Caring For Lindy: Feeling Guilty

I've been caring for a cat with chronic kidney disease (which I learned was the proper term today) for a long time. Years.

Normally, I don't feel too guilty about things with Lindy. However, I can still remember a few occasions of intense emotion and regret.

One was when she was first diagnosed. She was two years old and I was in veterinary technology school. I'd learned in school that polyuria (increased urination) and polydipsia (increased drinking, which is most often a result of the polyuria) were not normal. I'd also noticed that Lindy was significantly PU/PD (shorthand for polyuric/polydipsic) compared to Simon. I brought her into her veterinarian's office and requested blood work. The vet said I was nuts but if I wanted to waste my money running blood work on a healthy two year old cat then she'd do it.

She called the next morning to say that Lindy was azotemic and her urine was isosthenuric. In short, she had chronic kidney disease. I felt like someone had just punched me in the stomach, wishing I had caught it earlier. I put Lindy on a kidney diet and she did well for awhile...

(Note for all my veterinarian readers-- looking back at her paperwork from the rescue group, Lindy had a high creatinine when she was spayed at six months. I'll never know if her problems stemmed from congenitally deformed kidneys or from one or a number of UTIs either when she was a feral kitten or possibly silent/not clinically symptomatic UTIs while she was in my care-- ultrasound at age 2 didn't show any cysts, which was my fear then, just gross structural changes)

She continued to do fine for several years.. until I left her with my then girlfriend in the Santa Cruz mountains for a weekend, where she had her first acute on chronic episode-- I suspect because my girlfriend deprived her of water for a long time (since cats with chronic kidney disease cannot concentrate their urine they dehydrate easily which leads to the kidneys getting less blood flow which causes further damage in a vicious cycle) but I'll never be able to prove the neglect. I still feel guilty for leaving her there that weekend. She's been on fluids ever since, 175 ml LRS every night (she's a big cat).

She's also on aluminum hydroxide and pepcid. Why? Up until this week all I knew was that the aluminum hydroxide was to bind phosphate, which was high. And that pepcid was for the uremia resulting from high levels of toxins in her blood (BUN, creatinine).

Well, I learned a whole heck of a lot more this week.

Gastrin is a peptide that is normally filtered at the glomerulus, but due to the decreased glomerular filtration rate in chronic kidney disease, gastrin is filtered less and so builds up in the blood. Gastrin stimulates hydrochloric acid release by increasing histamine release from enterochromaffin-like cells and hence the drug used to block its action is a histamine receptor antagonist, pepcid.

Phosphorous is also filtered at the glomerulus, and like gastrin its levels in the blood become increased as a result of the decreased glomerular filtration rate seen with chronic kidney disease. In fact, renal failure is the most common cause of hyperphosphatemia according to my notes.
And here is the part I was totally clueless about up until Friday-- consequences of hyperphosphatemia. My notes list two:
1. Metabolic acidosis. Inorganic phosphorous is present in many acidic forms so with hyperphosphatemia there is a buildup of acids.
2. TISSUE MINERALIZATION !!! Hyperphosphatemia also promotes increased calcium complexing with phosphorous. If excessive, it can lead to precipitation of the calcium-phosphorous complexes, allowing mineralization and damage within the soft tissues.

I didn't realize that when I frequently skipped giving Lindy a phosphate binder for weeks at a stretch around the time of my neuroanatomy final that she was probably beginning to mineralize her stomach, kidney and lungs. It's so incredibly awful that it makes me feel sick just thinking about it.

It's not all my fault though. Client education, folks. You can bet that I will explain to my clients exactly WHY they are giving the phosphate binder to their pet with chronic kidney disease and what the results will be if phosphorous levels are not kept from becoming high.

I wanted to cry all Friday afternoon after my chronic kidney disease function/dysfunction rounds. Instead I studied with a bunch of classmates. But I still feel terrible about it.

Feeling Lucky To Be In Vet School: Fish Lecture

I got to go to a really neat lecture last night that made me feel lucky to be in vet school. The lecture was titled "Aquatic Pet Cases Important For All Vets To Know" and was given by a local veterinarian from Buffalo, Dr. Helen Roberts. She owns an exotic practice and sees many clients with pet fish. She also writes extensively on the subject and is involved in all aspects of pet fish medicine.

I feel lucky to be part of a profession that is so diverse. I don't know if I will ever treat pet fish, but this lecture definitely piqued my interest and made me want to learn more about fish anatomy and medicine (both of which are covered in separate distribution courses offered during the winter that I may elect to take).

It's just neat to know that I could treat anything from a pet fish to an Amazon parrot as a veterinarian (if I chose to develop expertise in those areas).

Here are a few interesting points that I gleaned from her lecture:

• Water quality evaluation is part of the minimum database for fish.

• Poor water quality is the most common stressor of fish and kills more fish than infectious diseases

• How long has the pond been around is an important question to ask when treating fish who live in ponds.

• Signs of parasites include weight loss, abdominal distension and buoyancy disorders.

• Fluorescin dye can be used to show superficial ulcers on the skin of fish.

• You can do a neurological exam on a fish.
  

Guide Dog Puppy Love

Check out this adorable, squishably lovable German shepherd puppy dog that is in training to be a guide dog for the blind. See how attentive she is to her trainer in the top photo, see the intelligent, inquisitive look on her face? (I know she isn't wearing a jacket, but she's just a baby). Her current trainer will have her for 16-18 months. It's the kind of thing I hope to be able to do someday...

A Different Kind Of Spooning

The top photos is with my new camera (thanks again!). The bottom photos are from my old camera. Note how neatly I always make my bed.

Back To The Law School To Hear Shannon Minter Speak

Above: The law school on a typical rainy spring day. It reminds me a lot of the style of buildings at Duke, where my father teaches.

It's the unusual veterinary student who makes the long trek down to the law school on two separate occasions within one week. But it was well worth the effort. Hearing Shannon Minter speak was way more of a treat than the same-sex marriage debate with Maggie Gallagher last week.

Once again, I feel woefully inadequate trying to summarize what I heard. I'm just not that conversant in legal matters. But it was the first time I had heard anything substantial about Perry v. Schwarzenegger so that was super interesting. The one name that stuck in my mind was Ilan Meyer, who gave expert testimony on the effects of stress on minorities. Minter said that Meyer stated that a situation that is not inherently very stressful becomes stressful for a minority because it invokes the reminder that the whole social and legal system opposes them. I would be more eloquent writing about this if I had taken any notes and if it weren't fairly late on a school night when I have a lot else to do.

One interesting legal tidbit that I picked up is that it matters how California's Supreme court interpreted the victory of proposition 8 and their interpretation of it being a denial of rights to a minority, or something like that, might matter immensely in how the courts handle the current appeal. This was something I hadn't understood before-- apparently no higher court can redefine the meaning once constructed by the California Supreme court. Again, sorry if this makes no sense as this is not my area of expertise by any means.

While certain areas of law are incredibly fascinating, I am still responsible for learning the entire physiology of the kidney this week and so must get back to work.

I definitely felt Minter's excitement and anticipation when he talked about current legal cases. Suffice to say that while a substantial portion of my class has spent the last few days taking breaks to watch vampire flicks, I'd much rather be at the law school when I'm not studying. It's not even that it's a more meaningful diversion, it actually is more thrilling to me, there is more plot tension in the same-sex marriage legal saga for me than in any movie.

Remind Me Why I'm Going To School Again: Problem Lists

As the year has gone on, I've become progressively more disillusioned with school. It seems like a lot of what we do is memorize and regurgitate copious volumes of information. And the worst part is, I don't even remember a good portion of it past the exam.

I'm tired of memorizing. Besides, you can look just about anything up on the internet these days, or if you are more old-fashioned, in a book.

I've had two brilliant professors remind me this past week of why I'm here and what I'm ultimately supposed to be learning.

The first introduced my class to POMS, the Problem-Oriented Medical Scheme. As part of this, we learned a mnemonic for coming up with differential diagnoses, DAMNIT-V. It stands for:
Degenerative (chronic, progressive)
Anomalous (i.e. congenital abnormality)
Metabolic (systemic metabolic derangement)
Neoplasia
Infectious, Inflammation
Trauma, Toxin
Vascular (compromise blood flow to an organ)

I'm thrilled to have been given a more systematic way to approach cases and have started trying to come up with differential diagnoses using this scheme every time I hear/see/read about a case.

He also introduced us to the concept of a problem list, which comes before the differential diagnosis. A problem list is made from the initial abnormality list and has to account for every single abnormality in the smallest number of possible listed problems. It is also critically important that the problems do not include any assumptions and are only "defined to the highest level of understanding," not beyond.

Then on Friday, in our Function/Dysfunction Rounds, the professor (a different one) started by emphasizing the importance of a problem list to us again. He said that one of the most important skills we can develop as students is the ability to generate a good (i.e. concise yet complete) problem list, because from that one can then quickly come up with a list of differential diagnoses that does not miss anything.

And as it turns out, not missing anything is the name of the game. And my Achilles heel. I want to jump straight to the most likely scenario/differential diagnosis based on my clinical experience. And that is the biggest pitfall I have to learn to avoid. Tunnel vision is not just my problem, it plagues all veterinarians at various times and judging from my professors' stories, can lead to some truly horrific mistakes.

The professor lecturing on Friday said that something like 80% of cases could be diagnosed by someone who compiled a list of signs and used the internet. It's the other 20% that are tricky. But if you always go straight to the most likely diagnosis without making a list of differential diagnoses and ruling in/out/down each one then you will miss that 20%.

I guess it's a good enough reason to keep memorizing in the meantime.

But what I'm really interested in is the analytical thinking. One year and at the very end I finally get to the problem list. The tantalizing part. Now the question is how to get good at generating one. Of course, part of that is oodles more memorization so that I can actually come up with differentials that I don't even know now (yay for my bacteriology, virology, parasitology class next year).

At least I know that some analytical, critical thinking lies ahead, thank goodness.

Beautiful, Lazy Saturday: Pileateds And Lucifer Falls

Today was one of the most beautiful days we have had all spring in Ithaca.

I had a nice breakfast of French toast and spicy buffalo sausage patties with my roommate and then headed out to the Farmer's Market to pick up my usual weekly staples, bread, salad and apples. The guy that I usually buy my free range eggs from had duck eggs, which is something I've wanted to try for awhile so I picked up a few of those. I really like trying out new things at the farmer's markets. In California, I got into cooking fish that way-- there was a guy I'd buy fresh fish from every week and it was how I got my first taste of sand dabs, sablefish and squid. Here in Ithaca, I've been experimenting with different varieties of buffalo (from steak to heart to sausage though I have not yet been brave enough to try tongue) as there is a nearby buffalo farm that sells meat at the farmer's market.

On the way home from the farmer's market, driving up Stone Quarry road, a crow-sized bird with flashes of black and white on its wings flew across the road in front of me. I slowed down, turned my head and saw the unmistakable shock of red feathers on the bird as it landed on a tree trunk-- a pileated woodpecker! That makes the third time I have seen a pileated woodpecker in my life, the other two were in Maryland two summers ago.

In the afternoon, I went on a four plus mile hike in Robert H. Treman state park. I stupidly decided not to take my camera because I didn't want to slow down my roommate by taking a ton of pictures. We hiked up to Lucifer falls, which is quite an uphill at the end, and then back down. Although I didn't take photos, you can find plenty of photos of the falls on the internet if you're curious about what it looked like.

Earth Day Books

I woke up this morning not thinking about Earth Day, but an article that I found in my inbox from the Cornell Chronicle shifted my attention back to the environment for a second time this week. The article, "Rattlesnakes Sound Warning On Biodiversity," is about research on the impact of roads on wildlife. The conclusion? "Roads-- even small, low-traffic roads-- can fragment wildlife populations genetically."

This isn't the first time I've thought about this issue. I became interested in the impact roads have on wildlife population diversity after reading _People And Predators: From Conflict To Coexistance_, a compilation of research in different areas put together by Defenders of Wildlife biologists. It's defintely on the academic side, but very interesting reading and has a chapter by Bill Ruediger, "Carnivore Conservation and Highways: Understanding the Relationships, Problems and Solutions" that summarizes the subject incredibly well.
Shortly after reading _People and Predators_, I visited Yosemite with my parents and the local newspaper ran an article on speeding killing wildlife in Yosemite ("Speed Can Kill In National Parks") and how they were putting up signs at the most perilous crossings for wildlife to try to mitigate the problem. (Looking up this article on the internet all these years later, I can see that Mutlow won the 2009 Yosemite Fund Award for his innovative prevention programs-- "Red Bear, Dead Bear" and studies on how roads affected wildlife in Yosemite, pretty neat).

Two other books that I highly recommend pertaining to the environment are:
Wisdom For A Livable Planet
and Learning To Listen To The Land

Just in case you're looking for some reading related to Earth Day:)
And I'd be really happy if anyone wanted to leave a comment with more recommendations of environmentally conscious, interesting reading. Thanks!

The Week In Review: Horsey Stuff, Same-Sex Marriage Debate At The Law School

Above: Mares and foals.
Below: Me and other students at the law school, protesting speaker Maggie Gallagher.

Among the useful skills I have learned this week (I wish I could say have mastered, but that is far from reality, more accurate would be to say "among the many skills I've been introduced to this week...")--
at any rate, are shoeing horses, de-shoeing horses (is there a term for this?) and restraining foals. I have no photos of the shoeing part because that involved cadaver feet and so was not particularly photogenic.

I was not surprised to find that shoeing or de-shoeing a horse, as it may be, requires some strength. I was, however, most definitely able to do it despite a bit of a struggle. The farrier informed us that it takes on average an hour and a half to shoe all four feet of a horse. It's a labor intensive, physically demanding job.

I was more surprised to find out that while foals appear cute and perhaps even cuddly to some, they are a pain to handle! They kick, bite, toss their head about and are generally unpredictable and uncooperative. And I'm told the foals we were working with were relatively easy to handle compared to most. I am glad, for the umpteenth time, that I am not going into equine medicine. It is definitely not my calling. I'm also incredibly impressed with my classmates who seem to be able to handle horses calmly and competently, and am exceedingly grateful that such people exist.

Sorry if the next part is a bit discombobulated... I am quite ignorant about law and so that makes it challenging to follow cases or write about them.

The debate on same-sex marriage at the law school between conservative Maggie Gallagher and Cornell Professor Cynthia Bowman was a nice change of pace from the issue du jour for first year students at the vet school this week, coagulation.

The main thrust of Maggie Gallagher's argument seemed to be that it is a misrepresentation to argue that the legalization of same-sex marriage will not have negative consequences for religious Americans. She did concede without argument that First Amendment protections would keep churches from being forced to perform gay marriages. What she purports to be concerned about is that anyone who does not support gay marriage in the future will be treated akin to someone who espouses racist views today, that there will be no acceptable room for dissent. She also brought up the impact of non-discrimination policies on church groups (and here she loses me a bit because non-discrimination policies that include sexual orientation are in place in some states that haven't legalized same-sex marriage as far as I understand it so the connection to same-sex marriage seems a bit fuzzy to me). Catholic charities in Boston apparently stopped operating its adoption agency after the legalization of gay marriage in that state because it did not want to have to be required to facilitate adoptions to gay couples. Gallagher would really, really like to see exceptions made for church groups in such cases, and made an argument that it would be akin to the exceptions granted to doctors who will not perform abortions.

Of course, the Ocean Grove, NJ case involving the beach front pavilion came up (I cannot summarize this case at this late hour other than to say it was church property that it has been contended was being used as public property and the church got into hot water when it denied use of the property to a lesbian couple that wanted to perform their civil union ceremony there). I barely follow legal arguments and am already sick of this case. I almost wish the ruling had gone the other way so that it wasn't used so much.

What didn't come up, interestingly, was a case heard in the Supreme Court this week regarding UC Hastings College of the Law's Christian Legal Society (read here and here). This seems to be exactly the kind of case that Gallagher is arguing will impinge on religious liberty (her terms) since the group is in court for wanting to deny the ability to vote and hold leadership positions to students who do not share their anti-homosexual beliefs and the law school believes that violates their non-discrimation policy. At least to the best of my understanding of the case, which is complicated.

Back when I was in high school, I believed in the importance of open dialogue between conservatives and liberals as a way to create understanding and tolerance (for acceptance is not always possible) on both sides. In fact, I gave my valedictory speech on this very subject, having been deeply affected by the then-recent assassination of Israeli Prime Minister Yitzhak Rabin by fellow Israeli and right wing extremist Yigal Amir. I hoped that by bridging the gap between polarized segments of society with debate, similar tragedy would be prevented in the United States.

Almost half a lifetime later, I am more skeptical of the usefulness of debate for creating understanding, more entrenched in my views and less inclined to try to be all-inclusive. I think gay marriage is long overdue. And I tend to agree with Gallagher that as gay marriage gains acceptance and becomes legal in more and more states, there will be less and less of a tenable position defending a position against same-sex marriage. I believe that in time, homophobia will be seen as analogous to racism. I'm OK with that. I don't want to create room for dissent about what constitutes discrimination when it comes to gay rights. I want it to be perfectly clear that gay rights are human rights.

And so I left the law school thinking about how I have changed in my views on the purpose of debate on such topics. And also pondering some of the legal nuances (at least nuances to me, about arguing from a point of religious liberty versus equality, something Professor Bowman said that I definitely cannot recapitulate at this late hour, sadly).

And in less than eight hours I will be sitting in CPS rounds on oncology, so it is definitely time for bed!

Supreme Court Rules Dog Fighting Videos Legal

I'm about to be late for cardiology rounds so I'll have to write more on this later, but I spent a little bit of time yesterday pondering free speech and dog fighting videos. If you didn't read about it yesterday morning, here's a link to the New York Times article and here's a link to CNN's article on the subject.

The only time the Supreme Court has ruled a form of speech undeserving of First Amendement protection was child pornography, back in 1982. Chief Justice Roberts stated that child pornography is a special case because "it is intrinsically linked to the underlying abuse."

How are videos of dog fighting not intrinsically linked to the underlying abuse?

Justice Alito, the lone dissenter, did argue for the similarity of child pornography to animal cruelty, stating that it is difficult to eliminate both practices without also eliminating their depictions and that neither make meaningful contributions to society. (per NYT article)

It seems the crux of the issue is not whether dog fighting videos are intrinsically linked to the practice of dog fighting but whether the law was too broad in its scope. Since the law made it illegal to sell depictions of animal cruelty, Justice Roberts argued that it makes the sale of videos or magazines depicting hunting illegal in places where hunting is banned. I'm pretty ignorant when it comes to law, but I don't totally see how this follows. I guess it depends on whether hunting is classified as animal cruelty, and perhaps if it is banned it is then classified as animal cruelty? I am personally not opposed to hunting and see a big distinction between hunting and dog fighting or crush videos but it seems the law somehow failed to make a distinction between these activities.

If it is the case that the law was struck down because it was too broad, then I certainly hope that it will be replaced by a law more narrowly defining animal cruelty in very little time. The Humane Society called for this, stating "Congress should within a week introduce narrowly crafted legislation to deal with animal crush videos and illegal animal fighting activities." (per NYT article)

In the absence of new legislation, it seems a given that there will be a surge in the sale and production of crush videos, in which women stomp animals to death. That would be a step backwards since the law had effectively curtailed the market for crush videos since being passed in 1999.

I have to get back to studying, but this is definitely interesting stuff to ponder and if I had a little more time I would go and pull the actual text of the rulings themselves. It's certainly interesting to me that the Humane Society, other animal rights groups and 26 states backed the government striking down this law (per CNN's article).

I also wonder about freedom of speech with regards to artistic expression. The whole debate also brings to mind one of my good friend's favorite films, Amores Perros, a 2000 Mexican film that includes graphic depictions of dog fighting (I don't know to what extent the dogs were injured in the filming but it is disturbing and meant to be so). I do think there is value in that film, and so I can see how it becomes a thorny question to protect both free speech and halt animal cruelty.

When I Retire: Volunteering For The Environment (Well, Actually, Even Before)

They always say it is never to early to start thinking about retirement, right?

I was happy to read that volunteering for the environment can do wonders for you in retirement (and I suspect before as well). A recent study done by researchers from Cornell found that "environmental stewardship is strongly linked to greater physical activity, better self-rated health and fewer symptoms of depression over a period of 20 years" in retirees. (I could only dig up the abstract for the original article but there is a review of it in the Cornell chronicle, you can access it here: "Study: Environmental Volunteering Linked To Improved Mental And Physical Health In Retirees." The review of the article emphasizes that, "researchers found that environmental volunteers are half as likely as non-volunteers to show depressive symptoms 20 year later, whereas other forms of volunteering lower one's risk by roughly 10 percent." Amazing stuff.

I particularly like this quotation from one of the study's authors, "Time spent outdoors in the natural environment is a critical factor linking volunteering to the health outcomes observed in this study." Interesting. Time spent outdoors is good for you!

Of course, I also noted that although the researchers were from Cornell, the study was done in Alameda, California. My idea of heaven as far as outdoors goes. So to reap the full benefits of environmental volunteerism in retirement you might have to move to California. I'm just saying...

At any rate, one more reason to care about the environment: it's good for you.

HT's Mean Electrical Axis

In lab last week, I calculated the mean electrical axis of my heart lying down, lying on my left side and standing (above). It's a bit of a rough calculation as the grid is very small so it is hard to denote small differences in numbers.

According to my notes, "If an ECG is read from all three leads, the MEA with respect to the plane of the chest can be defined by calculating a vector based on the directional component from each lead, as determined by the 'net amplitude' of the QRS in each lead."

Also according to my notes, the normal mean electrical axis for a human is +59 but anywhere from 45-90 is OK.

As I understand it, it is basically telling me the direction in which depolarization is occurring in relation to the rest of my chest.

The Wonders Of Adrenalin Rushes, aka β-adrenergic Agonist Effects On The Heart

For a long time, I've been fascinated, on a personal level, with what occurs mechanistically during an adrenalin rush. For as long as I can remember, I've suffered intermittently with nightmares, waking up occasionally to huge adrenalin rushes. Sometimes I lie in bed and try to picture what is going on at a molecular level in my body. Every year in school, I fill in the details in this picture a little more. This year I've flushed it out quite a bit.

Let's start with epinephrine or norepinephrine binding to the β1-adrenergic receptor in the heart. The β-agonist-receptor complex binds to a stimulatory guanine nucleotide binding protein (Gs), which is then activated. The activated Gs stimulates adenylyl cyclase to produce more cAMP, which leads to the activation of cAMP-dependent protein kinase (PK-A).
Activated protein kinase A phosphorylates several sites within the cardiac cell, notably:

• the L-type calcium channel
• phospholamban, a regulator of sarcoplasmic reticulum calcium pump activity
• troponin I
• the cardiac ryanodine receptor (RYR2)

Let's tackle the effects of these phosphorylation events one by one.

Phosphorylation of the L-type calcium channel makes it more likely that the channel will open when an action potential depolarizes the membrane potential. Calcium channels are different from sodium channels because in addition to voltage and time dependent gates they have a calcium dependent gate/regulatory component. My professor, Dr. Gilmour, writes, "In the resting state, a certain fraction of the phosphorylation-dependent gates are phosphorylated and are, therefore, open. However, no current can flow through the channel because the voltage-dependent activation gate is closed. As the cell is depolarized past the threshold for opening of the activation gate, the channel opens and calcium enters down its concentration gradient." He adds, "The primary physiological mechanism for increasing ICa is augmentation of calcium channel phosphorylation by activation of β-adrenergic receptors."
What does this mean? More open calcium channels means more calcium ions entering the cell and this leads to more calcium released from the sarcoplasmic reticulum via calcium-induced calcium release and this culminates in an increased strength of conraction. (From Dr. Fewtrell, "The calcium ions binds to troponin C which allows myosin to bind to actin. Calcium influx into mitochondria also stimulates mitochondrial metabolism to provide the ATP necessary to sustain contraction.") In short, by phosphorylating L-type calcium channels you get increased contractility (i.e. heart pounding)

What happens when you phosphorylate phospholamban? First off, phospholamban is an inhibitor of the sarco(endo)plasmic reticulum calcium-ATPase (SERCA) pump. The function of this pump is to pump calcium back into the sarcoplasmic reticulum (SR). When phospholamban is phosphorylated it can no longer inhibit the SERCA pump, which means that calcium is pumped back into the SR more rapidly. This leads to faster relaxation in the cardiac myocyte. As a result of being able to relax more quickly, the cardiac myocyte can also contract again more quickly, hence the ability to raise the heart rate significantly (it might seem counter-intuitive that relaxing more quickly would lead to a higher heart rate but in order to contract, a cell must first relax so that the ion channels are not in the refractory state where they can't be stimulated, i.e. closed).

Phosphorylating troponin I decreases its affinity for calcium ions, which also promotes relaxation, in this case by removing it from the myofilaments. Faster relaxation means that the cardiac cell can contract again more quickly, enabling a higher heart rate.

Phophorylation of the ryanodine receptor (RYR2 in cardiac myocytes) increases the permeability of the ryanodine receptor to calcium and leads to more calcium being released, which leads to more calcium binding to troponin C and more actin-myosin interactions and ultimately an increased strength of contraction.
*
This still doesn't answer the question of how adrenaline raises your heart rate, it just explains how it is possible to achieve a higher heart rate, not where the actual signal comes from. I know that epinephrine and norepinephrine bind to β1-receptors in the sinoatrial (SA) node. So I consulted the internet and found that they decreases the conductance for potassium and increases the conductance for calcium and sodium, which means the pacemaker current If (the funny current) is enhanced. As a result the pacemaker potential reaches threshold more quickly and there is a faster firing rate from the SA node that sets the heart rate (i.e. heart racing). Don't hold me to this because it is not from my notes.

So there, that's a fair amount to think about next time you are lying in bed at night awake. And I didn't even touch on the α1-agonist effects of epinephrine and norepinephrine that are occurring simultaneously!

Cardiology Confusion II

Above: My tutor group's depiction of our final understanding of heart failure.
Below: My notebook version of the whiteboard flow chart. I'm messy.
Overall it is a compilation of all my reading and flow charts from Ettinger's Internal Medicine, Duke's Physiology of Domestic Animals and Cunningham's Veterinary Physiology with the actions of drugs in hot pink. I'm creative like that:)

Cardiology Confusion I

It's been a long week. We're back in tutor group, which is Cornell's problem based learning format. I came to Cornell in large part for the problem based learning aspect of the curriculum, and as I anticipated, it definitely beats sitting in lecture all day. That said, it can be pretty exhausting. I forgot just how much work it can be since last being in tutor group in the fall.

What can make problem based learning so time consuming is that it is often very open-ended. My group made a big effort to make our "learning issues" very specific, but I still ended up researching subjects as enormous as "the progression of heart disease." In fact, I spent Wednesday afternoon, evening and part of the night as well as Thursday evening trying to teach myself everything there is to know about the progression of heart disease. In retrospect, this was a completely ridiculous expectation on my part as their are whole books written on the subject, and some important species variations/predisposing factors, but at the time it somehow seemed entirely reasonable to me. And to my credit, I did a good job of covering a whole heck of a lot of ground those twelve hours in the library.

So for those of you who are interested, here is an abbreviated chronicle of my discoveries.

First off, I approached the problem of the progression of heart disease with the wrong paradigm in mind. I assumed initially that it had to be anatomical changes, such as degenerating mitral valves, that were driving the disease progression. This is true sometimes. But what is more true is the principle that compensatory mechanisms that work in acute situations actually cause the progression of heart disease when they are chronically activated. This finally sunk in after reading that, "Clinical signs observed in heart failure are mainly the result of chronic activation of compensatory mechanisms to restore and maintain blood pressure." And, "A common characteristic of all compensatory responses is that the short term effects are helpful but the long-term effects are deleterious."

With my new perspective, I tackled the compensatory mechanisms that are triggered by heart disease rather than looking for anatomical changes leading to heart failure (however, the two are not totally unrelated). This was after reading a great deal about myxomatous degeneration, genetic factors leading to valvular degeneration, and other factors promoting degeneration of valves such as the loss of the endothelium.

I identified three separate compensatory pathways that result from low blood pressure and volume or pressure overload: activation of the sympathetic nervous system, activation of the renin-angiotensin-aldosterone-system and hypertrophy (eccentric or concentric) and followed each pathway until it led to decompensation (i.e. ultimately feeding back on low blood pressure and creating a vicious cycle).

Then I went and read about drugs that are commonly used to treat heart disease/failure-- their mechanisms and how they alter the compensatory pathways and progression of the disease.

I got really hung up on two points. First, I couldn't understand how mitral valve regurgitation (which is very common in older dogs and was part of the presenting problem in our case) led to low stroke volume. The equation for stroke volume is:
stroke volume= prelooad + contractility -afterload. Well, none of these were changed by the mitral valve regurgitation and so I went in circles trying to understand how the stroke volume was reduced. It turns out to be a special case-- stroke volume is decreased because a portion of the blood is flowing backwards into the left atrium, not due to the other parameters at all! Sometimes it pays to think outside the box a little bit.

I also got stuck on the subject of volume overload. I knew that there had to be volume overload because of the eccentric hypertrophy (which is triggered by volume overload and increased diastolic wall stress in simple terms, though as I discovered after consulting several sources, no one really knows exactly how these factors trigger hypertrophy/what the exact mechanisms are). The key to thinking about the cardiovascular system is that it is a CLOSED system. What the heart pumps out returns to the heart (except in special cases such as hemorrhage). So how does mitral valve regurgitation cause volume overload? I kept thinking that if more blood is showing up in the left ventricle, then it must somehow be lost from another part of the system, but where??? Of course, this doesn't makes much sense. What a kind and brilliant professor finally explained to me is that the volume overload is a result of the low blood pressure (that comes from the low cardiac output that comes from low stroke volume that comes from a significant portion of the blood flowing back into the left atrium instead of the aorta). As a result of the low blood pressure, glomerular filtration rate is reduced, and so less fluid leaves the system, leading to volume overload.

And then there is the whole subject of the renin-angiotensin-aldosterone system that kicks in to help raise blood pressure. But doesn't help long term. I spent quite awhile pondering this as well. From my beloved Boron and Boulpaep (yes, I'm having an affair with my physiology textbook): "Common to these edematous diseases is an abnormal shift of extracellular fluid away from the effective circulating volume... The reason that most of this added extracellular volume remains ineffective and does not restore the circulating volume is not intuitive but reflects the underlying disorder that initiated the edema in the first place. Thus treating these diseases requires generating a negative Na+ balance."

If you made it to the end of this post, you deserve an award. I'm so tired that I am going to bed shortly. Trying to learn the physiology of the cardiovascular system in one week was way too much work but I think I've got the core concepts finally:)

My Favorite Videos From Vet School Year One

This one, Lucy and Ethyl in the chocolate factory, was part of a meiosis lecture in block I. It pretty much sums up what it feels like to be in vet school, my all time favorite so far.

This one, Living Arrhythmias, was in our cardiology lecture today, pretty hilarious. (Note, it's old time, no sound).

And this one, Pinky and the Brain, shown at the end of our neuroanatomy course as comic relief to counter our stress about the final, was most people's favorite.

Mechanisms of Drugs Affecting the Parasympathetic and Sympathetic Nervous System

Our second week of physiology lecture ended with a laundry list of drugs whose mechanism of action we had to memorize (thankfully not too long). I feel grateful that I've seen some of these used in practice so have some context for their use. I also learned a fair bit about some of these drugs in tech school. Still, it gets tiresome having list after list of things to memorize (I know, welcome to vet school).

For anyone who cares to follow along here is a quick cheat sheet;
Nicotinic receptors are found at ganglia in the parasympathetic nervous system (PNS) and sympathetic nervous system (SNS) as well as at the neuromuscular junction. They are ionotropic channels.
Muscarinic receptors are found at the neuroeffector junction in the PNS and at the neuroeffector junction of sweat glands in the sympathetic nervous system (except in the horse, which has adrenergic receptors). They are metabotropic, or G-protein coupled receptors. There are five types of muscarinic receptors but their significance was not emphasized to us.
Adrenergic receptors are found at the neuroeffector junction in the SNS. They are also metabotropic receptors and come in several flavors, or subtypes.
α1: generally excitatory, contractile on postsynaptic membrane
α2: mostly on presynaptic membrane, part of negative feedback mechanism
β1: mostly found on heart
β2: blood vessels, bronchioles, liver (smooth muscle and metabolic)
β3: adipocytes

Cholinergics:

Atropine: Muscarinic antagonist. Competitive inhibitor at parasympathetic neuroeffector junctions. Can block nicotinic sites only at very high concentrations.
Heart: Tachycardia, but the degree depends on the species' vagal tone, which is high in horses and dogs, producing marked effects in those species.
Blood vessels: Very little effect. Will block vasodilation induced by choline esters.
GI and Urinary Tracts: Reduce tone, motility, secretions
Respiratory: Increase luminal diameter, decrease secretions of bronchioles
Eye: Mydriasis, cyclopegia, increase intraocular pressure
Sweating: Impaired (horse is an exception)
Salivation: Reduced (dry mouth)
CNS: Moderate doses stimulate medullary and higher centers, eventually death by medullary paralysis

Bethanecol: Muscarinic agonist. Parasympathomimetic. More resistant to hydrolysis by cholinesterases than acetylcholine, so it has a longer duration of action that Ach. Never heard of this drug and not sure why someone would use it.

Edrophonium: Anticholinesterase (inhibits enzyme that breaks down acetylcholine, the neurotransmitter at the muscarinic junction). Shortest acting anticholinesterase. Used to diagnose myasthenia gravis (an immune disease where the muscarinic receptors are attacked and subsequently decreased in number).

Neostigmine: Anticholinesterase. Lasts for a few hours. Can be used to treat myasthenia gravis.

Pilocarpine: Muscarinic agonist. Parasympathomimetic. Treatment for glaucoma, lowers intraocular pressure.

Adrenergics:

Albuterol: Selective β2 agonist. Bronchodilate while minimizing stiumlation of the heart. I saw terbutaline used more often to treat asthmatics than albuterol, not sure why from this class. (Maybe later, as a first year there is always later!)

Epinephrine: Directly acting adrenergic agonist. Non-selective for α or β receptors.

Phenylephrine: Directly acting adrenergic agonist. "Pure" α-receptor agonist. Not sure why I've never seen this used in practice, instead always saw use of epinephrine.

Isoproterenol: Directly acting adrenergic agonist. Non-selective for β-recptors.

Phenoxybenzamine: α-adrenergic antagonist. Irreversible non-competitive antagonist that covalently attaches to receptors. I saw this used in the treatment of UO (obstructed cats) with a urinary catheter in place. I always thought it decreased spasms in the urethra. Now I know it blocks the contraction of the urinary sphincters.

Phentolamine: α-adrenergic antagonist. Competitive antagonist. Not sure when this is used.

Propanolol: Non-selective β-adrenergic antagonist. Primarily used to decrease blood pressure, excitability and work of the heart (decrease in heart rate, force of contraction, and cardiac output). Since it blocks β2-receptors in addition to β1-receptors it also blocks bronchodilation and can cause hypoglycemia. Therefor it should not be used in asthmatics or in the case of allergic reaction. It is also contraindicated in diabetes with insulin treatment. Interestingly, this drug is now being used to treat stage fright in people since it prevents the racing heart without affecting the mood.

Metoprolol: Cardioselective β1 antagonist. More potent for cardiac effects. Avoids the side effects of blocking bronchodilation and potentially causing hypoglycemia associated with propanolol. Never heard of this or seen it used either but sounds useful in certain cases.

Pain Receptors And Chili Peppers, Garlic, Wasabi And Menthol Mints

We had an interesting lecture this week titled "Molecular basis of nociception." Hot chili peppers (specifically the chemical capsaicin) induce pain by binding to transient receptor potential vanilloid-1 (TRPV1), an ion channel of non-selective cation permeability that transduces specific noxious stimuli (in this case capsaicin) into electrical impulses. What's interesting is that the TRPV1 channel is also activated by temperatures higher than 43 degrees Celsius and acidic extracellular pH. My notes explain, "Because capsaicin activates TRPV1 as effectively or more effectively than noxious heat, it evokes a similar hot and burning sensation like hot temperature does."

My notes continue, "TRPA1 is an ion channel frequently co-expressed with TRPV1 in heat sensitive sensory neurons. TRPA1 is activated by pungent chemicals, including allicin from garlics and mustard oil from Japanese Wasabi roots." TRPA1 is also activated by THC (the active ingredient in Marijuana) and some pungent anesthetics like isoflurane, desflurane and propofol. Interestingly, "because TRPA1 positive neurons usually contain TRPV1, allicin and mustard oil evokes hot burning pain similar to how chili peppers do."

Finally, another channel in the TRP family, TRPM8, is "considered to be the molecular cold sensor for thermal sensation." It is activated by temperatures lower than 30 degrees Celsius. It is also activated by menthol, which explains the cool sensation associated with menthol mints.

Fugu (Puffer fish/Blowfish) Sushi, Black Widow Spider Venom And Other Interesting Toxins

Yesterday we had a lecture titled "Neuromuscular Pharmacology" which touched on some interesting toxins:

Fugu sushi is known for its potentially lethal toxicity if it is not prepared correctly. The toxin involved is called tetrodotoxin and is found mainly in the gonads of the fish, although it is also elsewhere in the body. Tetrodotoxin works by blocking voltage-gated sodium channels from the extracellular side. Supposedly fugu sushi gives you a little buzz when you eat it (I don't quite get this-- how does one get a buzz from a toxin that blocks action potentials?)

Saxitoxin is another toxin that works by the same mechanism-- blocking voltage-gated sodium channels. It is found in the single cell algae responsible for the red tide. During red tide, shellfish concentrate this toxin, which can lead to "shellfish paralysis" if the shellfish are consumed.

Latrotoxin is found in black widow spider venom and mediates fusion and release of vesicles containing acetylcholine at the motor neuron terminal even in the absence of calcium-- an impressive phenomenon whose mechanism remains a mystery. After this massive release of acetylcholine there is subsequent decreased synthesis and release of acetylcholine.

No, I don't expect to be treating domestic species for these toxins (with the possible exception of black widow spider bites), they are just illustrations of how toxins work at the neuromuscular junction, which I find pretty cool.

Equine Nigropallidal Encephalomalacia

I'm done with neuroanatomy (yay), at least for now, but this is one interesting disease that we learned about that I didn't write about at the time. Here's what my notes say:

Damage to the basal ganglia in humans causes debilitating motor and cognitive deficits [not surprising as they are involved in the cognitive aspects of motor coordination and planning] as demonstrated by Parkinson's disease (degeneration of the substantia nigra) and Huntington's disease (degeneration of caudate nucleus and putamen). In domestic animals, disease processes are rarely as restricted and specific as in these human diseases. One exception to this is Equine Nigropallidal Encephomalacia, which can be seen in horses that have eaten Yellow Star Thistle or Russian Knapweed (both found in the Western US). These horses develop motor dysfunction associated predominantly with their facial muscles and die of starvation because they cannot prehend food. Lesions can be identified in the substantia nigra and globus pallidus.

I know from living in California tha there is lots of Yellow Star Thistle around (at least in the Bay area) so I imagine this is of concern to horse owners, although I had never heard of the disease prior to this class. Interesting stuff.

On a related note, the Corticospinal (Pyramidal) pathway is the major pathway for voluntary control of motor movements in primates, particularly for fine motor movements of the digits. It is not nearly as developed in domestic animals, with the possible exception of raccoons who use their fingers extensively to almost "see" by feeling. However, in horses the related corticobulbar tract [note corticobulbar means going from cortex to brainstem rather than cortex to spinal cord as in the corticospinal] is the major pathway that innervates the muscles that control the lips. I remember my professor saying something like, "as horse people know, horses can do all kinds of amazing things with their lips." In a way, horse lips are akin to human fingers! Just in case you are wondering, the major pathway for voluntary movement in domestic animals is the Cortico-rubrospinal tract. But I won't get into that.

Sunny Springtime Day In Ithaca, New Camera Photos

I think this canal downtown is very picturesque. Simon was happy to have a few sunny days in a row. He could be found predictably in the first spot to get sun in the mornings in the far bedroom.

It's so nice to be able to take photos without smudges. Thanks, Dad for the new camera!

Round Three/Neuroanatomy: I Advance!!!

I got my grade for neuroanatomy this afternoon and was very pleased. I had worried quite a bit about the possibility of failing the course, but I was far from failing.

I also got my grade for ruminant anatomy, which I considered miraculous. I had been certain that I flunked the course coming out of the final exam, but I did just fine.

Distributions were the hardest semester of vet school so far. I felt discombobulated, overwhelmed and it didn't help that I live someplace fairly isolated and also that there was a lot of snow which made driving difficult.

I'm hoping that things won't be quite so hard this spring. So far block IIIa, function and dysfunction, aka physiology, doesn't seem any easier than last term, but I'm told it is a fairly manageable workload overall.

Things To Look Forward To

1. The Ithaca farmer's market re-opens Saturday morning. I know it might sound silly, but I have been looking forward to this all week. The farmer's market has been part of my weekend routine for years now and not going feels strange, almost sacrilegious.
2. Getting back my neuroanatomy exam. I'm one week into block 3a and I still don't know for sure if I passed my required neuroanatomy course. I don't know when we will get our exams back but it will be nice to know how I did instead of being left to wonder...
   
3. Summer vacation. Less than two months away. I'm going to get out of Ithaca for part of it and head back to California. I might also make stops in a few other states depending on what my friends and family are up to.
   
4. The Campbell farmer's market in California. One thing Ithaca does not have is fresh fish. Every Sunday I would buy sand dabs and squid. Delicious. I can't wait for that.