Dr. Hideyo Noguchi and University of Ghana Medical School

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In November 9, 1987, I visited Korle Bu Teaching Hospital.
University of Ghana Medical Scool, P.O. Box 4236, Accra, Ghana.

------------- sorry,  photos are missing

I surveyed the consultation rooms, wards, theater(operating room) of the 
Hospital. There were poor lighting in operation room, and damaged windows 
of wards. I saw childs with Malaria(Plasmodium falciparum), PCM(Protein-
Calorie-Malnutrition) and meningitis due to Tuberculosis.

Dr. Emmanuel Qvaye Archampong(Dean of Medical school) said

----------- Every year, around 60~70 in medicine and 6~10 in dentisty were 

graduated Ghana University and several docters went to England for study

abroad ----- but few, 5% came back to Ghana ------- .

2)  Noguchi Memorial Institute of Medical Research:

It was founded in 1979 by the aid of the Japanese government. When I visited

4 Japanese were there. One was Dr. Nakano from the department of Pediatrics,

Mie University. I handed over the drugs such as antibiotics, anti-cold medicine

, anti-diarrhea for children and ointments.

Nowadays, The institute is managed by Ghana.

                    see →　http://www.noguchimedres.org/
----------------------------------------------------------------------------------------------------------------
※Note : Hideyo Noguchi ( 野口 英世1876 – 1928):
In 1913, at the Rockefeller Institute of Medical Research, he demonstrated the presence
of Treponema pallidum (syphilitic spirochete) in the patient's brain of a progressive paralysis
, proving that the spirochete was the cause of the disease.

Dr. Noguchi's name is remembered in the binomial attached to another spirochete,
Leptospira noguchii. In 1928, Noguchi traveled to Africa to confirm his findings.
The purpose of this field work was to test the hypothesis that yellow fever was caused by
spirochaete bacteria instead of a virus. While working in Accra, he died from yellow fever
on May 21, 1928.
---------------------------------------------------------------------------------------------------------------
※Later studies showed that Yellow fever is caused by yellow fever virus.
To enter Ghana, Liberia and Guinea, required the certification of yellow fever vaccine.

Dr. Kanehiro Takaki and vitamin B1 deficiency

Japanese rice: right is the polished rice(Bran, outer layer of rice,

which contain vitamin B1, E , are removed)

~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~

Kanehiro Takaki（高木兼寛 in Japanese） and beriberi

~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~

1)  Below are excepts from the book "Arthur Kornberg: For the love of

enzymes. The odyssey of a biochemist. Harvard University Press. 1991."

~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~

Japanese naval records of deaths from beriberi

-----------------------------------------------------------------------------

Year               Diet               Total navy            Deaths from

                                             personnel                beriberi

-----------------------------------------------------------------------------

1880(M13)     Rice diet          4,956-------------1,725

1881(M14)----Rice diet          4,641-------------1,165

1882(M15)----Rice diet          4,769-------------1,929

1883(M16)  -  Rice diet          5,346                     -1,236

1884(M17) Change to new diet  5,638                  718

1885(M18)----New diet--------6,918                        41

1886(M19)     New diet--------8,475                          3

1887(M20)     New diet--------9,106                          0

1888(M21)     New diet          9,184                          0

------------------------------------------------------------------------------

One hundred year ago, epidemics of beriberi(vitamine B1, or thiamine deficiency)

were destroying the Japanese navy. More than half of a crew, after a few weeks at

sea, would become weak, listless, and paralyzed and would succumb to profound

weight loss, liver disease, and heart failure.

Barely twenty-five years after Perry's visit, Japan had replaced Samurai swordsmen

with a navy that would soon challenge one of the mightiest of the West.  But unlike

Western sailors, the Japanese were peculiarly vulnerable to beriberi despite the best

hygiene and the finest rice money could buy; the kernels, having been separated

from the ugly husks, were polished free of the protective silvery skins consumed

by the population at home.

It struck one K. Takaki, a ship doctor, that the Japanese had copied every detail of

British naval equipment and operations excepts for rations, and so he designed this

crucial experiment: the crew of 300 of one vessel on a long cruise was fed the

polished rice diet, while the crew of another was given the unappetizing fare of

British seaman: oatmeal, vegetables, fish, meat, and condensed milk.

Of those fed with rice, two-thirds contracted beriberi; the sailors fed the strange

British diet all remained hale and hearty. The dramatic effects of changing to a new

ration are preserved in Japanese naval records(see Table). Although Dr.Takaki could

not explain the causal relationship between diet and beriberi, to knowledgeable

microbiologists in Japan and Europe these was only one interpretation: the polished

rice rations must have been infected.

~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~

2)  Dr. Takagi's effort of diet change was resulted in the dramatic decrease of
----vitamin B1 deficiency in Navy .  In Russo-Japanese war(1904-1905), Japanese 
----navy completely defeated the Russian Bultic Fleet in the Battle of Tsushima(Sea 
----of Japan Naval Battle).

----But not the diet change in Army were done. At that times,  medical community 
----, especially, doctors in Army believed that a bacteria is the cause of disease.  
----In fact, researchers of Tokyo Imperial college of Medicine insisted that we
--- found the beriberi's bacteria.


----During the Japanese Army Campaigns in Manchuria, China,  so many soldier were------
----suffering from Beriberi.  The vitamin B1 deficiency killed more soldiers than that
----of fighting itself.

3) Dr. Takagi also founded Ji-Kei University School of Medicine and nursing school
----at Tokyo. He studied the Medicine at St Thomas' Hospital in London and learned 
-    the pragmatic approach to the disease.


Any questions: write to Keiji Hagiwara, MD
----------------------------Kami-Ube Pediatric Clinic,
----------------------------1-20-2 Tokiwadai, Ube 755-0097, Japan
--------------------------- keijihagiwara@gmail.com

Dr. Arthur Kornberg's comment on Penicillin

Dr. Arthur Kornberg and his family ---- from the book "For the love 

of enzymes: The odyssey of a Biochemist. Harvard University Press. 

1991.

Dr. Arthur Kornberg (1918-2007, who received the Nobel Prize

 of Physiology or Medicine in1959 and first done the chemical 

synthesis of a infectious phage, a virus of bacteria in 1967) wrote 

about penicillin.

---------------------------------------------------------------------------------

  Penicillin and other antibiotics are the most dramatic 

therapeutic advance in medicine in my lifetime. When I was a 

student and intern before the advent of antibiotics, the 

treatment of lobar pneumonia was discouraging ineffective. 

One out of four patients died. Subacute bacterial endocarditis 

was invariably fatal. Rheumatic fever and acute nephritis 

were prevent.        

Many people know that antibiotic therapy was not discovered 

at bedsides nor even in a clinical pharmacology laboratory. 

Bullrings in Spain have a statures of Alexander Fleming, 

who in 1929 noticed the inhibition of bacterial growth around 

penicillin mold contaminated his Petri plate.        

The apotheosis of Fleming gored bullfighters is exaggerated 

because the practical use of the penicillin mold was not 

discovered by Fleming. It took Ernst Chain, a biochemist, 

and Howard Florey, a pathologist, to apply this knowledge 

ten years later to isolate penicillin and demonstrated its 

clinical utility.        

   There is much more to the penicillin story than that. 

Basic inquiries and findings essential to Fleming's discovery 

started at least fifty years earlier. Fleming would never have 

made his observation without the agar Petri plate. But, more 

important, he would never have understood what he saw on 

the plate were it not for the firm foundations of bacteriology 

and immunology.       

One might assume that Chain and Florey undertook the 

isolation of penicillin because of its possible clinical potential. 

Not at all. With the encouragement of Florey, Chain started 

his research on penicillin only because he was curious about 

the dissolution of bacterial walls by enzymes such as lysozyme. 

He thought penicillin was an enzyme too and wanted to 

understand the mechanism of its action. He surprised to find 

that penicillin was a molecule small enough to pass readily 

through the pores of a dialysis membrane which stopped 

passage of molecules as large as enzymes. 

Penicillin was not enzyme at all. This discovery immediately 

presented the possibility that penicillin, as a low-molecular-

weight compound, could be administered as a drug to animals. 

With the technique of freeze-drying, which had just become 

available, Chain was able to concentrate and preserve 

penicillin and then to prove its therapeutic efficacy.       

  Why were Chain and Florey so quickly to test their very 

crude penicillin preparations for clinical efficacy?  Their 

prompt decision was likely conditioned by the discovery in 

the mid-1930s that sulfonamides inhibit microbes and yet are 

not toxic to animals. 

Thus, an agent could selectively interrupt growth of microbes 

without affecting the animal host, and this observation gave 

Chain and Florey the confidence to test their penicillin prepa-

rations in infected mice.       

It may also explain why Fleming, ten years earlier, believing 

that only the host immune system could combat infections, 

regarded chemotherapy as implausible and so failed to test 

his crude penicillin preparations for therapeutic value. 

I choose penicillin as an example of the importance of basic 

research because its history is so recent and dramatic.   

---------------------------------------------------------------------

Arthur Kornberg: For the love of enzymes: The Odyssey of a 

Biochemist. Harvard University Press. 1991.

Any questions:  write to Keiji Hagiwara, MD

                                      keijihagiwara@gmail.com

My publications

----------------------------------------------------------------------------------------------

Grants:

1) 1981. a grant-In-Aid for Scientific Research for the Ministry

of Education, Science & Culture of Japan

(Study on protein synthesis of Molar Trophoblasts)

2) 1984. a grant-In-Aid from MORINAGA MILK Co. LTD.

(Study on action of IgA protease from intestinal bacteria on secretory IgA)

3) 1985. a grant-In-Aid from Naito Memorial Medical Foundation with

Kobayashi K. (A separation procedure of parental secretory IgA by a lectin

and development of a method for elimination of IgA in human gamma-

globulin)

4) 1986. a grant-In-Aid from MORINAGA MILK Co. LTD.

with Kobayashi K. (Studies of anti-protease activity of pathogenic

bacterias present in human sIgA and serum IgA, IgG)

5) 1987. a grant-In-Aid from MORINAGA MILK Co. LTD.

(Biological roles of IgA protease-neutralizing antibody in mucosal defences)

6) 1989. a grant-In-Aid for Scientific Research for the Ministry of Education,

Science & Culture of Japan.

(Anti-bacterial antibody activity of IgA subclass in normal subjects)

→ http://kaken.nii.ac.jp/en/p/63570440/1989/6/en

7) 1990. a grant-In-Aid from Research Project for Adverse Effect of

Immunizations , the Ministry of Health & Welfare of Japan.

(A survey of acute neurological diseases in childhood in Yamaguchi

Prefecture)

8) 1991. a grant-In-Aid from Research Project for Adverse Effect of

Immunizations , the Ministry of Health & Welfare of Japan.

(A follow-up study of varicella's vaccinees in healthy children)

9) 1992. a grant-In-Aid from Research Project for Adverse Effect of

Immunizations, the Ministry of Health &Welfare of Japan.

(A follow-up study of varicella's vaccinees in healthy children).

(A survey of familial transmission of whooping cough in Yamaguchi

Prefecture) .

(A survey of mother's knowledge of Measles and Measles Vaccine)

10) 1997-8. a grant-In-Aid for Scientific Research for the Ministry of

Education, Science & Culture of Japan.

(Study on rapid diagnosis of sepsis in childhood by PCR method)

平成９年度−10年度　文部省科学研究（一般研究C，５００万)

　研究課題：敗血症の迅速診断に関する研究.

　研究代表者：萩原啓二

　分担者：山口医療技術短期大学部（塚原正人，山城安啓）

→ http://kaken.nii.ac.jp/en/r/50127776

------------------------------------------------------------------------------------------

Publications:

Omit the Japanese publication.

(Journal)

1) Monozygotic twins discordant for Rubinstein-Taybi syndrome.

(Kajii T, Hagiwara K, Tsukahara M, Nakajima H, Fukuda Y)

J. Med. Genet. 18 :312- 314. 1981.

2) Dispermic origin of XY hydatidiform moles.

(Ohama K, kajii T, Okamoto E, Fukuda Y, Imaizumi K, Tsukahara M,

Kobayashi K, Hagiwara K,)

Nature 292 : 551- 552. 1981.(Aug)

3) Esterase D polymorphism in hydatidiform mole.

(Hagiwara K, Kobayashi K, Kajii T)

Jpn. J. Hum. Genet. 27(2)180,1982.

4) Pfeiffer syndrome or Saethre-Chotzen syndrome?

(Tsukahara M, Hagiwara K, Kajii T)

Jpn. J. Hum.Genet. 30 :51- 56, 1985.(June)

5) J chain -like component in 18-S immunoglobulin of the skate,

Raja kenojei, a cartilaginous fish.

(Hagiwara K, Kobayashi K, Kajii T, Tomonaga S)

Molec. Immunol. 22 :775- 778, 1985.(July)

6) Isolation and characterization of immunoglobulin of hagfish,

Eptatretus burgeri, a primitive vertebrae.

(Kobayashi K, Tomonaga S, Hagiwara K)

Molec. Immunol. 22 : 1091- 1097, 1985.(Sep)

7) Studies of immunoglobulin and immunoglobulin-forming cells in

Heterodontus japonics, a cartilaginous fish.

(Tomonaga S, Kobayashi K, Hagiwara K, Sasaki K, Sezaki K)

Devel. Comparat .Immunol. 9 : 617- 626, 1985.

8) Purification and characterization of esterase D1 and D2 from human

erythrocytes: Evidence that they are monomers.

( Matsuo K, Kobayashi K, Hagiwara K, Kajii T)

Eur. J. Biochem. 153 : 217-222, 1985.

9) Double precipitin arcs of IgA myeloma sera on immuno-electrophoresis:

Origin and suggestion of IgA2,2m(2) allotype.

(Kobayashi K, Hagiwara K, Vaerman J-P, Kajii T)

Immunol. Invest. 14 :455- 468, 1985.

10) Serum proteins in vesicular fluid of hydatidiform moles: A lack of

selectivity of molar trophoblast in the transfer of maternal serum proteins.

(Hagiwara K, Kobayashi K, Kajii T)

Placenta 7 :199- 297, 1986

11) Gut-associated lymphoid tissue in Elasmobranchs.

(Tomonaga S, Kobayashi K, Hagiwara K, Yamaguchi K,Awaya K)

Zool. Sci. 3 :453- 458, 1986.

12) Jacalin, a jackfruit lectin, precipitate IgA1 but not IgA2 subclass on

gel diffusion reaction.

(Kondoh H, Kobayashi K, Hagiwara K, Kajii T)

J. Immunological Methods 88 :171- 173, 1986

13) Complexes of albumin and a1-antitrypsin with Fc fragment of IgA

monomer are disulfide bond to penultimate C-terminal cysteine in

the Ca3 domain.

(Vaerman J-P, Hagiwara K, Kobayashi K, Rits M)

Immunol. Letters 15: 67- 72, 1987.

14) Normal serum IgA as well as secretory IgA is resistance to most

bacterial IgA protease: Evidence for the presence of enzyme-neutralizing

antibodies in both serum and secretory IgA, and also in serum IgG

(Kobayashi K, Fujiyama Y, Hagiwara K, Kondoh H)

Microbiol.Immunol. 31 : 1097- 1106, 1987.

15) A simple procedure for the isolation of human secretory IgA of IgA1

and IgA2 subclassby a jackfruit lectin, Jacalin, affinity column.

(Kondoh H, Kobayashi K, Hagiwara K)

Molec.Immunol. 24 :1219- 1222. 1987

16) Immunoglobulins of primitive vertebraes.

(Kobayashi K, Tomonaga S, Hagiwara K)

Dev. Comp. Immunol. 12:414- 415, 1988.

17) Jacalin: isolation, characterization and influence of various factors

on its interaction with human IgA1, as assessed by precipitation and

latex agglutination.

(Hagiwara K, Collet-Cassart D, Kobayashi K, Vaerman J-P)

Molec. Immunol. 25 : 69- 83, 1988

18) Jacalin: Chaos in its immunoglobulin-binding specificity.

(Kobayashi K, Kondoh H, Hagiwara K, Vaerman J-P)

Molec. Immunol. 25 :1037- 1038, 1988.

19) Structural and functional variability of Jacalin.

(Pineu N, Aucouturier P, Preud'homme JL, Hagiwara K, Kobayashi K)

Molec. Immunol. 28:185- 187, 1991.

20) Involvement of the white matter in the initial stage of herpes

simplex encephalitis.

(Ichiyama T, Hayashi T, Yamaguchi E, Tanaka H, Hagiwara K)

Pediatric Radiology 22 :145, 1992

21) Isolation of human herpes virus 6 in an infant with Kawasaki

disease.

(Hagiwara K, Komura H, Kishi F, Kajii T, Yoshida T)

Eur. J. Pediatr. 151: 867- 868, 1992.

22) Terai I, Kobayashi K, Fujita T, Hagiwara K: Human serum

mannose binding protein (MBP): Development of an enzyme-linked

Immunosorbent assay(ELISA) and determination of levels in

serum from 1085 normal Japanese and in some body fluids.

Biochemical Medicine and Metabolic Biology 50:111-119, 1993.

23) Hagiwara K, Ouchi K, Tashiro N, Azuma M, Kobayashi K;

An epidemic of a pertussis-like illness caused by Chlamydia

pneumoniae.

The Pediatric Infectious Disease Journal 18:271-275. 1999.

(Books)

1) Separation of human sIgA1 and sIgA2 by affinity chromatography

on the jackfruit lectin, Jacalin.

(Kobayashi K, Hagiwara K, Kondh H, Vaerman J-P) .

In Recent Advances in Mucosal Immunology.

Ed. Mestecky J., McGhee JR. Bienenstock J. & Ogra PL

Plenum Publishing Corporation: New York pp1193-97. 1987.

2) IgA protease from Clostridium Ramosum that cleaves IgA1 and IgA2,

2m(1): The site of cleavageand digestion of secretory IgA.

(Kobayashi k, Fujiyama Y, Hagiwara K, Hodohara K,Hosoda S)

In Recent Advances in Mucosal Immunology. Ed. Mestecky J.,

McGhee JR.,Bienenstock J. & Ogra PL.

Plenum Publishing Corporation: New York pp1289-1296. 1987.

3) Application of the quantitative latex agglutination assay to study

glycoprotein-lectin interaction.

(Hagiwara K, Collet-Cassart D, Vaerman J-P, Masson PL)

In, Lectins: Biology, Biochemistry, Clinical Biochemistry.

Vol. 6: 505- 511. Sigma Chem Co., St Louis, Missouri, U.S.A.1988.

4) A worldwide survey of IgA1-binding lectin, Jacalin, a lectin from

genus Artocarpus.

(Hagiwara K, Kobayashi K)

In, Tsuchiya M et al eds. Frontier of Mucosal Immunology

Vol.1.pp205-208. Elsevier Science Publishers B.V. Amsterdam, 1991.

(Proceedings)

Immunoglobulin of the Hagfish: Molecular structure and evolution.

(Kobayashi K, Tomonaga S, Hagiwara K)In Uyeno T, Arai R, Taniguchi T,

Matsuura K, eds.Proceedings of the Second International Conference on

Indo-Pacific Fishes.The Ichthyological Society of Japan. pp922. 1986.

-------------------------------------------------------------

Grants:

1) 1981. a grant-In-Aid for Scientific Research for the Ministry

of Education, Science & Culture of Japan

(Study on protein synthesis of Molar Trophoblasts)

2) 1984. a grant-In-Aid from MORINAGA MILK Co. LTD.

(Study on action of IgA protease from intestinal bacteria on secretory IgA)

3) 1985. a grant-In-Aid from Naito Memorial Medical Foundation with

Kobayashi K. (A separation procedure of parental secretory IgA by a lectin

and development of a method for elimination of IgA in human gamma-

globulin)

4) 1986. a grant-In-Aid from MORINAGA MILK Co. LTD.

with Kobayashi K. (Studies of anti-protease activity of pathogenic

bacterias present in human sIgA and serum IgA, IgG)

5) 1987. a grant-In-Aid from MORINAGA MILK Co. LTD.

(Biological roles of IgA protease-neutralizing antibody in mucosal defences)

6) 1989. a grant-In-Aid for Scientific Research for the Ministry of Education,

Science & Culture of Japan.

(Anti-bacterial antibody activity of IgA subclass in normal subjects)

→ http://kaken.nii.ac.jp/en/p/63570440/1989/6/en

7) 1990. a grant-In-Aid from Research Project for Adverse Effect of

Immunizations , the Ministry of Health & Welfare of Japan.

(A survey of acute neurological diseases in childhood in Yamaguchi

Prefecture)

8) 1991. a grant-In-Aid from Research Project for Adverse Effect of

Immunizations , the Ministry of Health & Welfare of Japan.

(A follow-up study of varicella's vaccinees in healthy children)

9) 1992. a grant-In-Aid from Research Project for Adverse Effect of

Immunizations, the Ministry of Health &Welfare of Japan.

(A follow-up study of varicella's vaccinees in healthy children).

(A survey of familial transmission of whooping cough in Yamaguchi

Prefecture) .

(A survey of mother's knowledge of Measles and Measles Vaccine)

10) 1997-8. a grant-In-Aid for Scientific Research for the Ministry of

Education, Science & Culture of Japan.

(Study on rapid diagnosis of sepsis in childhood by PCR method)

平成９年度−10年度　文部省科学研究（一般研究C，５００万)

　研究課題：敗血症の迅速診断に関する研究.

　研究代表者：萩原啓二

　分担者：山口医療技術短期大学部（塚原正人，山城安啓）

→ http://kaken.nii.ac.jp/en/r/50127776

------------------------------------------------------------------------------------------