Hold Your Fire -- It's Just a Mitochondria, it's One of Us

One of the most intricate and fascinating aspects of physiology is the immune and inflammatory response and how it is triggered. At a 10,000 foot level, the immune system is triggered by the presence of some sign of an invading organism. Such a sign could come from, for example, detecting its genetic material through special receptors known as toll-like receptors (TLRs). 

One such receptor, TLR-9, is used to detect foreign DNA sequences. These sequences, which are rare in vertebrates, are considered to be pathogen-associated molecular patterns (PAMPs). Once this process is started the result is systemic inflammation in order to quell the infection.

However, not all systemic inflammatory reactions are due to a microbial pathogen. The ICU is literally full of people who are exhibiting systemic inflammatory response syndrome (SIRS) but without a clinical infection. Trauma and post-surgical patients are two common examples. In these settings it is thought that tissue damage leads to the release of damage-associated molecular patterns (DAMPs), and not PAMPs, triggering the inflammation. A new paper from the Medical University of Vienna, elegantly provides more information to help unravel this process.

Within our cells are special structures that basically serve as the power plant, generating energy from oxygen: the mitochondria. Mitochondria are special amongst our cellular organelles as they were once free-living bacteria that entered into a symbiotic relationship with the evolutionary precursors to our cells and now live within our cells. As such, they retain their own genetic material which is, for all intents and purposes, bacterial. 

Prior studies have demonstrated that mitochondrial DNA (mtDNA) levels correlate with illness severity in certain conditions such as trauma. In this fascinating study, this was taken one step further as the levels of circulating mtDNA as well as TLR-9 expression were measured in ICU patients. The findings show that high levels of mtDNA, when coupled with high TLR-9 expression, were found to correlate with mortality. 

The study will likely lead to interest directed at medications to block TLR-9's effect but even without such an application the whole process is very interesting to ponder: little bacterial creatures that live within our cells and are essential for life leak their DNA into our blood when we are sick or hurt and, because of their ancestry, our body (quite understandbly) mistakes for a bacterial invasion and launches an attack which could be fatal for us. 

So cool.

I am Thankful for Jonas Salk

To the general public, Pittsburgh is the land of sports superstars but to me it will always be the land of Dr. Jonas Salk. It was here that he developed the polio vaccine taming a virus that struck fear in the population. 

Reading the excellent new biography of Salk, Jonas Salk: A Life by Dr. Charlotte Jacobs, reinforced that conclusion. I have read several books about polio and the race for the vaccine but none focused exclusively on Dr. Salk. To me the strength of Dr. Jacobs' book is that it doesn't just end with the conquering of polio but spends much time on Dr. Salk's post-polio life. 

One might think that once he received the deserved acclaim from the development of the vaccine that all would be smooth-sailing for Dr. Salk. However, that wasn't totally the case. The trials and tribulations that Dr. Salk endured trying to establish and maintain the institution that still bears his name is a case in point.

The most intriguing part of the book is Dr. Salk's battle with HIV, which occurred in the last years of his life. At this time, Dr. Salk had closed his laboratory and was focused more on philosophy and the humanities than medicine per se. However, this man -- who believed he was destined to be a benefactor of humanity -- delved back into the field and developed an approach to a vaccine. As Dr. Jacobs writes, "When the desperate need for an AIDS vaccine became apparent, Salk found a raison d’être.”

The approach he favored was that of a therapeutic, as opposed to preventative, vaccine in which the vaccine would be administered to those already infected with HIV with the hope that it might boost immune responses to the virus. If successful, such a vaccine would provide a "functional cure" for HIV. Needless to say and not surprising, such an approach, with some modernization, is still alive.

I read biographies not just for their historical value, but for inspiration. In that vein, my favorite passage from the book is this (from the last pages):

“...he held strong convictions. Certain about the merit of the things he had done, the things he wanted to do, he rarely expressed self-doubt. Connected to this, he was unrelenting, repeating his view over and over, never seeming piqued or tired. Once he determined a course of action, he would not waver from it. His persistence exasperated those on the receiving end.”

As I write this on the eve of Thanksgiving -- a holiday that celebrates the abundance made possible by productivity -- I am thankful for Dr. Jonas Salk whose work to rid the world of polio not only saved countless lives and raised the standard of living of the entire race but provides inspiration.

Thank you Dr. Salk.

Giving the Rectal Thermometer its Due

One of the cardinal features of many infectious diseases is the presence of fever. Fever, usually defined as a temperature exceeding 38.3 degrees Centigrade (100.94 degrees Fahrenheit), is a defense mechanism employed to stifle the growth of microbes who prefer to grow at lower temperatures and augment the immune system which heightens its activities at higher temperatures. 

Fever also has a major diagnostic role as it is used to discriminate between those who are more ill and those who are less ill. Fever is also part of the criteria for employing the concept "systemic inflammatory response syndrome" to a patient--which can trigger an extensive evaluation for an inciting infection.

With that context, it becomes clear that accurately determining if fever is present in a patient is an important task. Sometimes fever can be obvious and felt directly by touch, however tactile temperature taking is fraught with error therefore thermometers are employed. While it is well known that peripheral temperatures obtained in the mouth, ear, arm pit or forehead can be inaccurate and subject to manipulation (think of the school child who sticks a thermometer in a hot liquid before putting it in his mouth) they generally are the primary means of temperature assessment employed in healthcare settings. The gold standard of temperature measurement is more invasive and would involve measuring the temperature of the blood, the bladder, the esophagus, or the rectum directly. 

Rectal temperatures, being the least invasive of the three, is employed variably to determine temperatures. Usually small children and critically ill adults may have their temperature measured in this manner. A new study, however, provides evidence that this form of temperature measurement should be employed more liberally if accurate temperature measurement will make a difference in clinical management. 

In this study, which was a systematic review and meta-analysis, 75 studies were pooled and revealed that peripheral thermometers level of agreement with central thermometers was unacceptable and could be off by 1-2 degrees Centigrade at extreme temperatures (higher or lower). The sensitivity for detecting fever, furthermore, was just 64%--not too much better than flipping a coin. Specificity, meaning the reliability of a peripheral thermometer's detection of a febrile range temperature, was good at 96%. Translation: if your oral thermometer detects a fever, it is likely a real fever but if it reads normal, fever may still be present. 

To me, the results of this study should lower the threshold for obtaining a rectal temperature in those patients in whom the result would change management (after a peripheral temperature is reported as normal). This does not mean that every parent or grandparent should subject children to routine rectal temperature measurement because in that setting -- an ill-appearing child -- temperature adds little to the treatment (fluids, acetaminophen, ibuprofen). The other implication is the need to better calibrate peripheral thermometers prior to use and the need for innovation in this market to spare all our rectums.

Living Weapons: A Scholarly Analysis of Biodefense

In many ways the field of biodefense is young and still developing a robust amount of scholarly materials from which the foundations of the discipline will develop and new work flourish. There are, however, several books which, in my estimation, are worthy of being described as foundational in their approach.  I read almost everything in this field and usually find my knowledge deepened and better integrated by the process so each latest book is progressively less impactful. George Mason University's Gregory Koblentz's Living Weapons: Biological Warfare and International Security (2011) is one such book that bucks the trend in a good way and is a book that I highly recommend to those in the field.

Koblentz's book is a comprehensive overview of the field of biological weapons that is not a mere cataloging of the pathogens and the history. The book provides extensive analysis of the field and is especially illuminating when it comes to the problem of intelligence gathering in this realm. This, to me, was the chief value of the book.

Using the historical examples of biological weapons programs in the Soviet Union, Iraq, and South Africa Koblentz meticulously analyzes what western intelligence knew and what they did not and why. The book includes important tables that basically score intelligence agencies on whether they correctly identified a biological weapons production facility or not. 

The other aspect of this book is a very in-depth critique of the intelligence shortcomings that led to the mistaken conclusions regarding Iraq's post-Desert Storm biological weapons capabilities and intentions. Koblentz approaches this task not with a partisan aim but to better understand the nuances of infamous informer Curveball's revelations in order to improve intelligence capabilities in the future (in 2003 just 6 analysts in the CIA were devoted to biological warfare). His ideas for intelligence improvements are reflected in some of the newly released recommendations for the Blue Ribbon Study Panel on Biodefense. 

For those wanting an intellectually rigorous overview of a fascinating field that provides a foundation for a viable path forward, Living Weapons is a great addition to one's library.

Why Do People Fear Pink Eye so Much?

One of my general frustrations is the inability of many people to be able to accurately weigh the risks of certain conditions. It was strikingly apparent with last year's panic over Ebola and the lackadaisical approach many take to the perennial killer influenza. 

A condition that strikes fear into the hearts of daycare operators and babysitters alike is pink eye. Pink eye is the colloquial term for conjunctivitis, inflammation of the white of a person's eye. It is extremely common, especially if you wear contact lenses. It has various causes some of which are actually contagious (or infectious for that manner).

Viral causes are largely due to adenovirus and can be extremely contagious, but disease is self-limiting and simple hygienic practices such as not sharing towels, face clothes, and frequent hand-washing are advised. No specific treatment other than topical decongestants is required. Bacterial forms, often characterized by the pus-induced matting of eye lashes after sleep, require topical antibiotic therapy. Allergic conjunctivitis is treated with topical anti-histamines and similar medications. 

While I don't dispute that it can be a real issue if a contagious form of conjunctivitis is marauding its way through a day care center, it strikes me as paradoxical when a child with conjunctivitis--a mild benign illness--is exiled from school but those lacking vaccinations against such diseases as measles and chickenpox are welcomed with open arms.

If one were to gauge the severity of an infection only by the degree of fear, preparation, evasive action, and urgency by the general public pink eye, lice, crabs, bed bugs, and scabies would easily outrank measles, influenza, tuberculosis, and everything else.