At the beginning of the first semester, there is a large discrepancy in the amount of biological knowledge between students who chose biology as an entrance exam subject and those who did not. We, faculty of biology division, have prepared a program entitled “Life and Death” for those who did not choose biology as an entrance exam subject. In that program, about 200 basic terms found in the glossary of a high school biology text books were used and explained repeatedly. As a result, at the end of the second semester, the gap seemed to be narrowed. Notwithstanding the presence of a gap, there was no difference among students in the ability to perform dissection or microscopic observation. To the question “Are you satisfied with your college?”, more than 90% of the freshpersons of Juntendo Medical School, answered “Yes” and the percentage rose to as high as 98.6 among sixth academic year students. These figures show that students are fully relying on the educational system of Juntendo University.

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Chronic pancreatitis is thought to be incurable. However, we suspected that the pancreas regenerates in cases of chronic pancreatitis. We examined the histological features of chronic pancreatitis mainly in surgically removed human specimens. Morphologically, regenerated pancreas was compared between experimental pancreas and human pancreas. To cause experimental pancreatitis, dl-ethionine, which is an antagonist of methionine, was used. Pathological similarities in human chronic pancreatitis and experimental pancreatitis were compared. The experimental animals comprised rats and dogs. Rats were principally used for studies on the phenomenon of destruction and regeneration in the pancreas. Dogs were used in the experimental study of chronic pancreatitis, and to assess quantitative changes of fibrous tissue and experimental regeneration of the pancreas. Experimentally, the damaged pancreas was examined immuno-histologically. Also, the influence of trypsin inhibitor during pancreatic regeneration was examined by BrdU. Quantitative changes of the fibrous tissue appeared after the destruction of the pancreas. The purpose of experiments was to elucidate the cause of the regeneration of chronic pancreatitis. In experimental pancreatitis, atrophy of the pancreas and the increase of fibrous tissue were almost similar to human chronic pancreatitis. A large quantity of fiber seen in human chronic pancreatitis reacted to α smooth muscle actin strongly. The factor that has been considered to disturb the regeneration of the pancreas is the myofibroblast, which is a subspecies of the fibroblast. In experimental pancreatitis, it was thought that a substance acting between acinar cells controls the amount of fibrous tissue in the pancreas. In addition, it was thought that myofibroblasts produce various mediators. It is suggested that an increase of myofibroblasts suppresses the regeneration of the pancreas in chronic pancreatitis.

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Life was given birth on the earth under existence of the atmosphere, water and minerals and light energy. The atoms of C, H, N, O, P and S work as the basic structure of life, and other molecules of Fe, Cu, Mn, Mg, Se, Mo, etc. function as the active center of molecules and signal transmitter, resulting in autonomic production of life, self-control function, and evolution. In photosynthesis of plants, light-induced activation of chlorophyll molecule in the thylakoid membrane takes electron out of water and produces oxygen molecule. The electron transfer through quinones, cytochromes b, f and other electron transporters, produces proton (H⁺) gradient across the inner membrane, thus synthesizing the ATP via H⁺-ATPase (F₀F₁ATPase) and carbohydrate produced from NADPH⁺ and CO₂ molecule. In contrast, mammals including human beings produces ATP coupled with electron transport in mitochondria (Mt) through NAD (P) H to oxygen via TCA cycle, producing water and CO₂, as well, forming energy circulation between plants and mammals. Long time ago I discovered that Complex III of electron transport system in Mt which deals with ATP synthesis, composed of two types of cytochrome b, by using light absorbance spectrophotometry, under extremely low temperature. One of these shows phosphate potential (ATP/ADP-Pi) dependent redox potential, possibly, playing a role in respiratory control. I found out that there also exists b type cytochrome in Complex II (SDH/fumarate reductase). This cytochrome b559 shows to be oxidized even in anaerobiosis, and it increases in the process of cancer growing and carcinogenesis as well. This protein is recently known as a cancer-related protein with mitochondrial gene abnormality. I found that mitochondrial respiration decreased in the fatty liver and in inflammatory and more in fibrotic livers, concomitant with increased insulin resistance. I also found altered mitochondrial respiratory cytochromes b and aa3 in these diseased livers. Thus, it is suggested that mitochondrial dysfunction in electron transport with decreased cellular respiration has close relation with progression of liver disease and lifestyle-related diseases as well. We hypothesize that long-term over-flow of electron through mitochondrial respiratory chain injures respiratory control system, thus electrons bypass to keep the TCA cycling, resulting in forming ROS formation. ROS causes disorder of mitochondrial DNA, and further nuclear DNA disorder after passing the nuclear membrane. This energy circulation is crucial to subsistence of life on the earth. Light absorbing substances, an effective system of transforming light (energy) into chemical energy, remains plenty in our bodies. Hemoglobin (Hb), myoglobin (Mb), cytochromes, CYP etc. are vital to life, both in supply and in utilization of oxygen in tissues and cells. Noninvasive spectrophotometric measurement of these light absorbing substances provides the information on the character of blood and cellular pigments, thus estimating the blood flow, intracellular oxygenation, cellular redox state and cytochromes abnormalities. By the endoscopic measurement of blood and cellular pigments using optic fiber, I have shown on the clinical basis that the mechanism of acute gastric mucosal lesion (AGML) and peptic ulcer formation, healing mechanism of ulcer, and drug-induced gastro-intestinal mucosal lesion are deeply related with decreased blood flow (ischemia and congestion) and mitochondrial dysfunctions, and clarified the efficacy of various medicines for preventive and therapeutic purposes. Also, I have characterized the hepatic bemodynamics in cirrhotics and non-cirrhotics and found that hemodynamic improvement by glucagon only occurs in non-cirrhotic liver and that cirrhotic liver shows the increased oxygen extraction from the blood, inducing hepatic hypoxia.

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We reviewed recent progress in the pathogenesis of Parkinson's disease (PD) and familial forms of PD. PD is thought to be initiated by the interaction of mitochondrial respiratory failure and oxidative damage inducing protein aggregation, disturbance of axonal transport, and apoptosis. Regarding familial forms of PD, 11 forms have been mapped to certain chromosome loci. Mutations of the alpha-synuclein, UCH-L1, and LRRK2 genes cause autosomal dominant forms and mutations of parkin, PINK1, and DJ1 cause autosomal recessive forms. Alpha-synuclein also plays a crucial role in the pathogenesis of sporadic PD, insoluble aggregates are accumulated in neurons. Parkin, which is the causative gene for autosomal-recessive young-onset PD, shows a proteinubiquitin ligase activity. Accumulation of parkin-substrates may be responsible for nigral neuronal death in this form. PINK1 and DJ-1 are causative genes for other forms of autosomal-recessive young-onset PD. PINK1 is a mitochondrial protein and DJ-1 shows a strong anti-oxidant property suggesting the importance of mitochondrial dysfunction and oxidative damage in nigral neurodegeneration. LRRK2 is the causative gene for a form of autosomal dominant PD. LRRK2 protein has a protein kinase domain suggesting that abnormal phosphorylation of proteins is also important in the pathogenesis of nigra neuronal death.

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I entered Juntendo University School of Medicine in April 1960 and retired in March 2006, So I had a good life for 46 years at Juntendo University. After graduating from Juntendo University, I studied pathology for two years, and then joined the department of gastroenterological surgery where I worked for 37 years. During this period, I studied the production of experimental cancer models, chemotherapy and clinicopathological examination of gastroenterological cancer. At that time, it was reported that Mastomys-a rodent from South Africa-spontaneously developed gastric tumor due to histamine-producing carcinoid. Then I demonstrated the production of serotonin in gastric carcinoid except histamine immunohistochemically. I was the first to succeed in producing canine models of gastric, colonic and pancreatic cancer by the administration of N-ethyl-N′-nitro-N-nitrosoguanidine (ENNG). With regard to chemotherapy, I studied 5-fluorouracil (5-FU) tissue concentrations in resected gastric and colonic cancer specimens, and serum concentrations prior to and after resection of gastric cancer, and the relationship between 5-FU and 5-FU-related enzyme genes in colorectal cancer. In the clinicopathologic examination of colon cancer, I examined the possibility of early detection by measuring the ratio of primary and secondary bile acids in the feces of colorectal cancer patients, and studied the immunohistochemical characteristics of colonic cancer using resected colonic cancer specimens. Finally, I analyzed genomic copy-number aberrations related with node and organ metastases, and the relationship between sex and chromosomal aberrations in colorectal cancer using comparative genomic hybridization (CGH).

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Thirty-eight years have passed since I joined to the Department of Pediatric Surgery of Juntendo University, which had been established as the first Department of Pediatric Surgery in Japan.The establishment of the identity of Pediatric Surgery not only at Juntendo but also in Japan has been the main theme throughout my career. During this period, Pediatric Surgery has advanced tremendously, including neonatal surgery, biliopancreatic surgery, liver transplantation, oncological surgery, urogenital surgery and endosurgery and others. Now the identity of Pediatric Surgery has almost been established now, although there remain some problems, for example, the regionalization of Pediatric Surgery is not yet well established in Japan.

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Between 1967 and 2006, the author's clinical and basic research have involved the following ; 1) pathogenesis of acute brain swelling in dogs and monkeys, (2) neuronal organizations of vestibular nystagmus, cervico-ocular reflex arc, vestibulo-spinal and tecto-spinal systems in cats, (3) pathophysiology of vestibular compensation, (4) eye-head coordination in humans, (5) basilar tip aneurysmal surgery, (6) significance of monitoring in patients with severe head injuries, (7) hypertensive hypervolemic hemodilution therapy for patients with severe cerebral vasospasm following subarachnoid hemorrhage, (8) skull base surgery (i ; modified Dolenc' pterional combined epi-and subdural approach for IC-juxta dural ring giant aneuryms, and sellar and parasellar tumors, ii ; transpetrosal transtentorial approach for petroclival meningioma and clival chordoma, iii ; transcondylar transtubercular approach for midline vertebral aneurysms and lower clival tumors), (9) mild hypothermia, (10) superior parietal lobule incision for trigonal meningioma in the dominant side, (11) neurogenic control of cerebro-vascular bed by the cholinoceptive pontine area, locus coeruleus complex, medial medullary reticular formation and basal forebrain, (12) analysis of local cerebral glucose utilization in a defect in klotho gene expression in the mouse (kl/kl) compared with that in the wild mouse (+/+)

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Pain is defined as an unpleasant sensory and emotional experience associated with actual or potential tissue damage, or described in terms of such damage by the International Association for the Study of Pain (IASP). Accordingly, pain is always subjective, so the objective evaluation of pain is very difficult. However, adequate evaluation of pain is useful for the selection of treatment methods and the judgement of treatment efficacy. Routine pain screening for the presence and intensity of pain for all patients using a Numeric Rating Scale (NRS) is recommended as a simple method for doctors and nurses in the USA. However, pain occurs by intricate mechanisms, so it should never be evaluated by only one scale such as the NRS. Pain evaluated by a simple scale is can bias the choice of treatment method for pain toward the use of opiates in the USA. It is necessary to understand not only the intensity of pain but also the type and nature of pain to administer suitable treatment to patients suffered from pain.

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Five years have passed since I was appointed as a chairman and professor in 2001. I have tried to show the aims of my Department and the outcomes of basic research and clinical achievements in terms of the numbers of laparoscopic surgeries, gynecologic malignancies treated and deliveries. My colleagues in the Department, being so active, will surely continue to achieve brilliant success in research and clinical activities under the leadership of the newly appointed professor, who will follow me.

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Objective : We experimentally examined the effect of a high fat diet on the generation and multiplication of colorectal cancer in rats with 1, 2-dimethylhydrazine (DMH) induced colorectal cancer. Moreover, the relation between high fat diet medication and the composition ratio of fecal bile acid (deoxycolic acid/colic acid : DCA/CA) was also examined. Materials : Four groups of 48 10-weeek-old male Wistar rats were used. Methods : The four groups consisted of Group I : control (MF diet) (n=5), Group II : Wilgram diet (n=5), Group III : MF diet+DMH (n=19), Group IV : Wilgram diet+DMH (n=19). Subcutaneous injection of DMH was performed once (40mg/kg) per week for a total of 10 times. Rats were them sacrificed and dissection was carried out 35 weeks after the start of the experiment. Result : As for DMH induced colorectal cancer, although there was no signifisant difference in the incidence or number of lesions generated with regard to advanced cancer and organized type, there was a tendency toward more undifferentiated cancer in the high fat diet group. The composition of fecal bile acid showed a higher ratio in the high fat diet group. Conclusions : Based on the above findings, in rats with DMH-induced cancer, high fat diet medication increased the composition ratio of fecal bile acids, and participation in the growth of colorectal cancer was suggested.

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Objective : We investigated the mitotic counts of the most severely invaded regions in advanced colon cancers that invaded the subserosal layer (ss) and showed poor prognosis despite curative surgery. Materials : Twenty-three patients who died of cancer within 5 years after curative surgery (poor prognosis group) and 26 patients who survived 5 years or longer after curative surgery. Methods : The two groups were compared based on the following factors ; 1) clinicopathological background factors ; 2) mitotic counts of cancer cells in individual layers, the superficial, intermediate, and deep layers ; 3) mitotic counts of cancer cells in the most severely invaded areas ; 4) mitotic counts of cancer cells in the most severely invaded areas stratified by duration of post operative survival (years). Measurement and Results : The mitotic counts of cancer cells were significantly higher in the most severely invaded area than in the superficial layer, and in the poor prognosis group than in the good prognosis group. Conclusions : Evaluation of the mitotic counts in the most severely invaded areas in colon cancers may be useful for predicting the prognosis of colon cancer showing ss invasion after curative surgery.

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Objective : To evaluate the prognostic significance and usefulness for predicting, survival of preoperative serum CA125 levels and chemotherapy in patients with advanced epithelial ovarian carcinoma. Materials : This retrospective investigation assessed 56 patients with stage III-IV, epithelial ovarian carcinoma who underwent initial surgery followed by paclitaxel/carboplatin chemotherapy and had shown serum CA125>35U/ml before surgery. Methods : To correlate serum CA125 regression with progression free interval, we analyzed variation of CA125 at the notarization point using Pearson's correlation coefficient and log-rank test. Measurement and Results : During the initial treatment period, 43 patients (77%) showed normalization of the serum CA125 level. The mean interval until achieving a normal level of CA125 was 19.5months (range 1-77months). Pearson's correlation coefficient between the interval until normalization and progression-free survival was 0.40 (p<0.01). Conclusions : The interval until serum CA125 levels normalized was shown to be a significant prognostic parameter.

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Objective : Type II diabetes mellitus is considered to be a risk factor for colorectal cancer. In diabetics, the recurrence rate is high, resulting in a poor prognosis. Insulin-like growth factor (IGF) -I may be involved in the pathogenesis. In particular, IGF-I receptors are present in colorectal cancer cells. Therefore, we performed immunohistological staining of IGF-I and IGF-I-transporting proteins, insulin-like growth factor binding protein (IGFBP) -1 and IGFBP-3 in patients who underwent surgery for colorectal cancer, and compared these to findings those in a group with liver metastasis and a group without liver metastasis. Subjects and Methods : The subjects were 45 patients with solitary mp or ss carcinomas of the sigmoid colon (histological type : wel, mod) who underwent radical surgery in our department between January 1995 and December 2000. In 15 of these patients, liver metastasis was detected after surgery. Immunohistochemical staining was performed. The data were compared between the two groups using chi square test or t-test. For multivariate analysis, logistic regression analysis was employed. Results : On immunohistochemical staining, 16 patients (35.6%) were positive for IGF-I, 34 patients (75.6%) were positive for IGFBP-1, and 31 patients (68.9%) were positive for IGFBP-3 There were no significant differences in the clinical findings or clinico-histopathological findings among these 3 groups. However, on immunohistological examination, the incidences of liver metastasis were significantly higher among IGF-I-positive patients and IGFBP-3-negative patients. Multivariate analysis showed a similar finding. Conclusion : Immunohistological staining of IGF-I and IGFBP-3 in patients with colorectal cancer may be important for predicting liver metastasis.

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Object : To investigate the chemopreventive effects of Hericium erinaceum (HE) on 1, 2dimethylhydrazine (DMH) -induced rat colon carcinogenesis. Materials and Methods : Male Wistar rats were allocated to six groups. Rats in the positive control group were given subcutaneous injections of DMH (40mg/kg body weight) once a week for 10 weeks to induce colon carcinogenesis; rats in the HE-treated groups, received the same DMH treatment as the positive group, but also received 0.01% or 0.1% HE; rats in the negative control group were given isovolumic subcutaneous injections of saline as well as DMH treatment; rats in HE-treated groups, with the same saline treatment as the negative group. Animals were sacrified and necropsied at the end of week 40. Results : Carcinomas had formed in all animals in DMH-treated groups. Compared to the DMH-treated group, HE-treated groups showed a tendency to have fewer tumors (5.10±4.41, 2.73±3.50 and 2.67±1.78) and smaller tumors (8.18±5.84mm, 5.78±3.61 and 6.63±4.21). Compared to the positive control group, the labeling index of proliferating cell nuclear antigen (PCNA) in HE treatment group was significantly reduced (77.5±7.75, 70.7±12.27 and 70.2±8.34). Conclusions : Hericium erinaceum may have chemopreventive effect on DMH-induced colon carcinogenesis. Such effect may be due to suppression of cell proliferation.

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[in Japanese]

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[in Japanese]

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[in Japanese]

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[in Japanese]

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