12th month

Physical examsAthletic abilityEndothelial functionAtherosclerosisPulmonary function

Nutritional survey

LifecorderⓇ

(Electric pedometer)

The study protocol

Observational items Pulse Wave Velocity

Athletic Ability

Carotid Echography

LifecorderⓇ

(Electric pedometer)

Chronological changes of HbA1c & Gｌｙco-albumin (GA)

Follow-up period （month）

The instructed groupThe control group

Follow-up period （month）

0 3 6 12 （M）

7.0

7.4

6.6

0 3 6 12（M）

20

22

18

GA

（%）

＊＊

6.4

0 0

＊＊

ΔG

A（%

）

2 1810

0

-10

5

ΔG

A（%

）

2 2810

0

-10

4

20

ΔG

A（%

）

0 1000500

0

-10

4

-5ΔG

A（%

）

0 700300

0

-10

4

r = -0.37P = 0.02

r = -0.35P = 0.02

The instructed group The control group

Daily walking steps (x 1000)

Daily energy consumption (kcal)

Relationship between the change of GA and the quality of exercise

N.S.

N.S.

The Medical Research Center for Environmental Effects on Japanese Emigrants, Hiroshima University

Director: Nobuoki Kohno, MD, PhDHawaii Island

Los Angeles

HiroshimaHilo

Kona

U.S. MainlandJapan

We have been conducting the Hawaii–Los Angeles–Hiroshima Study since 1970, mainly to determine the effects of environmental changes on various diseases by comparing Japanese-Americans with native Japanese subjects.

The Hawaii–Los Angeles–Hiroshima Study

Prev

alen

ce(%)

3030

2020

1010

003030

2020

1010

004040--4949 5050--5959 6060--6969 7070--

▼▼

▼▼

▼▼ ▼▼

▼▼▼▼▼▼

▼▼

Prevalence of diabetics among Japanese-Americans or Japanese （1980’s）

Age (years)

Male

Female

▼▼ ▼▼

HawaiiHawaiiHawaii

Los AngelesLos AngelesLos Angeles

JapaneseJapaneseJapanese

Hara H et al: Diabetes Res Clin Pract 24: S37, 1994.Hara H et al: Diabetes Res Clin Pract 24: S37, 1994.

Carotid intima-media wall thickness (IMT)

10mm10mm

CCA

ECA

ICA

ab cIMT

Carotid arteryCase A

Case B

Age （years）Age （years）

1.01.0

1.51.5

1010 2020 3030 4040 5050 6060 7070 8080 9090

IMT（mm）

IMT（mm）

2.02.0

JapaneseJapanese

00

Comparison of carotid intima-media wall thickness (IMT) between Japanese-Americans and JapaneseComparison of carotid intima-media wall thickness (IMT) between Japanese-Americans and Japanese

Japanese-AmericansJapaneseJapanese--AmericansAmericans

Watanabe H et al: Atherosclerosis, 2003

1.1mm1.1mm Cut-off15 years

We are trying to make novel useful diagnostics and therapeutics in the

Hiroshima University Hospital.