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NI FEATURE - COMMENTARY: JOURNEY THROUGH THE EONS
Year : 2017  |  Volume : 65  |  Issue : 5  |  Page : 948-963

Dr. Harry M. Zimmerman (1901 – 1995): Neuropathologist who autopsied Dr. Harvey Cushing, and his interactions with Indian colleagues


1 Department of Neurosurgery, Jaslok Hospital and Research Centre, Dr. G. V. Deshmukh Marg, Mumbai, Maharashtra, India
2 Department of Neuropathology, National Institute of Mental Health and Neurological Sciences, Bengaluru, Karnataka, India

Date of Web Publication6-Sep-2017

Correspondence Address:
Sunil K Pandya
Department of Neurosurgery, Jaslok Hospital and Research Centre, Dr. G. V. Deshmukh Marg, Mumbai - 400 026, Maharashtra
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/neuroindia.NI_730_17

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How to cite this article:
Pandya SK, Shankar S K. Dr. Harry M. Zimmerman (1901 – 1995): Neuropathologist who autopsied Dr. Harvey Cushing, and his interactions with Indian colleagues. Neurol India 2017;65:948-63

How to cite this URL:
Pandya SK, Shankar S K. Dr. Harry M. Zimmerman (1901 – 1995): Neuropathologist who autopsied Dr. Harvey Cushing, and his interactions with Indian colleagues. Neurol India [serial online] 2017 [cited 2019 Sep 17];65:948-63. Available from: http://www.neurologyindia.com/text.asp?2017/65/5/948/214072


Dr. Zimmerman was born in what is now Vilnius, Lithuania to a stonemason. He was brought to the United States in 1909 and grew up in New Haven.

Dr. Zimmerman graduated from Yale University Medical School in 1927 and trained initially under its distinguished professor of pathology, Dr. Milton Winternitz. Dr. Winternitz arranged for him to study neuropathology under Dr. Walter Spielmeyer (1879-1935) at the German Institute of Psychiatric Research in Munich in Germany.

Drs. Milton Winternitz and Walther Spielmeyer

In his interview with Dr. Roy Selby,[1] Dr. Zimmerman provided these details. Dr. Milton Winternitz (1855-1959), Professor of Pathology and Dean of the medical school ‘asked me to linger on in pathology year after year’ till Dr. Zimmerman gave up the idea of doing internal medicine and continued in pathology. Dr. Winternitz had set the course for Dr. Zimmerman whilst he was still a medical student by awarding him prestigious scholarships. After Dr. Zimmerman approached Dr. Blake, chief of internal medicine and was on the verge of getting an appointment in that department, Dr. Winternitz offered Dr. Zimmerman a year-long scholarship to study neuropathology after he had completed his training in pathology at Yale. This was on the condition that he would join the the department in Yale and set up a full-time department of neuropathology. In the 1920s and 1930s, there was no medical school having such a department and Dr. Winternitz thought that Yale would set an example that others would have to follow.

When Dr. Winternitz had looked around to find someone to head this department, he discovered that those who had studied neuropathology abroad had settled into practice as clinical neurologists or psychiatrists, doing part-time neuropathology to augment their incomes. Dr. Zimmerman also gave the example of Dr. Wilder Penfield who had gone to Dr. Cajal's laboratory to learn techniques for staining brain tumours and had returned to the Presbyterian Hospital, College of Physicians and Surgeons to develop what he had learnt. Neurosurgeons wishing to acquire the staining of glia then flocked to the College of Physicians and Surgeons to learn from Dr. Penfield.

As he scouted around America, Dr. Zimmerman found no department in the country that could provide him the training needed to set up a department. Dr. Winternitz gave him a free hand at deciding upon which institution in Europe would be the one most suitable for him. After a hurried survey of facilities available with Dr. Pio Del Rio Hortega (1882-1945) or Dr. Ramon y Santiago Cajal (1852-1934) in Madrid, Dr. Alfons Maria Jakob (1884-1931) in Hamburg, or Dr. Walther Spielmeyer (1879-1935) in Munich, Dr. Zimmerman chose Dr. Spielmeyer and was always happy at this choice. ‘Much of what I have accomplished in neuropathology since, stems from the influence that I received from Spielmeyer.'

Deutsche Forschungsanstalt für Psychiatrie, in which Dr. Spielmeyer headed the department of neuropathology, had been founded by Dr. Emil Kraepelin (1856-1926). Dr. Zimmerman recalled that Dr. Kraepelin believed that the understanding of psychiatry must be based on a study of organic derangements of the nervous system. Towards this end, he got experts in physiology, bacteriology and pathology to work with him. He picked Dr. Spielmeyer to succeed Dr. Franz Nissl (1860-1919) and Dr. Alois Alzheimer (1864-1915) at the department of pathology. (Dr. Nissl was a close friend of Dr. Alzheimer and served as his best man at the latter's wedding in April 1894. His popularization of Quincke's (Dr. Heinrich Quincke 1834-1924) technique of lumbar puncture earned him the nickname, from his students, of punctator maximus.)

Dr. Zimmerman's memories of Munich of the years 1929-1930, when he was there, were happy and he recalled the museums, art galleries, the Bavarian Alps and other places frequented by him with delight. He was witness to the early rumblings of unhappy events to come and the rise of Hitler and the Brownshirts.

On his return, Dr. Zimmerman set up America's first department of neuropathology at his alma mater at Yale. A friendship with Dr. Harvey Cushing and Dr. Arnold Klebs followed. Throughout the 1930s. as an associate professor of pathology, Dr. Zimmerman built a reputation as one of the medical school's most gifted teachers.

Robert McG Thomas, writing on Dr. Zimmerman in The New York Times (31 July 1995) commented: ‘As a dedicated researcher in a highly arcane field measured in microns at the end of a microscope, Dr. Zimmerman had a broader vision. When he looked up from the microscope, there was a twinkle in his eyes that attracted and charmed a range of diverse friends, from Dr. Harvey Cushing, the renowned neurosurgeon who collaborated with Dr. Zimmerman at Yale, to Adm. Chester W. Nimitz, once an aspiring physician.'

Early work at Yale

This was on experimental production of brain tumours in animals, including the effect of a single dose of X-rays in inducing gliomas.

His excellence as a diagnostic neuropathologist was soon recognized. Whenever a medical problem confronted his colleagues in their neurological practice, he dwelt on it to find the root cause and to seek solutions. This resulted in his pursuing varied topics in the broad field of neuropathology.[2],[3],[4],[5],[6]

He also studied the effects of pellagra and beri-beri on the nervous system. This sensitization to the effects of nutritional deficiencies on the nervous system may have been one of the reasons why he recognized the work of the Indian neuropathologist, Dr. Darab K. Dastur. Friendship between the two was followed by Dr. Zimmerman's recognition of Dr. Dastur's landmark publications. Dr. Zimmerman named Dr. Dastur as one of the thirty eminent neuropathologists of the twentieth century. Dr. Dastur was the only Indian to feature in this list.

Dr. Harvey Cushing

Dr. Harvey Cushing, chief of surgery at the Peter Bent Brigham Hospital in Boston, was subject to the mandatory retirement at the age of sixty-three.[7] Dr. John Fulton, professor of physiology at Yale, persuaded him to come to Yale. At Dr. Winternitz's urging, he joined the Yale faculty in 1934 as the Sterling Professor of Neurology. He was offered the position of Professor of Neurosurgery but declined.

Dr. Cushing brought with him his collection of 2000 brain tumors as well as his long-time collaborator, Dr. Louise Eisenhardt. She organized the collection along with Dr. Percival Bailey, and they co-founded the Brain Tumor Registry. Room for them was provided by Dr. Winternitz and Dr. Zimmerman. The fragile, wet specimens were arranged by Dr. Eisenhardt in the Brady Basement of the Pathology Department. Dr. Zimmerman had set up a museum to contain them. In his interview with Dr. Roy Selby, Dr. Zimmerman spoke of this as a valued museum. He was unaware of the location of these specimens after he left Yale but was horrified by Dr. Selby's statement that they may, since, have been discarded.

The space allocated to the museum was later increased by Dr. Harry Green and Dr. Lewis Thomas.

When space was needed in Brady by the Pathology Department, the Cushing brain collection was moved to be basement of Harkness Dormitory, which became the Brain Room. This was a physically inaccessible location. Appalling as it sounds, ‘it was not considered by the Dean to be of any value.’ The Cushing wet collection was irreparably damaged.

Dr. Cushing's painstaking records, and the remaining 600 brains were nearly lost to history after his death in 1939. They were scattered in various obscure basements at the Yale School of Medicine. The brains in their jars were shelved in the basement of a student dormitory. At one stage, the first-year medical students would break into the locked storage room and commune with what they called ‘Cushing's brains.'

Eventually, after much hard work at restoring the specimens, they were moved into the Cushing/Whitney Medical Library.

Dr. Zimmerman's home on Everit Street in New Haven had a contiguous backyard with that of Dr. Cushing's on 691 Whitney Avenue. They spent several evenings together, especially when he invited out-of-town visitors such as Dr. Ernest Sachs (1879-1958) of St. Louis for dinner, or when Dr. Cushing had just acquired a rare book (such as an edition of Vesalius's work) for his collection.

Dr. Zimmerman knew in detail about Dr. Cushing's poor circulation in his toes and the consequent difficulty in walking when he moved to New Haven. The ischemic symptoms in his lower limbs had made their appearance even while he was at Peter Bent Hospital. The earlier symptoms had occurred in 1918, while he was with the Harvard Unit of the Expeditionary Force in France during theFirst World War. When he developed ischaemic problems in his toes and feet, several eminent internists in Boston and in New Haven diagnosed the condition to be Buerger's disease.

Dr. Zimmerman did not know of Dr. Cushing's coronary artery disease. ‘He discussed various illnesses with me but he never complained of angina.'

He once told Dr. Zimmerman, ‘Eventually you may have the opportunity of seeing if I'm right. You will have to look in the postcentral gyrus on the right side. I have some peculiar feelings in the fingers of my left hand. There must be some lesion there.’ Dr. Zimmerman continues: ‘At autopsy, I confirmed his diagnosis. He had a small encephalomalacic plaque in the postcentral gyrus on the left side.'

Dr. Cushing's final illness was in October – during the fall season (3 – 7 October 1939). He complained of severe chest pain and became cyanotic. He was admitted to the hospital and placed in an oxygen tent. He had left word that he wanted a postmortem examination done. He was in the hospital for a short time. Since he had never complained of angina, it surprised Dr. Zimmerman and everyone else at the medical school that Dr. Cushing had a coronary attack. ‘He died of congestive heart failure.'

Dr. Zimmerman was finally able to identify the illness that had resulted in Dr. Cushing's admission to the hospital for three months in France in 1918.

Whilst conceding that Dr. Cushing did have peripheral vascular disease to the extent that the gangrenous left middle toe needed amputation in 1935, Dr. Reich (1987) termed Dr. Zimmerman's conclusion of an ischemic cause for Dr. Cushing's symptoms in the lower limbs erroneous. He postulated Guillain Barré syndrome instead.[8]

Guam and the Indian Colleagues

During World War Two, within days of the Allied invasion, Dr. Zimmerman served in Guam in the Pacific as a neuropathologist on the U. S. Naval Medical Research Unit. Dr. Thomas Milton Rivers (1888-1962), the eminent virologist to be, was the Commanding Officer of the unit. (Dr. Rivers eventually rose to the rank of Rear Admiral).

On Dr. Rivers' return to America, Dr. Zimmerman was appointed commanding officer. During his stay, over two years in Guam, Dr. Zimmerman shared his tent with the eminent virologist, Dr. Albert Sabin. They studied individuals with encephalitis. Dr. Zimmerman extracted brain tissue from a patient who had died from the disease. Dr. Sabin used this tissue to prepare a crude vaccine. This presaged Dr. Sabin's later work on poliomyelitis. The first complete autopsy report on Japanese encephalitis emerged from this research unit.

Amyotrophic lateral sclerosis (ALS) and Parkinson's disease were noted in the Chamorros, who are the indigenous peoples of the Mariana Islands. Their total population was estimated to be composed of 28,000 individuals. Many autopsies were carried out on the diseased native people. In six months, Dr. Zimmerman had autopsied twelve patients with ALS. This finding was transmitted to the authorities in Washington. Amazingly, this was stamped SECRET and filed away! [A reference to this incident is as follows: Zimmerman, Lt. Cmdr. H.M. (1 June 1945). “Progress Report of Work in the Laboratory of Pathology During May 1945” (Letter). Letter to Medical Officer in Command]. Lytico-bodig disease was discovered in 1945 by Dr. Zimmerman and subsequently reported by physicians of the US Navy and Public Health Service. Scientists noted a 50- to 100-fold greater occurrence of amyotrophic lateral sclerosis than the rest of the world, and a notable increase in  Parkinsonism More Details with dementia associated with it. By 1940, this elusive disease was the primary cause of death in adult Chamorros. Dr. Zimmerman pointed out that the Parkinson's disease encountered in Guam was not of arteriosclerotic origin but probably followed a viral infection.

Later, a team confirmed this high incidence and asked Dr. Zimmerman to give up his job at Montefiore and go back to Guam. As this was not possible, Dr. Zimmerman sent Dr. Asao Hirano instead. Over 18 months, Dr. Hirano also found patients with a combination of ALS, Parkinson's disease and Alzheimer's disease. He brought several brains back with him to America. His study resulted in a paper that has gained much attention. A review was also published by him in 1992.[9]

Dr. Arumugasamy, a senior pathologist from Chennai, South India was part of the team describing the pathological features in cases of ALS in Guam. (Dr. Arumugasamy, later became the Director of Institute of Pathology at Chennai. He was the husband of the neuropathologist, Professor Sarasa Bharati). In their publication, Drs. Hirano, Arumugasamy and Zimmerman (1967) showed how their ‘detailed epidemiological, clinical, and pathological studies confirmed the fact that the condition prevalent in Guam fulfilled the classical criteria of ALS.' However, three major unusual features were noted in these studies: (1) An extraordinarily high incidence, often with familial aggregation, (2) the development, in some instances, of clinical evidence of dementia and extrapyramidal symptomatology, and (3) the presence of histological changes characteristic of the Parkinsonism-dementia complex (PD), another endemic fatal neurological disease affecting the Chamorros in Guam. These features were not previously recognized among classical ALS cases. In addition, two clinical features which are not notable among classical ALS cases were discovered as a result of several investigations: (1) the frequent occurrence of ALS among young as well as middle-aged individuals, and (2) the existence of a sizable number of patients with unusually long clinical courses.

During the period that Dr. Zimmerman was in Guam, Dr. Carleton Gajdusek was also there along with his colleagues. With his usual tenacity, Dr. Gajdusek ensured that some of the brains collected in Guam were shifted to his laboratory at the National Institutes of Health (NIH). Dr. Gadjusek, Dr. Clarence J. Gibbs and others also studied Chamarro Indians with an unusual form of dementia with Parkinsonian features and upper motor neuron changes. This syndrome was later named the Parkinsonism-dementia complex of Guam.

One of us (SKS) had the the privilege to study the spinal cord of these cases at the NIH (1985-87). Subsequently, the role played by aluminum, silicon, low serum calcium levels and dietary supplementation of cycad was studied on a primate model.[10] The etiology of ALS remained hypothetical invoking toxic viral, environmental, and dietary factors, but was not confirmed. However, the pathology has been described which is rather non-specific and indicative of a chronic neurodegenerative disease (similar to Alzheimer's disease - a topic difficult to comprehend during those days as well as in the recent times). The Gaumanian ALS and PD does not appear to have a genetic basis, unlike idiopathic ALS – PD, where nearly 10% of cases have a genetic basis in the evolution.[11]

SKS met Dr. Hirano when he visited NIMHANS and exchanged notes on neuropathological subjects of mutual interest.

Dr. Subimal Roy trained in neuropathology with Dr. Zimmerman.[12],[13],[14],[15] Dr. Roy later headed the neuropathology department at the All India Institute of Medical Sciences, New Delhi and, in turn, was a teacher to one of us (SKS). Other Indians who worked with Dr. Zimmerman included Dr. Nithya Ghatak[16],[17],[18],[19],[20],[21],[22],[23],[24],[25],[26],[27],[28] and Dr. Sarasa Bharati.

Whilst with Dr. Zimmerman, Dr. Sarasa Bharati studied the pathomorphological features following the administration of chemical carcinogen, nitrosourea, to rodents; and, also described ‘virus like’ particles in the nuclei of malignant glioma cells. However, no viral association was confirmed.

Albert Einstein College of Medicine

Mr. Henry Moses, the President of Montefiore Hospital, New York), a 100-year old private hospital affiliated to Columbia University), a good friend of Dr. Thomas Rivers, needed someone to head the department of pathology. At Dr. Rivers' recommendation, Mr. Moses approached Dr. Zimmerman, who had returned from Guam and was then living in New Haven.[29]

Dr. H. Houston Merritt and Dr. Leo Davidoff persuaded him to accept the post of Director of Laboratories at Montefiore Hospital and Professor of Pathology at the Columbia College of Physicians and Surgeons.

Robert Thomas (1995) provides a fascinating account of the creation of a medical college to be attached to this hospital:[30] ‘In the early 1950's, when Yeshiva University decided to open a medical college, Dr. Zimmerman was named its first Director, partly because of the renown he had gained at Montefiore. This led to his persuading Dr. Albert Einstein to allow the university to name the college after him.

'Dr. Einstein, insisting that it would be more appropriate to name the hospital after a medical luminary, was adamant, rejecting all arguments to the contrary, until Dr. Zimmerman, turning up the twinkle, pretended to give in, even, as he later told it, “suggesting the name of an important but relatively little-known medical scientist.”

"Who is this person?” Dr. Einstein asked.

"You know, Professor,” Dr. Zimmerman replied, “no one would ever ask me, ‘Who is Dr. Einstein?’ “

'Dr. Zimmerman got his victory, but Dr. Einstein had the last laugh. “Tell me,” he said to Dr. Zimmerman, “are you a doctor or a lawyer?"

From 1950 to 1952, he served as the first director of the Albert Einstein Medical College, where he became a friend of the school's legendary namesake.

Dr. Zimmerman missed his work as a teacher, however, and returned to his former position at Montefiore and Columbia.

He rejoined the Albert Einstein faculty in 1964, when the school and Montefiore merged. He remained active at Montefiore/Albert Einstein as a Professor Emeritus and research scientist.

For having trained 77 neuropathologists in Japan, Dr. Zimmerman was awarded the Order of Sacred Treasure in 1973. Presented by the emperor, the order is the highest honour bestowed upon a foreigner.

Dr. Zimmerman and Einstein's brain

As Dr. Thomas Harvey's teacher, Dr. Zimmerman played a small role in the study of Dr. Einstein's brain. Dr. Harvey performed the autopsy on Dr. Einstein that showed the ruptured abdominal aorta that had caused death. Seizing the opportunity, Dr. Harvey preserved Dr. Einstein's brain.

Twelve sets of microscopic slides were painstakingly indexed to tissue blocks containing specific parts of Dr. Einstein's brain. They were sent to senior neuropathologists, including Dr. Zimmerman (Appendix 1).[Additional file 1]

We have no direct report from Dr. Zimmerman but Dr. Frederick Lepore reported ‘Dr. Zimmerman's assurance that Dr. Einstein's brain was normal for his age.'[31],[32]

Dr. Robert Terry, who retired as Professor Emeritus, Neuropathology, University of California at San Diego, in his letter to the editor, stated:[30],[31] ‘I was an assistant pathologist at Montefiore Hospital under Dr. Harry M. Zimmerman in charge of the day-to-day running of the Neuropathology section. One morning, Dr. Zimmerman called me into his office to tell me that Dr. Albert Einstein had died at Princeton Hospital. The pathologist at Princeton Hospital, Dr. Thomas Harvey, had gone to Yale Medical School and had, therefore, studied pathology and neuropathology under Dr. Zimmerman. Dr. Harvey called Dr. Zimmerman and asked him to study the Einstein specimen, since he did not feel adequate to the task. The whole Pathology Department, especially Neuropathology, at Montefiore Hospital became quite excited about the prospect of studying Dr. Einstein's brain. In addition, there were many calls from reporters. Shortly after, Dr. Harvey told Dr. Zimmerman that Princeton Hospital administrators would not allow the specimen to be transferred because of the loss of prestige.[32] The next thing I heard about the specimen was in the Dr. Diamond's paper many years later in Experimental Neurology.[33] She and her technician had obtained some tissue from Dr. Harvey, sectioned it, and stained it with luxol fast blue.[33] They believed that this stain differentiated between glia and neurons, but it does not. In normal aging, large neurons shrink. Consequently, Dr. Diamond counted these as glia and reported that Albert Einstein's genius was the result of having many more glia than normal. Unfortunately, it is not that simple.’ (https://www.einstein.yu.edu/uploadedFiles/EJBM/19terry79.pdf).[30],[31],[34]

Summing up

As a renowned teacher to generations of neuropathologists, who bloomed under his tutelage, Dr. Zimmerman took active interest in the education of future physicians, evolving the curriculum and the philosophy of medical education.[35],[36],[37] Like Dr. Darab Dastur, he also studied and published on the fine structure of viral inclusions in rabies and on neurotuberculosis. Pathology of cryptococcosis, ultrastructure of cerebral vessels, cerebral malformations and myelin pathology in the brain following hydrodynamic perturbations in cerebrospinal fluid, pathoanatomy of multiple sclerosis based on 70 autopsies, are some of the other seminal studies carried out by him in close association with Professor Asao Hirano, a Japanese neuropathologist in the same medical school.

Professor Zimmerman's mentoring of pathologists from many countries seeded his philosophy and expertise far and wide. He provided insights into the broad field of neuropathology, unlike the focused and tunnelled vision of present day neuropathologists pursuing a narrow field of interest.

With digitization and the development of new automated techniques, the classical neuropathology based on careful histological studies is dwindling. Professor Harry Zimmerman remains a leading light of the old order in this new and transformed world to remind us of the invaluable scientific studies that were conducted using a binocular microscope and classical histological slides.

Death

'Dr. Zimmerman liked weekend visits to his country home in beautiful Harwinton, Connecticut, where he enjoyed driving and fixing his tractor. He loved tending his garden.'

'Dr. Zimmerman once said to Mr. Okuno that whenever his father was asked his age he always replied that he was 104 years old. Dr. Zimmerman too lived a long life, dying at 93.'

'Dr. Zimmerman retained his lucidity until the last moment of his life. One day, he repeatedly asked, ‘It's July 28th today, isn't it?’ He had his fingernails cut and wished to shave, wash up, and brush his hair. It was the day of his death. As Dr. Toyokura said, he was like an old-time Japanese warrior taking to the field. He lived his life nobly and single-mindedly like a warrior. He will live forever in our hearts and minds.'[38]

He died of cancer of the colon at the age of 93, on July 28, 1995 in Montefiore Hospital.[36],[37],[38]

 
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Selby R. Harry Zimmerman M.D. interviewed by Roy C. Selby M.D. Available from: https://www.youtube.com/watch?v=pJxJHFp0yz8 and t=51s. [Last released on 2012 Feb 01].  Back to cited text no. 1
    
2.
Hirano A, Zimmerman HM. Alzheimer's neurofibrillary changes: A topographic study. Arch Neurol 1962;7:227-42.  Back to cited text no. 2
    
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Hirano A, Arumugasamy N, Zimmerman HM. Amyotrophic lateral sclerosis. A comparison of Guam and classic cases. Arch Neurol 1967;16:357-63.  Back to cited text no. 3
    
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Hirano A, Malamud N, Kurland LT, Zimmerman HM. A review of the pathologic findings in amyotrophic lateral sclerosis. In: Editors: F. H. Norris, Jr., L. T. Kurland. Motor Neuron Diseases: Research on Amyotrophic Lateral Sclerosis and Related Disorders (Contemporary Neurology Symposia, Vol. II. New York: Grune and Stratton 1968, pp. 51-60.  Back to cited text no. 4
    
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Hirano A, Ghatak NR, Wisoff HS, Zimmerman HM. An epithelial cyst of the spinal cord. An electron microscopic study. Acta Neuropathol 1971;18:214-23.  Back to cited text no. 5
    
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Shankar SK, Yanagihara R, Garruto RM, Grundke-Iqbal I, Kosik KS, Gajdusek DC. Immunocytochemical characterization of neurofibrillary tangles in amyotrophic lateral sclerosis and parkinsonsonism-dementia of Guam. Ann Neurol 1989; 25:145-51.  Back to cited text no. 11
    
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17.
Hirano A, Ghatak NR, Becker NH, Zimmerman HM. A comparison of the fine structure of small blood vessels in intracranial and retroperitoneal malignant lymphomas. Acta Neuropathol 1974;27:93-104.  Back to cited text no. 17
    
18.
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19.
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20.
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24.
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25.
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26.
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27.
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28.
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