Chronic and Systemic Inflammation

If I’m reading this correctly, there is no bright line between acute and chronic inflammation.  Chronic inflammation is acute inflammation that didn’t go away.  Over time this may lead to accumulated effects, and the distribution of mediators and their sources may shift, but there’s a lot overlap.

There’s a few ways chronic inflammation can hurt you.  One is that is releases immune cells (aka white blood cells)  into your tissues.  Didn’t I list that as one of the features of inflammation last time?  Yes, yes I did.  When you have an infection in the tissue, you want immune cells there to go after it.  But if letting immune cells run around organ tissue didn’t have any side effects, we’d do it all the time.    Immune cells are very very good at distinguishing foreign body from host , but not perfect.  The more time they spend in the trenches, the more likely they are to misidentify a host protein as dangerous and attack.  In the worst case this triggers a really ugly autoimmune disorder.  In a milder case it triggers more inflammation.   I think you can see where this is going. So much like being in a hospital or on crutches, you want your immune cells to be circulating in tissue for as long as you need, but no longer.

Similarly, some of the proteins released during inflammation (aka positive acute-phase proteins), which do useful things like signal inflammation, coagulate blood, or retard microbial growth, can change shape* and become insoluble.  These form fibrous  masses in intracellular space known as amyloids.  Amyloids are or are associated with some of our most terrifying diseases, like Alzheimers and Mad Cow Disease, and the amyloids from inflammation can contribute to these, although they’re not necessarily the most important part.

Chronic inflammation can be self-reinforcing in other ways.  Swelling is just about the least useful reaction to an ingrown toenail, but it’s what we do.

Everything I’ve talked about so far has been local inflammation, where the reaction is contained to one identified area.  There is also systemic inflammation, in which the vasodilation is body-wide.  It’s associated with all sorts of bad things, including overeating and obesity, which immediately makes me think we don’t know the real issue because both those topics are moral panics in our society.

*Quick lesson in proteins.  Proteins are made of up a long string of amino acids.  The order of amino acids is called the primary structure.  Individual bits of those string fold themselves into 3-d structures such as the ß-Hairpin and  Greek Key.  Those structures, also known as motifs, make up the secondary structures.  The motifs in turn interact to form the total three dimensional shape of the protein, which is the tertiary structure.  The tertiary structure is determined by the electrical charges and physical shape of the primary structure.

In general, a given primary structure has a single tertiary structure, because there’s only one island of stability.  However it is possible for a second island to exist, and the protein to convert to it- either it’s more stable in a new environment, or something catalyzed the reaction and it can’t go back.  Very, very rarely, this new tertiary structure is capable of catalyzing other proteins of the same type to its new shape.  These are known as prions (e.g. Mad Cow Disease) and they awesome and terrible.

Career stuff

I went to an open house for a local nursing graduate school.  I accomplished my main goal, which was to learn the practical difference between an MSN, DNP, and PhD.  Answer:  any one of these allows you to sit for the Nurse Practitioner licensing exam.  MSNs are purely applied.  PhDs are mostly research although you can maybe do some application (i.e. treating patients) if you really want to.  DNPs are about taking new research and applying it.  In an ideal world a DNP and a PhD pair up and the DNP applies the PhD’s research and tells them which of their theories were killed by ugly gangs of facts, and suggests new things.  I don’t see how anyone could what something other than a research heavy DNP or application heavy PhD, but I also don’t understand how anyone could want a specialty other than psychiatry.  Which reminds me, apparently there’s a lot more funding for psychiatric NPs than any other specialty because demand so outstripes supply, because psychiatry is stigmatized among both NPs and MDs.  Which is terrible for the world but super convenient for me personally.

Meanwhile, I have my day job as a software developer.  I don’t like it, and while I could always move companies I don’t think I’ll truly be happy in any programming position and the energy would be spent on my future nursing career.  But I might as well make the most of it while I’m stuck, and I’m looking for skills I can learn now that will apply later.  There’s not a ton of overlap between medicine and programming, but one thing that is always useful is public speaking, so I’m volunteering for every public speaking opportunity I can grab.  A day after I reached that conclusion I realized social skills are also universally useful, so maybe I should stop working so very hard to avoid my co-workers.  I do not like this conclusion.  Many of my co-workers are deeply unpleasant people + office is sensory hell = I spend most of the time feeling like I’m about to be eaten by a tiger.  These are not ideal circumstances in which to learn.  But I’m told hospitals are pretty noisy too, and while I strongly feel like I’ll handle it better when it’s in service of something I believe in, greater noise tolerance would greatly expand my options.  

Of course, that’s what the OT is for.  And it’s working.  It also spontaneously corrected my overbite, which is weird because we hadn’t done anything directly to my head. But I think it’s time to take some test runs of social interactions under my control, rather than wait to have them inflicted on me.

I wanted to talk about depression but first I have to talk about inflammation

Monday’s post was inspired by this paper on depression and inflammation.  Let’s dig in.

First question:  what is inflammation?  Allow me to translate the wikipedia article.

First, local cells detect that something is there that should not be.  Not every cell can do this.  Wiki’s list is:  macrophagesdendritic cellshistiocytesKupffer cells and mastocytes.  Every cell on that list is part of the immune system except for Kupffer cells, which are part of the liver.*  These cells all have pattern recognition receptors whose job is to identify molecules that represent a threat.  In a perfect world, they would recognize every threat and ignore every host molecule and harmless foreign matter.   In the real world, my body spent years convinced that tree pollen was a mortal threat and the only cure was blinding sinus pain.

When a particle activates the pattern recognition receptors they release mediators (the names, types, and specialities of these are easily a blog post in and of themselves) which cause blood vessels to increase in diameter (=vasodilation).  The most immediate obvious of this is increased blood flow, but the dilation also increases the permeability of the blood vessel walls, which allows fluid and protein to leak from the blood vessels into organ tissue.  With the help of a mediator, this also allows white blood cells, especially neutrophils ( the source of the best immune system chase scenes) into the organ tissue.  The additional fluid also increases flow to the lymph nodes, which is the in-body equivalent of getting a pathogen sample to the CDC: the lymph nodes study the fluid for pathogens in their tiny little lymph labs** and, having identified it, trigger the development of a counter-attack.    The mediators also increase the sensitivity of nerves to pain, to incentivize you not to re-injure the area.

And that’s how a physical insult becomes an acute inflammatory reaction.  If the insult is chronic, or if the inflammatory reaction becomes self reinforcing (e.g. inflammation makes an ingrown toenail more ingrown), it becomes chronic inflammation, which we will talk about on Friday, and hopefully get to the actual article on depression on Monday.

*If you’re me, you may have to remind yourself that dendritic cells != dendrites.

**Some day I’m going to learn how that process actually works and not pretend it’s a tiny reenactment of The Andromeda Strain, but the image will do for our purposes.

What I want to be when I grow up

Long ago, “fever” was considered an illness in and of itself, not a symptom.  Imagine yourself as an 18th century doctor with that mindset, but 21st century technology.  Sometimes people feel better after two days of rest and fluids, sometimes they die, sometimes they live but are permanently weakened.  Mostly it seems like the weaker people die, but not always.  Sometimes antibiotics help.  Sometimes they don’t.  Sometimes one antibiotic helps but another doesn’t.  Tylenol always seems to make people feel better initially, but sometimes the fever rebounds.  Sometimes interferon helps, sometimes it does nothing.  Some people who get a lot of fevers seem to benefit from anti-retrovirals (what we know now as the HIV cocktail), but lots of others don’t and they have pretty nasty side effects.  Vaccines don’t seem to affect lifetime fever numbers very much, but do reduce the occurrence of the fever with specific symptoms.  We can’t tell if working with animals makes you more or less likely to catch a fever.  You can make some guesses based on whether or not the person experienced recent trauma, associated symptoms, and the symptoms of people around them, but it’s essentially guess and check.

I think that’s where we are with depression and anxiety.  They’re real, just like fevers are real, but they are symptoms with many possible underlying pathologies.  We already know some of these: thyroid disorder, anemia, chronic abuse, vitamin D deficiency.  But we’re not even very good at screening for those, much less the fringier ones like sensory processing disorders or digestive disorders.*  And who knows what kind of neurological or developmental issues could produce.

It’s even trickier because depression/anxiety can cause a lot of physical problems.  It’s hard to eat well or exercise with a lead blanket on you.  The physical effects of stress are real and costly.  Whether the mental or the physical came first, they can rapidly form a self-reinforcing cycle.

As I’ve mentioned before, my hypochlorhydria was diagnosed when I went to a psychiatrist for anxiety.  It turns out a well founded subliminal fear of starving to death makes you antsy. I have a friend who had been diagnosed with dysthemia (mild depression) for years before she developed an eye thing and finally got diagnosed with adult onset, type 1 diabetes.  One possibility is that all the symptoms of depression were caused by insufficient insulin.  Another is that the anti-depressants damaged her pancreas and caused the diabetes.  This is why I want to be a psychiatric NP.  Therapists don’t get to do the physical side, medical generalists and other specialists don’t get to deal with the mind enough, and MD specialties are too isolated.  The idea of taking apart those vicious cycles and helping people rearrange the parts into what works for them is incredibly powerful to me.

Learning how to learn.

 My brother was a mathematical protege.  You know those kids who teach themselves to read as babies, and by the time anyone thinks to ask them to look at a letter flash card they’re already reading chapter books?  He was the mathematical equivalent.  He looked at problems and just knew what the answer was.  Sometime in elementary school he took at IQ test (a real one, administered by trained professionals) and scored perfect on the math section.  Meanwhile, I remember math as the only subject in elementary school I was bad at (it wasn’t- I also struggled with whatever foreign language they pretended to teach us that year.  But it was the only subject I was bad at that my parents cared about).

By age 18, I had finished three semesters of calculus and another of differential equations at community college, and I went on to take more when I matriculated at college for real.  I was very into computational biology, which involves very high level calculus. My brother got to pre-calc, maybe calculus, at high school, and never took any in college.  His first stumbling block was teachers that marked him off for not showing his work, even though his answer was correct.  They never understood that for him, there was no intermediate step.  The second stumbling block was when he met problems hard enough he stopped seeing the answer.  When I faced the same level of problems, I had toolkit of how to approach problems and derive answers, painfully derived from all the other, easier problems I’d seen but couldn’t solve.  He had nothing.  And so I eventually went much further in math.  Originally it was just because my parents insisted on a math class every semester and I wasn’t going to rock the not-going-to-high-school boat, but I eventually came to enjoy it because it was so easy and everyone else found it so hard.  I got a severe case of mono while taking differential equations and still got an A+, because the class simply wasn’t hard enough to measure the change.

I saw a miniature version of this playing Portal 2 with a friend (we were playing co-op after we’d each finished the individual campaign).  At lower levels he saw the solution before I’d even oriented myself in the room.  At higher levels he’d sit there stuck while I said things like “that’s the only piece of portalable wall, and clearly we need to use that wall paint for something, so let’s portal the paint over to there and see what happens.”  Translation for those of you who haven’t played Portal:  we have a bunch of parts, they can only connect in so many ways, let’s connect some likely looking ones and see what presents itself.  

I have several points I want to make about this.  First, I think we as a society tend to conflate the following: initial skill at a subject, speed of learning a subject, ceiling of ability in a subject.  My brother’s and friend’s initial abilities were higher than mine, but their ceilings appeared to be lower, in part because my initial skill level led me to develop skills we weren’t directly measuring.

The second one is more personal, more speculative, and will require more stories.  In a nutshell, I think math was the only thing I ever learned how to learn.

I mentioned I also struggled with languages.  When I struggled with math my parents put me down and painstakingly walked me through my homework until I got it right.  When I struggled with Spanish they said “yup, foreign languages are hard.”  I loved and love reading and writing, but when I started to get graded for them, and felt the grades were more about ability to fit the teacher’s conceptions than anything I enjoyed about reading or writing, I swore off all but the most mandatory English classes, and more generally anything “subjective.” I fell in love with behavioral biology at age 12 and took a staggering number of mandatory prerequisites in order to pursue it (seven semesters of chemistry, two of physics, plus all the biology you have to take before they let you get to behavioral*.)  But I don’t feel like I ever mastered any of the parts except those I was interested in.  I have this nasty tendency to just skim textbooks and fill in the complicated parts from context.  This worked way better than it has any right to- I graduated cum laude from Cornell University with a double major in computer science and biology- but not well enough.  I could have done better.  Not necessarily on anything Cornell was measuring, but better nonetheless.  

I was originally considering math for my second major at Cornell.  That died my first semester, when I was suddenly taught theory by people hired for their research rather than applications taught by people hired for their teaching.  Suddenly class was nothing but proofs, and I hated them.  Except that my eventual second major, computer science, also required proofs.  I hated them there too, for one semester, but they started to grow on me the second, and I went on to take multiple 600 level theory classes.  I loved the little logic puzzles.

I’ve been scared about nursing school because it’s a lot of physiology, which I did everything I could to avoid when I was studying biology.  I know I find it more interesting now than I did then, but that’s because everything I’ve done since is researching my own medical problems, at my own pace.  How will I handle having to learn what other people tell me to, on a timetable they set?

My first solution was a combination of denial, Trying Really Hard, and cramming all the knowledge I could into my head ahead of time.  This was not going to work.  But this kind of learning is a learnable skill, and that skill is something I can learn ahead of of time.

 

The implicit promise of good luck

Last summer, five year old Rebecca Meyers was diagnosed with brain cancer.   It was one of those bizarre situations where, aside from the malignant mass growing in her brain, she seemed to be really lucky.  Her family was vacationing far from home but near one of the best hospital she could hope to go to, and multiple family members and family friends were vacationing close enough to support her parents during the first few weeks.  The tumor extraction was a miracle of modern medicine.

Seven months later her brain is lighting up with new tumors.  She may not live long enough to have her Make-a-Wish Foundation wish granted.

I’ve been reading her father’s updates since she was diagnosed.  I have no connection to the family, but he’s a good writer and it’s a naturally dramatic story.  I didn’t realize till I read that she was definitely going to die that I had taken the initial luck as some sort of promise.  Subconsciously I believed that someone/thing must have arranged things so that she could receive such good care, and they wouldn’t bother unless they knew they could manage to pull her out on the other side.  I feel betrayed, and it’s definitely because of the initial good fortune, not the intervening positive results.

Maybe being by Children’s Hospital of Philidelphia was random chance.  Maybe there really was something magic taking care of her, but it ran out of juice or was given a higher priority or just screwed up.  And now a little girl is going to die and it just feels so unfair.

Flu Week/Book Review: Flu, by Gina Kolata

Flu‘s full title is Flu: The Story of the Great Influenza Pandemic of 1918.  It does not deliver what it promises, but what it does deliver is pretty neat.

From the title, I expected it to be about the biology and/or social effects of the 1918 flu pandemic.  I would have been perfectly fascinated by either of these.  The 1918 pandemic is one of very few plagues that was more deadly to healthy young adults than children and the elderly.  The only other disease I can think of that does that is HIV, and in that case it’s caused by the mechanism of transmission.  Both children and the elderly breathe, so that’s not the issue with the flu.  On a sociological level, the 1918 flu killed 3-5% of the world’s population, wiped entire villages off the map, and complicated the logistics of WW1.  How did people react to that?  How did it change society?  Flu talks a lot about how little the pandemic was talked about in the early aftermath, but nothing about how it affected society.

On the biological level, Flu raises several interesting mysteries. One, how did infections go from 0 to everyone so fast?  Even accounting for rapid transit, the disease seemed to spontaneously generate in multiple cities simultaneously.  Two, why did most of the victims suffer from an additional bacterial infection.  Was in opportunistic?  A co-infection that led to especially devastating outcomes?  She even hints that the answers may be related, but never returns to either.  My inner epidemiologist was heartbroken.

What Flu does talk about is how scientists have investigated these questions.  The anti-body work to demonstrate it was probably pig flu.  The ingenious methods of finding samples from a disease that died out 30-80 years ago.  Some of the politics of handling potential modern epidemics.  These are all fascinating, and important, and really hard to do well.  Demonstrating how science progresses is in many ways more valuable than any given scientific fact, which has a 50% chance of being proven wrong   I do wish Kolata hadn’t gotten my hopes up so high with the medical mysteries, but I would have happily read a book that promised exactly what this one delivered.