Month: April 2014

Health stuff is often cyclic, and I’m in the unpleasant part of the cycle right now.  When the first derivative is negative it’s easy to feel like everything will get worse forever, so here’s a list of things that are objectively better than they were a year ago, even after the recent backsliding.

1.  My overbite.  I’ve had it since childhood.  I was prescribed braces, but my mom eventually convinced my dentist my teeth were so bad that the increase in plaque due to difficulty in brushing would be even worse for me.  Two months ago, it disappeared.  I still pull my lower jaw in when I chew because I ground my back teeth down in the pattern of my overbite, but the resting position is now almost perfect.

2.  My dental health.  I’ve had on 4x/cleanings since childhood, and my last dentist spoke in terms of great Game of Thrones like battles to fight back the plaque.  She noticed a marked improvement as soon as I went on HCl, without me telling her anything had changed.  I just started with a new dentist and he’s less bracing for winter and more trying to make sure things tay as awesome as they are now.

3.  Oranges.  I used to hate oranges.  Two or three drops of orange juice in a full glass of water were all I could stand.  Now I eat them whole, without HCl.

4.  Auditory sensitivity (increased).  When I noticed discontinuities in the sound of my last audiobook (slight changes in the volume or tone) I put it down to cheap recording not standardizing between sessions.  But my current book does it too.  I wonder if every book has these, and I just didn’t notice until now.

I am so tired of medical shows having brave doctors lie to the evil transplant committee that is heartlessly denying a transplant request because the patient is deemed ineligible due to some stupid technicality.  Most recently I saw this on House, where a woman destroyed her heart with bulimia, which is apparently a disqualification for transplant, but it comes up on practically every medical show eventually.  The transplant rules didn’t arise out of some Puritan sense of punishing people for their sins: it’s because eating disorders have a high relapse rate, and a relapse would destroy the new heart too.  By lying and getting her the heart, Dr. House killed whoever would have gotten the transplant instead. 

I’m sure that transplant committees make mistakes, that they’re manipulated by fame and money, and that the guidelines are imperfect.  But they’re not there to be mean, or to “punish” people for their transgressions.  They’re there because there are far fewer donor organs available than are needed, and in light of that scarcity, we want to make sure the organ goes to the person who will get the most additional life out of it.   If a patient has a condition that will lessen the use they get out of the heart, that lowers their priority for a transplant.

Maybe I’m wrong.  I don’t know what went into creating the rules, maybe they’re biased and terrible.  But if so, the appropriate reaction is to say that and fight them.  Not kill someone else because it will make you sad to tell your patient they’re going to die.

Similarly, House, stop lying to get ineligible patients into clinical trials.  You mean well, but there are two options:  the treatment doesn’t work, and you bought your patient nothing, or it does, and you just artificially worsened the numbers, potentially taking it away from everyone else who would have benefited from it.

The other day I posted a link to this blog post on facebook.  The post reported on a study that showed a large difference in how law partners reacted to the same paper when told it was written by a black or white student- they wrote more negative comments, were less encouraging, and found more typos.  A friend of mine responded with “I believe there is systemic racism, but…”, which is never a great start.  He went on to make a bunch of criticisms which would have been  extremely fair to make in a journal club discussing a peer reviewed study, but in context came across as reinforcing the cultural pattern of “I refuse to believe in racism is a factor until it’s proven in each specific case.” Forcing victims of systemic discrimination to prove the discrimination gives them an additional burden on top of all that discrimination.  It’s not right and it’s not fair.  It’s also heavily intertwined with the idea that falsely believing something was affected by race is worse than ignoring discrimination.  

At the same time, I dislike the argument “you’re technically correct ” (which he absolutely was- the study was done by some consulting firm and didn’t even include statistics beyond the mean) “but don’t say it because it will encourage racists.”  Nothing good comes from quieting science.

Now that I know what inflammation is and have given you my personal view of depression, I can talk about depression as an inflammatory disease.  Most specifically, the article “So depression is an inflammatory disease, but where does the inflammation come from?” from BiomedCentral Medicine.  I’ll do some additional research as warranted, but mostly I want to talk about this article.  Prepare for deep dive.

Background: We now know that depression is associated with a chronic, low-grade inflammatory response and activation of cell-mediated immunity, as well as activation of the compensatory anti-inflammatory reflex system. It is similarly accompanied by increased oxidative and nitrosative stress (O&NS), which contribute to neuroprogression in the disorder. The obvious question this poses is ‘what is the source of this chronic low-grade inflammation?’

Translation:

• As I painstakingly established last week, inflammation means a chronic dilation of blood vessels allowing more stuff to leak into tissue.
• cell-mediated immunity involves producing new white blood cells in response to a specific antigen, as opposed to producing new antibodies in response to a specific antigen, or non-specific immunity that is not a response to anything in particular (example: skin).
• Almost every system in your body is moderated by a complex series of signals that can aid or inhibit one another.  Rather than just produce less of an activator to reduce a reaction, your body instead introduces an inhibitor.   Having high levels of both activators and inhibitors has similar primary effects to having low levels of both, but can be either cause weird secondary effects or be a symptom of something weird going on.  It’s also plain more stressful, just like keeping yourself steady against a strong wind is harder than standing still.  “[A]ctivation of the compensatory anti-inflammatory reflex system” implies that depressed people are falling in the “high levels of both” category.
• In the course of the day, your body naturally produces many types of molecules.  Some of those molecules contain oxygen, or nitrogen and oxygen, and a net negative charge.  These are the home wreckers of the molecular neighborhood, luring parts of other molecules to dump their other halves and bond with them instead.  This is a problem if that other molecule is doing something important, like being the blueprint for every other protein in your body.  The damage these homewreckers cause is called oxidative stress.  Your body has ways to contain it, but not perfectly.  Oxidative/nitrosative stress can arise either from producing too many of the reactive molecules, or from a deficiency in the post-processors.
• Fun fact: we don’t know if Nitric Oxide is a pro- or anti-inflammatory messenger.  It looks the answer may be “anti- under normal circumstances, pro- under times of stress”, which implies but doesn’t prove that it’s primary effects are anti-inflammatory, but the containment mechanisms break down under stress and cause a lot of damage.

Discussion: This review explores the role of inflammation and oxidative and nitrosative stress as possible mediators of known environmental risk factors in depression, and discusses potential implications of these findings. A range of
factors appear to increase the risk for the development of depression, and seem to be associated with systemic inflammation; these include psychosocial stressors, poor diet, physical inactivity, obesity, smoking, altered gut permeability, atopy, dental cares, sleep and vitamin D deficiency.

Translation:

• Two very common bad things seem to have a lot in common.  I think there’s a lot of merit to their hypothesis, but this venn diagram does not impress me.

Summary: The identification of known sources of inflammation provides support for inflammation as a mediating pathway to both risk and neuroprogression in depression. Critically, most of these factors are plastic, and potentially amenable to therapeutic and preventative interventions. Most, but not all, of the above mentioned sources of inflammation may play a role in other psychiatric disorders, such as bipolar disorder, schizophrenia, autism and post-traumatic stress disorder

Translation:

• If we are right, this suggests several really easy ways to treat, cure and prevent depression, and potentially other psychiatric issues.

Oh wow, apparently you can induce depression-like symptoms by activating the immune system, either by triggering it with a toxin or just injecting some cytokines (a broad class of messenger, many of which signal the immune or inflammatory system) directly.  SSRIs (the most common class of anti-depressants) decrease production of proinflammatory cytokines,* and a return of symptoms is often associated with the loss of these effects.

The authors then go on to cover in detail various things you already knew were bad or good for you (Sleep- good.  Chronic stress- bad).  The research isn’t at the stage where it’s generating novel recommendations yet.  Which is not a criticism, it’s an impressive set of basic science work and it takes time to translate that into practice.If you are deeply interested in the biochemistry I encourage you to check it out, but I have no more to add.

*SSRI stands for selective serotonin reuptake inhibitor.  Because serotonin is a neurotransmitter, we originally assumed SSRIs treated depression by making serotonin more available.  Except serotonin levels change within hours of taking an SSRI, but the anti-depressant effects takes weeks to show up (unless you’re bipolar, in which case they can trigger a manic phase almost immediately).

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.

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.

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:  macrophages, dendritic cells, histiocytes, Kupffer 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.

 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.