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Introduction:

Like other cancers, brain tumors could be benign or malignant, primary starting in the brain or secondary, metastasized from elsewhere. The brain tumors also could arise from its outside covering or meninges or from its own brain matter, which consists of grey (neurons) and white (glia cells). Half of the brain tumors are gliomas and about 8% of myelin or nerve sheath, both of white matter, over 20% meningiomas, 15% of Pituitary adenomas and only over 5% from the brain or grey matter tissue. The cause of most brain tumors are yet unknown and the genetic cases such as neurofibromatosis, tuberous sclerosis are very rare (2). This leaves epigenetic factors such as radiation and microbial invasions as the principal causative agents that will be the main focus of this article.

For over a century the medical field has been well aware of infesting cysts throughout the body that anchor in different tissues and organs including the brain, where hydatid cysts have been reported in the brain as primary and secondary target (3-5). Other than hydatid cysts that caused by parasitic tapeworms getting into humans from intermediate hosts (e.g. sheep, goats) and definite hosts (e.g. dogs), other microbial, fungal and viral infections such as tuberculosis and mycosis have been reported as different cysts and cystic tumors in the different parts of the brain since over a half century ago (6-7). Although majority of the microbial brain invasions are limited to the defensive wall (cover) of the brain or meninges or in the viral cases only causing a generalized encephalitis, some aggressive ones rise to create cysts and tumors often malignancies.

In their frontier and heroic study, Schuman, Choi and Gullen showed that the parasitic toxoplasma gondii infection that simply passes to humans from domestic chickens and other fowls could be the causative agents of several brain tumors. Investigating 171 primary central nervous system neoplasms over 18 months period in 1963-1964 from four Minnesota’s hospitals, they traced down the pathogenic routes of several cases of gilomas, acoustic neuromas, neurofibromatosis, mengiomas, pituitary tumors, craniopharyngiomas and miscellaneous brain tumors back to toxoplasmosis infestations (8).    

Finn, Ward and Mattison in 1972 reported previous tuberculosis infection in a quarter of 26 patients with cerebral gliomas (9). This group a year later to replicate their surprised finding, noted previous tuberculosis infection in 21.7% of 92 patients with cerebral gliomas compared with only 7% of 100 controls (10). Such association between previous tuberculosis and cerebral gliomas were replicated later on and in larger samples by others (e.g. 11). Of viral invasion causing brain tumors, Copeland and Bigner in 1977 inoculated an avian sarcoma virus in the brain of rats at different ages and showed 100% causation of brain tumors, with higher such chance at earlier age of inoculation (12). Similar result in rats was published a year later by Roszman, Brooks, Markesbery and Bigner who showed a parallel immunological suppression by the virus between rats and humans (13). Soon other viruses such as Herpes virus were also shown to be causative agents of different brain tumors in animal studies (e.g. 14).

A decade later in 1987, Corallini and colleagues demonstrated the presence of BK virus DNA in 25.6% of human brain tumors of 74 patients and 44.4% in 9 patients with pancreatic islets tumors (15). BK virus that is widespread worldwide except for isolated regions of Brazil, Paraguay, and Malaysia in its primary invasion or infection is mild and unapparent, manifesting generally as mild respiratory or urinary tract infections. During its primary invasion, the virus through blood spreads to several body organs and remains in a dormant state. The reactivation of virus to cause more damages and tumors across different organs occur upon immunological impairment (16-17). While the brain tumors have been reported to be the more common neoplasms caused by this virus (18-21), bone tumors, insulinomas, Hodgkin’s Lymphoma, Kaposic’s Sarcoma and urinary tract tumors have also been reported (e.g. 22-23). Other viruses such as human JC virus and HIV have also been reported causing brain tumors in animal and human studies (e.g. 24-26).

Soon the idea of vaccination therapy for brain tumors such as malignant gliomas started to grow and have an application. Different viral-mediated (Herpes Virus, Rertovirus, Adenoma Virus, and Epstein Barr Virus) gene therapy started to be applied effectively in animal then clinical studies as vaccinations (27-34). In the recent years the gene or vaccination therapy has progressed so that even RNA-binding and other gene proteins instead of viral vectors have been used in the treatment of different brain tumors such as medulloblastomas in children (e.g.35-36). Altogether these gene therapies in the cancer treatment research filed is known as Suicide gene therapy (SGT), as the brain tumor cells are killed and suppressed in growth (37).

Conclusion:

Even our precious brain with its defensive blood-brain barrier that protects our brains from many toxins and invasions, is not immune and exempted from the microbial invasions. From simple and acute brain infections such as meningitis and encephalitis to longer processes of developing tumors in different part and layers of the brain, microbes are the offending agents. From the tinniest viruses such as BK virus with unapparent and mild primary generalized body infection like a flu to the largest such as tapeworms all invade every parts of our being including our precious brain.

 Knowing the microbial invasions underlying brain tumors for almost a century, but calling the cause of these malignancies as idiopathic (unknown) in the official medical textbooks and literature is ignorance. Acknowledging the underlying pathogenesis of brain tumors by microbial invasions holds the vital promise of prevention and early intervention and right treatments. For example monitoring patients with past history of tuberculosis infections, we could identify and save a quarter of them from developing tuberculomas and gliomas. Also identifying and monitoring other viral, bacterial, fungal or even parasitic infections could prevent or early detect development of different brain tumors caused by these insulting agents.

Finally it has been the diligent observations of some medical scientists into the underlying pathogenesis of brain malignancies by microbes that has led to the recent developments of different viral-mediated or RNA- and related protein-mediated vaccines for the treatment of different brain tumors. In fact these novel treatments cleverly have used the microbial invasion strategies at the service of defense and treatment.

Dr.Mostafa Showraki, MD, FRCPC

Lecturer, School of Medicine, University of Toronto

Author: ADHD: Revisited Book, Amazon Kindle Books

www.adhdrevisited.com/www.medicinerevisited.com

Reference:

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3. Dew HR (1928). Hydatid Disease. Surg. Gynec. Obstet. 59, 321.
4. Langmaid C, Rogers L. (1940). Intracranial Hydatids. Brain. 63: 184.
5. Phillips G. Primary cerebral hydatid cysts. J Neurol Neurosurg Psychiatry. 1948;11(1):44–52.
6. Iwata K, Wada T. Mycological studies on the strains isolated from a case of chromoblastomycosis with a metastasis in central nervous system. Jpn J Microbiol. 1957 Oct;1(4):355-60.
7. Dastur HM, Desai AD, Dastur DK. A cystic cerebral tuberculoma treated surgically. J Neurol Neurosurg Psychiatry. 1962 Nov;25:370-3.
8. Schuman LM, Choi NW, Gullen WH. Relationship of central nervous system neoplasms to Toxoplasma gondii infection. Am J Public Health Nations Health. 1967;57(5):848–856.
9. Finn R, Ward DW, Mattison ML. Immune suppression, gliomas, and tuberculosis. Br Med J. 1972;1(5792):111.
10. Ward DW, Mattison ML, Finn R. Association between Previous Tuberculous Infection and Cerebal Glioma. Br Med J. 1973;1(5845):83–84.
11. Macpherson P. Association between previous tuberculous infection and glioma. Br Med J. 1976;2(6044):1112.
12. Copeland DD, Bigner DD. Influence of age at inoculation on avian oncornavirus-induced brain tumor incidence, tumor morphology, and postinoculation survival in F344 rats. Cancer Res. 1977 Jun;37(6):1657-61.
13. Roszman TL, Brooks WH, Markesbery WR, Bigner DD. General immunocompetence of rats bearing avian sarcoma virus-induced intracranial tumors. Cancer Res. 1978 Jan;38(1):74-7.
14. Adler R, Glorioso JC, Cossman J, Levine M. Possible role of Fc receptors on cells infected and transformed by herpesvirus: escape from immune cytolysis. Infect Immun. 1978 Aug;21(2):442-7.
15. Corallini A, et al. Association of BK virus with human brain tumors and tumors of pancreatic islets. . Int J Cancer. 1987 Jan 15; 39(1):60-7.
16. Brown P, Tsai T and Gajdusek DC. (1975). Seroepidemiology of human papovaviruses. Discovery of virgin populations and some unusual patterns of antibody prevalence among remote peoples of the world. Am. J. Epidemiol.,102,331–340.
17. Padgett BL and Walker DL. (1976). New human papovaviruses. Progr. Med. Virol.,22,1–35.
18. Do ̈rries K, Loeber G and Meixenberger J. (1987). Association of polyomaviruses JC, SV40, and BK with human brain tumors. Virology,160,268–270.
19. Martini F, et al. (1996). SV40 early region and large T antigen in human brain tumors, peripheral blood cells, and sperm fluids from healthy individuals. Cancer Res.,56,4820–4825.
20. De Mattei M, et al. (1994). Polyomavirus latency and human tumors.J. Infect. Dis.,169,1175–1176.
21. De Mattei M, et al. (1995). High incidence of BK virus large-T-antigen-coding sequences in normal human tissues and tumors of different histotypes. Int.J. Cancer,61,756–760.
22. Monini P, et al. (1996). Latent BK virus infection and Kaposi’s sarcoma pathogenesis. Int. J. Cancer,66,717–722.
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24. Wold WS, Green M, Mackey JK, Martin JD, Padgett BL, Walker DL. (1980) Integration pattern of human JC virus sequences in two clones of a cell line established from a JC virus-induced hamster brain tumor. J Virol. 33(3):1225-8.
25. Nagashima K, Yasui K, Kimura J, Washizu M, Yamaguchi K, Mori W. (1984). Induction of brain tumors by a newly isolated JC virus (Tokyo-1 strain). Am J Pathol. 116(3):455-63.
26. Gasnault J, Roux FX, Vedrenne C. (1988) Cerebral astrocytoma in association with HIV infection. J Neurol Neurosurg Psychiatry. 1988 Mar;51(3):422-4.
27. Ram Z, Culver KW, Walbridge S, Blaese RM, Oldfield EH. In situ retroviral-mediated gene transfer for the treatment of brain tumors in rats. Cancer Res. 1993 Jan 1;53(1):83-8.
28. Chen SH, Shine HD, Goodman JC, Grossman RG, Woo SL. Gene therapy for brain tumors: regression of experimental gliomas by adenovirus-mediated gene transfer in vivo. Proc Natl Acad Sci U S A. 1994 Apr 12;91(8):3054-7.
29. Kramm CM, et al. (1995). Gene therapy for brain tumors. Brain Pathol. 1995 Oct;5(4):345-81.
30. Wakimoto H, Yoshida Y, Aoyagi M, Hirakawa K, Hamada H. (1997). Efficient retrovirus-mediated cytokine-gene transduction of primary-cultured human glioma cells for tumor vaccination therapy. Jpn J Cancer Res. 88(3):296-305.
31. Rosolen A, et al. (1998). In vitro and in vivo antitumor effects of retrovirus-mediated herpes simplex thymidine kinase gene-transfer in human medulloblastoma. Gene Ther. 5(1):113-20.
32. Timiryasova TM, Li J, Chen B, Chong D, Langridge WH, Gridley DS, Fodor I. (1999). Antitumor effect of vaccinia virus in glioma model. Oncol Res. 11(3):133-44.
33. Benedetti S, et al. (2000). Gene therapy of experimental brain tumors using neural progenitor cells. Nat Med. 6(4):447-50.
34. Izumo T, Ohtsuru A, Tokunaga Y, Namba H, Kaneda Y, Nagata I, Yamashita S. (2007). Epstein-Barr virus-based vector improves the tumor cell killing effect of pituitary tumor in HVJ-liposome-mediated transcriptional targeting suicide gene therapy. Int J Oncol. 31(2):379-87.
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Introduction:

Human’s life as we know, goes through quite distinct stages. But these stages are not as simple as infancy, childhood, adolescence, adulthood and old age as most of us even medical fields recognize. That is why many medical studies including those in neuropsychiatry or neuropsychology plan their studies based on the above commonly known life stages. Even in many instances children including infants are mixed up with adolescents in studies or adults with elderly. As we know for example pediatrics cover the medical care of infancy, childhood and adolescents, while as we will read here with clear evidence by probing into the brain development that any of these stages are quite distinct. Here by probing into the brain development, a new classification and definition of different stages of life is presented that is vital to understand for medical, psychological and behavioural, even medical intervention of diseases and in a near future their preventions.

 Psychological, behavioural and cognitive classification of life stages:

Long time ego, Freud (1) the father of psychology and psychoanalysis divided early stages of life into: 1) Oral stage in the first year of life or infancy; 2) Anal stage in the second year of life; 3) Phallic stage in the 3-5 years of life; 4) Latency stage of 6-11, and 5) sexual stage from 12 to 18 years of age. Due to the sexual nature of his psychology, Freud’s classification of life stages was based on sexual development and the pressure on ego by id and superego and all speculative and not experimental and scientific.

 After Freud, Erik Erickson (2) tried to classify all stages of life from infancy up to old age as: 1) Birth-2 years (Infancy), that he believed the stage of learning Trust; 2) 2-4 years (Toddlers), when the child moves toward Autonomy; 3) 3-5 years (Preschoolers), when the child becomes Initiative; 4) 6-12 years (school age), when the child starts to become Industrious, more aware of themselves as individuals and responsible; 5) 13-19 years (Adolescents), when the teenager starts the process of Identity and role identification and self-confidence; 6) 20-40 (young adulthood), when the young adult enters Intimacy and serious and life long relationships; 7) 40-65 (middle adulthood) when the middle aged adults are at the stage of generativity vs. stagnation; 8) Late adulthood (65-death) when the individual facing integrity or despair. 

Later on Jean Piaget (3) classified the stages of life from a cognitive developmental perspective into: 1) Sensorimotor Stage: Birth-2 years, when the infant perceives the world around only through his senses and discovers the surroundings by his motor movements; 2) Preoperational stage: 2-7 years, when the child masters the language, expressing himself and controls surrounding somewhat by speech without yet having any sense of abstracts, logic and no mental power to operate well enough in the environment; 3) Concrete operational stage: 7-11 years, when the child is more logical, though still in a concrete manner without understating the abstracts; 4) Formal operational stage: 11-18 years, when the teen masters the abstract logic, hypothetical and deductive reasoning. Like Freud, Piaget did not go beyond adolescence and did not cover the cognitive development beyond age 18, even into adulthood.

None of the above classifications of the stages of life that were proposed in the first half of 20th century, based on the different stages of brain development and were strictly observational, though from quite distinct perspectives. The second half of the past century and the advent of neuroimaging and neurochemical studies brought to medical specially the filed of neuroscience, that the brain goes through different stages of development and that would not stop after the stall of the growth of the brain in size by age five. The neuroscientists cruising in the field of the brain development soon discovered not increasing in the number and sizes of neurons, but increasing in the surface of the brain by folding and making the convolutions and gyries, and specification in the development of the brain for different purposes throughout the different stages of life. Here I will present some of these discoveries as we walk through different years of life in an attempt to re-define the stages of life based on the development of the brain.    

The brain development during the fetal stage of life:

Read the full text here:

https://medicinerevisited.com/neurology/probing-brain-development-redefine-different-stages-life/

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Introduction:

Since age 14, when my younger brother in the early morning hours had his first fit of seizure, that shook us by surprise and terror, our family life changed for ever! Every day and every minute we were in anticipation of him having a fit, at the breakfast table in the morning, that happened the most, or during the day in school while we were not present to protect and taking him to medical attention. It took years until the seizure slowed down and came under control after many trials of anti-epileptics. At the time, nobody, even the medical experts knew the cause of a very common and ancient malady of humans. But while I was not yet even in medical school, I knew that during his childhood, he had several falls with head traumas, though I could not put things together and make a sense of the trauma as a common cause of epilepsy, that then was called “idiopathic”, meaning unknown cause!

Epilepsy or seizure that has been recorded as one of the oldest disease of the humans, as far back as 2000 BC in Akkadian records in Mesopotamia, has been affected commons and greats such as Julius Caesar and Alexander the Great. The disease for centuries had been known through ignorance as caused by “possession by evil spirits”, or named the “sacred disease”. First it was Hippocrates, the father of medicine who in the fifth century BC, rejected the idea that the disease was caused by spirits, and proposed that epilepsy was not divine or satanic in origin, but a medically treatable disease of the brain. He also proposed, heredity an important cause, and described worse outcomes if the disease presents at an early age, and instead of referring to it as the sacred disease, he called it the “great disease” giving rise to the modern term “grand mal” used for tonic–clonic seizures. Despite this landmark ancient work of the father of medicine, evil spirits continued to be blamed until at least the 17th century, and inflicted people with epilepsy were stigmatized, shunned, or even imprisoned, or put in asylums side by side with the mentally ills, or the criminally insanes. This was resolved and epilepsy was accepted as a disease of the brain only when in the mid-1800s, the first effective anti-epileptic medication, “bromide” relatively treated some cases. (1)

Read the full text here:

https://medicinerevisited.com/neurology/epilepsy-the-delayed-sequelae-to-early-head-traumas/

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Introduction:

One wonders how many people know “Stephen Hawking”! Is he well known as “Oprah Winfrey”, the late “Prince”, or “Michael Jordan. The last year movie of “The theory of everything” casted by the brilliant actor, Eddie Redmayne and earned him an Oscar, has perhaps introduced more people to the mastermind “Stephen Hawking” whom this article is dedicated.      

 Stephen Hawking, one of a few living genius of our time, is an English theoretical physicist and cosmologist, and the director of Research at the Centre for Theoretical Cosmology at the University of Cambridge. His scientific works include collaboration with Roger Penrose on gravitational singularity theorems in the framework of general relativity, and the theoretical prediction that black holes emit radiation, often called Hawking radiation. Hawking was the first to set forth a theory of cosmology explained by a union of the general theory of relativity and quantum mechanics, so called “The theory of everything”. Hawking has a rare early-onset, slow-progressing form of Amyotrophic Lateral Sclerosis (ALS), commonly known as motor neurone disease, that has gradually paralysed him over the decades. He now communicates using a single cheek muscle attached to a speech-generating device. Hawking has not limited his knowledge to the scientific arena for the experts, but has popularized it by writing easy read books such as “The brief history of time” for the public. (1-8)

 Neuromuscular Disorders:

Neuromuscular disorders encompass a large group of disorders, including ALS, that befell on Stephen Hawking slowly from his final year at Oxford until his formal diagnosis at age 21. These disorders that lead one way or another, to the impairment of the function of different muscles of the body, are caused by either the pathology in the neurons controlling such muscles, or the pathology at the junction of the neurons to the muscles. If just the neurons in the central nervous system are involved, such as in stroke or CVA (cerebrovascular accident), or Parkinson’s disease, they are classified as “upper motor neuron” disorders. If only the neuromuscular junctions are involved, such as spinal muscular atrophies, they are classified as “lower motor neuron” disorders. Some of these disorders such as ALS (Amyotrophic Lateral Sclerosis) are mixed of upper and lower motor neuron disorders. (9-10)

 Read the full text here:

A Tribute to the Mastermind, Stephen Hawking: Neuromuscular Disorders

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https://youtu.be/jvVbgnCiyo0

Dedicated to Dr. Peter Moran, a close friend of mine who’s has just been diagnosed with Parkinson’s disease, but he will fight it.

Introduction

Parkinson’s disease that has affected celebrities such as Muhammad Ali and Michael J Fox even at an early age than usual, was first described in 1817 by the English physician, James Parkinson, who initially called it paralysis agitans. (1) Parkinson described six cases with the disease, having classic symptoms of resting pill rolling tremor, abnormal posture and gait, paralysis and diminished muscle strength, with progression of the disease over time. (2) Later on, other neurologists, most notably Jean-Martin Charcot, the father of modern neurology, in his studies between 1868 and 1881 elaborated further on the understanding of the disease, and made the distinction between rigidity, weakness and bradykinesia, and renamed the disease in the honor of James Parkinson to “Parkinson’s disease” (1) In 1912 Frederic Lewy discovered the “Lewy bodies”, microscopic particles in the brains of these patients and in 1919, Konstantin Tretiakoff, reported that the substantia nigra was the main cerebral structure affected. (1) Levodopa, the main medication treatment for Parkinson’s, that increases the level of dopamine, deficient in the brain of subjects was actually first synthesized in 1911, but was not used in the treatment until 1967.(3)

Over time it was established that Parkinson’s disease is not only a movement disorder, presenting with hand tremors and bradykinesia or slow movement, and rigidity, but it is a progressive brain degenerating disease that ends in the dysfunction of higher cortical functions, leading to depression and dementia as well. This disease is the result of loss of dopamine-generating cells in substantia nigra of midbrain, caused by the accumulation of some proteins called Lewy bodies inside the neurons. (4) But there are many conditions looking like Parkinson’s disease, specially in regard with its movement disorder, that are collectively called “Parkinsonism”. This could be caused by a variety of known and unknown causes, e.g. infections such as AIDS and different encephalitis; toxins e.g. carbon monoxide, carbon disulfide, manganese and mercury; Paraneoplastic syndrome caused by antibodies associated with cancers; drug-induced e.g. antipsychotics and anti-emetics such as metoclopramide; vascular Parkinsonism associated with cardiovascular diseases; and punch drunk syndrome or Boxing Parkinsonism, etc. (5-6)    

Parkinson’s disease is considered to be “idiopathic” in contrast with the secondary parkinsonisms that have known causes, which in fact “idiopathic” due to our lack of knowledge about its real etiology. Genetics has a very minute role in Parkinson’s disease, i.e. 5-10%, surprisingly in contrast with other neurological or psychiatric disorders that may carry multi-genetic or epigenetic mode of inheritance, exhibiting a classical Mendelian type of inheritance. Nowadays, six genes, alpha synuclein, LRRK2, VPS35,Parkin, PINK1 and DJ-1, have definitely been associated with an autosomal dominant or recessive mode of inheritance in familial parkinson’s. (7) Lewy bodies the cardinal patho-histological feature of Parkinson’s disease is in fact an eosinophilic cytoplasmic inclusion aggregation of proteins (primarily alpha-synuclein) that in a highly regulated process, displace the dopamine containing neurons. The mere fact of such regulated killing machinery of the neurons of substantia nigra and other regions of the brain could be common sensibly discerned to have been done by actively programmed invasions of sophisticated organisms, that I will detail in the following.  

Read the full text here:

https://medicinerevisited.com/neurology/from-stomach-to-the-brain-the-evolution-of-parkinsons-disease/

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