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Meet the Guinea Worm

Screen Shot 2016-03-14 at 10.48.20 PM.pngGuinea worm disease is caused by a parasitic worm found in stagnant waters of Africa. It has been known since early recorded history with possible mentions in the Bible and a definite reference (along with a treatment method for removing the worm that is still used today) in the Ebers Papyrus, an ancient scroll written around 1500B.C.
Presently, only four countries, Chad, Ethiopia, Mali and South Sudan have reported cases of the disease. The worm, Dracunculus medinesis infects its (human) host through the drinking of unfiltered water inhabited by the larval forms that have been eaten by “water fleas.” When a person drinks water containing these water fleas, the larva are released from their insect host while in the stomach and burrow through the digestive tract into the body cavity where they grow into adult worms. After fertilization, male worms die in the host, but female worms can grow up to 2-3 feet long.

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A section of the Ebers Papyrus

The insidious nature of the beast is the way that it manipulates the host (human) when it is ready to release larvae. At this time, the worm will burrow to the surface of the skin (usually on the foot) where it will cause a blister. When the blister erupts, it causes a painful burning sensation that is somewhat alleviated when immersed in water.

Whenever the blistered area is immersed, the worm will eject a milky liquid containing millions of larvae into the water to repeat the life cycle. During this time, the pain can be disabling and the blisters are easily infected with bacteria.
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As the worm emerges, it can be captured and wound around a twig, etc. Pulling the worm will result in a break that worsens the condition, but if attended to, the worm can be removed a bit at a time as it emerges from the blister over the course of days to weeks.
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Since the 1980s eradication of the Guinea Worm has been aggressively pursued by a number of organizations, most notably the Carter Center, founded by President Jimmy Carter. The Carter Center has coordinated the efforts of the Nation Ministries of Health in affected countries, with the World Health Organization, The US Centers for Disease Control and Prevention, and UNICEF. Together, these organizations provide education to at risk populations, water filters, and pumps to obtain uninfected groundwater.
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These efforts have reduced the number of Guinea Worm Disease cases from 3.5 million in 17 countries in1986 to just 22 in four countries in 2015 (provisional total). Importantly, humans are the principal host of Guinea Worms, therefore, if all cases of infection can be eliminated for just one year, this should lead to complete eradication of the organism.

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Posted by on March 14, 2016 in Uncategorized

 

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Pediatric Presentation

2-131115150520392A patient presents in your pediatric office with her 5 yo son. She reports that he recently had a cold with a fever and still doesn’t look right after several days and has reduced micturition. He has obvious noticeable as puffiness around the eyes, and upon examination you find that he has a taut belly, and swelling of the hands and feet, which you interpret as generalized edema, or anascara.

You run some tests and find that he has hypoalbuminemia and proteinuria.

What is your diagnosis? And explain the bold type symptoms. (2pts)

 
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Posted by on April 26, 2015 in Uncategorized

 

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HCV, briefly

Viral Hepatitis comes in a number of flavors, named HAV, HBV, HCV, HDV, and HEV (not to mention any subtypes). HCV, identified as recently as 1990, is a serious form of Hepatitis causing cirrhosis of the liver, chronic infection, and often hepatocellular cancer. Prior to 1990, the most common way to become infected was through transfusion with contaminated blood. However, after identifying the virus, tests became available to prevent this form of passage, leaving the primary mode of transmission being sharing of needles between IV drug users and sexual contact.
Unlike other viruses (HAV), few people ever clear HCV and, instead, become chronically ill. This may, in part, be due to the inability of the body to generate protective, neutralizing antibodies. Those antibodies that are produced are mostly usable only as markers of disease. Symptoms of disease include fatigue, nausea, vomiting, loss of appetite, abdominal pain, jaundice, dark urine, and clay colored feces. The CDC definition of a case is: (sorry this isn’t clearer)

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Serum alanine aminotransferase (ALT) levels greater than 400 IU/L indicate hepatocellular damage. This enzyme is normally found only in
liver cells, but is released into the blood when these cells are injured. Normal ALT should not exceed 60 IU/L, providing a fairly clear altmeasure of cell injury.This can be seen clearly below as serum levels of ALT spike with symptoms of disease and then return (however not down to normal, ‘healthy’ amounts) to lower levels following resolution of symptoms.

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There is no vaccine against HCV, so the best way to avoid it is to avoid contact with blood or other bodily fluids that may be contaminated.


Don’t forget to check out my comments on the novel ‘Rosemary’s Baby’ on my other blog. I highly recommend this book to anyone who enjoys thrillers / light horror (a la Stephen King).

 
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Posted by on April 12, 2015 in Uncategorized

 

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The New Measles

leadApropos of class discussion about vaccine compliance and public policy, check out Adrienne LaFrance’s article from The Atlantic on how Measles is re-emerging in many countries – including the United States –  that have considered it eradicated for decades.

Click here to visit the article

The numbers in recent years are nothing like the devastation that Measles used to visit in the US, however, it is the trend that is disturbing. Prior to the introduction of the vaccine, cases numbered in the hundreds of thousands per year in the US. Globally, in 2013, there were 145 700 measles deaths compared to an estimated 2.6 million deaths each year prior to widespread immunization. (data from the WHO)

Measles cases in the US prior to and after the introduction of vaccine

Measles cases in the US prior to and after the introduction of vaccine Langmuir AD. Medical importance of measles. Am J Dis Child 1962;103:54-56

Some Data

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Measles Cases in the US 2001 – 2014

 
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Posted by on January 24, 2015 in Uncategorized

 

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Virus, Vaccine and Passive Antibody Therapy

The immune system is a many-layered construction that protects the body through barrier defences, additional non-specific responses including phagocytosis and chemokines, an antibody-mediated humoral response capable of neutralizing viral particles, and a cellular response for eliminating infected cells.

Ebola: Disease and Response

mapEbola is a viral disease first identified during a first appeared in 1976 in two simultaneous outbreaks, one in Nzara, Sudan, and the other in Yambuku, Democratic Republic of Congo.  It is reasonable to suspect that Ebola has infected humans prior to this time without being identified specifically. This is a reasonable assertion because, like the first, all subsequent outbreaks have occurred in remote areas of Western African countries that are largely isolated. Although infamous for its lethality, this remoteness has proved self-limiting in terms spread.

The current epidemic has defied these rules resulting in escape from the remote areas of West African villages to larger population centers, and for the first time ever, even resulting in at least one case presenting in the United States. (citation)

In general, although viral infections are not treatable by classical antibiotics, vaccines against these types of organisms have been largely successful. Although it is impossible to know exactly why a specific vaccine works, it is reasonable to assume that a humoral response (i.e. mediated by antibodies) is involved in most cases as antibody titer correlates well with protection.

I the case of Ebola, there is data regarding the type of immune responses mounted by patients who have survived the disease compared to those who have not. Baize et al report that “early and increasing levels of IgG, directed mainly against the nucleoprotein and the 40-kDa viral protein, were followed by clearance of circulating viral antigen and activation of cytotoxic T cells” in survivors of disease. While “fatal infection was characterized by impaired humoral responses, with absent specific IgG and barely detectable IgM.” Again, this supports the idea that an effective humoral response is key to protection.

More evidence of the centrality of the humoral response comes from data published by Villinger, et al (citation) showing that “IL-6 levels are unusually low among fatal cases.” They suggest that this points to a deficiency of the endothelial cells that produce this cytokine leading to failure to protect. An alternative explanation may be that macrophages, which are key targets of ebola infection – and are producers of IL-6, are also failing to respond appropriately due to their involvement as targets. This leads to an obvious defect in immune response as IL-6 supports the growth of B cells and is antagonistic to regulatory responses (i.e. regulatory T cells).

If antibodies are so important to response, what are the targets of these antibodies and what issues are there related to this response?

Ebola Virus:

Eboal5Ebola has only one known surface protein found on virions and infected cells. It is presumed that this protein, a ‘sugar-coated’ glycoprotein (GP), is what enables virions to adhere to target cells, a vital first step in the infection of host cells by animal viruses. As neutralizing immunity against viruses is presumed to be a result of the opsinization of viral particles by antibody, the Ebola GP is the obvious target of these antibodies. However, there are still a number of epitopes (regions of the protein to which immune reactions develop) on the GP protein to which antibodies bind. And, furthermore, two versions of GP are made, one in the viral envelope (membrane) and one that is secreted from infected cells. Together, this means that there are a lot of different spots for antibodies to bind, and some spots may be better for protective immunity, while others have no protective effect at all.

Vaccines against ebola are currently being developed with the hope of bringing these to affected areas to either prevent – or at least control- outbreaks at their source. The benefits of developing an effective vaccine include actively inducing life-long immunity.

A second method of fighting disease is to treat with previously generated antibodies in a way that the virus is neutralized, but life-long protection is not induced. One way of accomplishing this treatment is by harvesting serum from patients who were infected, but survived the disease. This has obvious limitations logistically and there is insufficient data on these treatments to know whether they were actually helpful in treating patients. Another way to transfer this sort of ‘passive’ immunity is by making large amounts of a single antibody in cell culture. These ‘monoclonal’ antibodies are highly standardized and can be produced in very large quantities.

A number of monoclonal antibodies targeting different epitopes on the Ebola GP have been developed and show protective effects when administered after viral exposure (i.e. therapeutically). One example of this kind of therapy is ZMapp  from Mapp biopharmaceutical. In studies with animals, they found that “a combination of monoclonal antibodies (ZMapp), optimized from two previous antibody cocktails, is able to rescue 100% of rhesus macaques when treatment is initiated up to 5 days post-challenge.”

Treatment of Ebola patients with Convalescent Serum

Treatment of Ebola patients with Convalescent Serum

I’ve written before in this space about one of the challenges that antibody treatment against ebola. Because ebola infects macrophages as one of its targets, and because one of the jobs of macrophages is to clear opsonized (antibody-coated) particles, ebola appears to have co-opted this function as a mechanism for penetrating and infecting cells. This characteristic is termed Antibody-Dependent Enhancement (ADE) of infection and has been shown to increase the infectivity of the embryonic kidney cell line, HEK-293, in vitro (Takeda et al 2003). Reportedly, the mechanism for this enhancement is via the complement protein, C1q, and receptors on the host cells.

Together, these data beg the question of whether antibody treatments, such as ZMapp, or vaccines leading to humoral responses will be helpful or harmful in the treatment and protection of patients.

“On 11 August, a group of experts convened by WHO reached consensus that the use of experimental medicines and vaccines under the exceptional circumstances of the Ebola epidemic is ethically acceptable.” So, we may find out the answers to these questions much sooner than we would otherwise expect.

 
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Posted by on November 5, 2014 in Uncategorized

 

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Polio Does Not Go Gentle into that Good Night

While, as recently as 1988, there were as many as 350,000 cases of Polio per year, there were only 417 cases of polio recognized in 2013. At that time Polio was endemic in just three countries.

Old age … burn[s] and rave[s] at close of day.

So far this year there has been nearly 3 times the global number of cases of Polio as there was last year at this time.

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Though wise men at their end know dark is right

It’s not often that scientists will rally around the idea of intentionally pushing an organism to extinction, but this is exactly what disease eradication is – and it is the ultimate goal of all vaccination programs. The eradication of Smallpox has been hailed as one of the great successes in modern medicine. In fact, the philosophical arguments against making eradication the goal are not meant to subvert eradication, but actually to prevent complacence in monitoring programs and to avoid wasting money on tracking down ‘one last case’ of disease.

This said, a goal of the World Health Organization does have an endgame strategy for polio and plans on having it eradicated by 2018.

Rage, rage against the dying of the light.

Despite our best efforts, The Polio Eradication Initiative, in its May 2014 Special Alert, reports, “WHO Director-General Margaret Chan declared the recent international spread of wild poliovirus a ‘public health emergency of international concern,’ and issued Temporary Recommendations under the International Health Regulations (2005) to prevent further spread of the disease as the high season approaches.” This declaration has the weight of international law for the 194 signee countries.

Curse, bless, me now with your fierce tears, I pray.

Obstacles to final eradication remain largely human and political. Thinkprogress.org’s Hayes Brown reports that, “Pakistan has been the epicenter of attacks on vaccination programs, following the revelation that the CIA in 2010 used a fake vaccination campaign to hide their intelligence gathering efforts to locate Osama bin Laden. Since then, the Pakistani Taliban have now come to see all health workers as suspect and prime for targeting”

War, especially civil war, has led to countries such as Somalia, Pakistan and The Gaza Strip of Israel becoming reservoirs for disease and expanding the number of countries with wild polio.

ImageNevertheless, Even as polio does Rage against our efforts, it is still much reduced and there is no reason to give up hope that a combination of political and medical interventions will be sufficient to add polio to that short list of diseases that are ‘forever gone.’

 
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Posted by on May 6, 2014 in Uncategorized

 

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It’s a Wide World

Have you ever asked yourself, “how is it that our immune system can fight off almost everything?”33707699

It’s one of those things that is easily ignored.

 It works. That’s all I care about.

If that’s not a good enough answer, then read on…

The answer lies somewhere between biology and statistics. And I want to  start with an analogy.

Think of a website that makes you log in when you visit (Google’s gmail, for instance). You come up with a password when you join and then use it every time you log in. Some annoying websites make you cycle your passwords regularly for security purposes. (I’m not saying there’s anything wrong with that, but it can be taxing to those who don’t use a password storage program. – by the way, I use Dashlane  and love it)

But every time you use a password, it’s off the list – you can’t use it again. So after about three changes, you start to sweat because you think your head is filling with all those old passwords and you can’t remember the latest one any more. As an analogy for the immune system, imagine a simple program that creates random passwords for you and ensures that they’re not repeats of any that you’ve used before.

Your immune system has no idea what you’ll come up against in the world. All it can do is make a vast repertoire of immune cells with the hope that it will be sufficient to react to anything. For simplicity, let’s just consider how cells make antibodies. To do this, your cells have a way of randomizing the protein sequence responsible for making these proteins.

The problem with this system, if it’s just a random grab-bag, is that sometimes those antibodies might bind to your proteins causing big problems. So, after the random process that generates antibodies, there is a second, non-random selection process that eliminates any that bind to you.

In my analogy, imagine that a random password is generated (the antibody), but then it checks to be sure it’s not the same as a previous password (no self – reactivity).

If you do any programming you can imagine outlining your code:

(let’s say passwords are 4-digit numbers from 0-9)

 

  1. generate a random number from 0001 – 9999
  2. cycle through old passwords
    1. check that the new password is not equal to the old password.
    2. If it matches, discard that password and go back to step I
    3. If it does not match, cycle to next old password
    4. Repeat until all old passwords have been checked
    5. Present new password to user

Now that I look at it this way, it is very much like evolution by natural selection. Random process à non-random selection.

ImageTo illustrate how this works with the actual proteins, it’s best to go to good old Janeway:

The top two panels show something more like the actual structure of the antibody. The bottom panel shows a simplified cartoon, highlighting the variable region and the constant region of antibodies. Think of the constant region as the backbone of the molecule – it comes in a few models, but doesn’t change.

The variable region is where the antibody binds its target. This is the region that gets scrambled up so the antibody will have a unique binding region.

The variable region is actually composed of several parts (V, D and J) that get pieced together, one of each sort. This accounts for some variability, but could only result in a handful of different types.

In addition to this mix-and-match, the joining of segments is also imperfect. Recall that DNA is ‘read’ in three-base codons. Because of this, adding one extra base in joining the elements will result in a frame-shift that creates even greater diversity. It also admits the real possibility that the protein made will be entirely unstable and useless. To account for this, each cell is positively selected for only ones that make stable receptors. It has two shots* at making this work. Once for each of the two chromosomes (one from your mom, and one from your dad) bearing this gene. If it succeeds, it goes on developing**; if it fails, it commits cellular suicide: apoptosis.

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Another figure adapted from Janeway

The result is a pre-immune repertoire of about 1012 antibodies available to protect you from any nasty ‘bugs’ out there.

 

* There is data supporting additional receptor editing. 

**         Heavy Chain is rearranged and interrogated first, then Light Chain.

 

 
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Posted by on May 2, 2014 in Uncategorized

 

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