Lectures on auto-intoxication in disease, or, Self-poisoning of the individual

Lectures on auto-intoxication in disease, or, Self-poisoning of the individual

Digitized by the Internet Archive in 2011 with funding from Open Knowledge Commons and Harvard Medical School http://www.archive.org/details/lecturesonautoinOObouc

LECTURES ON Auto-Intoxication in Disease OR SELF-POISONING OF THE INDIVIDUAL BY CHARLES BOUCHARD

Professor or Pathology and Therapeutics; Member or the Academy of Medicine, and Physician to the Hospitals, Paris

Translated, with a Preface and New Chapters added

THOMAS OLIVER, M.A., M.D., F.R.C.P.

Professor of Physiology, Uniyersity of Durham; Physician to the Royal Infirmary, New castle-hpon-Tyne ; Formerly Examiner in Medicine, Royal College or Physicians, London

SECOND REVISED EDITION

Philadelphia – F. A. DAVIS COMPANY, PUBLISHERS 1906

COPYRIGHT, 1894 BY THE F. A. DAVIS COMPANY COPYRIGHT, NOVEMBER, 1905

BY F. A. DAVIS COMPANY [Registered at Stationers’ Hall, London, Eng.]

Philadelphia, Pa., U. S. A.

The Medical Bulletin Printing House 1914-16 Cherry Street Continue reading Lectures on auto-intoxication in disease, or, Self-poisoning of the individual

Our Daily Bread

Our Daily Bread

~Content Source

In the northern Italian town of Ferrara hangs a little-known painting by Giuseppe Mentessi (1857-1931). Surrounded by a field of maize, a woman carries her exhausted child in her arms, her eyes downcast with suffering. Behind this painting lies a story of medicine, food, economics, and culture – the story of pellagra, perhaps one of the greatest tragedies of malnutrition known to the Western world.

Exhibited at the Venice Biennale in 1895, Mentessi’s image of a cornfield depicts what once was a common sight throughout the region. Maize or corn was first domesticated as a cereal crop in the Americas, making its way to Europe via traders in the sixteenth century. This new foodstuff proved to be a lifeline for Italian agricultural workers who labored under the pressures of wheat shortages and insecure employment. With its low cost and high yield, cornmeal or polenta was quickly established as the staple food of the poor. Landowners were eager to profit from maize production, and eventually forests, vineyards and pastures across the Veneto and Lombardy were replaced by fields of this single crop. It was fitting that Mentessi named his picture “Our Daily Bread” – for by the 1800s, northern Italian peasants were living on a diet made up almost exclusively of corn.

At the same time, increasing numbers of them were falling victims to a new disease. Characterised by a flaking rash on the sun-exposed skin of the arms and neck, they named it pellagra (from pelle agra, loosely translated as “rough skin”).  Symptoms included confusion, mania, lethargy, and eventual death. While the link between pellagra and maize dependence was quickly recognized by scientists at the time, the mechanism remained a mystery. Today, we know that pellagra is a disease of severe niacin (vitamin B3 or nicotinic acid) deficiency. Niacin is the precursor of two essential coenzymes of cellular activity – nicotinamide adenine dinucleotide (NAD) and NAD-phosphate (NADP) – both involved in DNA repair, cell signalling, and metabolism. Tissues with high energy requirements and high cell turnover are particularly vulnerable to their deficiency. Without sufficient dietary niacin – or tryptophan, the amino acid used in its biosynthesis – a systemic disease occurs affecting the skin, gastrointestinal tract, and nervous system. The resulting clinical features have been famously described as the 4 D’s: dermatitis, diarrhea, dementia, and death.

The unvarying cornmeal diet that poor Italians relied on in the lean winter months, without the addition of vegetables, dairy products, or meat, was severely deficient in both niacin and tryptophan.  An epidemic of pellagra resulted, with thousands of deaths attributed to the illness – particularly in women, who had increased nutritional needs because of pregnancy and breastfeeding, and whose inferior social position meant that they tended to have less food then the men in their family. So common did the neuropsychiatric effects of the illness become, that mental asylums such as Venice’s San Servolo and San Clemente were full of victims of what was then termed “pellagrous insanity.” For almost two centuries, pellagra was endemic in the agricultural lands of the Po valley across northern Italy.

It was this widespread suffering which Giuseppe Mentessi sought to depict in his painting. Born into poverty in Ferrara, Mentessi went on to have a successful career as an art teacher and professor at the Accademia di Brera in Milan. Nevertheless, his work maintained a deep affinity with his humble origins and he often used his art to highlight the social issues of the day. In “Our Daily Bread,” he shows the misery of the Italian rural poor, with the woman’s sickly countenance a mark of the effects of pellagra. What he depicted in paint, the writer Goethe described in words in his ‘Italian Journey:’ “Of the (Italian) inhabitants, I have little to say and that unfavourable … (the) sallow complexion of the women spoke of misery and their children looked just as pitiful …  I believe that their unhealthy condition is due to their constant diet of yellow polenta …”

It was not the diet of cornmeal alone which gave rise to pellagra in southern Europe, but also the method of preparation. While maize had been a staple food of central America for thousands of years, the indigenous peoples were accustomed to soaking the dried corn kernels in alkaline lye or quicklime before cooking. This process, known as “nixtamalization,” increased the bioavailability of bound niacin in the corn by converting it into the water-soluble free compound, allowing it to be absorbed by the gut. As a result of their traditional cultural methods of preparation, the native people of the Americas did not suffer from pellagra.

When corn was brought across the Atlantic to Europe, the tradition was lost. Furthermore, pellagra was then introduced to the Americas, where European colonizers grew and ate corn without realizing the benefit of nixtamalization or the importance of a varied diet. Particularly in the Southern states, in the economic downturn following the American Civil War, the daily fare for poor people consisted almost entirely of corn-based products such as cornbread and grits. Rural sharecroppers and populations lacking access to fresh produce – in prisons, coal-mining camps, and cotton-mill towns – were particularly vulnerable to niacin deficiency. The devastation occurred on a grand scale; across the United States from 1906 to 1940 approximately 3 million cases and 100,000 deaths were attributed to pellagra.

It was a US public health physician, Joseph Goldberger, who determined that pellagra was a nutritional deficiency and not (as was commonly supposed) an infectious epidemic. In 1915, he carried out a series of experiments in Mississippi prisoners which demonstrated that symptoms of pellagra appeared after six months of eating only corn-based foods; when fresh, varied produce was introduced, the illness resolved. He concluded that “no pellagra develops in those who consume a mixed, well-balanced diet,” yet struggled to convince the political establishment that poor social conditions might be responsible for the disease. It took several more decades of research – including the isolation of niacin itself from liver tissue by Conrad Elvehjem in 1937 – before federal recommendations to fortify flour supplies with vitamins led to the eradication of the condition in the United States by 1945.

In Italy, economic growth helped end the pellagra epidemic during the 1950s, but not before the illness had provoked widespread debate about the impact of social injustice and deprivation on human health, with commentators such as Flarer (1849) referring to pellagra as “malattia del padrone” – “illness due to the landlord.” Today, we understand more than ever the impact of socio-economic factors on our health, with recognition that the West’s adoption of a highly-processed, energy-dense diet has contributed to our modern epidemics of obesity and diabetes. Such “malnutrition in the midst of plenty” has echoes of Mentessi’s work. It is said that he had the idea for his painting when he was taking an afternoon walk through a field of corn and was struck by the contrast between the bountiful crop and the sickly peasant woman with her child: “misery, perhaps hunger, in the middle of that insolent and healthy wealth!” In both Europe and the United States, it is still the poorest sections of society who suffer the most from their dependence on an abundance of cheap calories. While it may have been largely forgotten, the story of pellagra ought to be a lasting lesson in how social structures, globalization, and economic change once conspired to cause thousands of deaths from an entirely preventable disease.


References

  1. Mariani-Costantini R, Mariani-Costantini A. An outline of the history of pellagra in Italy. J Anthropol Sci. 2007;85:163-171
  2. Ginnaio M. Pellagra in Late Nineteenth Century Italy: Effects of a Deficiency Disease. Popul (english Ed.) 2011.
  3. Gentilcore D. Peasants & Pellagra in 19th-century Italy. Hist Today. 2014
  4. Hegyi J, Schwartz RA, Hegyi V. Pellagra: Dermatitis, dementia, and diarrhea. International Journal of Dermatology. 2004.
  5. Gallery of Modern Art of Ferrara. http://artemoderna.comune.fe.it/index.php?id=1872. Accessed June 22, 2018.
  6. Goethe JW. Italian Journey [1786-1788].; 1970.
  7. Lanska D. Historical aspects of the major neurological vitamin deficiency disorders: the water-soluble B vitamins. Handb Clin Neurol. 2009.
  8. Bollet AJ. Politics and pellagra: The epidemic of pellagra in the U.S. in the early twentieth century. Yale J Biol Med. 1992.
  9. Elmore JG, Feinstein AR. Joseph Goldberger: An unsung hero of American clinical epidemiology. Ann Intern Med. 1994.
  10. Toffanello M. Giuseppe Mentessi. Opere nelle collezioni del Museo dell’Ottocento di Ferrara. 1999.

MEERA LADWA, MBBS, BSc qualified in medicine in 2008 and works as a clinical research fellow in London. Her interests include diabetes and metabolism, particularly the impact of the environment on human health and physiology. Currently, she is studying for a PhD in diabetes and nutritional sciences.

Skin Microbiota: A Source of Disease or Defense?

I believe the correct answer would be yes. As in yes to both options…8-/

This review will summarize current information on bacterial skin flora including StaphylococcusCorynebacteriumPropioni-bacterium, Streptococcus and Pseudomonas. Specifically, the review will discuss our current understanding of the cutaneous microbiota as well as shifting paradigms in the interpretation of the roles microbes play in skin health and disease.

Through an analysis of the limited current literature, we highlight a new hypothesis that suggests skin microbes directly benefit the host and only rarely exhibit pathogenicity. In this model, the delicate balance of the skin barrier and innate immunity combine to maintain healthy skin, and disturbance of this balance can predispose the host to a number of cutaneous infectious and inflammatory conditions.

Unlike the intestine, the role of microbes on the skin surface has not been well studied. An incomplete understanding of the fundamental biology of cutaneous microflora is the result of the limited research efforts to date…In light of symbiotic relationships of microbial mutualism and commensalism demonstrated as critical to human health in studies of gut microbiota, a need exists to expand this research in skin.

PDF Doc- Skin microbiota- a source of disease or defense or defense?

Microbial Relations

Facial Wriggles and Filarial Dance Signs

I certainly wasn’t ready for this fun one. Just another GREAT reason to watch my P’s & Q’s.


Filariasis Brugia MalayiImage Credit – CDC – Biology – Life Cycle of Brugia malayi

The typical vector for Brugia malayi filariasis are mosquito species from the genera Mansonia and Aedes. During a blood meal, an infected mosquito introduces third-stage filarial larvae onto the skin of the human host, where they penetrate into the bite wound.


Filarial dance sign in breast lump – PDF – Filarial Dance Sign in Breast Lump


Facial wrigglies: live extralymphatic filarial infestation in subcutaneous tissues of the head and neck

PDF – Facial wrigglies: live extralymphatic filarial infestation in subcutaneous tissues of the head and neck


Simply Younger

Some of you are aware that I have been fighting a long battle back to health. What I originally thought was an allergy to gluten back in 2012 ended up being a form of lymphoma. Accurate diagnosis didn’t happen till November 2018. My stubborn self and dislike of anything hospital was partially at play but also cutaneous t-cell lymphoma is one that goes misdiagnosed for some time with most. I was lucky enough to be informed by someone I was giving a ride to who had been diagnosed with the same thing and in treatment for many years before we met.
To add lucky duck icing on top of that good news I was fortunate enough to have a friend of the family that is an oncologist who’s specialty is lymphoma and leukemia. What luck to say the least.
Now here is the interesting twist. I had been through diet, supplementation and Dr. Google been addressing what I thought was something systemic but by no means did I really think that I had cancer. I had my primary Dr. do all of my blood tests to make sure that everything internal that I couldn’t see was functioning properly and continued on my path to recovery. I still am not sure I agree with the diagnosis but I have accepted it and respect it, however I reserve my right to remain a skeptic. Have I made all of the right decisions for treatment along the way? I don’t know. We will see.
Back to the diagnosis and oncologist. Though he recommended that I have further tests done, I chose not to. Many of the neoplasia(tumors) had already resolved or reduced in size significantly. In other words my immune system was doing its job and my skin was fixing itself and expressing all of the diseased tissues gradually over time. REEEEEALLY GROSS. On the other hand, no nasty scarring. Just a prolonged recovery and a lot of self care.
Cutaneous T-Cell Lymphoma which was originally called Mycosis fungoides was first described in 1806 by French dermatologist Jean-Louis-Marc Alibert. The name mycosis fungoides is very misleading—it loosely means “mushroom-like fungal disease”. The disease, however, is not a fungal infection but rather a type of non-Hodgkin’s lymphoma. It was so named because Alibert described the skin tumors of a severe case as having a mushroom-like appearance. Which is exactly why I had no clue that it was cancer. I frankly thought I was just a sick ass dirty bird that drank way too much and ended up with a really bad fungal infection that was paying the piper.
All this to say…I identify with Legion…LoL. I swear this guy had the same thing as me. Him and Job. Too much fun.
Now if I could just figure out how to write a book. How to publish. Because I have an amazing story to tell about my recovery from a disease I didn’t know I had. And how my recovery and principles learned in A.A. helped my mentally remain strong through my return to health.
I also want to help people. I want to help people not have to go through what I did. And here is why…
When all this started back in September of 2017 I made some drastic lifestyle changes and dedicated myself to learning how to optimize health and existence. Along the way I have explored many different diet trends and tried many a different thing eventually arriving where I am at today almost fully recovered.
I still have a little ways to go, but I expect that the full recovery process will take about 42 months or 3.5 years. I’ve been documenting some of it at https://3.5tolife.com
And the best part is my body looks and feels significantly younger and I don’t think it is anything magic that I have done. Just followed some basic ideas and rules.
What if cancer, dementia, diabetes and cardio vascular issues were all simply the process of aging taking its course? I imagine that would mean that all we have to do is figure out what it means to be simply younger and go there.
That is my starting point…Simply Younger

Cytokines, Inflammation and Pain

Darned microbial litterbugs…8)

LINK: For charts and complete context

PDF: cytokines-inflammation-and-pain


ABSTRACT

Cytokines are small secreted proteins released by cells have a specific effect on the interactions and communications between cells. Cytokine is a general name; other names include lymphokine (cytokines made by lymphocytes), monokine (cytokines made by monocytes), chemokine (cytokines with chemotactic activities), and interleukin (cytokines made by one leukocyte and acting on other leukocytes). Cytokines may act on the cells that secrete them (autocrine action), on nearby cells (paracrine action), or in some instances on distant cells (endocrine action). There are both pro-inflammatory cytokines and anti-inflammatory cytokines. There is significant evidence showing that certain cytokines/chemokines are involved in not only the initiation but also the persistence of pathologic pain by directly activating nociceptive sensory neurons. Certain inflammatory cytokines are also involved in nerve-injury/inflammation-induced central sensitization, and are related to the development of contralateral hyperalgesia/allodynia. The discussion presented in this chapter describes several key pro-inflammatory cytokines/chemokines and anti-inflammatory cytokines, their relation with pathological pain in animals and human patients, and possible underlying mechanisms.

Keywords: cytokine, inflammation, pain, hyperalgesia

  1. INTRODUCTION

Inflammatory responses in the peripheral and central nervous systems play key roles in the development and persistence of many pathological pain states []. Certain inflammatory cytokines in spinal cord, dorsal root ganglion (DRG), injured nerve or skin are known to be associated with pain behaviors and with the generation of abnormal spontaneous activity from injured nerve fibers or compressed/inflamed DRG neurons.

Cytokines are small secreted proteins released by cells have a specific effect on the interactions and communications between cells. Cytokine is a general name; other names include lymphokine (cytokines made by lymphocytes), monokine (cytokines made by monocytes), chemokine (cytokines with chemotactic activities), and interleukin (cytokines made by one leukocyte and acting on other leukocytes). Cytokines may act on the cells that secrete them (autocrine action), on nearby cells (paracrine action), or in some instances on distant cells (endocrine action).

It is common for different cell types to secrete the same cytokine or for a single cytokine to act on several different cell types (pleiotropy). Cytokines are redundant in their activity, meaning similar functions can be stimulated by different cytokines. They are often produced in a cascade, as one cytokine stimulates its target cells to make additional cytokines. Cytokines can also act synergistically or antagonistically.

Cytokines are made by many cell populations, but the predominant producers are helper T cells (Th) and macrophages. Cytokines may be produced in and by peripheral nerve tissue during physiological and pathological processes by resident and recruited macrophages, mast cells, endothelial cells, and Schwann cells. Following a peripheral nerve injury, macrophages and Schwann cells that gather around the injured site of the nerve secrete cytokines and specific growth factors required for nerve regeneration. Localized inflammatory irritation of the dorsal root ganglion (DRG) not only increases pro-inflammatory cytokines but also decreases anti-inflammatory cytokines []. Cytokines can also be synthesized and released from the herniated nucleus pulposus, synthesized inside the spinal cord [], the DRG soma [], or the inflamed skin []. Furthermore, cytokines may be transported in a retrograde fashion from the periphery, via axonal or non-axonal mechanisms, to the DRG and dorsal horn, where they can have profound effects on neuronal activity [] and therefore contribute to the etiology of various pathological pain states.


2. Cytokines and Pain

PRO-INFLAMMITORY CYTOKINES

Proinflammatory cytokines are produced predominantly by activated macrophages and are involved in the up-regulation of inflammatory reactions. There is abundant evidence that certain pro-inflammatory cytokines such as IL-1β, IL-6, and TNF-α are involved in the process of pathological pain.

IL-1β is released primarily by monocytes and macrophages as well as by nonimmune cells, such as fibroblasts and endothelial cells, during cell injury, infection, invasion, and inflammation. Very recently, it was found that IL-1β is expressed in nociceptive DRG neurons []. IL-1β expression is enhanced following crush injury to peripheral nerve and after trauma in microglia and astrocytes in the central nervous system (CNS) []. IL-1β can produce hyperalgesia following either intraperitoneal, intracerebroventricular or intraplantar injection []. Moreover, IL-1β was found to increase the production of substance P and prostaglandin E2 (PGE2) in a number of neuronal and glial cells []. IL-1ra, a specific IL-1 receptor antagonist, competitively binds to the same receptor as IL-1β but does not transduce a cellular signal, thereby blocking IL-1β-mediated cellular changes. Administrations of IL-1ra and other anti-inflammatory cytokines have been demonstrated to prevent or attenuate cytokine-mediated inflammatory hyperalgesia [] and nerve-injury induced mechanical allodynia [].

IL-6 has been shown to play a central role in the neuronal reaction to nerve injury. Suppression of IL-6R by in vivo application of anti-IL-6R antibodies led to reduced regenerative effects []. IL-6 is also involved in microglial and astrocytic activation as well as in regulation of neuronal neuropeptides expression []. There is evidence that IL-6 contributes to the development of neuropathic pain behavior following a peripheral nerve injury []. For example, sciatic cryoneurolysis, a sympathetically-independent model of neuropathic pain involving repeatedly freezing and thawing a section of the sciatic nerve, results in increased IL-6 immunoreactivity in the spinal cord []. In addition, intrathecal infusion of IL-6 induces tactile allodynia and thermal hyperalgesia in intact and nerve-injured rats, respectively.

TNF-α, also known as cachectin, is another inflammatory cytokine that plays a well-established, key role in some pain models. TNF acts on several different signaling pathways through two cell surface receptors, TNFR1 and TNFR2 to regulate apoptotic pathways, NF-kB activation of inflammation, and activate stress-activated protein kinases (SAPKs). TNF-α receptors are present in both neurons and glia []. TNF-α has been shown to play important roles in both inflammatory and neuropathic hyperalgesia. Intraplantar injection of complete Freund’s adjuvant in adult rats resulted in significant elevation in the levels of TNF-α, IL-1β, and nerve growth factor (NGF) in the inflamed paw. A single injection of anti-TNF-α antiserum before the CFA significantly delayed the onset of the resultant inflammatory hyperalgesia and reduced IL-1β but not NGF levels []. Intraplantar injection of TNF-α also produces mechanical [] and thermal hyperalgesia []. It has been found that TNF-α injected into nerves induces Wallerian degeneration [] and generates the transient display of behaviors and endoneurial pathologies found in experimentally painful nerve injury []. TNF binding protein (TNF-BP), an inhibitor of TNF, is a soluble form of a transmembrane TNF-receptor. When TNF-BP is administered systemically, the hyperalgesia normally observed after lipopolysaccharide (LPS) administration is completely eliminated []. Intrathecal administration of a combination of TNF-BP and IL-1 antagonist attenuated mechanical allodynia in rats with L5 spinal nerve transection [].

CHEMOKINES

A variety of cytokines are known to induce chemotaxis. One particular subgroup of structurally related cytokines is known as chemokines. The term chemotactic cytokines (CHEMOtactic CytoKINES) usually refers to this. These factors represent a family of low molecular weight secreted proteins that primarily function in the activation and migration of leukocytes although some of them also possess a variety of other functions. Chemokines have conserved cysteine residues that allow them to be assigned to four groups: C-C chemokines (RANTES, monocyte chemoattractant protein or MCP-1, monocyte inflammatory protein or MIP-1α, and MIP-1β), C-X-C chemokines (IL-8 also called growth related oncogene or GRO/KC), C chemokines (lymphotactin), and CXXXC chemokines (fractalkine).

Various chemokines including MIP-1α, MCP-1 and GRO/KC are up-regulated not only in models of neuroinflammatory [] and demylinating diseases, but also in various forms of CNS trauma [] and in injured peripheral nerve []. Receptors for MCP-1, MIP-1α and GRO/KC are expressed on DRG neurons []. Interestingly, mice lacking the CCR2 receptor completely fail to develop mechanical allodynia in the partial sciatic injury model although pain sensitivity in uninjured animals is normal. In the same study, normal mice showed a sustained upregulation of the receptors in both DRG and peripheral nerve after the injury []. This suggests that the chemokines, including MCP-1 in particular, play very key roles in neuropathic pain as well as in neuroinflammatory conditions.

ANTI-INFLAMMATORY CYTOKINES

The anti-inflammatory cytokines are a series of immunoregulatory molecules that control the pro-inflammatory cytokine response. Cytokines act in concert with specific cytokine inhibitors and soluble cytokine receptors to regulate the human immune response. Their physiologic role in inflammation and pathologic role in systemic inflammatory states are increasingly recognized. Major anti-inflammatory cytokines include interleukin (IL)-1 receptor antagonist, IL-4, IL-10, IL-11, and IL-13. Leukemia inhibitory factor, interferon-alpha, IL-6, and transforming growth factor (TGF)-β are categorized as either anti-inflammatory or pro-inflammatory cytokines, under various circumstances. Specific cytokine receptors for IL-1, TNF-α, and IL-18 also function as inhibitors for pro-inflammatory cytokines.

Among all the anti-inflammatory cytokines, IL-10 is a cytokine with potent anti-inflammatory properties, repressing the expression of inflammatory cytokines such as TNF-α, IL-6 and IL-1 by activated macrophages. In addition, IL-10 can up-regulate endogenous anti-cytokines and down-regulate pro-inflammatory cytokine receptors. Thus, it can counter-regulate production and function of pro-inflammatory cytokines at multiple levels. Acute administration of IL-10 protein has been well-documented to suppress the development of spinally-mediated pain facilitation in diverse animal models such as peripheral neuritis, spinal cord excitotoxic injury, and peripheral nerve injury []. Blocking spinal IL-10, on the other hand, has been found to prevent and even reverse established neuropathic pain behaviors []. Recent clinical studies also indicate that low blood levels of IL-10 and another anti-inflammatory cytokine, IL-4, could be key to chronic pain since low concentrations of these two cytokines were found in patients with chronic widespread pain [].

The family of TGF-β comprises 5 different isoforms (TGF-β1 to -β5). TGF-β1 is found in meninges, choroid plexus, and peripheral ganglia and nerves []. It is known that TGF-β suppresses cytokine production by inhibiting macrophage and Th1 cell activity; counteracts IL-1, IL-2, IL-6, and TNF; and induces IL-1ra 6 []. Its mRNA is induced following axotomy and may be involved in a negative-feedback loop to limit the extent of glial activation []. TGF-β1 also antagonizes nitric oxide production in macrophages []. Nitric oxide has been strongly implicated in the final common pathway of neuropathic pain []. It is expected that by its anti-cytokine action, TGF-β1 or agents that induce its activity may be effective therapy for neuropathic pain.

GLIAL ACTIVATION IN CNS AND PNS


In the CNS, there are two types of glial cells, microglia and astrocytes, which can be activated by excitatory neurotransmitters released from nearby neurons. These neurotransmitters include EAA, SP, PGEs, adenosine triphosphate (ATP), and nitric oxide. A novel neuron to glia signal is fractalkine, a protein expressed on the extracellular surface of neurons []. Fractalkine is tethered to the neuronal membrane by a mucin stalk. When the neuron is sufficiently activated, the stalk breaks, releasing fractalkine into the extracellular fluid. As immunocompetent cells, activated glia release several key pro-inflammatory cytokines, including TNF-α, IL-1β, and IL-6 [].

It has been well demonstrated that spinal glial activation is necessary for induction of the neuropathic pain state []. Spinal administration of glial activator, fractalkine, induces cutaneous hyperalgesia, whereas spinal administration of a fractalkine receptor antagonist blocks neuropathic pain []. Furthermore, blocking the activation of spinal cord glia with the inhibitor fluorocitrate blocks the pathological pain state in rats with peripheral sciatic nerve neuritis []. Recently, it was found that administration of a new glia-specific inhibitor, minocycline, blocked the development of neuropathic pain. Minocycline, a lipid-soluble tetracycline derivative with anti-inflammatory effects, inhibits an IL-1β-converting enzyme and inducible nitric oxide synthesis up-regulation. Minocycline also prevents glial cell proliferation and inhibits the activation of p38 MAPK [].

Non-neuronal cells in the peripheral nervous system also react to nerve injury. In addition to hematogenous macrophage infiltration, the satellite glia that surround the somata of sensory neurons proliferate [], elaborate processes [], and become immunoreactive for glial fibrillary acidic protein (GFAP) [].


4. MECHANISMS UNDERLYING CYTOKINES- MEDIATED PATHALOGICAL PAIN

There is evidence that pro-inflammatory cytokines (e.g., IL-1β, TNF-α) [] and chemokines (e.g., MCP-1) [] may directly modulate neuronal activity in various classes of neurons in the peripheral and central nervous system. In the peripheral nervous system, abnormal spontaneous activity can be evoked from nociceptive neurons by topical application of TNF-α to the peripheral axons in vivo [], or to the somata of the DRG neurons in vitro []. Large, myelinated fast conducting Aβ neurons can also be excited by topical application of TNF-α to the DRG [] or by an autologous HNP extract []. TNF-α can enhance the sensitivity of sensory neurons to the excitation produced by capsaicin and this enhancement likely is mediated by the neuronal production of prostaglandins []. It was found that TNF-α-induced neuronal excitation is mediated by cAMP-dependent protein kinase (PKA) pathway []. The p38 mitogen-activated protein kinase (MAPK) is also involved in TNF-α-induced cutaneous hypersensitivity to mechanical or thermal stimulation []. Results obtained from IL-6 knockout mice indicates that IL-6 plays a facilitating role in sympathetic sprouting induced by nerve injury and that its effect on pain behavior is indirectly mediated through sympathetic sprouting in the DRG []. Most recently, it is reported that localized inflammation of the DRG up-regulates a number of pro-inflammatory cytokines including IL-6 and induces abnormal sympathetic sprouting in the absence of peripheral nerve injury []. It suggests a possible correlation between inflammatory responses and sympathetic sprouting, which are two well-known mechanisms implicated in various chronic pain states.

In summary, proinflammatory cytokines are involved in the development of inflammatory and neuropathic pain. Just as specific cytokines and their neutralizing antibodies have been introduced into clinical trials for the treatment of stroke, Alzheimer’s disease, autoimmune diseases, wound healing, and amyotrophic lateral sclerosis, one could utilize local or systemic delivery of anti-inflammatory cytokines or inflammatory cytokine antagonists for the treatment of chronic pain. These specific cytokines or antagonists would act to disrupt the hyperexcitability cycle taking place in the sensory neurons, providing a new, non-opioid therapeutic approach for the treatment of pathological pain due to inflammation or peripheral nerve injury.


 

A Case of Pellagra Associated with Long Term Alcoholism

Content Source: The Journal of Psychiatry and Neurological Sciences

To the Editor,

Pellagra is a systemic, nutritional disease associated with deficiency of vitamin B3 (niacin) and/or tryptophan and often other B vitamins (1). Pellagra is mostly seen in chronic alcoholics as a result of nutritionally poor diet and malabsorption (2). We present a pellagra case with long history of alcohol use, admitted with psychiatric complaints to our clinic.

Mr. A. was a 44 year old, married, primary school graduate male, who was running a coffeehouse. His socioeconomic status was low. His complaints were irritability, nausea, vomiting and loss of appetite. He had been drinking alcohol every day, for 33 years; its amount had increased to about 100cl for the last 15 years. The longest duration of remission was 3 months, when he was 13 years old. He was experiencing sweating, tremor of hands, insomnia, and irritability as withdrawal symptoms. In the last 2 years, periodically, he had problems in focusing and maintaining attention, delay in reaction time in answering any questions. He had depressive symptoms for 1 year and he had attempted suicide. In the last 2 months, he had diarrhea, vomiting, loss of appetite and erythema, followed by dark discoloration on the dorsal surfaces of his hands. On physical examination, hyper-keratotic plaques with well-defined borders on the dorsal surfaces of both hands, squamous lesions between fingers of both feet, loss of villi and hyperemia on the tongue was detected. He had tremor of both hands and wide-based gait. On psychiatric examination, he was confused, his time orientation was disturbed, self care was poor. Affect was restricted; associations and psychomotor activity were slow. The possibility of pellagra was considered as dermatitis, diarrhea and distortion of cognitive functions were observed. Electrocardiography (ECG), complete blood count, routine blood biochemical tests, routine urine tests, thyroid function tests, VDRL, microscopic stool examination, electroencephalography (EEG), vitamin B12 and folate measurements, cranial MRI, echocardiography, esophago-gastro-duodenoscopy were performed and no significant pathology was detected. As the patient’s symptoms did not respond to oral niacin treatment, niacin malabsorption was considered and a mixture of vitamin B1, B2, B6, B12, nicotinamide and dexpanthenol was given by intramuscular injection and a dramatical recovery was observed.

Pellagra is characterized by photosensitive symmetrical skin lesions, gastrointestinal disturbances, neurologic and psychiatric manifestations. The syndrome is known as “4 D’s”: dermatitis, diarrhea, dementia and death (1). Skin lesions seen in pellagra are photosensitive rash, primarily on the dorsal surfaces of the hands, arms, face and feet. In acute phase, skin lesions are erythema and bullae which resemble sunburn (wet pellagra), but after exposure to sun light, progress to chronic, symmetrical, scaled lesions occurs. Typically they are located on the neck (Casal necklace), hands and forearms (pellagra gauntlet) (3). Irritability, concentration problems, anxiety, fatigue, restlessness, apathy and depression are common psychiatric and neurological manifestations. Even uncommon, psychosis can be seen in pellagra, especially in pellagroid encephalopathy mostly encountered in chronic alcoholics. Confusion and eventually death occurs as the disease progresses (4). Gastrointestinal manifestations are fissures on the tongue and mouth, sourness, loss of appetite, dyspepsia and abdominal pain. Enteritis, which can be severe with nausea, vomitting and diarrhea can also be seen (5). Diagnosis is based on patient’s history and physical examination. There are no chemical tests to definitely diagnose pellagra (6).

In conclusion, low socioeconomic status, long duration of alcohol use, poor diet and characteristic findings should suggest pellagra, although it is a rare disease nowadays. It shouldn’t be considered as a disease that is seen only in undeveloped countries and considering pellagra in the differential diagnosis in chronic alcoholics with psychiatric, dermatologic and gastrointestinal symptoms has vital importance.

REFERENCES

1. World Health Organization. Pellagra and its prevention and control in major emergencies. Geneva, World Health Organization, 2000 (document WHO/NHD/00.10).

2. Stratigos JD, Katsambas A. Pellagra: a still existing disease. Br J Dermatol 1977; 96:99-106.

3. Pipili C, Cholongitas E, Ioannidou D. The diagnostic importance of photosensivity dermatoses in chronic alcoholism: Report of two cases. Dermatol Online J 2008; 14:15.

4. Cook CC, Hallwood PM, Thomson AD. B Vitamin deficiency and neuropsychiatric syndromes in alcohol misuse. Alcohol Alcohol 1998; 33:317-336.

5. Karthikeyan K, Thappa DM. Pellagra and skin. Int J Dermatol 2002; 41:476-481.

6. Hegyi J, Schwartz RA, Hegyi V. Pellagra: Dermatitis, dementia, and diarrhea. Int J Dermatol 2004; 43:1-5.

Nutrient Deficiency Diseases

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Deficiency diseases – Scurvy, beriberi, pellagra, rickets, goiter, protein (amino acid) deficiencies, marasmus and kwashiorkor.


Nutrient deficiency diseases occur when there is an absence of nutrients which are essential for growth and health. Lack of food leading to either malnutrition or starvation gives rise to these diseases. Another cause for a deficiency disease may be due to a structural or biological imbalance in the individual’s metabolic system.

There are more than 50 known nutrients in food. Nutrients enable body tissues to grow and maintain themselves. They contribute to the energy requirements of the individual organism and they regulate the processes of the body. Carbohydrates, fats, and proteins provide the body with energy. The energy producing component of food is measured in calories. Aside from the water and fiber content of food, which are also important for their role in nutrition, the nutrients that serve functions other than energy production can be classified into four different groups: vitamins, fats, proteins, and minerals. All are necessary for proper body function and survival.

Early vitamin deficiency diseases

Polish-born Casimir Funk (1884-1967) originated the word vitamin in 1912, spelling it as vitamine, because he thought they were part of a group of organic compounds containing nitrogen, called amines. The final –e was later dropped in 1920 at the suggestion of the English nutritionist Jack Cecil Drummond who pointed out that these trace-like substances found only in food and essential for good health were not always amines. By 1914 Funk theorized that beriberi, scurvy, and pellagra were caused by a vitamin deficiency.

Scurvy

Scurvy is one of the oldest vitamin deficiency diseases recorded and the first one to be cured by adding a vitamin to the diet. Scurvy was a common malady of sailors of the age of exploration of the New World. It has been recorded that Vasco da Gama was supposed to have lost half of his crew to scurvy in his journey around the Cape of Good Hope at the end of the fifteenth century and Richard Hawkins reported that he lost 10,000 sailors from the disease a century later.

The main symptom of scurvy is hemorrhaging. Hemorrhage marks appear as spots under the skin or bruises, given the medical terms of petechiae and ecchymoses. The gums are swollen and usually become infected (gingivitis). Bleeding can take place in the membranes covering the large bones as well as in the membranes of the heart and brain. Wounds heal slowly and the bleeding in or around vital organs can be fatal. The disease is slow to develop and is manifested early by fatigue, irritability, and depression.

In 1747 a British naval physician, James Lind, in a response to a an outbreak of scurvy conducted a controlled experiment. He took 12 of the sailors who had developed scurvy and divided them up into six groups and gave each pair different medicines such as nutmeg, cider, seawater, and vinegar, while others were given lemons or oranges. The two men given the oranges and lemons both completely recovered in about a week after the experiment.

His Treatise of the Scurvy published in 1753 is the first example of a controlled clinical trial experiment. In his treatise, Lind gave a thorough review of other authors who had written on scurvy along with a careful clinical description of the condition. It was not until the end of the eighteenth century that the British navy finally had its sailors drink a daily portion of lime or lemon juice to prevent scurvy.

Vitamin C (ascorbic acid) is necessary for collagen formation, which is the protein component of connective tissue, strong blood vessels, healthy skin and gums, formation of red blood cells, wound healing, and the absorption of iron. In addition to scurvy, other scurvy-like conditions can develop from a deficiency of vitamin C, such as adult acne, easy bruising, sore gums, and hemorrhages around bones. Good sources for vitamin C are citrus fruit, broccoli, strawberries, cantaloupe, and other fruits and vegetables.

Beriberi

Discovering the causes for beriberi became part of the history of discovering vitamins. Christian Eijkman (1858-1930) was a Dutch physician who was a member of a government commission sent to the East Indies in the 1880s to study the disease beriberi, which was prevalent in southeast Asia, where the main diet is comprised of unenriched rice and wheat.

There are three forms of this disease: infantile beriberi, wet beriberi, and dry beriberi. Infantile beriberi occurs when a mother who breast feeds her child is lacking vitamin B1 thiamine. The mother who nurses the child may not manifest the disease, but the deficiency occurs through the breast feeding and the child usually dies after the fifth month. In the childhood and adult versions of the disease there is a preliminary condition of fatigue, loss of appetite, and a numb tingling feeling in the legs. This condition can then lead to either wet or dry beriberi.

In wet beriberi there is an accumulation of fluid throughout the body and a rapid heart rate that can lead to sudden death. In dry beriberi there is no fluid swelling, but there is a loss of sensation and a weakness in the legs. The patient first needs to walk with the aid of a stick and then becomes bedridden and easy prey to an infectious disease.

In Eijkman’s laboratory he noticed that some of the fowl he was experimenting with developed paralysis and polyneuritis, as in the dry form of beriberi. The director of the hospital forbade Eijkman from feeding these birds with table scraps which consisted mainly of polished rice. He therefore began to feed them with whole rice, after which he noticed that they regained their movement and there was no recurrence of paralysis.

The idea that the birds had some form of beriberi was rejected by Eijkman’s colleagues. His explanation for the cure was that the polished rice had some toxin in it which the unpolished rice did not have. This explanation was rejected by a fellow researcher, Gerrit Grijns (1865-1944), who also stayed on to study the disease after the commission had already left. He found that when the chickens were taken off the rice diet completely and feed with meat instead, they did not develop the characteristic paralysis, but if the meat were overcooked, then the condition would reappear. In 1901 Grijns showed that beriberi could be cured by putting the rice polishings back into the rice.

Vitamin B1 (thiamine) prevents the disease or symptoms of beriberi. Food sources for this vitamin are meats, wheat germ, whole grain and enriched bread, legumes, peanuts, peanut butter, and nuts.

Pellagra

Pellagra is a vitamin deficiency disease associated with poverty. The symptoms of pellagra are referred to as the “three D’s”: diarrhea, dermatitis, and dementia. If disease is not treated it may lead to death. Gaspar Casal (c. 1691-1759) was the first to publish a thorough explanation of pellagra in 1762 after his death. He studied and wrote about the disease which he observed in a region of Spain where it was called “mal de la rosa,” because of the reddened dermatitis which appeared around the back of the neck. Even though the belief of his time was the disease was caused by an infection, Casal believed origins were from inadequate nutrition.

The popular belief that pellagra was caused by infection lasted from the sixteenth century to the early twentieth century until Joseph Goldberger (1881-1929) a member of the United States Public Health Service studied the high numbers of cases in the southern United States. Goldberger established that pellagra was caused by an insufficient amount of niacin (vitamin B3) also known as nicotinic acid and the active form of niacin that the body uses called niacinamide.

Rickets

Rickets is a bone disease deficiency caused by a lack of vitamin D, called the “sunshine” vitamin because it is the only vitamin that can be produced by the effects of sunlight on the skin. It was a common disease of infants and children, but since all milk and infant formulas have vitamin D added to them, it is rarely seen today. In rickets, legs will become bowed by the weight of the body and the wrists and ankles are thickened. The teeth are badly affected and take a longer time to come in. All the bones are affected by not having sufficient calcium and phosphorous for their growth and development. Lack of exposure to sunlight, which helps to produce vitamin D, is a major cause for childhood rickets. Crowded slum conditions in areas where there was little or no sunlight were responsible for its appearance in the earlier stages of the industrial revolution.

An adult version of rickets caused by a deficiency of vitamin D, calcium, and phosphorous is called osteomalacia. The bones become soft and deformed and there is rheumatic pain. The disease is observed in the Middle East and Asia more so than in western countries. The way to prevent rickets and other bone diseases such as osteoporosis is a combination of calcium, phosphorous, and vitamin D.

Other vitamin deficiency diseases

Night blindness or the difficulty of seeing in dim light is caused by a deficiency in vitamin A which helps in the formation of visual purple needed by the eyes for night vision. The deficiency can also cause glare blindness when the eye is either exposed to too much light or a sudden change in the amount of light when entering a darkened room. Another eye disease caused by vitamin A deficiency is xerophthalmia which can lead to blindness. This condition affects the cells of the cornea, other eye tissues, and the tear ducts, which stop secreting.

Vitamin A deficiency can create a number of adverse skin conditions, problems with tasting and smelling, and it may also cause difficulties with the reproductive system.

Vitamin E and K deficiencies are rare. Vitamin E protects against substances that oxidize quickly and vitamin K promotes normal blood clotting. Vitamin B12 (cobalamin) provides protection against pernicious anemia and mental disturbances. Vitamin B 6can also protect against anemia as well as dermatitis, irritability, and convulsions.

Mineral deficiency diseases

There are about 25 mineral elements in the body usually appearing in the form of simple salts. Those which appear in large amounts are called macro minerals while those that are in small or trace amounts are micro minerals. Some that are essential are calcium, phosphorous, cobalt, copper, fluorine, iodine, iron, sodium, chromium, and tin. Aluminum, lead, and mercury are not as essential.

Goiter

Iodine is necessary for the proper functioning of the thyroid gland which controls the body’s basal metabolism rate through its production of two hormones, thyroxine, and triiodinethyronine. Without a sufficient amount of iodine in the diet the gland begins to enlarge its cells in its efforts to produce the hormone, thus producing a goiter, which is a swelling around the neck. Certain regions lack iodine in the soil which leads to cretinism, the physical and mental development of an infant passed on from the lack of iodine in the mother’s diet.

Protein (amino acid) deficiencies

Proteins are needed in the body for amino acids. Proteins are broken down in the digestive system to form amino acids which are then absorbed by the rest of the body to form new proteins in the form of vital body tissues such as muscle, connective tissue, and skin. There are two types of protein, fibrous and globular proteins. Fibrous protein is insoluble and goes into making the structural tissues of the body. Globular protein forms amino acids that become enzymes and hormones and other vital parts of cellular functioning within the body.

Adults rarely suffer from protein deficiency diseases unless there is an impairment in the intestinal tract, but in countries plagued by insufficient food children will develop protein deficiency diseases that lead to very high mortality rates.

Marasmus and kwashiorkor

A specific wasting away disease caused by protein deficiency in third world countries that lack adequate food supplies is called kwashiorkor. It is a word which describes the condition of an infant who has to be weaned away after a year to make room for the next baby. The weaning food, which is mainly sugar and water or a starchy gruel lacks protein or has a poor quality of protein. The weaning diet for these young children leads to other nutrient deficiency diseases as well.

Symptoms of kwashiorkor are apathy, muscular wasting, and edema. Both the hair and the skin lose their pigmentation. The skin becomes scaly and there is diarrhea and anemia, and permanent blindness can result from this condition. Marasmus is another condition of a wasting away of the body tissues from the lack of calories as well as protein in the diet. In marasmus the child is fretful rather than apathetic and is skinny rather than swollen with edema. Aside from contrasting symptoms between the two diseases, there may be converging symptoms which would be described as marasmic kwashiorkor.

There is a wide variation of deficiencies between energy and protein deficient diseases as in the cases described by marasmus and kwashiorkor. The term protein-energy malnutrition (PEM) is used to describe those differences. PEM is the result of poverty as well inadequate information on diet. In some countries there is the mistaken belief that the child should not be given high protein food, which is served to the father, while the child drinks the fluid the meat was cooked in.

In cases of severe PEM it is necessary to hospitalize the child and to administer antibiotics to prevent infections which accompany the condition. Diets rich in protein should be continued after hospitalization, using skimmed milk powder for an energy basis. Legumes (beans) and fish meal are also good sources for protein. Social and political problems have to be managed to allow relief workers to help and to provide an ongoing source of food preparations that can be consumed for adequate nourishment by those in need.

Treatment and prevention

The amounts of most nutrients, especially vitamins, needed to both prevent and treat deficiency diseases are small. The average intake of 1mg of vitamin B1 is sufficient to prevent a deficiency disease of that vitamin, while 10mg of B1 could cure an advanced case of someone about to die of beriberi. Although small doses of vitamins cure deficiencies, large doses of some vitamins such as A and D can be harmful since these two vitamins are already stored by the liver. Vitamins A and D are fat soluble vitamins and can accumulate to the point of becoming toxic. Most other vitamins are water soluble and are excreted in the urine throughout the day.

Diet and supplements

Most nutritionists insist on a well-balanced diet consisting of the major food substances as an effective and economical way of obtaining nutrients for health. On the other hand, advocates of health food stores maintain that the FDA’s required daily allowances (RDAs) for nutrients are much too low and that cultivation of much of our food supply and its preparation robs our diet of much of its nutrient value.

The American Dietetic Association (ADA) recommends that nutrient needs should come from a variety of foods taken from different dietary sources rather than self-prescribed vitamin supplementation. In order to avoid either the problem of nutrient deficiencies or excesses they recommend that physician’s or licensed dietician’s should be the source of prescribing supplementation.

The ADA, however, does make allowances for supplement usage under the following conditions: Iron supplements may be required by women when there is excessive menstrual bleeding. Pregnant and breast-feeding women need supplements, especially iron, folic acid, and calcium. People who are dieting and are therefore are on very low calorie diets may require supplementation if they are not getting the right amount of the nutrients they need. Vegetarians may need boosts of vitamin B-12, calcium, iron, and zinc. Newborns are sometimes given vitamin K to prevent abnormal bleeding. Those people who have diagonsised disorders or diseases or are being treated with medications which affects the absorption or metabolism of the nutrient may require supplementation.

KEY TERMS

Amino acid —An organic compound whose molecules contain both an amino group (-NH2) and a carboxyl group (-COOH). One of the building blocks of a protein.

Calcium —An essential macro mineral necessary for bone formation and other metabolic functions.

Controlled experiment —Also called a controlled trial. The dividing into groups of experimental subjects to see what the effects of a drug will be when tested along with a dummy drug or placebo (a drug other than the one being tested).

Dermatitis —An inflammation of the skin. A symptom of vitamin deficiency.

Edema —An abnormal collection of fluids in the body tissues. One of the forms of the disease beriberi called wet beriberi.

Essential nutrients —Those nutrients that must be obtained from food for good health and to prevent nutrient deficiency diseases.

Iodine —A mineral necessary for the proper functioning of the thyroid gland.

Niacin —An essential B vitamin needed to prevent pellagra.

Night blindness —Inability to see at night due to a vitamin A deficiency.

Recent research on vitamins A and C

Research using 22,000 physicians under the supervision of the Department of Medicine at Harvard is studying the long-term effects of beta carotene (vitamin A) in lowering the incidence of cancer and boosting resistance to infection. It is also being studied in the treatment of AIDS. Beta carotene is a safer version of vitamin A than the preformed oil form called retinol. It is found in carrots, sweet potatoes, broccoli, spinach, collards, turnip greens, kale, and many other vegetables that.

Vitamin C, also known as ascorbic acid, is used as a supplement by more people than any other supplement. Its popularity is due to the work of the two-time Nobel laureate, Linus Pauling who maintained that vitamin C was effective in preventing and lessening the effect of colds and in the treatment of cancer. Pauling’s vitamin C program called for megadoses that far exceeded the government’s RDA recommendations. Pauling recommended a daily dose of between 2,000 and 9,000 milligrams (mg). The National Research Council recommends 60 mg for adult daily and 100 mg for smokers.

The discovery of micro nutrition was made in the early twentieth century as a result of finding the cure for certain diseases, the nutrient deficiency diseases such as scurvy, beriberi, and pellagra. The new dimensions of fully understanding and using our knowledge of nutrients remain to be established from the ongoing research in this area of nutritional science.

Resources

BOOKS

Encyclopedia of Human Nutrition, edited by Benjamin Caballero, et al. London: Academic Press, 2005.

Hendler, Sheldon S. The Doctor’s Vitamin and Mineral Encyclopedia. New York: Simon and Schuster, 1990.

Kok, Frans J., et al. Introduction to Human Nutrition. Oxford: Blackwell Publishing, 2002.

Williams, Sue R. Nutrition and Diet Therapy. Boston: Mosby College Publishing, 1989.

Jordan P. Richman