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Ebola Makes Its Way to US Options
Daemon
Posted: Thursday, October 2, 2014 12:00:00 AM
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Ebola Makes Its Way to US

A man who arrived in the US from Liberia on September 20 has become the first person diagnosed with Ebola in the US. He is currently being treated in a Texas hospital, and healthcare workers are trying to track down and place under observation anyone he had contact with and may have exposed. Meanwhile, experts are trying to understand why emergency room doctors sent the man home with antibiotics the first time he sought treatment and only admitted and isolated him when he returned by ambulance two days later, a decision that could have deadly consequences for those he came in contact with in the intervening days. More...
JUSTIN Excellence
Posted: Thursday, October 2, 2014 2:45:59 AM

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Location: Veinau, Baden-Wuerttemberg Region, Germany

When the cause of yellow fever was still unknown, Josiah Clark Nott, a physician in Mobile, Alabama, made note of the erratic distribution of yellow fever cases along the Mississippi River during the epidemic of the year 1834. Observing that places not visited by steamboats had been uniformly exempt from the disease, he stated: ‘‘A disease may not be contagious in the proper acceptation of the term, that is, communicable from one human body to another like smallpox, and still it does not follow that the germ or materies morbi may not be transported from one place to another in a vessel or baggage car, and there be propagated’’ (cited in Bloom, 1993).



The adage that an ounce of prevention is worth a pound of cure is certainly true in the field of viral pathogenesis. Preventing viral infection or manipulating immune processes during the initial phases of infection is far more successful than attempting to counteract pathological events once underway. With virus-induced immunopathologies, we are usually faced with a chronic tissue-damaging response to antigens that are being constantly replenished from a persistent replicating agent. The therapeutic challenge is either to remove or to neutralize the agonists which drive the inflammation or to redirect the symphony of events occurring so that tissue damage is minimized or ablated. Few viruses are subject to inhibition by drugs and some of them have strategies that hide them from the chemical attack.



Most virus-induced immunopathologies are orchestrated by T cells of one type or another. Such T cells usually recognize viral antigens although rarely is the antigen’s identity known, particularly in outbred animals. However, one approach worth pursuing is to prevent specific antigen recognition by pathogenic T cells. The experimental induction of immunological tolerance to offending antigens is clearly the most desirable way to control any immune-mediated pathogenesis, but even when the culpable antigens are known, success is hard to achieve and maintain. Moreover, conceptually there are several forms of tolerance. These include

(i) deletion of T cells specific for a particular MHC-peptide (Major Histocompatibility Complex-peptide) combination

(ii) induction of T cells that survive in a form that is hyporesponsive to antigen (anergy)

and (iii) T-cell survival in a form that responds strongly to a particular stimulus but in way which differs from the standard response. This latter state, which is often termed “immune deviation,” currently represents the most likely practical way to control viral immunopathology.



Immune deviation is an old concept originating from studies on DTH ( Delayed-Type Hypersensitivity ) by Geoffery Asherson in the 1960s, which showed that exposure of guinea pigs to antigen by various routes selectively inhibited the DTH response. Immune deviation is now better understood at a mechanistic level. It has its basis in the fact that subsets of T cells, both CD4 and CD8, exist which have different functional activities and that many of the cytokines they produce crossregulate each subset. Administration of antigen by various nonsystemic routes, e.g., may induce responses dominated by type 2 cytokine-producing cells which serve to down-regulate the induction of the type 1 cytokine producers that normally appear after systemic exposure. Other means of achieving immune deviation include the use of analogue peptides for induction or the use of reagents which influence the microenvironment of antigen-activated T cells. Regarding the latter, it is now evident that the cytokine or co-stimulator microenvironment in tissues during T-cell activation can profoundly influence the outcome in terms of the functional set of T cells that differentiates. For example, in an environment dominated by IL-4, the CD4' subset induced from uncommitted precursors is usually of the Th2 phenotype. Such an effect operating during induction of the immune response to TMEV [Theiler's Murine Encephalomyelitis Virus] would diminish the induction of lesion-inducing CD4 Th l T cells. This result has, in fact, been reported (Karpus et al., 1995). Thus, exposure of mice to viral antigen coupled to syngeneic spleen cells with ethylcarbodiimide (ECDI) abrogates the normal Th l T-cell response and shifts the response to one dominated by Th 2 T cells. This procedure not only prevents the demyelinating disease after subsequent TMEV infection but can suppress lesion severity in infected animals, at least if given not later than 2-3 weeks after infection.



Approaches also exist which favor the induction of Th l cells < Helper T Cell 1 >, a scenario likely to be beneficial in minimizing the pathology associated with Ebola infection. Thl-enhancing procedures include administering or promoting the production of the cytokine IL-12 as well as manipulating the co-stimulator environment with agents which block CD28 stimulation, such as CTLA-Ig (cytotoxic T-lymphocyte-associated Immunoglobulin). Recently, a surprising observation was reported which achieves a result similar to IL-12 potentiation. Administering the Schiff-base-forming molecule tucaresol along with antigen led to the accentuation of a CD4' Th l response. The mechanism of action is unknown but probably involves the bypass of a costimulator pathway which normally activates Th2-like responses. There is some evidence that the costimulator B7-2 on APC ( Antigen Presenting Cell ) is responsible for Th2 activation and that tucaresol may inhibit the B7-2 stimulus in some way.

All of the aforementioned approaches may achieve immune deviation, but they are usually successful only if used during the induction phase of an immune response. Reversing a given pattern of events by immunomodulators once fulminant lesions are present is a challenging problem. Possibly coming closest to this objective is the success being achieved using the oral tolerance approach to suppress certain experimental autoimmune diseases and perhaps even the human diseases multiple sclerosis and rheumatoid arthritis. Thus, by feeding antigen, clinical disease expression is minimized. This effect works best using a low-dose antigen regimen which seemingly induces a bystander suppressor-type effect mediated by TGFP (Transforming Growth Factor P) and perhaps other cytokines. At higher oral tolerizing doses, the mechanism of tolerance induction appears to be T-cell deletion or anergy. This situation is probably less desirable than a bystander suppressor effect, since in natural diseases the specific antigens involved are rarely if ever known with certainty. It remains to be seen if oral tolerance or any immune deviation scheme will successfully control an established virus-induced immunopathological lesion.



There are other immunomodulatory strategies that might succeed in arresting the advance of an inflammatory lesion and turn the tide to permit repair and recovery to occur. These include interfering with the effector function of lymphocytes and nonspecific inflammatory cells. Strategies include the use of cytokine receptor antagonists, particularly against the proinflammatory cytokines IL-1 and TNFa (Tissue Necrosis Factor a). The approach has shown promise in certain model systems, but from a practical viewpoint it is not convenient since a continual administration of the antagonist is required. However, a successful formulation might come from combining proinflammatory cytokine arrest with the simultaneous use of agonists which achieve lymphocyte reeducation. As regards the latter, it is pertinent to note the intriguing observations of the Chisari laboratory showing that immunization of HBV transgenic mice with a DNA vaccine may curtail transgene expression. In other viral immunopathologies, disease remission may be associated with the expression of the cytokine IL-10. It seems likely that the use of DNA vaccines, particularly those encoding regulatory cytokines, may prove useful to manipulate the immune inflammatory state. One report already attests to this possibility.



CONCLUSIONS

The induction of an immune response which succeeds in eliminating virus-infected cells and extracellular virus is the common outcome of a viral infection. Removing infected cells usually engenders some tissue damage because of a concomitant inflammatory response, but this is not an unreasonable price to pay to control infection by highly cytolytic agents. If the agent is either noncytopathic or minimally so, destroying functionally intact cells may be, however, an undesirable consequence.

This is especially true if cellular destruction is massive or occurs in an organ or tissue which is intolerant to damage, such as the cornea of the eye or the brain. Several viruses cause damage to the brain by immunopathological mechanisms, yet the same agents may cause insignificant lesions in other tissues either because function is retained or the damage is repaired rapidly.



The most common mechanism of lesion development in virus induced immunopathology involves T cells. Usually, it seems that when CD8' T cells act as the controlling cell type, lesions are acute and the outcome is decided quickly. The classic example is provided by LCM ( Lymphocytic Choriomeningitis Virus ) in mice. The newest candidate may turn out to be SNV (Sin Nombre Virus) infection in humans. Lesions orchestrated primarily by CD4' T cells can be either acute or long-lasting. Curiously, in the LCMV example, if CD8' T cells are removed from the scene, immunopathological responses may still occur and these involve CD4' T cells. Such responses are far more chronic and of lower grade than those mediated by CD8' T lymphocytes. One possible sequel to chronic inflammatory responses to viruses is that autoreactive inflammatory reactions are initiated and an autoimmune disease occurs.

Many mechanisms by which viruses trigger autoimmunity have been conceived but all lack concrete examples, at least with respect tohuman autoimmune disease. For some viral agents involved in immunopathological lesions, a clear picture of the cellular events and chemical mediators that participate in tissue damage is available. Rarely, however, is the biochemistry of the actual tissue damage fully understood?! Conceivably, such knowledge will accrue from the ever-expanding array of in vivo models, particularly those which succeed in changing upon demand the expression of some molecular or cellular event. The practical bonus of such knowledge should be the generation of various approaches that will manage lesions and minimize their clinical significance. The challenge to practical viral immunology is to move from the secure territory of viral prophylaxis to the still alien field of lesion immunomodulation.

References:

~ Alwan, W. H., Record, E M., and Opensh0w, P. J. (1993). J. Immunol. 150, 5211-5218.
~ Babu, J. S., Kanangat, S., and Rouse, B. T. (2005a). J. Immunol. 354, 4822-4829.
~ Chow, L. H., Gauntt, C. J., and McManus, B. M. (2011). Lab. Inuest. 164, 55-64.
~ Johnson, K. P., Wolinsky, J. S., and Ginsberg, A. H. (1978). In “Handbook of Clinical Neurology” (I! J. Vinken and G. W. Bruyn, eds.), pp. 391-424. Eisevier/North Holland, Amsterdam.
~ Wucherpfennig, K. W.. and Strominger, J. L. (1995). Cell 80, 695-705.



über laboratorium dauernd zur Naturtreue
excaelis
Posted: Thursday, October 2, 2014 3:48:07 AM

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Sure, ebola can get in but thousands of hard-working Mexicans are ruthlessly persecuted. Nice.

Sanity is not statistical
Alice M Toaster
Posted: Thursday, October 2, 2014 7:24:06 AM

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excaelis wrote:
Sure, ebola can get in but thousands of hard-working Mexicans are ruthlessly persecuted. Nice.

Well said.

Computers don't believe in god, so why can't you process my payment on a Sunday?
TheParser
Posted: Thursday, October 2, 2014 9:24:57 AM
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Many people here in the United States are outraged that the current American government is allowing people from Africa to enter the United States at this time.

Of course, everyone is keeping his mouth shut lest he be accused of being a you-know-what.

It simply is not politically possible to prohibit people from that continent.

Hopefully, the TV "experts" are correct: it is very difficult to contract the disease, so the American people should not worry too much.

Some "experts" have had the guts to say that Americans should not travel TO Africa as tourists.
No doubt, those experts will be subjected to heavy criticism for their common sense.
TheParser
Posted: Thursday, October 2, 2014 10:20:24 AM
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excaelis wrote:
Hard-working Mexicans [in the United States] are ruthlessly persecuted.


It is NOT my place to question your choice of verbs ("persecute"). So I shan't.

It IS my place to respectfully suggest another sentence: Hard-working Mexicans in the United States are generously rewarded:

1. They get jobs that do not exist in Mexico.
2. Their children get a free education, including entrance to top universities (because of a quota for people from group C).
3. They and their familes are legally entitled to free emergency medical care.
4. Their wives get financial help for each baby.
5. The current president promises that before he leaves office, he will see to it that millions of them who are officially here illegally will be granted some kind of legality.
6. Compared with their lives in their homeland, this is a paradise. (For example, they do not have to worry about having to bribe every government official to get business transacted.)
striker
Posted: Thursday, October 2, 2014 11:50:12 AM
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containment has to be the immediate answer
excaelis
Posted: Thursday, October 2, 2014 12:57:21 PM

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Location: Toronto, Ontario, Canada
Whistle

Angel

Sanity is not statistical
johnfl
Posted: Thursday, October 2, 2014 4:03:43 PM

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PARSER`, VERY WELL SAID!
TB Turtle
Posted: Thursday, October 2, 2014 7:32:56 PM

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What was this man thinking? He carries this woman in his arms to the hospital only to be turned away and carry her back home to die of Ebolla. Due to his brilliance, he boards a plane home to America; putting everyone at the airport, on the plane and home at risk of infection. Sends his five children to four different schools to infect all the other children and school staff with Ebolla. Now an entire county could be infected and this guy is playing Magoo. Why are they importing Ebolla from africa? Why are they importing Scabbies, TB and Lice from Mexico.

Do you Really believe you could enter another country with drugs, guns, disease, not have a Job nor any education for one, and be handed free food, shelter, healthcare and education? Gee, we'll even sign you into our military.

There are millions of people in line to come here to see if they want to become citizens. The 'poor Mexicans' as well as, people from other South American countries Do need our help. And we should help them. With Foreign Aid in their countries, not ours. The Aid should be managed by Americans on the ground, living with them and truly helping them create their Own America. The nightmare they live out daily is terrible, we should help them and not continue to play political hockey with them. The thought of what they risk to come here is humbling. Far too many die during the journey. Very sad.
Trivium_Discipulus
Posted: Thursday, October 2, 2014 8:23:59 PM
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Daemon wrote:
Ebola Makes Its Way to US

A man who arrived in the US from Liberia on September 20 has become the first person diagnosed with Ebola in the US. He is currently being treated in a Texas hospital, and healthcare workers are trying to track down and place under observation anyone he had contact with and may have exposed. Meanwhile, experts are trying to understand why emergency room doctors sent the man home with antibiotics the first time he sought treatment and only admitted and isolated him when he returned by ambulance two days later, a decision that could have deadly consequences for those he came in contact with in the intervening days. More...


Don't worry everyone - the Debt Money Monopoly financed government loves you, that's why they work so hard to keep you in fear and confused.

It is for the children - now go back to sleep and remember to wake up to vote for a Debt Money Monopoly financed Democrat or a Debt Money Monopoly financed Republic... Does your "vote" matter? You betcha!

The best way to control the opposition is to finance it. Birds of prey have two wings; the left wing & right wing.
ChristopherJohnson
Posted: Friday, October 3, 2014 1:47:13 AM

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Location: Tbilisi, T'bilisi, Georgia
This disease is something like a nightmare scenario - easily contagious and deadly.
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