Causation and Correlation

Melissa found this video that is a good discussion of causation and correlation and discusses some evolutionary concepts of vaccination.

http://www.youtube.com/watch?v=VW1IEqKuf6s

Antibiotic Resistance Week

The week of October 6th is antibiotic resistance week. We will explore how pathogens evolve resistance to antimicrobial agents and how medical professionals and researchers can develop strategies to reduce the evolution of resistance.

On tuesday we will discuss 4 strategies for reducing bacterial evolution of resistance.

1) Limiting use of antibiotics to proven bacterial infections and making sure that patients take their full course. This is what the CDC recommends. Some doctors are valiantly trying to make this a reality. Will they be successful?

2) Designing new antibiotics as the old ones become obsolete. Pharmacologists are screening thousands of plant and insect and other organisms for antimicrobial activity. There can be great financial reward in inventing a new antibiotic. Therefore the free market and the impressive capabilities of modern biotechnology should meet the needs of people into perpetuity. (Right?)

3) Cycling antibiotics. If you have 4 classes of antibiotics, you would use only one class for a certain period of time, then switch to the next, and so on over a predetermined period of time. The idea would be that just when bacteria might start to develop resistance, you switch to another. By the time you return to any given antibiotic in a cycle, hopefully the bacterial population would be sensitive to it. The rationale for persistence of sensitivity is that in between the times that antibiotic #1 is used, the bacterial population would have been selected for resistance to different antibiotics (#2, 3, 4)and they would lose resistance to the antibiotic #1. Seems logical doesn’t it?

4) Holding some antibiotics in reserve. Because much of the time resistance is incomplete, sometimes doctors can get some benefit from increasing dosages or increasing the schedule of older drugs. Then when necessary we pull the bigger guns off the shelf.

It turns out that some of these have been tested. Some work better than others, and there is an interesting quirk of bacterial biology that gives promise to strategy #4.

Tuesday’s discussion will borrow heavily from the work of Miriam Barlow PhD (of UC Merced, California), who gave a lecture at UNM last spring. I will present some evidence of hers to the group for discussion.

See you then,

Joe Alcock MD

Guest Lecturers and Week of 10/6/09

Faculty and students in the biology and anthropology departments are welcome to attend guest lectures for the evolutionary medicine course this month.

Roland Cooper PhD will give a lecture for the class on Thursday October 8th at 4pm. Lecture entitled “Evolution of Chloroquine Resistance in Plasmodium falciparum”. Dr. Cooper is a parasitologist at Old Dominion University, Norfolk, VA.

Later in the month, Otto Appenzeller MD will lecture on tuesday October 27th at 4pm. He will be speaking about his work on genetic adaptation to altitude in Ethiopian Highlanders. Dr. Appenzeller is a neurologist at the New Mexico Health Enhancement and Marathon Clinics (NMHEMC) Research Foundation, Albuquerque, NM. More to come on this…

Next week, we will be talking about resistance to antimicrobials in bacteria and protozoans. On tuesday, we will present hypotheses about strategies that clinicians can take to alter the evolution of resistance in bacteria

Reference for tuesday: Barlow, 2008

Because Dr. Cooper is coming on thursday, there will be discussion that day.

Main reference for thursday: cooper05

Virulence Recap and Writing Assignment

Thanks to everybody for a lively discussion of the evolution of virulence today; pictured here is a rabbit victim of myxoma virus, the classic example used to promote the idea that pathogens will evolve towards a more benign state.

Key points from today:

1) Pathogens do not always evolve towards commensalism.

2) Pathogens that exclusively use vertical transmission – mother to baby – will evolve to a more benign state than those transmitted horizontally.

3) The mode of transmission matters: directly transmitted pathogens are less virulent than vector borne pathogens, and environmentally (or waterborne) illnesses tend to be the most severe.

4) Opportunities for transmission affect pathogen evolution – increased transmission selects for more virulent pathogens with a decreased duration of infectivity (and greater mortality). Decreased transmission selects for less virulent pathogens.

5) Competition between pathogens in a single host or single population can select for increased virulence.

6) Humans may be able to affect the evolution of pathogen virulence with some public health measures – but the definitive test awaits!

The writing project due next tuesday is as follows: Suppose the New Mexico Legislature is taking up the following bills for consideration. Bill 1 promotes the use of hand sanitizer before every handshake and every human interaction; it would be illegal for somebody to not use hand sanitizer before interacting with another person. Bill 2 promotes the use of condoms; it would be illegal under Bill 2 to engage in sexual intercourse without a condom, except at specially designated times reserved for procreation. Suppose that both bills would be accompanied by a massive public information campaign and incentive program, e.g free condoms and/hand santitizer. Explore the effects of these bills, assuming that they changed behavior, on the trajectory of pathogen evolution. Consider either directly transmitted or sexually transmitted diseases (or both). How would these bills change virulence, the duration of infectivity, transmission rates, and mortality of these illnesses? Would these bills have a chance of really altering pathogen behavior if they were enacted into law, knowing something about human nature?

Good Luck!

Evolution of Virulence

Next tuesday we are going to discuss the evolution of virulence, using the mosquito borne dengue fever as an example. (Handout and readings are at the end of this post)

The dengue virus causes dengue fever, aka breakbone fever. As the name suggests, sufferers of breakbone fever are typically laid up in bed.  Immobility is usually associated with high virulence (pathogen replication within its host). Immobility is also a trait that benefits the transmission of vector-borne diseases. An immobile victim cannot effectively swat a blood-sucking insect. Caretakers might also be at risk from bites from vectors because they have to stay in close quarters with the victim.

The virus that causes the common cold generally is transmitted better when its victims are not immobile. This is because it is transmitted by direct contact, not vectors. Pathogens that are transmitted by direct contact are generally less virulent than those that are vector-borne. If the cold virus made its victims unable to move and leave the house, then it would be less likely to spread like wildfire through offices and schools and universities!

Three main modes of transmission of pathogens include, direct, vectors, and environmental.

1) Direct contact diseases (like colds) are transmitted best when the victim is active. These are generally the least virulent.

2) Vector-borne diseases usually require the victim to be alive but are better transmitted if the victim is not moving. These are usually more virulent.

3) Environmentally transmitted diseases can be the most virulent. These do not require the victim to be active. Some are like vector borne diseases (cholera), in which the attendants who wash the soiled bedclothes in the river promote transmission of the bacteria. Some do just fine even after they kill the victim (anthrax), when the corpse releases infectious spores! In general, environmentally transmitted diseases might have very high virulence.

Hospital-acquired infections are like vector borne diseases. Doctors and nurses act like mosquitos. This is not because we are always drawing blood (although we are), but because our stethoscopes and hands are in contact with an immobile victim and then we often touch another patient.  Pathogens that are quite virulent and serious may attract even more attention from doctors and nurses (buzzing around the sicker patients like mosquitos!). So for the hospital acquired pneumonia, there is no downside to becoming more virulent and making the patient more immobile. Transmission of the hospital acquired pathogen depends on interaction with vectors: hospital workers who do not always wash their hands! This is in contrast to the community acquired pneumonia. Community acquired pneumonia might require direct contact (like the cold virus) for its transmission between patients. For this reason, a hospital acquired pneumonia is generally much more serious than a community acquired pneumonia.

Joe Alcock MD

Readings for 9/29/09

Elliott – Vector

Galvani – Epidemiology

Ewald – Virulence

Brown – Evolution of Virulence

Kyle Harris – Dengue

Try to read all 5. But pay special attention to the Kyle Harris and Brown readings. Be sure to read those carefully prior to lecture.

Handout is here:

Vector Virulence

All Stings Considered

The subject of the next lecture 9/22/08 will be evolutionary considerations of venoms, toxins, and antibodies to these molecules.

What is the difference between a venom and a toxin? Are biologic toxins different from organic toxins? Who benefits from a toxin?  (not including Phillip Morris )

What if a “toxin” actually can be good for you, and what if the “toxin” does not benefit the organism that produces it? Is it still a toxin? Or something else entirely? Much work on intensive care patients relates to dramatic reaction to “endotoxin”, otherwise known as lipopolysaccharide. Endotoxin is a basic component of the cell wall of certain bacteria. Endotoxin can result in a drop in blood pressure, widespread inflammation in the body, fever, and leaking capillaries. When severe, these symptoms can kill.

Endotoxin has these effects when it appears in the human bloodstream. It also occurs in huge quantities in the intestines and colon, a result of the vast numbers of E. coli and other bacteria that reside there. Clearly endotoxin has different effects depending on where it occurs. Why might endotoxin have inflammatory effects in the blood? Do you suppose that the bacterium makes endotoxin because it has these inflammatory effects? Alternatively, perhaps bloodstream endotoxin is a signal that bacteria have left the location where they are tolerated (the gut) and have entered the circulation.

Lets think of toxins the way we think of fever. (There is good evidence that in many animals, fever is a host defense that helps destroy pathogens!). Which party does a toxin benefit, the pathogen or the host? Streptococcus is a bacterium that causes strep throat. Streptococcus toxins kill host cells by puncturing holes in their membranes. Strep “perforins” allow bacteria to escape after they have been phagocytosed. These toxins that create conditions favorable to bacterial reproduction and transmission and are harmful to the host.

Endotoxin might be different. Endotoxin initiates an inflammatory response that puts immune cells on high alert to kill invading pathogens. Is it in the bacteria’s best interest to advertise its presence in the blood? Or would the bacteria do better if they were not detected?

If the reaction to endotoxin benefits the host and not the pathogen, we would expect that antobodies to endotoxin would be harmful during bloodstream infections. This proposition has been tested! Which way do you think it turned out?

The following is an excerpt from: “Targeting the lipopolysaccharides: still a matter of debate? Curr Opin Anaesthesiol. 2008 Apr;21(2):98-104.”:

Antiendotoxin antibodies

“A clinical study with antiendotoxin antibodies using nonspecific intravenous immunoglobulins failed to show survival benefit [14]. Clinical studies with the more specific human antiserum applied to heat-killed Escherichia coli (E5) and humanized (HA1A) antibodies against lipid A were nonconclusive [15,16]. Some clinical studies seemed promising [17,18]; however, the results were not universally reproducible [15,16,19,20]. The lack of success may have been due to the inability of the agent used to appropriately neutralize lipopolysaccharide [16,18]. A more recent study [21] supports the benefit of antisera from healthy patients immunized against lipopolysaccharide from E. coli. Lipopolysaccharides extracted from E. coli O111:B4 (E. coli J5) have been noncovalently combined with outer membrane protein of Neisseria meningitides and proven to be protective against fulminant Gram-negative sepsis in animal models [22–24]. The proposed mechanism of this benefit is production of antibodies against core lipopolysaccharide [25]. One limitation is the inability to determine the fraction of antibody required to show benefits [15,26,27]. Clinical studies suggest a correlation between the presence of anticore lipopolysaccharide antibody and onset and survival in sepsis [28–30]. Patients who survived severe sepsis secondary to Gram-negative bacilli were found to have higher levels of anticore lipopolysaccharide immunoglobulin G (IgG) [28–30]. The potential beneficial effect of antiendotoxin antibodies remains unclear and none have been approved for therapy.”

These authors posit that:

“Failure of previous antiendotoxin trials may be for a number of reasons:

1. failure to enroll enough patients with significant amounts of circulating endotoxin;

2. Enrollment of patients too late following release of endotoxin and associated triggering effects, that is the ‘cat is out of the bag’; or

3. ineffectiveness of endotoxin neutralization in general in severe sepsis”

They conclude by saying: “Since endotoxin is the ultimate toxin and is associated with much morbidity and mortality, continued attempts to counter its effects seem warranted.”

Hmmm? What do you think about that?

REQUIRED READINGS (THERE IS ONLY ONE)

1) The one journal article for this week is available here:

endotoxin

THE HANDOUT IS HERE:

All stings considered

Diving and Altitude Handout

Handout from last week’s lecture.

Mismatch part 2

Journal Club

As we discussed in class, journal articles will be assigned to 5 groups of students.

Group 1: Adaptive Value of Fever

Group 2:Biofilms & the human vermiform appendix

Group 3:Factor V Leiden Mutation

Group 4:Nausea in Pregnancy

Group 5:Osteoporosis

If you did not get assigned a group, please contact Melissa.

You will present these articles net week on Thursday. Since this is a group effort, I would recommend that each individual in the group take part in part of the presentation. Powerpoint is not necessary for these presentations. Most articles have more than one idea or topic that can be discussed. It is not necessary to discuss every bit of every paper. Groups can decide how to present and whether the study or review can be critiqued in any way. Please fell free to email us if you have questions.

On another note: This article is a recent piece in the LA Times that reports that the pace of human evolution is speeding up, in large part due to mismatch! Now aren’t you happy that you learned that concept from the last two weeks!

Joe Alcock MD

Handout for 9/15/09

Pathogen Trap

In tuesday’s broad-ranging discussion, I will present a hypothesis that might explain why blood clots and inflammation are inextricably linked, why heart attacks are common in older age groups, and why novel diseases fool the immune system into thinking it is under attack.

Joe Alcock MD

Reading for 9/15/09

This is an article of mine that was published last year. It describes a phenomenon in which immune cells are fooled into attacking the body in a variety of disease states. These mimic states look like infections to the immune system. See you tuesday!

Hemostatic Containment

Joe Alcock MD