CONTENTS · tion, derangement in metabolism of carbo-hydrate and lipid and acanthosis nigricans have * Percentage of overweight (%) [(Actual body weight Standard body weight)/Standard

Vol.48, No.2 February 2005

CONTENTS

Obesity

Obesity in Later Childhood and Countermeasures

Takehiko OHZEKI . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 53

Practical Aspects of Exercise Therapy for Obesity

Yuzo SATO . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 59

New Prospects for the Treatment of Obesity—Leptin and the discovery of anti-obesity drugs—

Yoshihiro OGAWA . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 64

Regenerative Medicine

Regenerative Medicine for the Central Nervous System—Transplantation of neural stem cells into the injured spinal cord—

Shinjiro KANEKO et al. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 68

Development of Novel Advanced Cell and Gene Therapy andGMP-Controlled Cell Processing

Taira MAEKAWA et al. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 81

Cataract

Timing of Cataract Surgery

Yoshitaka OBARA . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 85

Karoshi

Death due to Overwork (Karoshi )Causation, health service, and life expectancy of Japanese males

Shunichi ARAKI and Kenji IWASAKI . . . . . . . . . . . . . . . . . . . . . . . . . 92

Pediatric healthcare

How to Secure the Personnel for Pediatric, andSpecifically Neonatal, Healthcare

Masanori FUJIMURA . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 99

JMAJ, February 2005—Vol. 48, No. 2 53

Obesity in Later Childhood andCountermeasuresJMAJ 48(2): 53–58, 2005

Takehiko OHZEKI

Professor, Department of Pediatrics, Hamamatsu University School of Medicine

Abstract: Major criteria for the diagnosis of obesity as a disease (obesity-disease)in children include being at least 20% overweight, an increased percentage of bodyfat, hypertension, sleep apnea, type 2 diabetes mellitus, and increased visceral fatclosely related to metabolic syndrome. Although body mass index (BMI) is the keymeasure for diagnosing obesity in adults, percentile values are required to assessobesity in children because BMI varies with age in childhood. Thus, the percentageof overweight is often used for the continuous evaluation of obesity in childhood.Tracking of obesity from childhood to adulthood is commonly seen. BMI rebound(adiposity rebound) in early childhood is likely to be associated with the subse-quent increase in body weight indicating a critical period in the development ofobesity. There is a difference in serum leptin concentrations between males andfemales in adolescence. Eating disorders such as anorexia nervosa and bulimianervosa are frequent among adolescent girls, and are usually accompanied byaversion to obesity. The basic principle of intervention for reducing obesity is todecrease caloric intake and increase energy expenditure. Attention also should bepaid to the involvement of hereditary predisposition and prenatal factors. It isnecessary to review the lifestyle habits of the entire family, and, in so doing, the roleof the mother seems essential. School life is also important. Prophylaxis is ofgreater value in children than in adults.

Key words: Obesity; School children; Children; BMI

ing the need for a policy to deal more appropri-ately with obese patients who have healthproblems or are at high risk of impaired health.Obesity, viewed from the aspect of daily prac-tice, as it is in this document, represents acritical area in modern health care.

Although obesity-disease generally manifests

Introduction

Because obesity is an important lifestyle-related disease,1) it is of great clinical signifi-cance to understand it as a disease entity.Therefore, the concept of obesity as a disease(obesity-disease) has been proposed,2) indicat-

This article is a revised English version of a paper originally published inthe Journal of the Japan Medical Association (Vol. 130, No. 1, 2003, pages 45–49).

�Obesity

54 JMAJ, February 2005—Vol. 48, No. 2

discusses countermeasures.

Guidelines for the Diagnosis ofObesity-Disease in Children

Diagnostic criteria for obesity-disease areneeded in the clinical care of children as well asadults. Obese children represent a populationat risk for developing various complications,and proper intervention and treatment are

T. OHZEKI

in adulthood, its presence can be seen in ado-lescence, childhood, and even infancy, andthere has been great progress in research onthe prenatal factors involved in obesity. Wehave also reported on this topic.3–9) Children ofschool age are in the process of developing life-long habits, and require guidance and supportboth at home and at school.

This paper presents an outline of the char-acteristics of obesity in later childhood, and

Table 1 Diagnostic Criteria for Obesity-Disease in Children

Determination of obesity in children: Percentage of overweight of 20% or more in children agedless than 18 years and having a significantly increased body fat percentage.• Reference values for body fat percentage are as follows (regardless of method of measurement)

Boys (entire childhood): 25%Girls younger than 11 years: 30%, 11 years old or older: 35%

Definition of obesity-disease: Obesity-disease is a condition complicated by health impairment(medical abnormality) derived from or related to obesity and requiring treatment to medicallyreduce weight. This condition is dealt with as a disease entity.

Diagnosis of obesity-disease: Obese children at least 5 years (60 months) old who conform toany of the following requirements:

(1) Having at least one item of section A.(2) Having the percentage of overweight of 50% or more and at least one item of section B.(3) Having the percentage of overweight of less than 50% and at least two items of section B.A. Medical problems particularly requiring obesity treatment

(1) Hypertension(2) Abnormal pulmonary ventilation including sleep apnea(3) Type 2 diabetes mellitus, impaired glucose tolerance (abnormal elevation of HbA1c)(4) Increased abdominal circumference or visceral fat accumulation as determined by CT

at the umbilical levelB. Metabolic disorders and other abnormalities closely related to obesity

(1) Liver dysfunction (abnormal ALT levels)(2) Hyperinsulinemia(3) Hypercholesterolemia(4) Hypertriglyceridemia(5) Hypo-HDL-cholesterolemia(6) Acanthosis nigricans(7) Hyperuricemia

(In cases of hepatopathy, fatty liver should be confirmed by ultrasonography. Blood samplesfor TG and IRI assays should be obtained in the early morning following overnight fasting.)

• If no improvement is achieved even after the weight is reduced, these findings are presumedto be unrelated to obesity.

Reference items: Physical factors and issues in daily living (the presence of two or more itemscorresponds to one item of section B.)

(1) Skin findings including striae cutis and intertrigo(2) Bone fracture or arthropathy caused by obesity(3) Menstrual disorder (secondary amenorrhea lasting for 1.5 years or more)(4) Decreased ability to run and jump, which causes prominent difficulty in, e.g., taking a

physical education class(5) School avoidance and being bullied because of obesity

HbA1c: hemoglobin A1c, ALT: alanine-aminotransferase, HDL: high-density lipoprotein,TG: triglyceride, IRI: immunoreactive insulin.(From Asayama, K. et al.: Diagnostic criteria for obesity in children. Himan Kenkyu 2002; 8:204–211.)


OBESITY IN CHILDHOOD

necessary, particularly for those who requireprompt care.1,3,5,10) However, the frequency ofcomplications is lower in obese children than inadults, and therefore obesity in children alsoplays a greater role as a predictor of futurerisk.11,12)

Table 1 presents a summary of diagnosticcriteria for obesity-disease in children.13) Basicrequirements for the diagnosis in children 5 to18 years of age include an percentage of over-weight* (degree of obesity) of at least 20% anda high percentage of body fat. In addition, adiagnosis of obesity-disease is made in thepresence of concomitant morbidities such ashypertension, sleep apnea, type 2 diabetesmellitus, or increased visceral fat, which isclosely related to metabolic disorders. In addi-tion, derangement in metabolism of carbo-hydrate and lipid and acanthosis nigricans have

* Percentage of overweight (%)�[(Actual body weight�Standard body weight)/Standard body weight]�100** BMI�[Body weight (kg)]/[Height (m)]2

been cited as essential features.In adults, body mass index (BMI)** is an

important tool in diagnosing obesity.2,6) How-ever, BMI varies according to age amongchildren. In children above 5 years of age,BMI values continue to increase until thechild reaches his or her adult height (Fig. 1).Therefore, the percentage of overweight isoften used for the continuous evaluation ofsubjects in childhood. In Western countries,percentiles of BMI are used to determineobesity in children.6)

Significance of the Diagnosis andTreatment of Obesity in Children

According to calculations made in the US,costs related to take care of obesity in childrenbetween 6 and 17 years old have tripled during

(cm) 180

170

160

150

140

130

120

110

100

90

80

70

60

50 10

20

30

40

50

60

70

80

90

(kg)

0 1 2 3 4 5 6 7 8 9 1011121314151617181920Age (yr)

(cm) 180

170

160

150

140

130

120

110

100

90

80

70

60

50 10

20

30

40

50

60

70

80

90

(kg)

0 1 2 3 4 5 6 7 8 9 1011121314151617181920Age (yr)

�2SD

�2SD

�1SD

�1SDMean

�2SD

�2SD

�1SD

�1SDMean

�2SD

�2SD

�1SD

�1SD

Mean

�2SD

�2SD

�1SD

�1SDMean

25BMI

20

15

Girls (0–18 yr)

25BMI

BMI

BMI

Weight (kg)

Wei

ght (

kg)

Wei

ght (

kg)

Height (cm)

Hei

ght (

cm)

Hei

ght (

cm)

Height (cm)

Weight (kg)

20

15

Boys (0–18 yr)

Fig. 1 Variations in BMI according to age(Adapted from Ohzeki, T.: Determination of obesity and overweight in childhood: current status andfuture prospects in Japan and other countries. Himan Kenkyu 2001; 7: 21–26.)


the past 20 years, generating alarm and drawingattention to the healthcare costs of obesity.14)

The prevalence of impaired glucose toler-ance concomitant with severe obesity is 25%among 4- to 10-year-old children and 21%among 11- to 18-year-olds.1) When the meta-bolic disorders that constitute “metabolic syn-drome” are examined in terms of the factorsincluded—lipids, blood pressure, and insulin—such disorders are frequently found in obesechildren, with the most important causativefactor being insulin resistance.10)

The diagnosis and treatment of obesity inchildhood and adolescence is critical not onlybecause of their importance at this stage of lifeitself but also because they are closely relatedto metabolic syndrome and obesity in adult-hood (Table 2). Tracking of obesity from child-hood onwards is common, with a number ofrecent reports documenting tracking fromchildhood to adulthood.4,10,12)

BMI varies with age, showing rather highvalues in early infancy and beginning to declineone year after birth, reaching its lowest point atthe age of 5–7 years. Thereafter, BMI graduallyincreases with age, reaching an adult levelwhen the child reaches his or her adultheight.15) This phenomenon of a rise in BMI asthe child ages, is called adiposity rebound16) orBMI rebound. Earlier adiposity rebound isreported to increase the possibility of adultobesity. Thus, adiposity rebound is considered acritical period for the development of obesity.Based on our clinical experience with pediatricobesity, children with simple obesity tend to beprecocious. Adiposity rebound in younger age

seems therefore almost synonymous with theirprecocity.3,4)

Issues in Adolescence

Adolescence is the period that ranges fromthe manifestation of secondary sex characteris-tics to the completion of sexual maturation.17)

The mean age at menarche among Japanesegirls is 12.3�0.03 years (mean�standard devia-tion). Among boys, an increase in testicularvolume is noted initially, with this increasing to15–20 ml with maturation.

Paralleling sexual maturation in adolescenceare differences in physique and body composi-tion between males and females. This is chieflyderived from the actions of sex hormones. Inassociation with the amount of body fat, differ-ences in serum leptin concentration are notedbetween males and females in adolescence.5,8,17)

Variations in body composition during adoles-cence, particularly physiological increases inbody fat among girls, should be consideredseparately from the progression of obesity.

Another feature of adolescence is the pres-ence of eating disorders that occur frequentlyamong adolescent girls,4,17) such as anorexianervosa and bulimia nervosa usually accompa-nied by strong feelings of aversion to obesity.One view is that the treatment/intervention ofobesity is the main causative factor. However,the main factors in the onset of eating disordersare considered to be mental predisposition andpsychological status.

Girls who are not obese and fall within therange of standard body weight often regard a

T. OHZEKI

Table 2 Significance of the Diagnosis and Treatment of Obesityin Childhood and Adolescence

1. Tendency to increased incidence2. Tracking into adulthood obesity3. Predictive of abnormalities of body weight and metabolism in adulthood4. Adulthood obesity originates in childhood and adolescence (adiposity rebound)5. Relation with eating disorders and underweight in adolescent girls6. Manifestation of disorders of carbohydrate and lipid metabolism


lower weight as desirable. This goal of a lowerweight may lead to several health problems.According to the National Nutrition Surveyconducted by the Japanese Ministry of Health,Labor and Welfare, about one in four (24.2%)Japanese women in their 20s have a BMI of lessthan 18.5, a frequency that is nearly double thecorresponding percentage of 12.4% in the1980s.

Countermeasures to Obesityin Children

The basic principle for reducing obesity is,obviously, to decrease caloric intake andincrease energy expenditure. When this prin-ciple is employed in clinical practice, certaincaveats apply, particularly in pediatric cases.

One point to consider is the involvement ofhereditary predisposition and prenatal fac-tors.3,5,7,18) These are important for the occur-rence of obesity, including adult cases. There-fore, children with a history of obesity in thefamily should be considered at high risk. It canbe presumed that differences between childrenwith high and low hereditary risk will occur inthe progression of obesity and development ofcomplications, even if the children have similarlifestyles. Although high-risk family history isnot included among the diagnostic criteria forobesity-disease, it is an important factor thatrequires serious attention, particularly in pedi-atric cases.

When obesity is found frequently within afamily, acquired, or lifestyle, factors may becommon to the patients, in addition to heredi-tary causes. More specifically, it is not uncom-mon for many of the family members in ques-tion to have the same tendencies towardcertain habits of eating and exercise that pre-cipitate obesity. It therefore is necessary toreview the lifestyle habits of the entire family inconsidering the treatment and prevention ofobesity in children.

In terms of the involvement of family mem-bers in lifestyle and obesity, it should be recog-

OBESITY IN CHILDHOOD

nized that the mother plays a particularlyimportant role. Although both parents areresponsible for the upbringing of children,under current circumstances in Japan mothersplay greater roles, particularly in regard toactivities related to the life habits of children. Anumber of previous studies in Japan as well asother countries on the correlation between theobesity of parents and children have revealed ahigher correlation with obesity in the mother.5)

Therefore, approaches to the obese child arechiefly made via the mother.

Another major factor is school for the devel-opment of lifestyle of children. School is thecenter of a child’s social life, and the childspends a considerable amount of time inschool. It is difficult to consider schools collec-tively because the situation varies widely fromone school to another, but a proper under-standing of obesity enables early detection anddiagnosis as well as effective intervention andtreatment.

In comparison with adults, greater impor-tance should be attached to the prevention ofobesity in children. Since some life habits areestablished during childhood, it is necessaryto set good life habits as the goal of guidance.Corrective measures and actions taken duringchildhood, to lead to more appropriate eatinghabits and preferences, joy in exercise, skill inphysical activities, and non-sedentary leisure,are of critical importance because lifestylepatterns formed in childhood may affect thelifestyle, health, and quality of life of individu-als for the rest of their lives.

Conclusion

Many of the signs of obesity are alreadypresent in childhood, necessitating early careand guidance. Childhood is a period in whichlife habits are established and the effects ofprenatal factors become apparent. Thus, it is animportant period in the diagnosis and treat-ment of obesity.


T. OHZEKI

REFERENCES

1) Sinha, R., Fisch, G., Teague, B. et al.: Preva-lence of impaired glucose tolerance amongchildren and adolescents with marked obesity.N Engl J Med 2002; 346: 802–810.

2) Obesity-Disease Diagnosis Guideline Prepa-ration Committee of the Japan Society for theStudy of Obesity (Matsuzawa, Y., Inoue, S.,Ikeda, Y. et al.): New evaluation of obesity anddiagnostic criteria of obesity as a disease forJapanese. Himan Kenkyu 2000; 6: 18–28. (inJapanese)

3) Ohzeki, T., Nakanishi, T. and Fujisawa, Y.:Lifestyle-related diseases in children. InAnnual Review: Endocrinology, Metabolism2003 (ed. Kanazawa, Y.), Chugai Igakusha,Tokyo, 2003; pp.1–7. (in Japanese)

4) Ohzeki, T., Nakagawa, Y., Hirano, K. et al.:Nutrition and diseases in adolescence.Shishunkigaku 2002; 20: 440–445. (in Japa-nese)

5) Ohzeki, T., Nakagawa, Y., Nakanishi, T. et al.:Characteristic features of obesity in childrenand their management. Nippon Rinsho 2001;59: 597–602. (in Japanese)

6) Ohzeki, T.: Determination of obesity andoverweight in childhood: current status andfuture prospects in Japan and other countries.Himan Kenkyu 2001; 7: 21–26. (in Japanese)

7) Liu, Y., Nakagawa, Y., Ohzeki, T. et al.: Leptinactivation of corticosterone production inhepatocytes may contribute to the reversal ofobesity and hyperglycemia in leptin-deficientob/ob mice. Diabetes 2003; 52: 1409–1416.

8) Nakanishi, T., Li, R., Liu, Z. et al.: Sexualdimorphism in relationship of serum leptinand relative weight for the standard in normal-weight, but not in overweight, children as wellas adolescents. Eur J Clin Nutr 2001; 55: 989–993.

9) Saegusa, H., Nakagawa, Y., Liu, Y.J. et al.:Influence of placental 11 beta-hydroxysteroid

dehydrogenase (11 beta-HSD) inhibition onglucose metabolism and 11 beta-HSD regula-tion in adult offspring of rats. Metabolism1999; 48: 1584–1588.

10) Maffeis, C., Moghetti, P., Grezzani, A. et al.:Insulin resistance and the persistence of obe-sity from childhood into adulthood. J ClinEndocrinol Metab 2002; 87: 71–76.

11) Srinivasan, S.R., Myers, L. and Berenson, G.S.:Predictability of childhood adiposity and insu-lin for developing insulin resistance syndrome(Syndrome X) in young adulthood. TheBogalusa Heart Study. Diabetes 2002; 51:204–209.

12) Steinberger, J., Moran, A., Hong, C.P. et al.:Adiposity in childhood predicts obesity andinsulin resistance in young adulthood. JPediatr 2001; 138: 469–473.

13) Asayama, K., Murata, M., Ohzeki, T. et al.:Diagnostic criteria for obesity in children.Himan Kenkyu 2002; 8: 204–211. (in Japanese)

14) Wang, G. and Dietz, W.H.: Economic burdenof obesity in youths aged 6 to 17 years: 1979–1999. Pediatrics 2002; 109: e81.

15) Freedman, D.S., Kettel, K.L., Serdula, M.K.et al.: BMI rebound, childhood height andobesity among adults: The Bogalusa HeartStudy. Int J Obes Relat Metab Disord 2001; 25:543–549.

16) Dietz, W.H.: “Adiposity rebound”: Reality orepiphenomenon? Lancet 2000; 356: 2027–2028.

17) Fujisawa, Y. and Ohzeki, T.: Physical charac-teristics of adolescents. Mod Physician 2002;22: 953–956. (in Japanese)

18) Seckl, J.R., Cleasby, M. and Nyirenda, M.J.:Glucocorticoids, 11 beta-hydroxysteroid dehy-drogenase, and fetal programming. Kidney Int2000; 57: 1412–1417.

19) Faith, M.S., Berman, N., Heo, M. et al.: Effectsof contingent television on physical activityand television viewing in obese children. Pedi-atrics 2001; 107: 1043–1048.


Practical Aspects of Exercise Therapyfor ObesityJMAJ 48(2): 59–63, 2005

Yuzo SATO

Professor, Department of Health Science, Faculty of Psychological andPhysical Sciences, Aichi Gakuin University

Abstract: It has become apparent from many clinical and epidemiological follow-up studies that appropriate dietary restriction and physical exercise improve in vivoinsulin resistance and are useful for the prevention and treatment of lifestyle-related diseases, including obesity. The field of clinical practice in Japan haswitnessed the implementation of Healthy Japan 21, a project aimed at preventingthe development of lifestyle-related diseases and prolonging healthy life, as well asthe enactment of the Health Promotion Law. Specifically, it is recommended thataerobic exercises such as walking and jogging should be carried out for 10–30minutes at least 3–5 times per week, at mild to moderate intensity (generally at apulse rate of 120 beats/min, or 100 beats/min for those in their 60s and 70s).Resistance training of mild intensity with the use of light dumbbells and stretchcords should be combined in elderly individuals who have decreased musclestrength. Because obesity is related to lifestyle, those who are too busy to desig-nate a specified time for exercise should be encouraged to incorporate exerciseinto their daily life activities, e.g., using stairs rather than elevators or escalators.

Key words: Lifestyle-related disease; Insulin sensitivity; Aerobic exercise;Resistance training

Introduction

Evidence-based medicine (EBM) is an impor-tant component of medical care and research.1)

In the field of exercise therapy for obesity,the results of a number of large-scale clinicalstudies2–4) have demonstrated that weight lossresulting from lifestyle modification, includingphysical exercise, is useful for decreasing the


development of diabetes mellitus among obesepeople with impaired glucose tolerance (IGT).The mechanisms of the effects of exercise alsoare being elucidated by molecular biologicalapproaches.5) These and other studies haveaccumulated evidence that suggests the useful-ness of exercise therapy for reducing obesity.

The Japanese Ministry of Health, Labor andWelfare has emphasized the concept of lifestyle-

�Obesity


obesity, playing an important role in the devel-opment and progression of the pathologicalcondition known as syndrome X, multiple-risk-factor syndrome, the deadly quartet, the insulinresistance syndrome, the visceral-fat syndrome,or the metabolic syndrome.6)

2. Results from epidemiological studiesMany epidemiological studies have demon-

strated that appropriate dietary restrictionsand physical exercise improve in vivo insulinsensitivity, and thus are useful for the preven-tion and treatment of all diseases related to in-sulin resistance (metabolic syndrome/lifestyle-related diseases).2,6)

(1) Our follow-up study carried out in obesestudents demonstrated that level II life activity,which represents daily physical activity of mod-erate intensity (5th edition of “Dietary Allow-ances in Japanese People”), was significantlymore frequent in students with improvedobesity than in those with unimproved obesity(Fig. 1).7)

(2) Diet therapy and implementation ofexercise (3 times per week) improved insulinresistance in people with mild obesity (OsloDiet and Exercise Study, Norway).8)

(3) When 522 patients with IGT, includingobese patients, assigned to either the lifestyleintervention group or the control group, werefollowed, the incidence of diabetes was lowerin the intervention group than in the controlgroup. In addition, the effects of guidance ondiet therapy, exercise, and weight loss werescored, and the incidence of diabetes was foundto be significantly lower in patients who hadhigher achievement rates in both the interven-tion and control groups (Finland Diabetes Pre-vention Study, Finland).3)

(4) A total of 3,234 patients with IGT whohad a mean body mass index of 34.0 weredivided into a group subjected to lifestylemodification (group L: 7% weight loss by exer-cise of moderate intensity, 150 minutes perweek, together with caloric restriction and alow-fat diet), a group subjected to drug therapy

Y. SATO

related diseases, including type-2 diabetes mel-litus as a typical example. In addition, HealthyJapan 21, a large-scale project aimed at decreas-ing diabetes and other lifestyle-related diseaseshas been enacted. This project aims to prolonghealthy life by reducing obesity and other riskfactors through physical activity/exercise andthe modification of nutrition, eating habits, andother components of lifestyle.1) As a legal basisfor this program, the Health Promotion Lawwas enacted in May 2003.

Because obesity is a condition in which thebody accumulates excessive amounts of fat,the basis of its treatment is to reduce adiposetissue by manipulating food intake and outputof energy over a prolonged period of time.More specifically, in addition to dietary restric-tion, physical exercise should be implementedto increase the body’s basal metabolic ratio,which tends to decrease with dietary restric-tion, and to induce lipolysis in adipose tissueand efficient consumption of its product, freefatty acid (FFA), in skeletal muscles.6)

However, as described later, the reduction ofadipose tissue tends to be slight with high-intensity exercise. Therefore, the goal in pre-scribing exercise is to create increased physicalactivity in the patient’s daily life, rather thanprescribing specific sports.6)

Physical Activity and Obesity:Results of Epidemiological Studies

1. Increased insulin resistance caused bylack of exercise

As modern life has become increasingly lessdemanding, physical activity has decreased whileobesity and other lifestyle-related diseases haveincreased. Further, the adoption of an increas-ingly high-fat western diet has exacerbated theproblem of obesity. Lack of exercise inducesinsulin resistance in muscle, leading to disordersof carbohydrate metabolism. Insulin resistanceresults in compensatory hyperinsulinemia, lead-ing to type-2 diabetes mellitus, hypertension,hyperlipidemia, and atherosclerosis, as well as


by skeletal muscle. Physical exercise combinedwith dietary restriction prevents or eliminatesobesity.

(2) Exercise, particularly that of higherintensity, causes increased secretion of insulincounter-regulatory hormones, such as gluca-gon and catecholamine. High-intensity, heavyexercise induces an increase in lipid perox-ides [thiobarbituric acid reactive substances(TBARS)] in blood as a result of free-radical production, and causes organ damagethat facilitates the progression of age-relatedchanges.1,2)

(3) During exercise of moderate or lowerintensity, both carbohydrates and FFA are usedas sources of energy for muscle. However, asthe intensity of exercise increases, the propor-tion of energy derived from carbohydratesincreases, leading to a decrease in the bloodFFA level (phenomenologically, inhibition oflipolysis). In exercise therapy for obesity, it isnecessary to elevate the rate of utilization of fatstored in adipose tissue, in addition to muscletraining. Therefore, exercise of moderate orlower intensity [lactate threshold (LT) level] ispreferable.1,2)

EXERCISE THERAPY FOR OBESITY

(group M: metformin 850 mg, twice a day), andthe control group (group C: placebo adminis-tration), and followed up for 2.8 years on aver-age. The results showed that the incidence ofdiabetes developing from IGT was 58% lowerin group L, and 31% lower in group M, than inthe control group (Fig. 2) (Diabetes PreventionProgram, USA).4)

Effects of Physical Exercise onObesity

1. Acute metabolic effect(1) A large amount of energy is consumed

Fig. 1 Daily physical activity levelsA: Concerning intensity of daily physical activity, 88.3% of

subjects in the current obese group and 74.4% of subjectsin the current non-obese group selected the lightest inten-sity (class I) involving deskwork. Furthermore, 10.0% ofsubjects in the current obese group and 24.4% of subjectsin the current non-obese group selected intensity class II.A significant difference in distribution was found betweenthe groups.Chi-Square�9.58, D.F�3, P�0.05.

B: In other words, concerning intensity of daily physicalactivity, 86.3% of subjects in the group with continuedobesity and 54.5% of subjects in the group showingimprovement in obesity selected the lightest intensity(class I) involving deskwork. Furthermore, 11.8% of sub-jects in the group with continued obesity and 45.5% ofsubjects in the group showing improvement in obesityselected intensity class II. There was a significant differ-ence in distribution between the groups.Chi-Square�10.41, D.F.�3, P�0.01.

(Fujii, T. et al.: The association of physical activity level char-acteristics and other lifestyles with obesity in Nagoya Univer-sity alumni, Japan. Scand J Med Sci Sports 1998; 8: 57–62)

100%

100%

80%60%40%20%

88.3

86.3 11.811.811.8

54.5 45.545.545.5

74.4 24.424.424.4

10.010.010.0

0%

8060%40%20%0%

Current obese

Current non-obese

Continued obesity

Improvement in obesity

A

B

Key: I (light), II (moderate), III (light heavy), IV (heavy).

Fig. 2 Cumulative incidence of diabetes according tostudy group

The diagnosis of diabetes was based on the criteria ofthe American Diabetes Association. The incidence ofdiabetes differed significantly among the three groups(P�0.001 for each comparison).(Diabetes Prevention Program Research Group: Reduc-tion in the incidence of type 2 diabetes with lifestyleintervention or metformin. N Engl J Med 2002; 346: 393–403)

40

30

20

10

00

Cum

ulat

ive

Inci

denc

eof

Dia

bete

s (%

)

Placebo

Metformin

Lifestyle

Year

0.5 1.0 1.5 4.02.0 2.5 3.0 3.5


2. Physical training effectsRegular physical exercise improves in vivo

insulin sensitivity. We previously investigatedthe effects of exercise from various aspects usingthe glucose clamp technique, and obtained thefollowing results.1,2)

(1) Ongoing physical exercise combinedwith dietary restriction improves the insulinresistance of peripheral tissue, particularly adi-pose tissue and weakened muscle, in obesepeople.

(2) If patients with simple obesity or obesetype-2 diabetes continue appropriate dietaryrestrictions and physical exercise, insulin resist-ance improves markedly together with weightloss, and body fat, mainly in the abdominal vis-ceral region, is selectively decreased, whereaslean body mass (LBM), representing muscleand other non-fat tissue, is unchanged. There isa significant positive correlation between im-provement of in vivo insulin resistance andnumber of steps taken per day as determinedby pedometer. In contrast, extreme dietaryrestriction without accompanying exercise ther-apy achieves no decrease in body fat, butcauses a decrease in LBM and fails to improveinsulin resistance.

(3) Long-term physical exercise of mild in-tensity that does not affect maximal oxygenuptake (VO2max) in non-obese people increasesinsulin sensitivity even when there is no changein body weight.

(4) Aerobic exercises such as jogging aremore useful for improving in vivo insulin resist-ance than anaerobic exercises such as weight-lifting. However, resistance training usingstretch cords or light dumbbells is also usefulfor elderly people who have decreased mus-cular strength and mass.9)

(5) The training effect characterized byimprovement of insulin resistance attenuateswithin 3 days and disappears within 1 week.

(6) Visceral fat, rather than subcutaneous fat,promotes the formation of insulin resistance-related atherosclerosis. Physical exercise selec-tively decreases visceral fat.

(7) The implementation of exercise bringsabout a decrease in plasma triglyceride level,an increase in high-density lipoprotein (HDL)cholesterol, and improvement of mild hyper-tension. Thus, physical exercise exerts an inhib-itory effect on the development and progres-sion of atherosclerosis through a number ofmechanisms.

(8) Continued exercise increases basal met-abolic ratio (BMR), which tends to decreasewith dietary restriction, and diet-induced ther-mogenesis (DIT) in obese individuals.

Practical Aspects ofExercise Prescription

1. Indications of exercise therapy andmedical examinations

Before initiating exercise therapy, variousexaminations should be carried out to deter-mine whether the patient has conditions(including knee or ankle joint problems) thatcould worsen as a result of exercise. Patientsfor whom exercise therapy is not indicated,e.g., those with secondary obesity, should beexcluded and referred to the respective special-ists, including surgeons.10)

2. Types of exercise and methods of practiceFree fatty acids produced from lipolysis

through physical exercise are converted toacetyl coenzyme A (CoA) via �-oxidation, andare metabolized in the tricarboxylic acid (TCA)cycle. Therefore, it is easy to understand whythe exercises prescribed for exercise therapyare restricted to those of an aerobic nature.

Specifically, patients are instructed to engagein aerobic exercises that involve the muscles ofthe entire body, e.g., walking, jogging, gym-nastic exercises, bicycle ergometer, and swim-ming, with the latter two particularly suitablefor obese patients. Exercise of moderate inten-sity, generally aiming at pulse rate of 120/min(100/min for patients aged 60–70 years), shouldbe performed for 10–30 min at a time (60 minfor patients who have sufficient physical

Y. SATO


EXERCISE THERAPY FOR OBESITY

strength), at least 3–5 days a week. In regard toexercise intensity, LT (lactate threshold) shouldbe determined if possible, to perform exerciseof the LT level. If the patient has no time tocarry out a regular exercise regimen, he or sheshould be instructed to incorporate physicalactivity into daily life activities, such as usingstairs instead of elevators, or getting off thebus one bus stop early and walking to work.Pedometers and Lifecorder® are useful forassessing the amount of exercise in daily living.The goal should be at least 10,000 steps/day (orat least 7,500 steps/day), and the patient’snumber of steps should be checked at visits tothe outpatient clinic.

3. Cautions in implementation of exercise therapy

(1) Exercise alone is not sufficient and needsto be combined with diet therapy.

(2) Proper warm-up and cool-down shouldbe performed before and after exercise, re-spectively.

(3) Since obese patients are likely to sufferinjuries to the knee or foot, the use of athleticshoes with thick soles is recommended.

(4) Exercise should begin at mild intensityand for a short period of time, then gradu-ally increase to higher intensity and a longerperiod.

(5) Patients should be instructed to eat fruitsand vegetables to prevent any increase in freeradicals caused by exercise, and vitamins C andE should be administered if necessary.

(6) Techniques of group therapy and behav-ior modification therapy should be introduced.

Conclusion

Evidence for the usefulness of exercisetherapy for obesity has been described, with anoutline of the practical aspects of exercise pre-scription. Obesity is a typical lifestyle-relateddisease, requiring long-term modification ofeating and exercise habits. It should be empha-

sized that it is important to instruct the patientto incorporate exercise of mild or moderateintensity into daily life activities.

REFERENCES

1) Sato, Y.: Current issues in exercise therapy fordiabetes mellitus. J Jap Soc Clin Sports Med2003; 11: 1–9. (in Japanese)

2) Sato, Y.: Diabetes and life-styles: Role ofphysical exercise for primary prevention. Br JNutr 2000; 84(Suppl 2): S187–S190.

3) Tuomilehto, J., Lindström, J., Eriksson, J.G.et al.: Prevention of type 2 diabetes mellitusby changes in lifestyle among subjects withimpaired glucose tolerance. N Engl J Med2001; 344: 1343–1350.

4) Diabetes Prevention Program ResearchGroup (Knowler, W.C. et al.): Reduction inthe incidence of type 2 diabetes with lifestyleintervention or metformin. N Engl J Med2002; 346: 393–403.

5) Winder, W.W., Holmes, B.F., Rubink, D.S.et al.: Activation of AMP-activated proteinkinase increases mitochondrial enzymes inskeletal muscle. J Appl Physiol 2000; 88: 2219–2226.

6) Sato, Y.: Exercise therapy for overweight andobesity: Theory and practice. J Jap Soc StudyObes 1998; 4: 211–216. (in Japanese)

7) Fujii, T., Ohsawa, I., Nozawa, A. et al.: Theassociation of physical activity level character-istics and other lifestyles with obesity inNagoya University alumni, Japan. Scand JMed Sci Sports 1998; 8: 57–62.

8) Torjesen, P.A., Birkeland, K.I., Anderssen,S.A. et al.: Life-style changes may reversedevelopment of the insulin resistance syn-drome. The Oslo Diet and Exercise Study;A randomized trial. Diabetes Care 1997; 20:26–31.

9) Takeshima, N.: Effects of resistance training.In Exercise Prescription for the Elderly—Clinical Guidelines— (ed. Sato, Y.), Nankodo,Tokyo, 2002; pp.23–32. (in Japanese)

10) Ohsawa, I.: Practical aspects of exercise pre-scription for diabetes. In A Teaching Guide forTherapeutic Exercise in Diabetes Mellitus (ed.Sato, Y.) 2nd ed. 2001; Nankodo, Tokyo,pp.49–89. (in Japanese)


New Prospects for the Treatment of Obesity—Leptin and the discovery of anti-obesity drugs—JMAJ 48(2): 64–67, 2005

Yoshihiro OGAWA

Professor, Department of Molecular Medicine and Metabolism,Medical Research Institute, Tokyo Medical and Dental University

Abstract: Obesity is a typical multifactorial disease that results from complexinteractions between hereditary predisposition and environmental factors, makingit extremely difficult to approach from a molecular level. At the end of 1994, anobese gene product, leptin, was discovered, and, since then, obesity research hasproduced a variety of new findings. Leptin is secreted from the adipose tissue andto act directly on the hypothalamus, causing appetite suppression and acceleratedenergy metabolism, thereby denoting a relationship to obesity and weight gain.A number of hypothalamic appetite regulators have been found, and it has recentlybecome apparent that many of these regulators are controlled by leptin. In contrast,many genes that are known to cause human obesity and to develop from single-gene mutations regulate energy metabolism by leptin, and they have attractedattention as possible anti-obesity drugs. This paper outlines new anti-obesity drugresearch and development that have emerged since the discovery of leptin.

Key words: Leptin; Hypothalamus; Development of anti-obesity drugs;Neuropeptides

Introduction

Obesity is a typical multifactorial diseasethat results from complex interactions betweenhereditary predisposition and environmentalfactors, making it extremely difficult to approachfrom a molecular level. After leptin, whichcauses obesity in the ob/ob mouse when itmutates, was found at the end of 1994, researchon obesity took a new direction. It is speculated


that leptin is released from the adipose tissueand acts directly on the hypothalamus to con-trol various appetite regulators, leading tostrong suppression of the appetite and increasedenergy metabolism. Thus, leptin is consideredto be involved in the control of obesity andweight gain. Although various appetite regu-lators have been uncovered, it has recentlybecome apparent that many are controlled byleptin, causing leptin to become the target of

� Obesity


trast, about 5–10% of patients with obesity havedecreased blood concentrations of leptin; thus,leptin compensatory therapy may be promisingin such subjects. It has recently been reportedthat compensation for decreased leptin causedby diet therapy prevents oxygen consumptionfrom decreasing during the weight-loss process,suggesting the possibility that diet therapycombined with compensatory leptin adminis-tration produces efficient weight loss.

Possible anti-obesity drugs targeting leptininclude leptin analogues, leptin agonists, andleptin resistance-improving agents.

Hypothalamic Neuropeptides

The production of many neuropeptides inthe hypothalamus is reported to be regulatedby leptin. These neuropeptides have attractedattention as potential targets of new anti-obesity drugs.

1. Neuropeptide Y (NPY)Neuropeptide Y (NPY) is a 36-amino acid

peptide present in large quantities in the cen-tral nervous system. NPY administered intothe cerebral ventricle of rodents causes strongappetite enhancement, and the administrationof consecutive daily doses of NPY inducesobesity in these animals. The NPY-containingneurons in the arcuate nucleus (Arc) of thehypothalamus suggests an important connec-tion to appetite regulation, and leptin is knownto decrease the NPY gene expression in theArc.

The NPY receptor is a seven-transmembrane,G-protein-coupled receptor. Five subtypes (Y1,Y2, Y4, Y5, Y6) of this receptor are known toexist. Antagonists of the NPY Y1 receptor (Y1-R) and Y5 receptor (Y5-R), among other sub-types, are attracting attention as possible anti-obesity drugs. Several Y1-R antagonists havealready been developed, and their appetite-suppressive effects have been noted in normalanimals and Zucker (fa/fa) rats and db/dbmice, which have leptin receptor gene muta-

potential new anti-obesity drugs (Fig. 1).This paper outlines potentially new anti-

obesity drugs that have become apparent as aresult of leptin’s discovery, and describes futureprospects in the treatment of obesity.

Leptin

In ob/ob mice, which are devoid of leptin,and in patients with leptin-deficient obesity,leptin selectively decreases body fat, inducingprominent weight loss. Therefore, leptin washeralded as a new anti-obesity drug almost assoon as it was discovered. However, manycases of obesity are considered leptin-resistantbecause blood concentrations of leptin increasein proportion to weight gain. The brain deliv-ery of leptin and abnormalities of the leptinreceptor or post-leptin-receptor hypothalamicneuronal pathways, have been cited as leptinresistance molecular mechanisms, although thedetails remain unclear.

The interim report of a clinical trial of leptinin non-obese and simple obese subjects showedweight reduction as a result of 20- to 30-foldhigher blood concentrations of leptin than nor-mal in some obese subjects, demonstrating theefficacy of mass administration of leptin even inpatients with leptin-resistant obesity. In con-

Fig. 1 Hypothalamic neuropeptides related to the molecularmechanisms of appetite regulation by leptin

Hypothalamic arcuate nucleus (Arc)

Leptin receptor

Leptin

Adipose tissue Suppression of appetiteand weight gain

Appetite-enhancing neuropeptides�(e.g., NPY, AGRP)

Appetite-suppressing neuropeptides�(e.g., �-MSH, CART)

LEPTIN AND ANTI-OBESITY DRUGS


3. Cocaine- and amphetamine-regulatedtranscript (CART)

CART-containing neurons are present in theArc and dorsomedial hypothalamic nucleus(DMH). In the Arc, CART is present in thesame neurons as those containing POMC. Ithas been demonstrated that the CART geneexpression in the Arc is enhanced by leptin.Although no CART receptor has been iden-tified to date, CART receptor agonists couldhave the potential to be anti-obesity drugs.

4. Melanin-concentrating hormone (MCH)Melanin-concentrating hormone (MCH) in

mammals is a cyclic 19-amino-acid peptide thathas one disulfide bond in its molecule. MCH-containing neurons are present in the zonaincerta and lateral hypothalamic area (LHA),and MCH gene expression in the hypothalamusis decreased by leptin. It has been reportedthat intraventricular administration of MCHcaused no changes in total daily food intake,although food intake increased immediatelyafter administration; consecutive daily intra-ventricular administration of MCH resulted inno weight gain. On the other hand, MCH-deficient mice exhibit decreases in food intakeand body weight, showing increased basalmetabolism.

Type-1 and type-2 MCH receptors (MCH-1Rand MCH-2R) have been identified as humanMCH receptors, but their respective functionsin the regulation of energy metabolism remainunknown. When antagonists that are highlyselective for the two receptor subtypes aredeveloped and their properties are clarified,the development of new anti-obesity drugs isanticipated.

5. OthersIt has recently been reported that neuro-

trophic factors such as ciliary neurotrophicfactor (CNTF) and brain-derived neurotrophicfactor (BDNF) have anti-obesity activity. CNTFis known to activate the intracellular signalingpathway JAK-STAT, overlapping with those

Y. OGAWA

tions. In addition, a report has documentedthat intraventricular administration of Y5-Rantisense nucleic acid caused marked appetitesuppression. Moreover, the results of an analy-sis using NPY Y2 receptor-deficient mice sug-gested the importance of Y2-R in the appetitesuppressive effect of leptin. However, the pos-sibility of this receptor as a target in the devel-opment of anti-obesity drugs remains unclear.

2. �-Melanocyte-stimulating hormone(�-MSH) and agouti-related protein(AGRP)�-Melanocyte-stimulating hormone (�-MSH)

is a neuropeptide produced when pro-opio-melanocortin (POMC) is processed. Neuronscontaining this neuropeptide are also presentin the Arc. POMC gene expression in the Arcis decreased by leptin. Intraventricular admin-istration of �-MSH or MT-II, an agonist oftype-3 or type-4 melanocortin receptor (MC3-R and MC4-R), is reported to cause strongappetite suppression, an effect presumed to bemainly mediated by MC4-R.

In genetically obese agouti yellow (Ay/a)mice, agouti protein, which normally appearsonly in hair follicles, is seen over the entirebody, and consequently, these mice developyellow hair and obesity. Agouti protein acts asan MC1-R and MC4-R antagonist. Obesity inAy/a mice is believed to be due to the blockadeof MC4-R signals by agouti protein in the hypo-thalamus. Agouti-related protein (AGRP) hasbeen identified as a neuropeptide homologouswith agouti protein. It acts as an MC3-R andMC4-R antagonist. AGRP is expressed in thesame neurons as those of NPY in the Arc, andAGRP gene expression is decreased by leptin,similarly to NPY. Therefore, the hypothalamicmelanocortin system is a unique system ofappetite regulation that is doubly controlledby increased �-MSH (agonist) and decreasedAGRP (antagonist), due to leptin.

Thus, �-MSH analogues and MC3-R or MC4-R agonists may become anti-obesity drugs.


pathways activated by leptin. CNTF and BDNFare also effective in high-fat diet-induced obe-sity model animals that are leptin resistant.Low-dose CNTF was indicated to be a poten-tially useful anti-obesity drug in a US phase-Iclinical study.

Gene expression of these neurotrophic fac-tors is not controlled by leptin. However, elu-cidation of the molecular mechanisms of appe-tite regulation by CNTF and BDNF may leadto clarification of the molecular mechanismsof leptin resistance and, eventually, to the dis-covery of new anti-obesity drugs.

Conclusion

The basics of obesity treatment includelifestyle modifications, particularly diet. How-ever, following the discovery of leptin, therehas been rapid progress in the developmentof new anti-obesity drugs that target variousneuropeptide/receptor systems involved in thecentral regulation of appetite. This paper hasoutlined the targets of anti-obesity drug devel-opment that have come to light since the dis-covery of leptin. Readers are referred to otherreviews for information that has not beenincluded in this paper.

Obesity is a chronic disease that often re-quires long-term treatment. Ordinary obesitytreatment often achieves temporary weightloss, but such weight loss can be difficult tomaintain (rebound phenomenon). It is thusimportant to develop effective anti-obesitydrug therapies with minimal side effects. Theadvent of new anti-obesity drugs and theirclinical application are expected due to ex-panded research into obesity that has beenfueled by the discovery of leptin.

REFERENCES

1) Friedman, J.M. and Halaas, J.L.: Leptin andthe regulation of body weight in mammals.Nature 1998; 395: 763–770.

2) Farooqi, I.S., Jebb, S.A., Langmack, G. et al.:Effects of recombinant leptin therapy in achild with congenital leptin deficiency. N EnglJ Med 1999; 341: 879–884.

3) Heymsfield, S.B., Greenberg, A.S., Fujioka, K.et al.: Recombinant leptin for weight loss inobese and lean adults: A randomized, con-trolled, dose-escalation trial. JAMA 1999; 282:1568–1575.

4) Rosenbaum, M., Murphy, E.M., Heymsfield,S.B. et al.: Low dose leptin administrationreverses effects of sustained weight-reductionon energy expenditure and circulating con-centrations of thyroid hormones. J Clin Endo-crinol Metab 2002; 87: 2391–2394.

5) Lundberg, J.M., Modin, A. and Malmstrom,R.E.: Recent developments with neuropeptideY receptor antagonists. Trends Pharmacol Sci1996; 17: 301–304.

6) Ollmann, M.M., Wilson, B.D., Yang, Y.K. et al.:Antagonism of central melanocortin recep-tors in vitro and in vivo by agouti-related pro-tein. Science 1997; 278: 135–138.

7) Kristensen, P., Judge, M.E., Thim, L. et al.:Hypothalamic CART is a new anorectic pep-tide regulated by leptin. Nature 1998; 393: 72–76.

8) Qu, D., Ludwig, D.S., Gammeltoft, S. et al.:A role for melanin-concentrating hormone inthe central regulation of feeding behaviour.Nature 1996; 380: 243–247.

9) Lambert, P.D., Anderson, K.D., Sleeman, M.W.et al.: Ciliary neurotrophic factor activatesleptin-like pathways and reduces body fat,without cachexia or rebound weight gain,even in leptin-resistant obesity. Proc NatlAcad Sci USA 2001; 98: 4652–4657.

10) Nakagawa, T., Tsuchida, A., Itakura, Y. et al.:Brain-derived neurotrophic factor regulatesglucose metabolism by modulating energybalance in diabetic mice. Diabetes 2000; 49:436–444.

LEPTIN AND ANTI-OBESITY DRUGS


Regenerative Medicine forthe Central Nervous System—Transplantation of neural stem cells into

the injured spinal cord—JMAJ 48(2): 68–80, 2005

Shinjiro KANEKO*1,2, Masaya NAKAMURA*1, Yuto OGAWA*1,Kota WATANABE*1, Akio IWANAMI*1,2, Yoshiaki TOYAMA*1,and Hideyuki OKANO*2

*1Department of Orthopaedic Surgery, Keio University School of Medicine*2Department of Physiology, Keio University School of Medicine

Abstract: Advances in the stem cell biology of the central nervous system (CNS)and other studies enhance the possibility of regeneration of the damaged CNS,which has previously been considered to be almost impossible. The availability ofsignals to induce the appropriate differentiation of the transplanted and/or endoge-nous neural stem cells (NSCs) as well as the timing of the transplantation are vitalfactors for improving the functional recovery of the damaged CNS. Because theimmediate post-traumatic microenvironment of the spinal cord is in an acute inflam-matory stage, it does not favor the survival and differentiation of the transplants.Furthermore, in the chronic disease stage after injury, glial scars that inhibit theregeneration of neuronal axons form in the injured site. Thus, we consider that theoptimal period of transplantation is 1–2 weeks after injury.

Key words: Central nervous system; Regeneration; Spinal cord injury;Transplantation; Neural stem cells; Axonal growth inhibitors

Regenerative Medicine for the CentralNervous System

Ever since the famous neuroanatomistRamon y Cajal wrote in the early 20th centurythat the central nervous system (CNS, i.e. thebrain and spinal cord) does not regenerate onceit is injured,1) this theory has been generally


accepted.The lack of regenerative properties of the

mammalian CNS, especially in the spinal cord,may be attributable to a combination of factors,including the inhibitory character of CNS mye-lin and injury-induced glial scars, the apparentinability of endogenous adult neural stem cells(NSCs) in the spinal cord to induce de novo

� Regenerative Medicine


new interconnections, the replacement ofdamaged interneurons within a structure, theformation of an interconnecting bridge thatreceives inputs from a healthy brain region andprovides modulated in puts to a damaged partof the brain, the formation of a barrier toabnormal collateral growth of axons, or theproduction of a substrate that facilitates thegrowth of axons; (b) for its trophic effects, i.e.to produce neurochemically active substancessuch as neurotransmitters, growth factors, anti-bodies, or growth substrates; and (c) to pro-mote the remyelination of axons.11)

Experiments on neural transplantation forspinal cord injuries started in 1981 with peri-pheral nerve transplantations performed byAguayo and coworkers.4,12) The advantage ofthis approach is that the CNS myelin-derivedinhibitors of axonal regeneration is absent inthe peripheral nervous system (PNS) (Thisissue on CNS myelin-derived inhibitor is dis-cussed later). In 1993, Bregman and coworkersreported transplantation of fetal spinal cord,which does not yet express the CNS myelincomponent in immature and adult rats in whichthe thoracic spinal cord had been partiallytransected. The rats receiving the transplantshowed elongation of the injured axons in addi-tion to functional recovery, and this result wasmore pronounced in immature rats.5) Suchtransplants survive and integrate with the hosttissue, and may be associated with functionalimprovement.

In fact, the transplantation of fetal CNStissue has already been performed in humanpatients with Parkinson’s disease, resulting insome clinical improvement.13) For spinal cordinjury, however, such treatment has not yetbeen established. One underlying reason forthe lack of research is that a large number offetuses are needed to obtain enough tissue totreat even one patient (for Parkinson’s disease,4–8 fetuses are required), a requirement thatgenerates both practical and ethical problems.

On the other hand, recent progress in thebiology of NSCs has made it possible to rou-

neurogenesis upon injury,2) and the lack ofsufficient trophic support.3) However, in the1980s, studies reported the promising trans-plantation of peripheral nerves4) and fetalspinal cord5) for spinal cord injuries.

These studies indicate that introducing anappropriate environment into the injured sitecan cause injured axons to regenerate. In addi-tion, some reports describe spinal cord regen-eration, including the promotion of the regen-eration of injured axons by neurotrophic fac-tors,6) and the identification of axonal growthinhibitors.7) These studies suggest the feasibilityof the regeneration of the injured spinal cord.Although researchers first focused on the effec-tiveness of fetal spinal cord transplantation forspinal cord injuries,8–10) the shortage of donorsand growing ethical problems precluded thepractical clinical application of this approach.

As a result of remarkable advances in neuro-science in recent years, NSCs have beenregarded as a feasible transplant material.This paper outlines the current state and theprospects of basic studies on NSC transplanta-tion for the damaged CNS including spinalcord injuries.

Rationale behind Cell Transplantationfor Spinal Cord Injury andDamaged CNS

Spinal cord injury affects people of all agesand can result in severe damage, leading toparaplegia, tetraplegia and death. Strategiesincluding surgical, pharmacological, neuro-physiological, and technological approacheshave been used in attempts to develop newtherapies that will allow patients to regainthe use of their paralyzed limbs. One suchapproach is cell transplantation into the dam-aged spinal cord.

The rationale for this approach can be sum-marized as follows: (a) to promote the func-tional reconstruction of neuronal circuits, i.e.the production of new inputs to a deafferentedregion that form new synaptic connections or

TRANSPLANTATION OF NEURAL STEM CELLS


two major areas of research to develop stem-cell therapeutic strategies for CNS injuries anddiseases using NSCs: (i) the activation ofendogenous NSCs and (ii) the transplantationof NSCs. Stem cell biologists, such as thosestudying hematopoiesis, include the ability torepair post-traumatic tissue in the stem celldefinition. Stem cells fitting this definition werenot thought to exist in the CNS until evidenceappeared that endogenous NSCs contributeto the recovery of the damaged CNS.15–17)

Owing to the development of a selective cul-ture technique for NSCs (the neurospheretechnique),14,18,19) enormous progress has beenmade in elucidating the biological properties ofneural stem cells and their location in the body.In this culture technique, cells harvested fromthe CNS are cultured in a non-adhesive culturedish containing a serum-free medium supple-

S. KANEKO et al.

tinely expand neural progenitor cells obtainedfrom a small amount of fetal CNS tissue invitro, as floating cell aggregates called neuro-spheres14) (Fig. 1). The expansion of neural pro-genitor cells in vitro may overcome the practi-cal and ethical problems associated with fetaltissue transplantation and provide a potentialreliable source of graft material for clinicalefforts to regenerate injured spinal cord.

Neural Stem Cells

NSCs are undifferentiated nervous systemcells that are capable of proliferation, repeatedsubculture (self-replicating capacity), and dif-ferentiation into the three types of cell compos-ing the central nervous system, that is, neurons,astrocytes, and oligodendrocytes (multipotency).Studies are in progress throughout the world in

Fig. 1 Neural stem cell culture using the neurosphere methodWhen incubated as a suspension culture in the presence of EGF and/or bFGF, neural stem cells with multipotencyand self-replicating capacity grow selectively to form cell masses called “neurospheres.” Subsequent dissociationof these neurospheres and incubation in the same conditions lead to the reformation of neurospheres.

�Growth factors(EGF, bFGF) Plated onto adhesive culture plates

Removal of growth factorsAddition of serum

Repeat

Neuron

Astrocyte

Oligodendrocyte

�Neural stem cell

�Cells other than neural stem cells

Neuron

Astrocyte

Oligodendrocyte


mented with a high concentration of eitherepidermal growth factor (EGF) or fibroblastgrowth factor-2 (FGF-2), or both. A small num-ber of NSCs present among the cells respond tothe growth factor(s) and selectively proliferatein suspension to form balls of cells (neuro-spheres). When these balls are dissociated andeach individual cell is cultured under the sameconditions, they form neurospheres again, and,with repeated subculture they generate a pro-lific number of NSCs (self-replicating capac-ity). If these cells are plated in adhesive culturedishes and cultured in a growth factor-freemedium supplemented with serum, they candifferentiate into neurons, oligodendrocytes,and astrocytes (multipotency) (Fig. 1). Thus,once the desired CNS tissue is obtained, thisculture technique allows the acquisition of alarge volume of NSCs, resolving the donor pro-curement problem associated with fetal tissuetransplantation.

Nevertheless, previous reports suggest thatendogenous NSCs in the adult rat spinal cordproliferate and differentiate exclusively intoastrocytes, but not into neurons, upon in-jury. 2,20,21) Furthermore, although recent resultsshow that forebrain damage due to ischemiacan be recovered by activating endogenousNSCs to induce de novo neurogenesis,16,17) sucha strategy has not been successful in the injuredspinal cord. This observed inability of endog-enous NSCs in the adult spinal cord to executede novo neurogenesis cannot be solely attrib-uted to their intrinsic properties, since adultspinal cord-derived NSCs are able to makenew neurons when transplanted into an adultneurogenic site (i.e. the hippocampal dentategyrus).22)

Nakafuku and coworkers suggest that thestatus of the Notch signal pathway contributesto the apparent restriction of de novo neuro-genesis in the adult spinal cord.23) In the adultspinal cord, neural progenitors and/or NSCsare thought to be surrounded by many maturecells (including both neurons and glial cells)that express Notch ligands and can inhibit the

differentiation of neurons from endogenousprogenitors. Considering this situation, thechallenge is to successfully induce neuro-genesis by transplanting exogenous NSCs orneural progenitor cells in the apparently non-neurogenic adult spinal cord. In fact, previousstudies have reported that neural progenitorsor NSCs cannot differentiate into neurons whentransplanted back into the spinal cord.21,24)

However, in our recent work, we showedthat by using in vitro expansion and transplantingthe cells at the appropriate time point, whichwe regard to be very important, neural progeni-tor cells derived from rat fetal spinal cord candivide and differentiate into neurons in vivo andintegrate into the host tissue in the injured spi-nal cord.25) Furthermore, functional recoverywas achieved by this NSC-transplantation pro-cedure. Relevant studies have recently beenpublished corroborating our findings. In onestudy, a rat spinal cord injury model wassuccessfully treated by the transplantation ofneural progenitor cells that had been inducedto differentiate from mouse ES cells by retinoicacid treatment.26) Despite some positive out-come, there are some important limitations tothis method. For instance, retinoic acid treat-ment of ES cells induces a variety of differentcell types in addition to neural progenitor cells.It is possible that a small number of poorly dif-ferentiated cells in the grafted cell suspensioncould result in tumorigenesis from the trans-plant or induce the formation of non-neuraltissue. Furthermore, there are current limitationin developing this application for human EScells to treat human spinal cord injury, becausehuman ES cells are not currently readily avail-able for therapeutic purposes in many coun-tries. Moreover, the conditions required toinduce the differentiation of neural cells fromES cells in vitro and to select them once theyhave differentiated have not been optimized.In another study, Vacanti and coworkers trans-planted adult rat-derived NSCs packed withgels into rat models of thoracic spinal cordtransection, with similar results.27)



Cytokines Involved in the Inductionof NSC Differentiation:Consideration of the Optimal Timingof NSC Transplantation

To establish efficient NSC transplantationinto the injured spinal cord, it is essential toelucidate the regulatory mechanism of NSCdifferentiation. Previous studies reported thatcytokines are involved in this process. Weissand coworkers reported that brain-derivedneurotrophic factor (BDNF) promotes thedifferentiation of fetal mouse striate body-derived neural stem cells into neurons.28) Ghoshand Greenberg reported that neurotrophin-3(NT-3) promotes the differentiation of fetal ratcerebral cortex-derived NSCs into neurons.29)

McKay and coworkers reported that platelet-derived neurotrophic factor (PDNF), ciliaryneurotrophic factor (CNTF), and thyroid hor-mone (T3) induce fetal rat hippocampus-derived NSCs into neurons, astrocytes, and oli-godendrocytes, respectively.30) More recently,Taga and coworkers reported that leukemiainhibitory factor (LIF) and bone morphogenicprotein-2 (BMP-2) promote the differentiationof fetal mouse neuroepithelium-derived NSCsinto astrocytes.31)

Common to the results of these studies isthat members of the so-called interleukin-6(IL-6) superfamily, such as CNTF and LIF,induce NSCs to differentiate into astrocytes,indicating that gp130-mediated signaling playsa role in this process. However, their resultsdiffer in the conditions for differentiation intoneurons and oligodendrocytes, presumably re-flecting differences in the timing of cell collec-tion, tissue of origin, and method of culture.

Consistent with these findings indicating thatvarious cytokines affect the cell fates of NSCsin a context-dependent manner, the host micro-environment influences the survival and dif-ferentiation of NSC transplants.32) Olson andcoworkers have reported relevant results indi-cating that NGF, BDNF, and CNTF increasemoderately upon spinal cord injury, but they

unfortunately do not reach levels sufficient forspontaneous axonal regeneration.3) Recentstudies have shown that neural stem and pro-genitor cells also exist in the normal adult ratspinal cord, proliferate after injury, migrate tothe injured site, and differentiate, mostly intoastrocytes.2,20,33)

In light of the previously reported in vitroresults, we believe that the post-traumaticincrease in CNTF expression in the spinal cordis one of the factors inducing endogenousNSCs to differentiate into astrocytes, and thatthe low expression of NT-3 and BDNF, whichpromote the induction of endogenous NSCdifferentiation into neurons and oligodendro-cytes, creates a microenvironment that doesnot favor NSC differentiation into neurons andoligodendrocytes. Achieving success usingNSC transplantation requires both induction ofthe differentiation of transplanted cells andimprovement in transplant survival rates.Within the injured spinal cord, the levels ofvarious inflammatory cytokines (TNF��, IL-1�, IL-1�, and IL-6) peak 6–12 h after injuryand remain elevated up to 4 days after injury.Because these inflammatory cytokines havebiphasic actions, neurotoxic and neurotrophic,their actions within the injured spinal cordrequire careful interpretation. We believe thatthe highly increased expression of thesecytokines within 7 days after injury is neuro-toxic, resulting in a microenvironment unfit forthe survival of NSC transplants. In fact, whenwe performed NSC transplantation 24 h afterinjury, almost none of the grafted cells sur-vived, or, in limited cases, a small number ofcells survived that formed only a small mass.On the other hand, the expression of anti-inflammatory cytokine TGF� does not increaseimmediately after injury, but gradually increaseslater, peaking on the fourth day after injury.Thus, it appears that TGF� relieves the inflam-matory situation.34)

To summarize the above discussion on thesurvival and differentiation of NSC transplants,we believe that the optimal time to transplant

S. KANEKO et al.


NSCs is not immediately after injury. At thisstage, IL-1� and IL-6 levels rapidly increasewithin the injured spinal cord; these cytokineswould induce Jak/Stat signaling, which is likelyto direct the endogenous NSCs within the adultspinal cord exclusively into astrocytic fates,35)

and they would have no chance to becomeneurons. This hypothesis may explain why theinjured spinal cord is non-neurogenic. Fortu-nately, this acute inflammatory phase only lastsup to 1 week after injury, which indicates thatthis period should be avoided for NSC trans-plantation. However, if too much time passesafter injury, a glial scar forms around theinjured site, which inhibits the regeneration ofaxons; therefore, we currently consider theoptimal time to transplant NSCs to be 7–14days after injury (Fig. 2). In fact, our recentreports demonstrate that the transplantation ofin vitro-expanded NSCs results in mitogenic-neurogenesis when the transplantation into the

injured adult rat spinal cord is performed9 days after injury, but not when the trans-plantation is done within a few days of theinjury.25,34,36)

In addition to the neurogenesis from thetransplanted NSCs, the benefits of NSC trans-plantation at this time point may also resultfrom microvascular regeneration in the host,considering previous findings from fetal neuraltissues transplanted into the cerebral cor-tex.37,38) Correspondingly, a recent report indi-cates that the formation of new vessels occursmost actively 7–14 days after a contusion injuryto the rat spinal cord.39)

To investigate the properties of new neuronsderived from donors in more detail, we tookadvantage of the fact that the 1.1-kb promoterelement of the T�-1 tubulin gene is only activein cells with neuronal lineage (including neu-ronal progenitors and post-mitotic neurons),and not those with glial lineage.40–43) Here we

Injury Acute phase

Chronic phase

Subacute phase

Cyst

Inflammatoryreaction

04

714

Cyst

Reduced inflammation by anti-inflammatory cytokines Glial scar

(Post-injury days)

Optimal transplantation period

Glial scar formation

HemorrhageHemorrhage

BreakdoBreakdownwnof BBBof BBB

Infiltration ofation ofinflammatorammatory cellsy cells

etc.etc.

Hemorrhage

Breakdownof BBB

Infiltration ofinflammatory cells

etc.

Inflammatorammatory cytokinesy cytokines(TNF-(TNF-�, IL-1, IL-1�, IL-6 etc.), IL-6 etc.)

CNTFCNTF etc. etc.

Inflammatory cytokines(TNF-�, IL-1�, IL-6 etc.)

CNTF etc.

Fig. 2 Optimal period for neural stem cell transplantation in relation to the microenvironmentof the injured spinal cord

The microenvironment of the injured spinal cord at the subacute phase post-injury is consideredto be most appropriate for transplanted neural stem cells.



used rats that had been treated with trans-planted neurospheres derived from the fetalspinal cords (E14.5) of T�-1-EYFP transgenicrats. By injecting BrdU intraperitoneally, wecould label cells that had divided after theBrdU injection. The presence of post-mitoticneurons that were double positive for BrdU-labeling and EYFP expression demonstratedthat donor-derived progenitor cells undergomitotic neurogenesis within the host spinalcord.25)

Reconstruction of Neuronal Circuitsand Functional Recovery

Our studies showed that transplantation ofNSCs at the appropriate time after the injury isa key factor in inducing their neuronal differ-entiation within the injured host spinal cord.25)

However, functional recovery cannot result

from neurogenesis alone. The ensuing synapseformation, myelination, and various othersequential events are equally important require-ment. Thus, we investigated whether donorNSC-derived neurons integrate into host neu-ronal circuits by making synapses. Five weeksafter transplanting neurospheres derived fromthe fetal spinal cords of T�-1-EYFP transgenicrats, donor-derived EYFP-positive neuronsextended their axons within the host spinalcord. We observed EYFP-positive pre-synapticstructures with pre-synaptic vesicles that wereconnected with EYFP-negative post-synapticstructures with post-synaptic densities. We alsofound EYFP-negative pre-synaptic structuresthat were connected with EYFP-positive post-synaptic structures. Interestingly, we foundsome cases in which EYFP-positive neuronshad formed a synapse with host motor neuronsat the injury site.25)

Fig. 3 Axonal growth inhibitors in the injured spinal cordAxonal growth inhibitors in the injured spinal cord include myelin-associated proteins such as Nogo-A,MAG and OMgp, and extracellular matrix molecules derived from scar tissue formed at the injury site suchas CSPGs and Sema3A.

MAG

Axonal growth inhibition

NgR

OMgp

p75

Oligodendrocyte

Growth cone

GTP Rho

Myelin-associated proteins Extracellular matrix

Cavity

Scar tissue

Semaphorin3A

Fibroblast scar

Glial scar

CSPGs

• NG2

• Brevican etc.

Axonal growth inhibition

Growth cone

Plexin-A

Neuropilin-1

p35

Cdk5

P Y

Fyn

Tau

P T

P S

Regenerating axons

Nogo66

S. KANEKO et al.


Present in the CNS are factors inhibitingaxonal regeneration not present in the PNS.Regardless of how excellent the transplanta-tion material the NSCs are, an effectivemethod of NSC transplantation cannot beestablished without resolving the problem ofaxon growth inhibitors in the CNS (Fig. 3).The axonal growth inhibitors in the CNS thathave been discovered to date are broadlyclassified into myelin-associated proteins(i.e. Nogo,44,45) myelin-associated glycoprotein(MAG),46) and oligodendrocyte-myelin glyco-protein (OMgp)47)), and extracellular matrixmolecules derived from scar tissue formed inthe injured site (i.e. chondroitin sulfate pro-teoglycans (CSPGs),48) and Semaphorin3A(Sema3A)49,50)). Acting in concert, these in-hibitors may account for the lack of axonalregeneration in the CNS after trauma in adultmammals.

Bregman and coworkers have alreadyreported that the concomitant use of the IN-1monoclonal antibody, which recognizes Nogo-A, in fetal spinal cord transplantation for spinalcord injuries results in excellent regenerationof injured axons and motor function recovery.51)

Recently, Strittmatter and coworkers demon-strated that intrathecal administration of pep-tide antagonist NEP1-40, which blocks thebinding of the extra-cellular domain of Nogo(Nogo-66) to its receptor, Nogo receptor(NgR), into rats with a mid-thoracic spinal corddorsal hemisection results in significant axonalregeneration in the corticospinal tract, andimproved functional recovery.52) NgR wasshown to play a major role in the inhibition ofaxonal outgrowth by Nogo and in limitingaxonal regeneration after CNS injury. Further-more, MAG and OMgp, other CNS myelin-derived inhibitors for axonal regeneration,were found to be other functional ligands forthe NgR.47,53,54) In addition, an NgR knockoutmice study demonstrated that NgR plays animportant role in preventing axonal regenera-tion after spinal cord injury.55)

The next question is whether better func-

tional recovery is actually achieved by NSCtransplantation. In our study of adult rats withspinal cord contusion injury,25) we observedbehavioral improvement in skilled forelimbmovement in the rats that had received trans-planted neural progenitor cells compared withthe control rats. A behavioral test, known asthe “pellet retrieval test,” which examines theskilled forelimb movement by measuring theability of animals to retrieve food pellets,demonstrated a significantly favorable effectof NSC transplantation. Because a deficit ofupper limb skilled movement is an importantsymptom in patients with spinal cord injury,this finding strongly indicates the possiblebenefit conveyed to patients through futuretherapeutic application of neural progenitorcells. Taken together, our results indicate thatif NSCs are transplanted in the subacute phase,and not in the acute phase after spinal cordinjury or in the chronic phase characterizedby marked glial scarring, they survive and con-tribute to some degree to functional recovery(Fig. 2).

The possible effects of NSC grafts for func-tional recovery would be similar to the effectsof transplanting fetal neural tissues9) discussedabove. In terms of referring neuronal circuits,previous studies indicate that the ascendingsensory fiber components of the dorsal col-umns may play an important role in mediatingthe performance of such skilled forelimb reach-ing movements as pellet retrieval. Namely,the damage to the ascending fibers withinthe dorsal column may be responsible forsevere reaching hypometria due to the rat cer-vical spinal cord contusion injury we observedin our study. Thus, a possible explanation forthe behavioral improvement in the rats thatreceived transplanted NSCs is that the neuronsderived from the grafted cells “relayed” signalsfrom the disrupted fibers in the host, includingascending fibers that existed in the dorsalcolumn.

Another possible explanation is that glialcells derived from grafted cells contribute to



the behavioral improvement. Oligodendro-cytes derived from grafted cells might haveremyelinated fibers that had been demyeli-nated as a result of injury and had restored thesalutatory conduction along the neuronalaxons of long projection neurons. In addition tothe oligodendrocytes, astrocytes differentiatedfrom donor neural progenitor cells may haveplayed an active role in the generation of neu-ronal cells,25) the axonal regeneration of hostneuronal axons, the enhancement of axonalextension of donor-derived neurons, synapseformation, and/or the physiological matura-tion of neuronal cells. Astrocytes derived fromthe transplanted fetal spinal cord NSCs arelikely to have similar functions as those derivedfrom the fetal brain, which regulate the precisegrowth of neuronal axons56) and promote thematuration of neuronal cells physiologically.57)

In addition, these functions of fetal spinal cordNSC-derived astrocytes may be distinct fromthose of the reactive astrocytes that wereinduced after spinal cord injury. Gage and

coworkers reported that astrocytes in an adultneurogenic site (the hippocampus) play anactive role in inducing neurogenesis.58) Notably,astrocytes from adult spinal cord do not havethese activities. Attractive future experimentswill be to characterize such astrocytes-derivedneurogenic inducing activities in more detailand to examine whether fetal spinal cord NSC-derived astrocytes possess such activities.

It is also important to note that fetal spinalcord NSC-derived neurons extend theirneurites well (visualized by T�1-EYFP expres-sion) within the host spinal cord, even in thepresence of CNS myelin, which should includeinhibitors against axonal extension and regen-eration. Recently, Filbin and coworkers showedthat an elevation of cAMP in neurons can over-come the inhibition of axonal growth by MAGand CNS myelin.59) The elevation of cAMPresults in the synthesis of polyamines, due to anup-regulation of Arginase I, a key enzyme intheir synthesis. Interestingly, endogenous Argi-nase I levels are high in young dorsal root gan-

Blastocyst

Fertilized ovum

in vivo

in vitro

in vitro

ES cells

Induction ofdifferentiation

Induction ofdifferentiation

Neural stem cells

Fetal CNS

Transplantation

Specifically differentiated cells

Neurosphere

Fig. 4 Various strategies for the regenerative medicine of CNSThere is a variety of strategies, including the transplantation of neural stem cells in the form of single-cellsuspension or as neurospheres, or the transplantation of specifically differentiated cells from neural stemcells or ES cells. The concomitant use of cell transplantation with other treatments such as the administrationof neurotrophic factors or the blockade of axonal growth inhibitors is considered to be more effective.

S. KANEKO et al.


glia (DRG) neurons but drop spontaneouslywhen the DRGs reach an age that coincideswith the switch from promotion to inhibitionby MAG/myelin. This finding may correspondto our above-mentioned behaviors of neuronalaxons derived from grafted fetal spinal cordNSCs.

Conclusions and Perspectives

We have shown that in vitro-expanded NSCscan contribute to repairing the injured spinalcord in a rat model when they are transplantedat the appropriate time point. The differentia-tion of transplanted neural progenitor cells,including NSCs, into neurons and oligodendro-cytes, which may correspond to the behavioralrecovery we observed, depends on the micro-environment25) (Fig. 2). To achieve more effi-cient therapeutic strategies, it is likely that theconcomitant use of NSC transplantation, theblockade of axonal regeneration inhibitors,and the administration of neurotrophic fac-tors60,61) would improve the method (Fig. 4).

To apply these basic experimental results toclinical practice in the near future, we are seek-ing to establish a pre-clinical experimentalsystem using primates, which are geneticallycloser to humans.62) It is also essential to estab-lish a system of producing and supplying large-scale human NSCs for clinical use. We areworking towards achieving this goal in collabo-ration with the Tissue Engineering ResearchCenter (TERC) at the National Institute ofAdvanced Industrial Science and Technology(AIST) in Japan. We recently produced a rela-tively large-scale culture of human NSCs,19) butthe conditions need to be improved to maintainthe safety and stability of these cells in largecultures before they can be used in futuretherapeutic applications. In terms of large-scale culture, we found that it is more efficientto use fetal brain-derived NSCs than to usefetal spinal cord-derived NSCs. We also foundthat fetal brain-derived NSCs are as effectiveas transplants for spinal cord injury as fetal

spinal cord-derived NSCs.63)

It is very important to approach the appli-cation to humans responsibly, linking animalexperiments with studies using progressivelymodified technology in a small number ofpatients, using well validated assessment proto-cols.64) We hope that once these problems areresolved, it will be possible to apply regenera-tive therapy using NSCs for spinal cord injuries.

REFERENCES

1) Ramon y Cajal, S.: Degeneration and regen-eration of the nervous system. Oxford. OxfordUniversity Press, 1928. [Day, R.M., Trans.; fromthe 1913 Spanish ed.].

2) Johansson, C.B., Momma, S., Clarke, D.L.,Risling, M., Lendahl, U. and Frisen, J.: Identi-fication of a neural stem cell in the adult mam-malian central nervous system. Cell 1999; 96:25–34.

3) Widenfalk, J., Lundstromer, K., Jubran, M.,Brene, S. and Olson, L.: Neurotrophic factorsand receptors in the immature and adult spi-nal cord after mechanical injury or kainic acid.J Neurosci 2001; 21: 3457–3475.

4) Richardson, P.M., McGuinness, U.M. andAguayo, A.J.: Axons from CNS neuronsregenerate into PNS grafts. Nature 1980; 284:264–265.

5) Bregman, B.S.: Spinal cord transplants permitthe growth of serotonergic axons across thesite of neonatal spinal cord transection. DevBrain Res 1987; 34: 265–279.

6) Cai, D., Shen, Y., De Bellard, M., Tang, S. andFilbin, M.T.: Prior exposure to neurotrophinsblocks inhibition of axonal regeneration byMAG and myelin via a cAMP-dependentmechanism. Neuron 1999; 22: 89–101.

7) Chen, M.S., Huber, A.B., van der Haar, M.E.,Frank, M., Schnell, L., Spillmann, A.A, et al.:Nogo-A is a myelin-associated neurite out-growth inhibitor and an antigen for mono-clonal antibody IN-1. Nature 2000; 403: 434–439.

8) Miya, D., Giszter, S., Mori, F., Adipudi, V.,Tessler, A. and Murray, M.: Fetal transplantsafter the development of function after spinalcord transection in newborn rats. J Neurosci1997; 17: 4856–4872.



9) Diener, P.S. and Bregman, B.S.: Fetal spinalcord transplants support the development oftarget reaching and coordinated postural ad-justments after neonatal cervical spinal cordinjury. J Neurosci 1998; 18: 763–778.

10) Diener, P.S. and Bregman, B.S.: Fetal spinalcord transplants support growth of supra-spinal and segmental projections after cervicalspinal cord hemisection in the neonatal rat. JNeurosci 1998; 18: 779–793.

11) Freed, W.J.: Neural transplantation: an intro-duction. Cambridge, MA. MIT Press, 1999.

12) Aguayo, A.J., David, S. and Bray, G.M.: Influ-ences of the glial environment on the elon-gation of axons after injury. Transplantationstudies in adult rodents. J Exp Biol 1981; 95:231–240.

13) Piccini, P., Brooks, D.J., Bjorklund, A., Gunn,R.N., Grasby, P.M., Rimoldi, O. et al.: Dopa-mine release from nigral transplants visual-ized in vivo in a Parkinson’s patient. NatNeurosci 1999; 2: 1137–1140.

14) Reynolds, B.A. and Weiss, S.: Generation ofneurons and astrocytes from isolated cells ofadult mammalian central nervous system.Science 1992; 255: 1707–1710.

15) Magavi, S.S., Leavitt, B.R. and Macklis, J.D.:Induction of neurogenesis in the neocortex ofadult mice. Nature 2000; 405: 951–955.

16) Nakatomi, H., Kuriu, T., Okabe, S., Yamamoto,S., Hatano, O., Kawahara, N. et al.: Regenera-tion of hippocampal pyramidal neurons afterischemic brain injury by recruitment of endog-enous neural progenitors. Cell 2002; 110: 429–441.

17) Arvidsson, A., Collin, T., Kirik, D., Kokaia, Z.and Lindvall, O.: Neuronal replacement fromendogenous precursors in the adult brain afterstroke. Nat Med 2002; 8: 963–970.

18) Svendsen, C.N., ter Borg, M.G., Armstrong,R.J.E., Rosser, A.E., Chandran, S., Ostenfeld,T. et al.: A new method for the rapid and long-term growth of human neural precursor cells.J Neurosci Methods 1998; 85: 141–152.

19) Kanemura, Y., Mori, H., Kobayashi, S.,Yamamoto, A., Kodama, E., Nakanishi, Y. etal.: Evaluation of in vitro proliferative activityof human fetal neural stem/progenitor cellsusing indirect measurements of viable cellsbased on cellular metabolic activity. JNeurosci Res 2002; 69: 869–879.

20) Namiki, J. and Tator, C.H.: Cell proliferationand nestin expression in the ependyma of theadult rat spinal cord after injury. J Neuro-pathol Exp Neurol 1999; 58: 489–498.

21) Horner, P.J., Power, A.E., Kempermann, G.,Kuhn, H.G., Palmer, T.D., Winkler, J. et al.:Proliferation and differentiation of progenitorcells throughout the intact adult rat spinalcord. J Neurosci 2000; 20: 2218–2228.

22) Shihabuddin, L.S., Horner, P.J., Ray, J. andGage, F.H.: Adult spinal cord stem cells gen-erate neurons after transplantation in theadult dentate gyrus. J Neurosci 2000; 20: 8727–8735.

23) Yamamoto, S., Nagao, M., Sugimori, M.,Kosako, H., Nakatomi, H., Yamamoto, N.et al.: Transcription factor expression andNotch-dependent regulation of neural pro-genitors in the adult rat spinal cord. J Neurosci2001; 21: 9814–9823.

24) Chow, S.Y., Moul, J., Tobias, C.A., Himes, B.T.,Liu, Y., Obrocka, M. et al.: Characterizationand intraspinal grafting of EGF/bFGF-dependent neurospheres derived from embry-onic rat spinal cord. Brain Res 2000; 874: 87–106.

25) Ogawa, Y., Sawamoto, K., Miyata, T., Miyao,S., Watanabe, M., Toyama, Y. et al.: Transplan-tation of in vitro expanded fetal neural pro-genitor cells results in neurogenesis and func-tional recovery after spinal cord contusioninjury in rats. J Neurosci Res 2002; 69: 925–933.

26) McDonald, J.W., Liu, X.Z., Qu, Y., Liu, S.,Mickey, S.K., Turetsky, D. et al.: Transplantedembryonic stem cells survive, differentiateand promote recovery in injured rat spinalcord. Nat Med 1999; 5: 1410–1412.

27) Vacanti, M.P., Leonard, J.L., Dore, B.,Bonassar, L.J., Cao, Y., Stachelek, S.J. et al.:Tissue-engineered spinal cord. Transpl Proc2001; 33: 592–598.

28) Ahmed, S., Raynolds, B.A. and Weiss, S.:BDNF enhances the differentiation but notthe survival of CNS stem cell-derived neu-ronal precursors. J Neurosci 1995; 15: 5765–5778.

29) Ghosh, A. and Greenberg, M.E.: Distinctroles for bFGF and NT-3 in the regulation ofcortical neurogenesis. Neuron 1995; 15: 89–103.

30) Johe, K.K., Hazel, T.G., Muller, T., Dugich-

S. KANEKO et al.


Djordjevic, M.M. and McKay, R.D.: Singlefactors direct the differentiation of stem cellsfrom the fetal and adult central nervous sys-tem. Genes Dev 1996; 10: 3129–3140.

31) Nakashima, K., Yanagisawa, M., Arakawa, H.,Kimura, N., Hisatsune, T., Kawabata, M. et al.:Synergistic signaling in fetal brain by STAT3-Smad 1 complex bridged by p300. Science1999; 284: 479–482.

32) Nakamura, M. and Bregman, B.S.: Differencesin neurotrophic factor gene expression pro-files between neonate and adult rat spinal cordafter injury. Exp Neurol 2001; 169: 407–415.

33) Frisen, J., Johansson, C.B., Torok, C., Risling,M. and Lendahl, U.: Rapid, widespread, andlong-lasting induction of nestin contributes tothe generation of glial scar tissue after CNSinjury. J Cell Biol 1995; 131: 453–464.

34) Nakamura, M., Houghtling, R.A., MacArthur,L., Bayer, B.M. and Bregman, B.S.: Differencein cytokine gene expression profile betweenacute and secondary injury in the adult ratspinal cord. Exp Neurol 2003; 184: 313–325.

35) Bonni, A., Sun, Y., Nadal-Vicens, M., Bhatt,A., Frank, D.A., Rozovsky, I. et al.: Regulationof gliogenesis in the central nervous system bythe Jak/Stat-signaling pathway. Science 1997;278: 477–483.

36) Okano, H.: Stem cell biology of the centralnervous system. J Neurosci Res 2002; 69: 698–707.

37) Miyoshi, Y., Date, I. and Ohmoto, T.: Three-dimensional morphological study of micro-vascular regeneration in cavity wall of the ratcerebral cortex using the scanning electronmicroscope: implications for delayed neuralgrafting into brain cavities. Exp Neurol 1995;131: 69–82.

38) Miyoshi, Y., Date, I. and Ohmoto, T.: Neo-vascularization of rat fetal neocortical graftstransplanted into a previously prepared cavityin the cerebral cortex: a three-dimensionalmorphological study using the scanning elec-tron microscope. Brain Res 1995; 681: 131–140.

39) Casella, G.T., Marcillo, A., Bunge, M.B. andWood, P.M.: New vascular tissue rapidlyreplaces neural parenchyma and vessels de-stroyed by a contusion injury to the rat spinalcord. Exp Neurol 2002; 173: 63–76.

40) Gloster, A., Wu, W., Speelman, A., Weiss, S.,

Causing, C., Pozniak, C. et al.: The T�-1-tubulin promoter specifies gene expression asa function of neuronal growth and regenera-tion in transgenic mice. J Neurosci 1994; 14:7319–7330.

41) Wang, S., Wu, H., Jiang, J., Delohery, T.M.,Isdell, F. and Goldman, S.A.: Isolation ofneuronal precursors by sorting embryonicforebrain transfected with GFP regulated bythe T�-1 tubulin promoter. Nat Biotechnol1998; 16: 196–201.

42) Roy, N.S., Wang, S., Jiang, L., Kang, J., Restelli,C., Fraser, R.A.R. et al.: In vitro neurogenesisby neural progenitor cells isolated from theadult human hippocampus. Nat Med 2000; 6:271–278.

43) Sawamoto, K., Yamamoto, A., Kawaguchi, A.,Yamaguchi, M., Mori, K., Goldman, S.A. et al.:Visualization and direct isolation of neuronalprogenitor cells by dual-color flow cytometricdetection of fluorescent proteins. J NeurosciRes 2001; 65: 220–227.

44) Chen, M.S., Huber, A.B., van der Haar, M.E.et al.: Nogo-A is a myelin-associated neuriteoutgrowth inhibitor and an antigen for mono-clonal antibody IN-1. Nature 2000; 403: 434–439.

45) GrandPre, T., Nakamura, F., Vartanian, T. etal.: Identification of the Nogo inhibitor ofaxon regeneration as a Reticulon protein.Nature 2000; 403: 439–444.

46) Shen, Y.J., DeBellard, M.E., Salzer, J.L.,Roder, J. and Filbin, M.T.: Myelin-associatedglycoprotein in myelin and expressed bySchwann cells inhibits axonal regenerationand branching. Mol Cell Neurosci 1998; 12:79–91.

47) Wang, K.C., Koprivica, V., Kim, J. et al.: Oligo-dendrocyte-myelin glycoprotein is a Nogoreceptor ligand that inhibits neurite out-growth. Nature 2002; 417: 941–944.

48) Jones, L.L., Yamaguchi, Y., Stallcup, W.B. etal.: NG2 is a major chondroitin sulfateproteoglycan produced after spinal cordinjury and is expressed by macrophages andoligodendrocyte progenitors. J Neurosci 2002;22: 2792–2803.

49) Pasterkamp, R.J., Anderson, P.N. andVerhaagen, J.: Peripheral nerve injury fails toinduce growth of lesioned ascending columnaxons into spinal cord scar tissue expressing



the axon repellent Semaphorin3A. Eur J ofNeurosci 2001; 13: 457–471.

50) Winter, F.D., Oudega, M., Lankhorst, A.J. etal.: Injury-induced class 3 semaphorin expres-sion in the rat spinal cord. Exp Neurol 2002;175: 61–75.

51) Bregman, B.S., Kunkel-Bagden, E., Schnell,L., Dai, H.N., Gao, D., Schwab, M.E.: Recov-ery from spinal cord injury mediated by anti-bodies to neurite growth inhibitors. Nature1995; 378: 498–501.

52) GrandPre, T. and Li, S.: Strittmatter S.M.Nogo-66 receptor antagonist peptide pro-motes axonal regeneration. Nature 2002; 417:547–551.

53) Liu, B.P., Fournier, A., GrandPre, T. andStrittmatter, S.M.: Myelin-associated glyco-protein as a functional ligand for the Nogo-66receptor. Science 2002; 297: 1190–1193.

54) Domeniconi, M., Cao, Z., Spencer, T. et al.:Myelin-associated glycoprotein interacts withthe Nogo66 receptor to inhibit neurite out-growth. Neuron 2002; 35: 283–290.

55) Kim, J.E., Liu, B.P. and Park, J.H.: StrittmatterSM. Nogo-66 receptor prevents raphespinaland rubrospinal axon regeneration and limitsfunctional recovery from spinal cord injury.Neuron 2004; 44: 439–451.

56) Garcia-Abreu, J., Mendes, F.A., Onofre, G.R.,De Freitas, M.S., Silva, L.C., Moura Neto, V. etal.: Contribution of heparan sulfate to thenon-permissive role of the midline glia to thegrowth of midbrain neurites. Glia 2000; 29:260–272.

57) Blondel, O., Collin, C., McCarran, W.J., Zhu,S., Zamostiano, R., Gozes, I. et al.: A glial-derived signal regulating neuronal differentia-tion. J Neurosci 2000; 20: 8012–8020.

58) Song, H., Stevens, C.F. and Gage, F.H.:Astroglia induce neurogenesis from adultneural stem cells. Nature 2002; 417: 39–44.

59) Cai, D., Deng, K., Mellado, W., Lee, J., Ratan,R. and Filbin, M.: Arginase I and polyaminesact downstream from cyclic AMP in overcom-ing inhibition of axonal growth MAG andmyelin in vitro. Neuron 2002; 35: 711–719.

60) Olson, L., Wingenfalk, J., Josephson, A.,Greitz, D., Klason, T.K., Ityotani, T. et al.:Experimental spinal cord injury models: pro-spective and repair strategies. Tissue Engi-neering for Therapeutic Use 5 (Ikada, Y. andOshima, N. ed.) Amsterdam, Elsevier, 2001.pp. 21–36.

61) Olson, L.: Regeneration in adult central ner-vous system: experimental repair strategies.Nat Med 1997; 3: 1329–1335.

62) Kaneko, S., Iwanami, A., Nakamura, M.,Kanemura, Y., Ishii, H., Tanioka, Y., Tamaoki,N., Nomura, T., Momoshima, S., Kaneko, A.,Toyama, Y. and Okano, H.: Transplantation ofhuman neural stem cells promote axonalgrowth and functional recovery after spinalcord injury in primates. Abstract Viewer/Itinerary Planner. Washington, D.C., Societyfor Neuroscience, 2002. CD-ROM. ProgramNo. 203.18.

63) Watanabe, K., Nakamura, M., Iwanami, A.,Fujita, Y., Kanemura, Y., Toyama, Y. andOkano, H.: Comparison between fetal spinalcord- and forebrain-derived neural stem/pro-genitor cells as a source of transplantation forspinal cord injury. Dev Neurosci. in press.

64) Okano, H.: Neural stem cells: progression ofbasic research and perspective for clinicalapplication. Keio J Med 2002; 51: 115–28.

S. KANEKO et al.


Development of Novel Advanced Cell andGene Therapy and GMP-Controlled CellProcessingJMAJ 48(2): 81–84, 2005

Taira MAEKAWA, Shinya KIMURA and Yasunari KASAI

Department of Transfusion Medicine and Cell Therapy,Center for Cell and Molecular Therapy, Kyoto University Hospital

Abstract: High scientific and ethical practices and reliability in compliance withthe ICH-GCP (International conference on harmonization-good clinical practices)are properly required for clinical trials/research involving human subjects. Celltherapy is a general term for treatment modalities conducted by transplantation ofhuman cells, such as blood transfusion, hemopoietic stem cell transplantation, celltransfer immunotherapy, gene therapy, and regenerative therapy. A productionsystem called cell processing including human cell preparation, cultivation, andgene transduction is essential for the development of therapies using cells, andthe quality control thereof must be performed in compliance with the good manu-facturing practice (GMP). At the moment, however, Japan is far behind in theformulation of rules for cell processing, which should be evolved without delay inorder to promote the development of advanced therapy. In particular, it is urgent toconstruct an institutional GMP (iGMP) specialized for academic institutions andcenters, where development of advanced therapy such as regenerative therapyand cell therapy is being undertaken.

Key words: Development of novel advanced therapy; Cell therapy;Regenerative therapy; Gene therapy; Cell processing

patients with incurable diseases. The term “celltherapy” includes much of regenerative ther-apy, immunotherapy and gene therapy thatprogress based on novel theories or strategies.High scientific and ethical practices and reli-ability are required for the development ofsuch edge-cutting advanced therapies.


Introduction

In view of the life science research evolvingwith remarkable progresses since the begin-ning of the 21st century, it is eagerly awaitedthat the results of basic research would be fruit-fully translated into effective therapeutics for

�Regenerative Medicine


duction of human cells for therapeutic use,particularly to prevent transmission of infec-tions, and finalized in November, 2004.1) Fur-ther, the sterile drug products produced byaseptic processing was also finalized by theCenter for Drug Evaluation and Research(CDER) in September 2004.2)

It states, “Poor cGMP conditions at a manu-facturing facility can ultimately pose a life-threatening health risk to a patient” in theintroduction section, and provides concretedescriptions of an aseptic processing facilitydesign layout, aseptic processing techniquesand management. The CBER focuses primarilyon the aseptic processing for drugs, but alsogives consideration to applicability of the stan-dards to cell processing.

In Japan, it is stipulated in the AmendedPharmaceutical Affairs Law enforced as of July30, 2003, that “regarding ‘Biological Products’which require advanced production processcontrol, the premises and the procedures ofproduction and quality control at the manu-facturing facility (annotation by the author: theso-called GMP) shall comply with the manu-facturing standards for ordinary drugs andmedical devices and, in addition, shall complywith the supplementary standards laid down bythe Ministry of Health, Labour and Welfare”.A subordinative law will be issued in April,2005.

FDA’s Guiding Principles forDevelopment of Advanced Cell Therapy

When intending to carry out development ofcell therapy in the States, researchers or clinicalinvestigators should prepare a clinical trial pro-tocol and submit documents required for GMP-controlled cell processing to the FDA. TheFDA evaluates the cells for therapy as an INDto be used in translational research, inspectsthe manufacturing facility, and guides the appli-cant in preparing GMP-related documents.

The FDA officer recognizes the disparitybetween the GMP for conventional drugs and

T. MAEKAWA et al.

Currently, drugs used in clinical settings aremanufactured in compliance with the currentgood manufacturing practice (GMP), the stan-dards for production and quality control ofdrugs. In Europe and the United States, GMP-controlled cell processing is mandatory for thedevelopment of translational research usinghuman cells per se to treatment.

Rationale of the Need forGMP-Compliant Cell Processing

Development of a new drug, based on basicresearch data, proceeds to preclinical studiesand further to phase I trials. The drug used inthese studies should be produced under GMPcontrol. In the States, an investigational newdrug (IND) authorized by the Food and DrugAdministration (FDA) is used in clinical trials,and a similar system is being implemented fordrugs in Japan as well. Deduced from theseprinciples, it is readily understandable thatproduction of human cells for clinical use mustalso be in compliance with the GMP whenthose cells are considered to represent “cellpharmaceuticals”.

The prototype of cell therapy is blood trans-fusion, and blood products are prepared inaccordance with the GMP at blood centers orblood banks. It is essential that individualproducts be checked for potentially transmis-sible infectious agents since human cells, whichunlike drugs do not constitute batches, areused. Most translational researches with theuse of human cells are conducted at academicinstitutions and centers for novel advancedtherapy. No one would allow the transplanta-tion of cells prepared at a conventional labora-tory without any defined standards or records.

The System in the United States andCurrent Status in Japan

In January 2001, the US FDA proposed thecurrent good tissue practice (cGTP), whichspecifies those matters required for the pro-


of basic research, and are yet to be determinedas to whether they can be established as noveltherapeutics.

It is difficult for a pharmaceutical companyto make a positive entry into the developmentof GMP-controlled cell processing withoutrunning a risk at such a stage of translationalresearch. Therefore, researchers, clinical inves-tigators, pharmacists, medical technologists(biologists), engineers, GMP consultants, andresearchers of corporate advanced medicinaldevelopment divisions should closely collabo-rate in constructing the standards based onglobal rules specialized for academia and cen-ters for advanced therapy.3)

Summary and Conclusion

It has become recognized at length in Japanthat the cell processing control bodies must beready for the development of cell therapy andregenerative therapy. However, some institu-tions are still carrying out parallel incubation ofcells from several different individuals withinthe same incubator with a clean bench settledin a conventional laboratory, or are performing

NOVEL CELL THERAPY & CELL PROCESSING

that required for cell processing, and is readyto lend his/her cooperation in establishing aninstitutional GMP necessary for translationalresearch, with actual situations in academiataken into account, based on full GMP requiredfor pharmaceutical manufacturers to follow inthe production of commercial products (Fig. 1).Thus, in the States, a national strategic stance isbeing taken to actively aid academic institu-tions in the development of a novel therapy,concerning that the motivation for develop-mental research will be diminished because ofthe lack of clearly established standards.

Points at Issue in Japan

There is an opinion that “construction ofGMP-controlled cell processing may well beleft to the hands of enterprises or companies”.It is anticipated, indeed, that manufacturerscan make inroads into the area such as culturedskin, where products are already in clinicalapplication. However, what are developed inacademia or centers for advanced therapy arefor the most part those products manufacturedthrough translational research based on results

Fig. 1 Stepwise approach: regulatory requirements increase with product developmentInstitutional GMP should be established to advance translational research in academia

Institutional Facility

Blood Center

CompanyProducts Characterization GMP

Preclinical Studies Institutional GMP Full GMP

QA/QC (Quality Assurance/Quality Control), Clinical Monitoring Program

Prior to Phase I: need product safety and basic characterization information

Phase Phase IIIPhase III

Phase Phase IIPhase IIPhase Phase IPhase ITranslational Researchanslational ResearchTranslational Research


co-cultivation with murine cells or administra-tion of cells grown in cultures with fetal bovineserum simply because such has been approvedby a local ethical committee. No one wouldallow, even though indirectly, a transplantationof or being injected with an article which oneeven hesitates to eat.

There is no law to regulate such a situation atpresent in Japan. GMP-controlled cell process-ing is thus definitely needed all the more forculturing human cells and performing genetransfection in the advanced medical treatmentwhere safety and efficacy have not been fullyverified, especially in cell therapy and regener-ative therapy. This constitutes basic rules thatall individuals engaged in the development ofadvanced medical treatment must observe.Stringent regulation is required all the more insuch experimental exploratory treatment ofwhich safety and therapeutic effects are yetto be established. Research and developmentstarting in a slovenly manner will yield ir-reparable results. It should be done in strictaccordance with regulations until “the cellprocessing is thought to be infallibly safe up tothe proven level”, so that due deregulationthen may gradually follow.

Establishment of institutional GMP for aca-demia and centers for advanced therapy ismandatory for the development of advanced

T. MAEKAWA et al.

therapy in terms of cell therapy, and a keeninsight from those concerned are greatlyexpected.

Acknowledgment

This work was supported in part by a grant-in-aid from the 21st Century Center of Excel-lence (COE) Program “Establishment of Inter-national COE for Integration of Transplanta-tion Therapy and Regenerative Medicine”.

REFERENCES

1) Current good tissue practice for manufacturesof human cellular and tissue-based products;inspection and enforcement; final rule. 21CFR Part 16, 1270, and 1271, November 24,2004.

2) Guidance for industry. Sterile drug productsproduced by aseptic processing—currentgood manufacturing practice. PharmaceuticalcGMPs. CDER, September, 2004.

3) Maekawa, T.: Current good manufacturingpractices (cGMP) controlled cell processingfor the development of novel advanced celland gene therapy. The 65th Annual meetingof Japanese Society of Hematology and The45th Annual meeting of Japanese Society ofClinical Hematology. Education ProgramBook 2003; pp. 43–48.


Timing of Cataract SurgeryJMAJ 48(2): 85–91, 2005

Yoshitaka OBARA

Professor, Department of Ophthalmology, Dokkyo University School of Medicine

Abstract: As the population of elderly increases, management of patients withcataract is becoming an issue of increasing importance. Progress in surgical equip-ment and techniques has increased the safety of cataract surgery, and the insertionof an intraocular lens at the time of surgery has ensured many patients of goodpostoperative visual function. The mainstay of current cataract treatment is sur-gery, and it is possible to obtain improved vision if patients and surgical techniquesare properly chosen. The timing of surgery is also an important factor. Visual acuityis not an infallible index because it may vary according to the conditions of mea-surement and the patient’s physical and/or mental status. The level of visual acuityrequired may also vary among different patients according to their lifestyle. Surgeryis indicated for patients with nuclear cataract or posterior subcapsular cataractbecause daylight vision is affected even if the patients have good indoor vision.Surgery should be considered when decreased contrast sensitivity and increasingglare are noted. Since the visual field and fusional amplitude are narrowed whenvisual acuity is less than 0.5, such changes help in deciding when to performsurgery. The timing of surgery in elderly patients should be determined afterconsultation with an internist, because cataract patients often have concomitantsystemic diseases.

Key words: Incidence of cataract; Visual acuity; Contrast sensitivity;Visual field; Small-incision cataract surgery

This article is a revised English version of a paper originally published inthe Journal of the Japan Medical Association (Vol. 129, No. 11, 2003, pages 1763–1767).The Japanese text is a transcript of a lecture originally aired on February 5, 2003, by the Nihon ShortwaveBroadcasting Co., Ltd., in its regular program “Special Course in Medicine”.

Introduction

Since the number of elderly patients withcataract is increasing as the population ages,the management of vision in cataract patients isan important issue. Because the general publicis largely aware of the possibility of cataract,

visual impairment in the elderly is likely to leadpeople to think of cataract as the probablecause. The management of cataract includespreventive measures against development ofthe condition as well as drug and surgicaltreatments. When the patient has no significantdifficulties in daily living, the main treatment

�Cataract


is medication with anticataract drugs. Surgicaltreatment is generally indicated as the diseaseprogresses.

Remarkable changes in cataract surgery havetaken place in recent years. Large incisions inthe surgical procedure have given way tosmaller incisions, and surgical extraction hasbeen replaced by ultrasound phaco-emulsifica-tion and aspiration as the main technique oflens removal. Even in the postoperative restingphase, absolute bed rest has been replaced withearly release from bed rest and a shorter periodof rest. Pain from the anesthetic procedure alsohas been reduced since retrobulbar anesthesiaand blink anesthesia were replaced by sub-conjunctival (in Tenon’s capsule) or eye-dropanesthesia. In addition, safe insertion of intra-ocular lenses has improved the quality of post-operative vision, in comparison with earliermethods of postoperative vision correctionsuch as eyeglasses or contact lenses. Currently,small-incision cataract surgery plus the inser-tion of an intraocular lens is the basic surgicaltreatment for cataract.

The established new surgical techniques andprogress in surgical equipment have achievedsafer cataract surgery and thus allowed moreaggressive application of surgical treatment.However, cataract surgery itself has never beena simple procedure. Although some ophthal-mologists note that surgery can be completedwithin a short period of time, this is not aproper goal for surgery. Errors in patient selec-tion and incomplete adjustment of surgicalequipment may cause unexpected complica-tions. In addition, serious intra- or postopera-tive complications such as endophthalmitis andbullous keratopathy and the postoperative issueof secondary cataract remain to be addressed.

Even if cataract surgery is completed safelyand good vision is obtained, visual functionwith pseudophakia (presence of artificial intra-ocular lens replacing normal human lens) maypresent particular problems. The patient maycomplain of postoperative photophobia, changesin color tone, and impaired stereognosis, none

Y. OBARA

of which were present preoperatively. There-fore, proper selection of amenable patients andproper timing of surgery are important. It isalso necessary to obtain informed consent aftera full explanation of the surgical proceduresand postoperative visual function with pseudo-phakia has been provided. It is important forthe patient to view surgery with an attitude ofconfidence and to have a clear understandingof what is likely to be involved.

The present communication describes therelationship between disease type and progres-sion of opacities and between patient age andthe incidence of cataract, and discusses theproper timing of surgery from the viewpoint ofvisual acuity and visual function.

Fig. 1 Opacities of lens (cortical cataract)

Fig. 2 Opacities of lens (nuclear cataract)


Types of Cataracts

Cataracts are generally classified into threemain types, cortical, nuclear, and posteriorsubcapsular, according to the location of lensopacity. Cataract with mixed opacities is re-ferred to as mixed-type cataract. Among thesetypes of cataract, the cortical type (Fig. 1) andnuclear type (Fig 2) are most common, whereasthe posterior subcapsular type is less frequent.Mixed-type opacities are frequent in elderlypeople.

Incidence of Cataract by Age and Sex,and Course of Progression byDisease Type

1. Incidence of cataract (Fig. 3)The respective incidence rates of age-related

cataract including initial opacities are 37–54%,66–83%, 84–97%, and 100% for those in their50s, 60s, 70s, and 80s or older.1) Figure 3 showsdata from our department concerning the inci-

dence of cataract in 1993; some kind of opacitywas found in 40% of women in their 40s. Theincidence of cataract was higher in women thanin men in all age groups except those in their70s. Moderate or more advanced cataract hasbeen reported in 10–13%, 26–33%, 51–66%,and 67–83% of those in their 50s, 60s, 70s, and80s or older, respectively.2)

2. Course of cataract progressionThere is no evident correlation between age

and the rate at which opacities progress. Therate of progression of pre-existing opacitiesafter 5 years is reported to be 16.2% for thecortical type, 50% for the nuclear type, and55% for the posterior subcapsular type.3)

Although the progression of cortical cataract isslower than that of the other types, posteriorsubcapsular cataract progresses rapidly onceit has developed and may cause markedlydecreased daylight vision if opacities reachthe pupil area. Early surgery is indicated forpatients with this type of cataract even whenthey have good indoor vision.

After the age of 70 years, cataract surgery isindicated for 30.3% of patients, and the inci-dence of surgery is significantly higher forfemales than males.4)

Mixed-type cataract is frequent among sur-gical cases, whereas simple cortical or nuclearopacities are infrequent. Cataract surgery ofone eye does not cause cataract progression inthe other eye.

Indications and Timing ofCataract Surgery

1. Visual acuityIt is difficult to assess visual acuity accurately

because a number of factors are involved inthe examination of vision: conditions of mea-surement, the physical and mental status anddegree of concentration of the patient, the tech-nical skills of the examiner, and the environ-ment in which the examination is performed.The level of visual acuity considered to hinder

TIMING OF CATARACT SURGERY

10

40 50 60 70 80 years

20

Males

Females

30

40

50

60

70

80

90

100

%

Fig. 3 Incidence of cataract


daily living varies among different individualsaccording to the social lives they lead. Elderlypatients with a limited range of activities whousually spend time at home watching TV orreading may not feel inconvenienced at a visualacuity of about 0.5. On the other hand, some-one like a taxi driver may have difficulty evenat a visual acuity of 0.9. Therefore, it is difficultto determine indications for surgery based onvisual acuity alone.

Nevertheless, visual acuity is a necessarygeneral index of the need for surgery. In theauthor’s opinion, surgery should be indicatedfor patients with a visual acuity of 0.5 or less.Two decades ago it was common for surgery tobe indicated when the patient became “unableto see.” Currently, however, surgery is consid-ered when a patient feels inconvenienced indaily life.

Whether surgery for age-related cataract isperformed in a patient with good vision or poorvision has no marked influence on surgical out-come as long as the patient has no other com-plications. However, patients are discouragedfrom undergoing surgery if they are not experi-encing much inconvenience, because vision inthe patient’s own eye (i.e., with a natural lens)is superior in quality to vision in the operatedeye (i.e., with an artificial lens). On the otherhand, the affected eye may develop glaucoma ifleft untreated for an extended period. There isalso risk of delay in finding lesions, if any, in theocular fundus.

Patients with cataract may suffer decreasedeyesight not only for far distance but also fornear distance. A visual acuity of 0.5 or more isrequired for reading books and newspapers,and surgery is indicated for patients with ahigher visual acuity if their occupation requiresreading fine print.

2. Types of opacities and visual acuityAs mentioned previously, cortical cataract is

slow to progress, and therefore its effects onthe patient’s visual acuity tend to be in-conspicuous. However, nuclear and posterior

subcapsular cataracts, even if mild, affect thepatient’s vision; patients suffer evidently de-creased visual acuity in daylight even whentheir indoor visual acuity is 1.2. Such patientsare inconvenienced by bright sunlight (hem-eralopia) in the daytime and by car headlightsat night. Therefore, early surgery is recom-mended for patients with nuclear or posteriorsubcapsular cataract even if they have goodindoor vision.

3. Contrast sensitivity and visual acuityIn patients with mild cortical and nuclear

cataracts, contrast sensitivity to high spatialfrequency is decreased.5) It is important todetermine the timing of surgery by measuringcontrast sensitivity in patients who have goodvision. As cataract progresses, contrast sensi-tivity decreases significantly. Such decrease obvi-ously will be improved by surgery.

4. GlareThere is no difference in glare sensitivity

between patients with mild cataract and thosewithout cataract. That is, problems caused byglare are not significantly greater in patientswith early cataract than in those without cata-ract. However, as opacities progress, visualacuity and contrast sensitivity decrease signifi-cantly under conditions of glare. Because it isnot certain that there is improvement in glareafter cataract surgery, the results of glare test-ing are of limited value in determining thetiming of surgery.

5. Visual field and visual acuity (Table 1)The visual field reflects the status of the

visual pathway from the retina to the visualcortex; the lens is not directly related to it.When measurement conditions such as the sizeand brightness of targets are varied duringmeasurement of the visual field, the test mayshow a narrow visual field in patients with cata-ract because the ability to recognize targets isaffected by insufficient illumination.

With a large visual target (4/V isopter) in

Y. OBARA


Goldman perimetry, the area obtained at avisual acuity of 0.1 was about 80% when thearea obtained at a visual acuity of 1.0 was set at100%. Thus, the decrease was only 20%, whichis not especially conspicuous. However, underpoorer conditions with a smaller target (2/Iisopter), the area obtained at a visual acuity of0.3 was markedly decreased to about 10%,demonstrating decreased visual field sensi-tivity. The worsening of perimetric conditionscarries the same meaning as seeing in dim lightor attempting to identify a small object. There-fore, reduction of the visual field is regarded asa helpful test result in determining the timingof cataract surgery. Judging from the areameasured by Goldman perimetry, a decrease invisual acuity to 0.5 or less indicates the appro-priateness of surgery.

6. Fusional amplitude and visual acuity(Table 2)

Fusion enables visual images from both eyesto be recognized as a single image, and the

range of vergence for maintaining fusion iscalled fusional amplitude. Cataract patientsappear to have decreased ability for fusion.People with a visual acuity of 1.0 or more havea fusional amplitude of about 30�. In contrast,in those with a visual acuity of 0.5 or less,fusional amplitude is reduced by about half.The ability to recognize images deteriorateswith decreasing visual acuity. A visual acuity of0.5 is also considered to be an index of surgeryfrom the viewpoint of the faculty for fusion.

7. General condition (Table 3)Because elderly patients tend to be involved

in cataract surgery, the decision to operatecannot be based solely on the status of the eye.Many cataract patients have abnormalities intheir overall condition. When 150 patients


Table 1 Visual Field Area in Patients with Cataract

Visual acuity Visual field area (cm2) % Visual field area (cm2) %(4/V isopter) (2/V isopter)

1.0 190 100.00 22.0 100.000.8�0.9 160 84.21 16.0 72.730.6�0.7 165 86.84 9.0 40.910.4�0.5 190 100.00 7.0 31.820.3 175 92.11 2.5 11.360.2 170 89.47 3.0 13.640.1 150 78.95 3.0 13.640.02 135 71.05 0 0.00

Table 2 Fusional Amplitude in Patients with Cataract

Visual acuity Fusional amplitude (�) %

1.0� 29�10 100.000.6�0.9 22� 8 75.86� 3.240.3�0.5 14�10 48.27�13.27

Table 3 Concomitant Diseases in Inpatients withAge-Related Cataract

Disease No. of cases %

Hypertension 51 37.0Neuralgia, arthralgia 23 16.7Heart disease 20 14.5Respiratory disease 15 10.9Diabetes mellitus 8 5.8Dementia (senility) 3 2.1Others 18 13.0

Total 138 100.0


Y. OBARA

admitted under a diagnosis of age-related cata-ract were examined as to their general condi-tion, the frequency of concomitant disease washigh, as individual patients tended to havemore than one disease. If the concomitantdisease(s) is in the acute phase, priority shouldbe given to the treatment of the disease. How-ever, since the concomitant disease is usually inthe chronic phase, cataract surgery is appli-cable in many cases. However, it is important tocooperate with specialists in the relevant fields,not only to obtain an understanding of thepatient’s general condition, but also to adjustmedications related to surgery, because mostpatients are already on drug therapy for thedisease.

Patients with heart disease may suffer ag-gravation of symptoms as a result of surgicalstress. Therefore, close communication withthe patient’s cardiologist may be necessary.Hypertensive patients are most frequent. For-tunately, we have not recently encounteredpatients whose general condition was aggra-vated owing to marked variations in bloodpressure. In patients with dementia, a condi-tion that is likely to increase in the future,recovery of visual acuity may improve symp-toms. Surgery for such patients requires theunderstanding of the patient’s family. If there isdifficulty in communicating with the patientbecause he or she lacks the ability to under-stand, general anesthesia under the support ofan anesthesiologist should be employed.

Conclusion

Human beings obtain most of our informa-tion through the visual sense faculty. It is ofgreat importance to manage visual acuity inthe increasing population of cataract patients,both to maintain their vitality and that ofsociety as a whole. The techniques of cataractsurgery have been established, and the inser-tion of intraocular lenses provides vision ofgood quality. However, such vision is inferiorin quality to that provided by a normal, natural

lens. Therefore, surgical treatment is not ben-eficial unless the patient has been complainingof poor vision.

On the other hand, the extent of inconve-nience varies among individuals according totheir visual requirements. Therefore, it isimpossible to determine uniformly the level ofinconvenience at which surgery would be indi-cated. The fact that about half of patients withcataract over the age of 70 years have moderateopacities indicates the presence of a greatnumber of patients with visual impairment.The rate of progression and influence on visualacuity vary according to the type of opacity.Based on analyses of objective data includingvisual acuity, contrast sensitivity, glare, visualfield, and fusional faculty, a visual acuity of 0.5seems to serve as a yardstick for the applicationof surgery.

Although cataract surgery is safer now thanpreviously, any surgical invasion of the livingbody is likely to be associated with compli-cations. Surgery should be performed afterthe patient’s consent has been obtained onthe basis of accurate information regardingthe risks and benefits of surgery, includingthe need for surgery, details of the surgicalprocedure, and possible complications. Natu-rally, the patient’s willingness to undergo sur-gery is also important.

REFERENCES

1) Fujisawa, K., Zeinuddin, D., Kojima, M.,Sakamoto, Y. and Sasaki, K.: Population-based cataract epidemiological survey (II).Nippon Ganka Kiyo 1989; 40: 615–620. (inJapanese)

2) Sasaki, H.: Epidemiologic study of cataract infour areas with different ethnic groups andliving environments. Nippon HakunaishoGakkaishi 2001; 13: 13–20. (in Japanese)

3) Leske, M.C., Chylack, L.T. Jr. and He, Q.:Incidence and progression of cortical andposterior subcapsular opacities: the longitu-dinal study of cataract. The LSC group.Ophthalmol 1997; 104: 1987–1993.



4) Carlsson, B. and Sjostrand, J.: Increased inci-dence of cataract extractions in women above70 years of age. A population-based study.Acta Ophthalmol Scand 1996; 74: 64–68.

5) Yuge, T., Kozasa, K. and Yamade, S.: Correla-

tion between opacities and visual acuity orcontrast sensitivity in patients with cataract.Nippon Ganka Gakkai Zasshi 1993; 97: 619–626. (in Japanese)


Death due to Overwork (Karoshi )Causation, health service, and life expectancy ofJapanese malesJMAJ 48(2): 92–98, 2005

Shunichi ARAKI* and Kenji IWASAKI**

*President, National Institute of Industrial Health**Senior Researcher, National Institute of Industrial Health

Abstract: As a member in the Expert Study Committee of the Ministry of Health,Labour and Welfare of Japan (MHLW), which conducted a large-scale review ofliteratures as well as medical evaluations, the author (Araki), together with hisco-author, summarized the rulings of the Supreme Court on karoshi (death due tooverwork), the statutory revision of the standard recognizing labour accidents, theeffects of overwork on the onset of brain and heart diseases, and a comprehensiveindustrial health service that prevents karoshi. We suggested that the mortality rateand life expectancy of Japanese males can be improved by such preventivemeasures as well as by promoting pathophysiological, clinical and socio-medicalstudies.

Key words: Karoshi ; Overwork; Brain and heart diseases; Life expectancy;Industrial health service; Ministry of Health, Labour and Welfare;Japan

This article is a revised English version of a paper originally published inthe Journal of the Japan Medical Association (Vol. 128, No. 6, 2002, pages 889–894).The Japanese text is a transcript of a lecture originally aired on May 29, 2002, by the Nihon ShortwaveBroadcasting Co., Ltd., in its regular program “Special Course in Medicine”.

Introduction: Life Expectancy ofJapanese Males and Females

The average life expectancy of the Japanese,especially for females has been higher than anyother nation for many years. In 2003, the lifeexpectancy for Japanese females reached arecord high of 85.3 years.1) The life expectancyfor males, however, was only 78.4 years for the

same year. While Japan still ranked as one ofthe countries with a high average life expect-ancy for males along with Iceland and Sweden,it was certainly not high enough to claim thatJapanese males have a significantly longer lifeexpectancy than other nations.1)

This relatively short life expectancy of Japa-nese males compared to Japanese females,when viewed on an international scale, may be

� Karoshi


DEATH DUE TO OVERWORK (KAROSHI )

attributed to a difference in the effects of occu-pational and social life factors on males andfemales. In particular, it is possible that thegender difference in the impact of risk factors isgreater in Japan than in Western countries. Thisis compatible with the results from the studiesconducted by the author for the entire Japa-nese population, and they have been summa-rized as follows.(1) Social life factors such as living in rural

areas (a few causes of death are attributedto urban living), a low income (and un-employment), and elderly or younger agedistribution of the population are majorrisk factors affecting life expectancy,2,3) all-causes mortality (age-adjusted death rate),4)

infant mortality rate,5) and death rate fromlifestyle-related diseases such as cerebro-vascular disease,4,6) ischemic heart disease4,6)

and cancer.4,7) These factors are also majorrisk factors for marriage8) and birth.8)

(2) The influence of these risk factors on theaverage life expectancy2,3) and all-causesmortality4) for males was greater thanfemales.

(3) The effects of such factors were also evi-dent for occupation-specific mortality ratesamong males.9)

The “Expert Study Committee on StandardRecognizing Brain and Heart Diseases” (here-after referred to as “Expert Committee”)10) ofthe Ministry of Health, Labour and Welfare(MHLW) was organized in November 2000 torevise the standard recognizing labour acci-dents that cause death by brain and heartdiseases stemming from overwork (commonlyreferred to as karoshi). In this paper, theauthor, as the committee member representingthe epidemiological and public health disci-plines, introduces the conclusions that werereached by the Expert Committee concerningthe effect of overwork on the onset of brainand heart diseases, the prevention of karoshi,and the comprehensive industrial health ser-vice. The effectiveness of the preventive mea-sures that are expected to improve the mor-

tality rate and life expectancy of the Japaneseis also discussed. It is notable that almost alldeaths induced by brain and heart diseases,which have been recognized as labour acci-dents in recent years, have occurred in males.10)

Supreme Court’s Ruling andStatutory Revision

In July 2000, the Supreme Court ruled ontwo male cases demanding compensation forlabour accidents.10) The cases were related to a54-year-old driver assigned to a branch man-ager, who developed a subarachnoid hemor-rhage, and a 51-year-old driver of a large tourbus who developed hypertensive brain hemor-rhage. The verdict passed in the former casewas that a cerebral aneurysm was exacerbatedby chronic fatigue stemming from long operat-ing hours and continuous excessive stress. Forthe latter case, the verdict reached was thatrepeated increases in blood pressure due todriving and exposure to cold had weakened thedriver’s blood vessels. It was concluded thatthese conditions led to the development of thesaid diseases.

Four months after these two legal rulingswere delivered by the Supreme Court, MHLWestablished the Expert Committee mentionedabove, which conducted a large-scale reviewof publications and medical evaluations con-cerning the relationship between accumulatedfatigue due to overwork and the developmentof brain and heart diseases; and it later com-piled a report on its findings in November2001.10) Based on this report, the standard rec-ognizing brain and heart diseases stemmingfrom labour accidents was revised on the fol-lowing day.11) Furthermore, the “Comprehen-sive Program for the Prevention of HealthImpairment Due to Overwork” was estab-lished in February 2002, and the Director-General of the MHLW Labour Standards Bu-reau notified the Labour Bureaus in each pre-fecture about the Comprehensive Program.12)


Effect of Overwork on the Onset ofBrain and Heart Diseases

Table 1 shows the conclusions of the MHLW’s

Expert Committee on the causal relationshipbetween overwork and the onset of brain andheart diseases.10) According to the former Stan-dards on Recognition of Labour Accidents(Labour Standards Bureau Notifications No. 38issued in February 1995 and No. 30 issued inJanuary l996), only excessive work during veryshort periods before the onset of cerebro-vascular disease, ischemic heart disease andarrhythmias, i.e., between the previous day andthe time immediately before the disease onset,or within a week before the onset, wasaccepted as a direct cause. Overwork prior tothat period was not legally accepted as a directcause, but it was only taken into account inmaking general judgments.10)

In contrast, based on the results of the epi-demiological research conducted later, theExpert Committee reached the conclusion thistime that overwork carried out over a longperiod of time from one to six months prior to

Table 1 Causal Relationship between Overwork and the Onset of Brain and Heart Diseases: Conclusions ofthe Expert Study Committee on Standard Recognizing Brain and Heart Diseases, Ministry of Health,Labour and Welfare, Japan

1. The work, which is obviously an excessive amount, conducted in the period close to the onset of brain or heart disease,has been proven to be a possible direct cause to the onset of the said disease according to current medical knowledge.Therefore, the present accreditation standard introduced based on this idea shall be judged to be valid.

2. Accumulated chronic fatigue may impact the onset of brain and heart disease. Hence an accumulation of chronicfatigue, not limited to periods close to the onset of brain and heart diseases but also periods prior to that should beconsidered as an obvious work overload.

3. Assessing the extent of work overload shall be specifically and objectively based on an examination of work conditionssix months prior to the onset of the disease, and the extent shall be assessed from the perspective of whether theaccumulation of fatigue at the time of the onset was at a level that significantly deteriorates vascular lesions and suchbeyond its natural course, leading to an onset of brain and heart diseases.

4. Specifically, it is appropriate to comprehensively assess the effects of various factors including working hours, irregu-larities of labour, work restrictions, shift work system and work environment, as well as the factors of mental strainoriginating from work.

5. Focusing on working hours, i.e., the most important factor in accumulation of fatigue, if a worker had (1) consecutivelyengaged in long working hours which is recognized to be of an especially significant length (basically more than 100hours of overtime) during one month prior to the onset of the disease, or (2) consecutively engaged in long workinghours (basically more than 80 hours of overtime per month) which is recognized to be of a significant length during twoor six months prior to the onset of the disease, then the work shall be judged to be strongly related to the onset.

6. When basically more than 45 hours of overtime per month is not evident during one or six months prior to the onset,the relationship between work and the onset is judged to be weak. The relationship between work and the onset is judgedto be stronger with the greater number of overtime working hours basically exceeding 45 hours per month.

7. Hypertension, alcohol consumption, and smoking are some risk factors that could trigger the onset of brain and heartdiseases. An individual with multiple risk factors is more prone to develop said diseases. Therefore, the state of worker’shealth, the extent of pre-existing diseases, and the overload of work must be fully studied when determining compre-hensively the relationship between these factors and the brain or heart disease developed in the worker.

(From the MHLW Expert Study Committee Report on Standard for Recognition of Brain and Heart Diseases10))

Fig 1 Progression of vascular lesions etc. due to over-work and onset of brain and heart diseases

(From the MHLW Expert Study Committee Report onStandard for Recognition of Brain and Heart Diseases,10)

partly revised)

Onset

Accumulation of fatigue

Natural course

A

B C

Pro

gres

sion

of

vasc

ular

lesi

ons,

etc

.

Chronological progress

A. Significant deterioration of vascular lesions, etc. due to accumulated fatigue related to work

B. Induction of the onset of disease due to acute workloadC. Onset of disease due to acute work overload

S. ARAKI and K. IWASAKI


Table 2 Summary of Epidemiological Research Papers on the Causal Relationship betweenLong Working Hours and Onset of Brain and Heart Diseases

Average workingObservation

Study design and results

hours or average period Diseases Causes Study Results Statistical Authorsovertime hours studied method significance

Work for 10 hours 3 years Hypertension Working Follow-up Decreased hazard ratio (0.54) Yes N. Nakanishior more per day hours, study compared to work for less than et al. (1999),including lunch break lifestyle 10 hours per day*1 in Japanese

Work for 10.9 hours 10 years Myocardial Lifestyle Case-control Unhealthy life style compared Yes K. Shidoper day or for 277 prior to infarction study to control group of 9 working (1995),hours per month onset of hours per day or 221 working in Japanese

disease hours per month

Work above 11 hours One month Acute Working Case-control Increased odds ratio (2.44) Yes S. Sokejimaper day prior to myocardial hours, study compared to work for 7–9 et al. (1998)

onset of infarction risk factors, hours per daydisease height,

weight, etc.

Portal to portal hours 2.8 years Brain and Working Follow-up Hazard ratio (i.e., relative risk Yes S. Uchiyamaof 11 hours or more heart situation, study for brain and heart diseases et al. (1992),per day diseases lifestyle corrected for other factors) in Japanese

is 2.7

Office and one-way Working Comparison Increased systolic blood pres- Yes K. Iwasakicommuting hours of hours, between sure in workers aged 50–59 et al. (1998)61.3 hours or more subjective workers years compared to those withper week symptoms with long short working hours

and short (56.5 hours)workinghours

Work for 60 hours or Juvenile Prolonged Patient 46% of patients worked 60 H. Russekmore per week myocardial emotional study hours or more for a long period et al. (1958)

infarction stress before onset of symptoms

Work for 60 hours or 1.5 years Hypertension Occupational Nested Increased odds ratio (2.2) for Yes T. Uehatamore per week stress case-control patients with new onset of et al. (1994),

study hypertension in Japanese

Increased odds ratio (2.0) for Yespatients with new administra-tion of antihypertensives

Overtime work of 1.5 years Hypertension Occupational Nested Increased odds ratio (1.5) for No50 hours or more stress case-control patients with new onset ofper month study hypertension

Increased odds ratio (3.2) for Yespatients with new administra-tion of anti-hypertensives

Overtime work of 24-hour Case-control Increased blood pressure Yes T. Hayashi60 hours or more average study compared to the group with et al. (1996)per month blood overtime work for 30 hours

pressure or less per month

Overtime work for 24-hour Case study Increased blood pressure and Yes96 hours per month average shortened sleeping hours

blood compared to the months ofpressure overtime work for 43 hours

Overtime work for Subjective Question- Complaint of lack of sleep in Occupational100 hours per month symptoms of naire study 50% or more Fatigue

fatigue Handbook(1995),in Japanese

6 months Acute Working Case-control No difference in working hours, No H. Yoshidamyocardial situation, study overtime working hours, and et al. (1993),infarction lifestyle holidays from healthy controls in Japanese

*1Reduction in the occurrence of hypertension due to long working hours is explained as a result of decreased obesity caused by increased energyconsumption. (From the MHLW Expert Study Committee Report on Standard for Recognition of Brain and Heart Diseases,10) partly revised)



the onset of the diseases would be deemed asthe principal cause of disease onset.10) Further-more, according to the new Standard, longworking hours (overtime work hours per month)were introduced as an indication of overworkand accumulated fatigue, enabling clear andprompt judgment of the extent of overworkwhen certifying labour accidents. Figure 1shows the progression of vascular lesions etc.and the onset of brain and heart diseases dueto overwork; it was illustrated by the ExpertCommittee.10)

Table 2 summarizes the content of the epi-demiological research papers concerning therelationship between long working hours andthe onset of brain and heart diseases, on whichthe conclusions in the Expert Committee werebased (see Table 1).10) In addition, the original

English papers written by the present authorsconcerning the effects of work stress on ische-mic heart disease,13,14) hypertension,15) and theimmune system16) are included in the refer-ences at the end of this paper.

Prevention of Karoshi and Its Effecton Life Expectancy

1. Comprehensive industrial health serviceA comprehensive industrial health program

to prevent karoshi was issued in the form of anotification from the Director-General of theLabour Standards Bureau, MHLW.12) Based onthis notification, Table 3 shows the relationshipbetween overtime work hours and the onset ofbrain and heart diseases as well as preventivemeasures which should be taken by employers.

Table 3 Onset of Brain and Heart Diseases and Preventive Measures To Be Taken by Employers for Overtime Work

Relation of hours ofCategory Hours of overtime work*1 overtime work to onset of Preventive measures to be taken by employers

brain and heart diseases

Basically 45 hours or less per Weak NoneI month for the past one or

six months

Basically 45 to 100 hours for Becomes gradually stronger Employers shall provide industrial physicians orthe past one month or 45 to as overtime working hours physicians qualified to be selected as industrial80 hours per month for the increase physicians such as physicians registered with localpast 2 or 6 months, prior to industrial health centers in the case of workplacesonset of disease without any obligation to select industrial

physicians (hereinafter, “Industrial physicians etc.”)II with information about the work environment,

working hours, number and hours of night work,past medical examination results, etc. concerningworkers who are involved in the work.Employers shall be advised and instructed byindustrial physicians etc. concerning healthmanagement at the workplaces (Measure A).

Basically more than 100 hours Strong In addition to Measure A mentioned above,for one month or more than employers shall provide workers involved in the80 hours for the past 2 or 6 concerned labour with health guidance throughmonths prior to onset of meetings with the industrial physicians etc. Whendiseases the industrial physicians etc. recognize such as

III necessary, the workers shall have medicalexaminations which the industrial physicians etc.judge to be necessary. The opinion of the industrialphysicians etc. shall be sought concerning theresults of medical examinations and the necessarymeasures to be taken by employers (Measure B).

*1Overtime work is defined as more than 40 hours of work per week. (Compiled by Iwasaki and Araki based on the Notificationfrom the Director-General of MHLW’s Labour Standards Bureau in February 200212))



In addition, Table 4 presents comprehensiveindustrial health measures to prevent karoshithat should be taken by respective governmentoffices, employers, labour unions, and indi-vidual workers. These measures were compiledbased on the Expert Committee report.10)

The source of the data, which served as thebasis for developing the new standard on rec-ognizing labour accidents, was limited pri-marily to past cases of labour accidents andepidemiological research papers. There werevery few papers which clarified the mechanismor pathological changes that overwork (mentalstress, irregular work, long working hours, etc.)exacerbated the blood vessel lesions in thebrain and heart causing death. Consequently,as an industrial health measure conducted bythe government, it is necessary to promotepathophysiological, clinical and socio-medicalstudies on the relationship between overworkand karoshi. These studies will define the effectof overwork on brain and heart diseases moreclearly from qualitative and quantitative view-points; thus, a more accurate recognition stan-

dard can be established.

2. Effects of industrial health service onmortality rate and life expectancy

The benefits derived from measures toprevent karoshi are not simply limited to areduced number of worker deaths caused bybrain and heart diseases. Improving overworkconditions over an extended period of time willreduce risk factors for lifestyle-related diseasessuch as hypertension, obesity, alcohol con-sumption and smoking. As a result, the onsetand progression of brain and heart diseases inthe labour force, that comprises the majority ofthe whole population, will also be prevented.Furthermore, this would also contribute to animprovement in the mortality rate and lifeexpectancy of Japanese as a whole. If the gov-ernment, employers, and individual employeesrespectively strive to prevent karoshi, the onsetof brain and heart diseases of employees wouldbe prevented and karoshi would decrease.Moreover, the life expectancy of working Japa-nese males, who account for a greater portion

Table 4 Comprehensive Industrial Health Service to Prevent Karoshi

1) Shorten working hours1. Promote taking annual paid holidays2. Promote a long holiday system3. Reduce nonprescribed workGovernment

2) Publicize the national subsidy system for secondary health examinations andother occupational health services

3) Encourage night shift workers to undergo voluntary health examination4) Strengthen preventive medical care and other health administration measures

1) Shorten working hours2) Comply with overtime work limitation standards3) Conclude appropriate overtime work agreement

Both labour unions4) Comply with requirements about introducing an irregular working system,

and employersdiscretionary labour system, and flexible working hour system

5) Improve participation rate for medical examinations6) Fully implement measures after medical examinations7) Enhance medical care to maintain and promote worker’s health8) Create a comfortable work environment

Individual employees1) Recognize excessive fatigue and the need to take rests2) Practise primary, secondary and tertiary prevention of lifestyle-related diseases

(Compiled by Araki and Iwasaki based on the MHLW Expert Study Committee Report on Standard forRecognition of Brain and Heart Diseases10))



of the working population than females, isexpected to be prolonged.

REFERENCES

1) Health and Welfare Statistics Association(ed.): Trends in National Health for 2004.Health and Welfare Statistics Association,Tokyo, 2004; pp.45–56, pp.67–68. (in Japanese)

2) Araki, S. and Murata, K.: Factors affectingthe longevity of total Japanese population.Tohoku J Exp Med 1987; 151: 15–24.

3) Uchida, E., Araki, S. and Murata, K.: Socio-economic factors affecting the longevity ofthe Japanese population: A study for 1980 and1985. J Biosoc Sci 1992; 24: 497–504.

4) Araki, S. and Murata, K.: Social life factorsaffecting the mortality of total Japanese popu-lation. Soc Sci Med 1986; 23: 1163–1169.

5) Araki, S. and Murata, K.: Social life factorsaffecting stillbirth, and infant and adult-disease mortality. Tohoku J Exp Med 1986;149: 213–219.

6) Araki, S., Murata, K. and Yokoyama, K.:Socioeconomic risk factors for cerebrovas-cular, ischemic heart and hypertensive mor-tality in Japan. Tohoku J Exp Med 1986; 149:367–377.

7) Araki, S.: Social life factors affecting majormalignant neoplasms in Japan. Tohoku J ExpMed 1986; 149: 221–228.

8) Uchida, E., Araki, S. and Murata, K.: Socio-economic factors affecting marriage, divorceand birth rates in Japanese population. JBiosoc Sci 1993; 25: 499–507.

9) Araki, S. and Murata, K.: Mortality of work-ing and non-working populations in Japan:Effects of social life factors. J Human Ergol1985; 14: 89–98.

10) MHLW Expert Study Committee on Standardfor Recognition of Brain and Heart Diseases:

Report by the MHLW Expert Study Committeeon Standard for Recognition of Brain andHeart Diseases. Occupational Disease Recog-nition Office of the MHLW Labour StandardsBureau, Tokyo, November 16, 2001; pp.1–5,pp.86–111, pp.131–132. (in Japanese)

11) Ministry of Health, Labour and Welfare: Revi-sion of the Standard for Recognition of Brainand Heart Diseases. Press release, MHLW,Tokyo, December 12, 2001; pp.1–5. http://www.mhlw.go.jp/houdou/0112/h1212-1.html.(in Japanese)

12) Director-General of the MHLW Labour Stan-dards Bureau: Comprehensive Program forthe Prevention of Health Impairment due toOverwork (2002). Labour Standards BureauNotification No.0212001, February 12, 2002.MHLW Labour Standards Bureau, Tokyo,2002. http://www.jaish.gr.jp/hor_s_shsi/100297.(in Japanese)

13) Araki, S., Murata, K., Kumagai, K. et al.: Mor-tality of medical practitioners in Japan: Socialclass and the “healthy worker effect”. Am JInd Med 1986; 10: 91–99.

14) Kawakami, N., Haratani, T. and Araki, S.:Job strain and arterial blood pressure, serumcholesterol, and smoking as risk factors forcoronary heart disease in Japan. Int ArchOccup Environ Health 1998; 71: 429–432.

15) Iwasaki, K., Sasaki, T., Oka, T. et al.: Effect ofworking hours on biological functions relatedto cardiovascular system among salesmen ina machinery manufacturing company. IndHealth 1998; 36: 361–367.

16) Nakata, A., Araki, S., Tanigawa, T. et al.:Decrease of suppressor-inducer (CD4�

CD45RA�) T lymphocytes and increase ofserum immunoglobulin G due to perceivedjob stress in Japanese nuclear electric powerplant workers. J Occup Environ Med 2000; 42:143–150.



How to secure the Personnel for Pediatric,and Specifically Neonatal, HealthcareJMAJ 48(2): 99–106, 2005

Masanori FUJIMURA

Director, Osaka Medical Center and Research Institute for Maternal and Child Health

Abstract: It is necessary to understand the value, where the challenges of thejob lie for young pediatricians, and to ascertain what their current concerns andperceived obstacles to future career prospects are. Finding hard-and-fast solutionsto these problems will bring satisfaction to the physicians working in this field, andopen up the prospects for future career development, as well as serving to inducemore physicians to choose to “take on the care of children” as their specialty. Tosecure personnel, it is essential to furnish specific solutions to these issues, andto offer career prospects to physicians considering this branch of medicine. Thefuture system should fulfill the functions outlined below. (1) Promote centralized,function-sharing pediatric practice in the regions. (2) Assign pediatricians workingin a region to a central pediatric department, and have teams of pediatriciansmaintain the general pediatric services available at satellite clinics. (3) Create theconditions to allow personnel to take specialist training in pediatric and/or neonatalcare, and provide clinical training programs for new incumbents at the centralpediatric department and satellite clinics. (4) Develop employment conditionsensuring that doctors who have been on night duty are not required to work thefollowing day. (5) Create the conditions to ensure that female physicians are ableto take maternity leave before and after childbirth as well as leaves of absence forchildcare.

Key words: Pediatric healthcare provision system; Work environment;Female pediatricians; Emergency care for children

The “needs for specialist services for chil-dren” are increasing, with parents seekingdiagnosis and treatment from pediatriciansirrespective of how sick their child is.

This article is a revised English version of a paper originally published inthe Journal of the Japan Medical Association (Vol. 131, No. 10, 2004, pages 1591–1596).The Japanese text is a transcript of a lecture originally aired on March 9, 2004, by the Nihon ShortwaveBroadcasting Co., Ltd., in its regular program “Special Course in Medicine”.

Introduction

Japan is approaching a major turning pointin the field of pediatric healthcare.

�Pediatric Healthcare


What is Preoccupying YoungPediatricians?

Young pediatricians have preoccupations withthe current state of pediatric medical practice.

Looking at current conditions in pediatricmedicine, while recent years have seen reduc-tions in the number of patients suffering fromcertain illnesses, pediatricians are, in fact,confronting greater workloads. This is due toimprovements in the treatment for rare andcomplicated diseases and to increases in de-mand for psychological and primary care ser-vices. At the same time, parent expectations arealso growing in that more and more parents areseeking to have their child examined by physi-cians specializing in pediatric care.

What are working conditions like for pedi-atricians working in emergency care for chil-dren? A 2002 survey of 109 pediatricians in theOsaka area found that physicians were onemergency callout an average of 55 hours permonth, and that emergency duty averaged 8.5times per month, i.e. one weekday night dutyand two full-day holiday shifts. Asked theiropinion on the desirable number of shifts, thephysicians put forward a figure of four timesper month.

In other words, duty obligations are morethan double the desired level, and physiciansare experiencing numerous difficulties. Manypointed specifically to psychological burdens:the impact on their performance the follow-ing day (36%), concerns about their physicalstrength/health (35%), less spare time andfewer days off (16%), and concerns aboutmalpractice (8%). Ninety-seven percent are onroutine duty after working nights or holidays.Asked about how exhausting emergency call-out is, seventy-two percent responded that theywere “at a breaking point” or “extremely tired”(see Fig. 1).

Asked their opinions as to how the pediatricemergency healthcare system could be im-proved, many physicians pointed to the needfor the establishment of an efficient system,

M. FUJIMURA

There is exceptionally high demand forout-of-hours services in the regions, and withpatients congregating at hospitals with pedi-atricians on their rosters, physicians are fastbecoming overworked. In consequence, it isproving difficult to maintain the current systemof out-of-hours services.

Due to increases in the number of femalepediatricians, it is becoming necessary to guar-antee maternity leave before and after child-birth as well as childcare leave, and to establisha new system for maintaining pediatric practice.

Highly-publicized shortages of pediatriciansis a major obstacle to tackling these issues.Without doubt, an increased number of pedi-atricians would make it possible to provideout-of-hours services, allow female physiciansto take maternity leave, and reduce on-callfrequency. However, it would be unwise toattempt to tackle the disruption occurring inpediatric healthcare merely by increasing thenumber of physicians working in the field. Thisis because, as is discussed below, there arelongstanding problems with the system ofestablishing pediatric departments at smallhospitals per se, and in order to meet the expec-tations of young physicians considering enter-ing the field of pediatric medicine and steerthem optimistically down the path of pediatrichealthcare, it is critical that the pediatrichealthcare provision system be reformed.

Coincidentally, in August 2003, Japan’s Min-istry of Health, Labour and Welfare announcedtheir “Vision for reform of the healthcare pro-vision system”. In specific terms, the Ministry’svision stated that (1) a high-quality, efficienthealthcare provision system would be con-structed with separate functions, assigned pri-orities, greater efficiency; (2) manpower wouldbe secured, and the qualifications of medicalpersonnel improved; and (3) the healthcaresystem would be reviewed in the light ofchanges in the external environment. Thesetrends at the national level represent a favor-able opportunity for studying reforms of thepediatric healthcare system.


the increase. The following relates to findingsfrom a survey of twenty-eight pediatric depart-ments at hospitals in the Osaka area. The ratioof female physicians in the 20–40 age bracket is42 percent; this figure reaches 67 percent atsmall facilities employing three physicians orless. In recent years 70 percent of newly-appointed physicians have been women. Asignificant number of female physicians are

REGIONALIZATION OF PEDIATRIC SERVICE

including the setting up of multi-district pri-mary care emergency centers, the separation ofprimary care emergency services for patientswith minor ailments and/or injuries and sec-ondary care emergency services for patientswith comparatively severe ailments and/orinjuries, and the centralization of medical in-stitutions (see Fig. 2).

Numbers of female physicians are also on

Fig 1 Current conditions for pediatricians

Concerns about physical strength/health

Impact on performance the following day

Impact on research/regular duties

Less free time/fewer holidays

35%

20%

16%

16%

8%

98/109 pediatricians are onroutine duty after

emergency callout(90%)

78/109pediatricians are

“at breaking point” or“extremely tired” (72%)

Concerns about malpractice

0 20 30 40 5010 (%)

Difficulties experienced (by pediatricians)

(Funamoto, J.: Osaka Pediatric Emergency Care Providers Association, 2002)

Establishment of multi-district primary care emergency centersSeparation of primary and secondary careCentralization of emergency care facilities

Use of rotational systemEnhancement of nurses and co-medicals

Handling of non-pediatric patientsSystem extending beyond university bounds

Establishment of tertiary emergency care system for pediatric patientsCreation of an environment conducive to female physicians

Emergency center capable of providing primary through tertiary care

(Osaka Pediatric Emergency Care Providers Association, 2002)0 10 155

Fig. 2 Development of pediatric emergency care system


seeking more flexible working conditions inorder to be able to continue pursuing theircareers whilst raising children.

Notwithstanding, it is only medical facilitieswith large pediatric departments that arecapable of reducing the workloads of pregnantfemale physicians and of granting maternityleave. All pediatric wards with sixteen beds or

more allow female physicians to take maternityleave, but because similar measures have notbeen adopted at facilities with twelve beds orless, and such facilities tend to appoint replace-ment physicians, many female physicians arebeing asked to leave. Improving the environ-ment and working conditions for these womenwill make it possible to continue securing sig-

M. FUJIMURA

Table 1 Treatment of Female Physicians According to Numbers of Full-Time Physicians

No. of full-time Reduced hours for Maternity leave Early retirement of Child-care Day-care centerphysicians pregnant physicians possible pregnant physicians leave possible available

1 No No No No Yes

2 Yes Yes No No No

2 Yes No Yes No No

2 No Yes No Yes Yes

2 Yes Yes No Yes No

2 No No No No No

3 No No No No No

3 Yes No Yes No No

3 No No No No Yes

3 Yes No No No No

4 Yes Yes No Yes No

4 No Yes Yes Yes No

5 No No No No No

6 Yes Yes No No Yes

6 Yes Yes No No No

7 Yes Yes No Yes No

7 Yes Yes No Yes No

8 Yes Yes No No Yes

8 Yes Yes No Yes No

9 No Yes No No Yes

9 Yes Yes No Yes Yes

11 Yes Yes No Yes No

12 Yes Yes No No No

(Survey of pediatric departments/physicians at hospitals (in Osaka) 2002, Health, Labour and Welfare Research Institute,Almanac of Data on Japanese Children: “Research on Securing & Developing Young Pediatricians”)


nificant numbers of female physicians. Onepractical solution to this problem is to increasethe scale of pediatric departments (see Table 1).

Pediatricians working at hospitals are doingtheir utmost to ensure that children and theirparents are able to receive the best possiblemedical care at all times, which means that theyare forced to work long hours. However, it isproving extremely difficult to secure youngphysicians, and to continue to provide high-quality pediatric care under a healthcare pro-vision system that poses risks to the health andprivate lives of pediatricians and their families.Pediatricians also want to be able to maintain abalance between work and their personal lives,and if work patterns cannot be improved so asto enable female physicians to continue work-ing whilst raising a family, then the shortages ofpersonnel underpinning the pediatric health-care system will only worsen, which in turncould lead to a vicious cycle where more pedi-atricians become overworked. These circum-stances are not only disadvantageous to pedi-atric physicians, but are also conducive tofalloffs in the quality and content of pediatrichealthcare.

So, what direction should we be aiming in forthe (pediatric) healthcare provision system ofthe future? With favorable working conditionsit is likely that physicians will tackle routineclinical duties willingly, and the development ofpediatric departments in medium-size hospitalsas core pediatric facilities is one means of fur-nishing this type of environment. At the sametime, so as to be able to continue providing thesame level of pediatric care in the regions, itwill also be necessary to restructure the pedi-atric departments of small hospitals so thatthey have a small number of beds, and canconcentrate on providing out-patient care.

Prerequisites to SecuringNeonatal Physicians

I would next like to explore the issue of neo-natal healthcare. The majority of treatment for

low-birth weight (premature) infants and sicknewborns is undertaken in neonatal intensivecare units (NICU). In 2000, the Japanese Neo-natologist Association — a nationwide organi-zation for neonatal specialists — surveyed theworking conditions of 260 physicians employedat ninety-five NICUs covered by social insur-ance for neonatal intensive care.

Their findings reveal that 77 percent haveabsolutely no time off and are required to workon the day after NICU night-duty, 82 percentare on-duty in the NICU at least four timesa month, and 20 percent are on-duty at leasteight times a month. As regards holidaysworked during the past twelve weeks, 48 per-cent worked at least nine Saturdays, 66 percentworked at least six Sundays and/or nationalholidays with 36 percent working nine or more.This fact suggests that many physicians areworking straight through two or three weeksper month. The survey also found that 73 per-cent have less than three days off during theyear-end and New Year holidays. Seventy-three percent used fewer than three days oftheir annual paid leave entitlement, with 67percent doing an average forty hours of over-time per month, and 26 percent doing morethan one hundred hours. These circumstanceshave changed little in the eight years since theprevious survey was conducted.

Asked about their concerns should currentworking conditions persist, 89 percent citedconcerns about their physical wellbeing, and 79percent about their psychological wellbeing. Interms of the conditions necessary to continueworking in neonatal care, “leisure time” toppedthe list, followed by “living to save patientlives” in second place and “prospects for clini-cal learning” in third. This suggests that neo-natal practice is a highly challenging field that istrapped in a vicious cycle where “the job ishighly demanding, leaving little room for freetime” � “young physicians are avoiding neo-natal practice, and mid-career physicians areretiring at around 40” � “shortages of neo-natal doctors”.



A 2000 survey of physicians employed in thepediatric departments of the 1,291 hospitalswith departments of pediatrics, and obstetricsand gynecology nationwide, conducted by theJapan Pediatrics Society, found that just 35 per-cent of NICU have nine beds or more. Of the1,291 hospitals, 208 (16.1%) had five pediatri-cians or more working in their pediatric depart-ments, of which 31 percent were involved inpediatric care and 85 percent in neonatal prac-tice. Of note is the fact that 960 of the 1,291hospitals, or around 70 percent, employ fewerthan four pediatricians.

Vision for Reform of the Pediatric/Neonatal Healthcare Provision System

As evidenced above, Japan’s pediatric care,emergency care, and neonatal care system con-sists of pediatrics departments at small hospi-tals and small-scale NICUs. As a result, a smallnumber of pediatricians are required to be oncall far more frequently than any of their col-leagues working in other departments. Theyare compelled to work holidays, and with moreand more patients seeking specialist pediatriccare, these physicians are struggling to stem theflood of out-of-hours patients. The Japan Pedi-atrics Society has thus compiled a “Vision andaction plan for reform of the pediatric health-care system”, which puts forward the followingthree points.1. Consolidation of the in-patient pediatric

healthcare system as a structural reformtargeting greater efficiency.

2. The development of a system of pediatricemergency care in multi-district serviceareas. Specifically, this will involve: a) allpediatricians in a given region cooperate inproviding out-of-hours care 24 hours a day,365 days of the year, and b) the develop-ment of tertiary emergency care services inthe field of pediatric practice.

3. The realization of working conditions forpediatricians that are in conformity with theLabor Standards Law.

In order to provide a concrete model of this,it will be necessary to establish several sec-ondary care regional pediatrics centers withinexisting pediatrics departments, and to developthem as regional centers of pediatric care.These pediatric centers will handle both pedi-atric emergencies and neonatal intensive care,or should be equipped to provide both func-tions, with existing hospital pediatrics depart-ments positioned as satellite facilities to thepediatric centers. Physicians and medical internswill work on a rotational basis at the pediatricscenters providing routine pediatric care that isbased on out-patient treatment, with physi-cians being on-call for patients with minor ail-ments on a needs-based basis as opposed todoing hospital duty shifts (thereby reducing thenumber of shifts worked). The centers wouldthus need to employ at least ten physicians,which would enable the number of physiciansin general pediatric departments to be scaledback to three. In other words, general pediatri-cians would not be required to handle pediatricemergencies at their own hospitals, but wouldbe on a roster to provide primary emergencycare at their regional pediatric center. If pos-sible, these pediatricians would also replace thephysicians working at the pediatrics centers ona regular basis. This means that the pediatri-cians working at regional hospitals would playa role in providing both services at the centersand in general pediatric clinics (see Fig. 3).

As to pediatric emergencies, nighttime emer-gency clinics should be established with thepediatrics centers as the parent organization sothat the region’s pediatricians can participatejointly in providing out-of-hours (primary care)services for patients with mild ailments, leavingthe pediatrics centers free to handle patientswith severe ailments and/or injuries requiringhospital admission.

In the field of tertiary care, at minimum onecentral pediatrics department should be estab-lished centering on universities and pediatrichospitals; this department would provide ad-vanced pediatric treatment, and would be re-

M. FUJIMURA



Pediatric clinics

PPCC�pediatric primary care center General hospitalpediatrics department

Pediatric clinics

Pediatric hospital departments insparsely-populated areas

Primary & secondaryemergencies

�NICU

Tertiary emergencies

Central hospital

Pediatric center hospital

Doctor rotation

PPCC

PPCC

Centralization of inpatient/emergency cares

Wider emergency/inpatient careStronger links between hospitalsContinuous provision of routine careMore female physiciansConsideration for working conditions

Highly-specialized servicesPerinatal centerPediatric emergency departmentPediatric ICUEmergency transportation

sponsible for educating and training physicians.In order to make this vision a reality, it will

be necessary to construct the following system.1. Promote centralized, function-sharing pedi-

atric practice in the regions.2. Assign physicians working in secondary

medical care to a central pediatric clinic,and have teams of pediatricians maintainthe general pediatric services available atsatellite facilities.

3. Create the conditions to allow personnel totake specialist training in pediatric and/orneonatal care, and provide clinical trainingprograms for new incumbents at centralpediatric clinics and satellite facilities.

4. Develop employment conditions ensuringthat physicians who have been on night dutyare not required to work the following day.

5. Create the conditions to ensure that femalephysicians are able to take maternity leavebefore and after childbirth as well as leavesof absence for childcare.

The board of the Japan Pediatrics Societyhas determined that surveys and present stateanalysis must now be accompanied by concrete

action, and is resolved to be vigorous in push-ing ahead with this plan. However, proactiveefforts on the part of regional pediatricians willbe critical to advancing this plan with steadyefforts so that the reforms conform to actualconditions in individual regions.

At the same time, the following basic condi-tions will need to be installed in order to facili-tate the establishment of this pediatric health-care system.1. The fees for treatment at general pediatrics

departments must be set at a level thatenables the departments to make a profit.

2. The understanding and cooperation of localauthorities and communities must be ob-tained in order to realize regional networksof pediatric emergency care that extendbeyond municipal boundaries.

3. University pediatric departments, which arecurrently involved in human resources issuesin the form of dispatching physicians, needto understand the new pediatric healthcaresystem and to participate proactively in itsdevelopment.

Fig. 3 Model pediatric/emergency care system

(Japan Pediatric Society, 2004)


Conclusion

It is necessary to understand the value andwhere the challenges of the job lie for theyoung pediatricians who are working day inand day out in the care of young patients,and applying themselves diligently to theirresearch. It is also needed to ascertain whattheir current concerns and perceived obstaclesto future career prospects are. Finding hard-

and-fast solutions to these problems will bringsatisfaction to the physicians working in thisfield and open up the prospects for futurecareer development, as well as serving toinduce more physicians to choose to “take onthe care of children” as their specialty. Tosecure personnel it is essential to furnishspecific solutions for these issues, and to offercareer prospects (to physicians considering thisbranch of medicine).

M. FUJIMURA

Documents

CONTENTS · tion, derangement in metabolism of carbo-hydrate and lipid and acanthosis nigricans have * Percentage of overweight (%) [(Actual body weight Standard body weight)/Standard