Nov 09

Mea Culpa

I’ve spent most of my life identifying as an engineer and only recently would I say I identify more as a scientist. But while I find there’s enormous overlap with the two fields, I’ll concede I get especially annoyed with the area of nutrition science in particular.

While frustrated yesterday, I tweeted the following:

Naturally, this resonated with quite a few people and led to some lengthy follow up threads. At one point today Brad Dieter chimed in with “I think you are conflating mass media with scientists in the field.” and I retweeted with a reply:

To be sure, I certainly believe everything I’ve written above. In fact, I’ve had a handful of PhDs at conferences effectively say the same thing. The pressure to publish is something very real in the world of science, and the potential to grab headlines and propel the careers of the teams behind these papers should be acknowledged.

However… 

If I’m being honest with myself, I’m stepping more into the role of an advocate than scientist here. Even if I’m right, and even if these kinds of statements get more likes and retweets and followers than the typical informative tweet, they ultimately risk positioning me and this is bad in two ways:

  1. It can siphon time away from the real prize — my lipid research. Sure, maybe after I get it through these first few phases I can devote more time to advocating on the larger subject of study sensationalism. But right now it’s an unneeded distraction.
  2. It risks pushing away valuable counter voices who take pride in this field. Now Brad Dieter isn’t exactly pro-Keto, but he’s not a card-carrying establishmentarian either. I’ve learned a lot from him thus far and hope to learn more in the future. I value relationships I have with non- (or even anti-) ketoers who provide valuable resources to keep moving my knowledge in this field forward.

Indeed, I think you can tell a lot about someone’s intention for independent thought by how engaged they are in discussing their ideas with those who disagree. But more than that, you have to be mindful of what is off-putting to your opponents beyond voicing the arguments they disagree with.

Describing intent is especially dangerous because it suggests you know what is going on in someone’s head. So while it’s true I believe the intent is pretty obvious with these headline-y papers, a much better approach would’ve been showcasing one and presenting the data to back it up rather than make a broad claim.

While I’m sure I’ll still express frustration on Twitter in the future, I’m going to endeavor to refine my approach better.

Nov 06

Basics of Cholesterol on Low Carb – Part I

I’ve been meaning to do this for a while and I’ve finally come around to the first installment. This is to be a series of short videos (5-10m) covering topics related to cholesterol and from a very simple, layperson perspective.

I’ll have several more to come as shown on the new page I’m adding for the series.

As always, you can do further reading with my Simple Guide series as well.

Nov 01

Beyond the Lipid Hypothesis (Part 2): LDL Modification

Recap and Lingering Questions

In part one of Beyond the Lipid Hypothesis, I covered the general process of plaque development, from the appearance of endogenous and exogenous pathogens, all the way up to plaque rupture and artery blockage. I studied this to truly examine the mechanisms and development of these fatty streaks and lesions that I had heard about growing up. Not to find root causes, as I had seen detailed in-depth by others (such as Ivor Cummins) over the past year, but to look at the tiniest pieces of the machine that make up atherosclerosis and truly understand how they fit together.

Photo courtesy of Npatchett

I had often heard about “foam cell formation” and “cholesterol in the arteries” but the explanations of why and, perhaps most interestingly, how this happens often left me in doubt or only with a vague understanding of how it allegedly works. As I continued to study foam cell formation and gained a greater understanding of the pathways for their development, I became increasingly curious as to the actual particles that contributed to foam cell formation, and the worsening of atherosclerosis.

A Familiar Particle

Based on the textbooks I had read and research I had done already, I knew that at least one type of “modified LDL” existed: oxidized LDL (oxLDL). However, I wasn’t quite sure why the LDL particles become oxidized. 

One of the earlier hypotheses I had heard was that LDL somehow becomes lodged in the arterial wall and becomes oxidized as a consequence of exposure to the natural “environment” of the bloodstream. The theory proposes a similar, passive mechanism as leaving a shovel out in the yard resulting in rust to form. This example is easy to imagine and easy to understand given we’ve all left things out where the natural elements could get to them and cause problems. We don’t blame the environment, we blame ourselves for forgetting to bring it inside.

However, as explained in part one, what I found seemed to suggest the opposite sequence of events, namely oxidation of LDL occurs in circulation first and only afterward is it taken into the artery wall. What causes this to happen was still unclear to me up to this point. So to learn more about this process, I decided to focus on oxLDL first in the hopes of gaining a better understanding of the immune response involved in atherosclerosis as a whole.

What I discovered was that LDL can be oxidized in a wide variety of ways, and can include oxidation of the phospholipid shell, oxidation of Apolipoprotein B on the LDL particle1, as well as oxidation of the cholesterol and triglycerides inside of it.2 The oxidation of the cholesterol carried by LDL results in the formation of oxysterol which can be found in many atherosclerotic lesions3 and excess accumulation of which contributes to macrophage death4, 5. Which, as explained in Part 1 of this series, is a contributor to plaque destabilization.

Frustratingly, I found that oxidized LDL was usually described in terms of how it interacts with different parts of the system, such as the interaction with scavenger receptors and macrophages, rather than how it was actually oxidized. Generally, a study regarding oxLDL uptake was referring to LDL oxidized in laboratory conditions, instead of how it would be oxidized in vivo (in the body). In an attempt to find real-world causes of LDL oxidation, I decided to look more into how LDL could be oxidized under “natural” conditions that may occur in the life of the everyday person.

 A Balancing Act

One example of LDL being oxidized in a “real life” situation, outside of laboratory conditions, was exposure to reactive oxygen species and reactive nitrogen species6. The terms free radical, reactive oxygen species (ROS), and reactive nitrogen species (RNS) refer to entire classes of particles that come in many forms. Their key feature is that they have at least one free electron and thus can “steal” an atom from another particle. In the case of lipoprotein oxidation, hydrogen is taken from some of the lipid (fat) that forms the phospholipid shell of the LDL particle.7 The free space left by the stolen hydrogen is then filled by an oxygen molecule on the recipient particle and thus becomes “oxidized”.8 This oxidized LDL is damaged or altered, in such a way that it is no longer recognizable by LDL receptors and thus must be cleared via alternate pathways.

Photo courtesy of Healthvalue

Free radicals aren’t solely a villain in their role, however, and can be produced for or from beneficial purposes like cellular signalling mechanisms9, and as a defensive and signalling tool produced by macrophages and other cells in reaction to bacteria and other pathogens10, 11, 12, as well as produced by muscle cells especially during exercise13. Like many things, it appears that it is not the presence of free radicals in itself that is deleterious but rather the overwhelming of normal neutralization methods wherein it becomes dysfunctional and can lead to disease14.

Considering the signaling and defense uses, endogenous production of ROS (production in and by the body), may be unavoidable but moderate levels present in normal circumstances appear to be beneficial if not necessary for normal function15. I found that there are many uses for this potentially destructive class of particle, and as is true for most things in the body, it is hard to classify as “good” or “bad”. Rather, these particles must be looked at in the context of their necessary function, as well as the potential unbalancing that can occur within the system.

Infection and Oxidative Stress

The destruction comes when this unbalancing occurs resulting in a shift towards a free radical dominant environment and depletion of antioxidants which help neutralize reactive oxygen species. This state is called oxidative stress16 and can cause OxLDL17, resulting in foam cell formation and worsening of atherosclerosis if chronic and severe enough, and the death of cells (such as smooth muscle cells in the arteries)18. I also found that infections, both viral19 and bacterial20, can also cause oxidative stress as a result of the production of Reactive Oxygen Species and Reactive Nitrogen Species21, and this too can manifest harmful effects under the right conditions. Not only that, but this damaging effect of chronic or highly acute oxidative stress mediated by infection has been shown to contribute to the development of cardiovascular disease in some animal models22 and the possibility of the same in human in vitro (laboratory settings working with isolated tissue) studies23 and very preliminary data involving infections of chlamydia pneumonia (C. Pneumonia)24 and cytomegalovirus25.

The increase in risk in human models may, however, be partially due to the direct contribution of the particle clearance pathways involved in the development of plaque mentioned in Part 1. Among these direct contributions are LOX-1 (a scavenger receptor that recognizes oxLDL and other pathogenic particles) being able to take in C. Pneumoniae, directly26, as well as both enhancing expression of scavenger receptors27, 28, and an increased uptake of oxLDL by macrophages29, 30.  Meaning that C. Pneumonia and Cytomegalovirus appears to contribute directly, through the aforementioned mechanisms, as well as peripherally31 (e.g. via oxidative stress, and oxidation of LDL), to the overwhelming of the immune response pathways involved in the development of atherosclerotic plaque.

Outside Sources

Beyond contributions of oxidation from responses to defense and signaling there also exist outside sources of free radicals that can contribute to oxidative stress inside the body. The most common example I found was smoking32, 33, along with exposure to radiation34, 35 and air pollution36. The mechanistic link between smoking and heart disease had never been clear to me before, until I understood that smoking increases the oxidative stress in the body via free radical introduction, and ultimately increases the amount of damaged LDL in the system that must be cleared. Various other dietary factors also appeared to increase oxidative stress and LDL modification including high intake of Polyunsaturated Fatty Acid (PUFA) such as those found in seed oils37,as well as high refined carbohydrate intake38, 39.

A Little Different

Additionally, I found that certain types, or classes, of LDL are more easily oxidized and production of these types increases during an inflammatory response. After digging further, I came across multiple studies referring to an increase in the production of VLDL (the initial stage of LDL)40 during inflammation41, mediated by pro-inflammatory cytokines – signalling molecules that help promote inflammation – in mouse studies42, 43, and emerging evidence for a similar reaction in humans44. This reaction, demonstrated by in vitro mouse studies, results in hypertriglyceridemia(45) (increased levels of triglycerides) which, in other studies, appears to lead to the increase in “small, dense” LDL (sdLDL)46, 47. We can additionally see this same lipoprotein profile in humans with inflammatory conditions as well48, and sdLDL has been demonstrated to be far more prone to modification49, 50. I was quite curious as to the cause of this vulnerability to oxidation, as it did not make sense to me why two different types of LDL would be more or less prone to damage just based on size alone.

I found that there appeared to be several factors in this vulnerability, and that it has been speculated that the protein content and structure of the sdLDL may increase the exposure of the polyunsaturated fatty acids that contribute to the structure of its phospholipid shell – increasing sdLDL’s vulnerability to oxidation.51 These structural differences leads to a difference in ‘lag time’  – a term which refers to the amount of time it takes for LDL to deplete of antioxidants before the LDL particle itself is subject to oxidation.52 Not only that, but the PUFA content of this type of LDL is also higher than the “light, fluffy” LDL we typically see that is used for energy transportation throughout the body.53 Clearly the oxidative susceptibility of small dense LDL is not a simple process, but rather a multifactorial one involving many different aspects of the physiological structure and composition of the particle, all appearing to lend itself to quicker donation of antioxidants, and a faster rate and deeper level of oxidative modification to the particle.

Not So Sweet

Beyond oxidated LDL, I found that there was an additional type of modified LDL called glycated LDL54. Glycation refers to damage of a particle caused by glucose binding to a protein or lipid molecule on said particle – a sticky candy coating that damages the particle (like LDL or a red blood cell).  Before discovering this, I was already familiar with a different type of glycation involving hemoglobin, or red blood cells, which is measured via Hemoglobin A1c (HbA1c). HbA1c can go up in the case of high blood sugar, as seen in cases of advanced diabetes, as does glycation of LDL particles. Some amount of LDL glycation occurs in the healthy system, as is also true of glycation of hemoglobin, but higher levels of glycated LDL may cascade into further problems down the road. Not only is glycated LDL a form of modified LDL which is recognized by scavenger receptors55, but higher levels of this glycated LDL may lead to higher levels of oxidated LDL, as well. According to the research I read on the topic, the process of glucose damaging both apolipoprotein B and the phospholipid shell leaves the LDL particle more at risk of oxidation. This appears to be due to this modification crippling the usage of antioxidants, like vitamin E, in the LDL particle during this so-called “glycation phase”. As a result, this shortens the lag time in the particle and speeds up the accumulation of damage from oxidation56. This creates not only a glycated LDL particle, but a glycoxidized one yet again resulting in increased dependence on clearance pathways previously discussed – contributing to an overwhelming of clearance mechanisms and detrimental development of atherosclerosis over time if the cause of the damage is chronic.

Two Factors

It became evident that there are two major factors to the level of oxidation of LDL that contribute to this chronic “high alert” of damage and inflammation. Perhaps the most obvious factor is a source of oxidation. In order for LDL to become oxidized, there must first be an increase in oxidative particles (Reactive Oxygen Species, for example) severe (or chronic) enough to deplete the system of available antioxidants within the body (e.g. oxidative stress). LDL normally carry fat soluble vitamins as part of their “cargo” and if they come across reactive oxygen species, they can use these antioxidants to safely neutralize them and get away unscathed. The depletion of the antioxidants carried by LDL (this can be thought of as LDL running out of ammo) is what causes the lag time between oxidative agents being introduced, and LDL actually becoming oxidized and damaged. Thus, in order for there to be wide-scale oxidation of LDL, there must also be a wide-scale presence of oxidative stress as well, if the logic holds. The source of this oxidative stress can come from many different sources, only a few of which are covered by this post.

The second important factor to LDL oxidation is the susceptibility of the LDL particles to become damaged by it, as opposed to merely using up its antioxidant “ammo” as a preservative measure without taking any damage from the encounter. Before I truly delved deeply into the topic I thought that low density lipoproteins were the same when it came to oxidative susceptibility. However, this does not appear be true. Not only is LDL that has been damaged by glycation more susceptible to oxidation, due to the damage done to it, but small dense LDL likewise is more susceptible to oxidative damage far more than its so-called “large, fluffy” counterpart. This susceptibility isn’t because small dense is “damaged”, at least as far as I am aware, but rather that the physical structure makes it more vulnerable. The mere fact that there are LDL particles that are more quickly and thoroughly oxidized that appear ‘on scene’ during oxidative stress and inflammation is an interesting prospect that leaves me with more questions than I had before I had discovered this aspect of LDL

Shared Causes and Conclusion

Graphic courtesy of Ivor Cummins

If one wants to understand what increases the formation of foam cells (which also worsens atherosclerosis along the way) over the course of years, one must look at the type of LDL particles that contribute to them (modified LDL) and what causes the modification of LDL in the first place. Very quickly I learned that the topic of LDL oxidation, and modification, is a deeply complicated one. This post, by no means, covers all factors of LDL modification but at the very least I began to better understand it. I began to notice that the more chronic sources of oxLDL tended to mirror Ivor Cummins graph of contributing factors to chronic disease. This does seem to point to shared mechanisms, and shared root causes, of heart disease and insulin resistance as he has suggested previously. The role of insulin in heart disease is where I will explore next, in part 3 of Beyond the Lipid Hypothesis to see what hints lie in insulin’s contribution to the disease on a mechanistic level.

 

Sources

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30Carlquist, John F., et al. “Cytomegalovirus Stimulated MRNA Accumulation and Cell Surface Expression of the Oxidized LDL Scavenger Receptor, CD36.” Atherosclerosis, Nov. 2004, doi:10.1016/j.atherosclerosis.2004.07.010.

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39Siri, Patty W., and Ronald M. Krauss. Influence of Dietary Carbohydrate and Fat on LDL and HDL Particle Distributions. Current Atherosclerosis Reports, Nov. 2005.

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43Aspichueta, Patricia, et al. “Endotoxin Promotes Preferential Periportal Upregulation of VLDL Secretion in the Rat Liver.” Journal of Lipid Research, 4 Jan. 2005, doi:10.1194/jlr.M500003-JLR200.

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46Ivanova, Ekaterina A., et al. Small Dense Low-Density Lipoprotein as Biomarker for Atherosclerotic Diseases. Oxidative Medicine and Cellular Longevity, 2017, doi:10.1155/2017/1273042.

47Hirayama, Satoshi, and Takashi Miida. Small Dense LDL: An Emerging Risk Factor for Cardiovascular Disease. Clinica Chimica Acta, 24 Dec. 2012. doi:10.1016/j.cca.2012.09.010

48Feingold, Kenneth R., and Carl Grunfeld. The Effect of Inflammation and Infection on Lipids and Lipoproteins. Endotext, 12 June 2015.

49Chait, Alan, et al. Susceptibility of Small, Dense, Low-Density Lipoproteins to Oxidative Modification in Subjects with the Atherogenic Lipoprotein Phenotype, Pattern B. The American Journal of Medicine, Apr. 1993, doi:10.1016/0002-9343(93)90144-E.

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51Ohmura, Hirotoshi, et al. Lipid Compositional Differences of Small, Dense Low-Density Lipoprotein Particle Influence Its Oxidative Susceptibility. Metabolism Clinical and Experimental, Sept. 2002, doi:10.1053/meta.2002.34695.

52Tribble, Diane L., et al. Greater Oxidative Susceptibility of the Surface Monolayer in Small Dense LDL May Contribute to Differences in Copper-Induced Oxidation among LDL Density Subfractions. Journal of Lipid Research, Apr. 1995.

53De Graaf, J, et al. Enhanced Susceptibility to In Vitro Oxidation of the Dense Low Density Lipoprotein Subfraction in Healthy Subjects. Arteriosclerosis, Thrombosis, and Vascular Biology., 1 Mar. 1991, doi:10.1161/01.ATV.11.2.298

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55Lam, Michael C.W., et al. Glycoxidized Low-Density Lipoprotein Regulates the Expression of Scavenger Receptors in THP-1 Macrophages. Atherosclerosis, Dec. 2004, doi:10.1016/j.atherosclerosis.2004.08.003.

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Oct 28

The Game of Glucose Part II

A couple months ago I showed how wildly different glucometers could be from each other and how this compared to lab results themselves in The Game of Glucose. At that time I wasn’t frequently taking glucose measurements within minutes of the actual blood draw for my lipid experiments. Fortunately, with my eye on the prize, I managed to wrap this last experiment into just such an exercise.

This time I tested glucose on both the Precision Xtra and Keto Mojo minutes after each blood draw. In fact, I had a deal with the lab that I could actually jump into an empty phlebotomy bay right after the draw to do my “extra homework.”

Full Disclosure

Before I begin, let’s get some disclosure out of the way.

  1. Like PTS Diagnostics, KetoChow, and Keto and Co – Keto Mojo has provided product and/or service in support of my research. While I ordered the initial kit on my own, they sent additional strips without any request on my part. As always with every company, I make clear the product support does not guarantee my speaking favorably of the company.
  2. Jimmy Moore promotes this product, and I will be speaking at the Low Carb Cruise next year at his invitation.
  3. As always, I do not accept any direct financial support or personal compensation of any kind from any business entity. I have been approached several times at this point for affiliate programs or direct advertising with this site and have had to turn them all away. This is primarily to maintain the integrity of the research as much as possible. I accept only funding by individuals.

In the case of Keto Mojo, I want to further concede that I instantly liked the owner, Dorian, when I met him at Low Carb USA before my presentation. He seemed particularly attentive to the Low Carb community and was clearly tailoring his products to this demographic. I told him I’d test his glucose/keto meter alongside the Precision Xtra and that I was “rooting” for him.

However, data is king. I told Dorian this in person and repeated it later in a Facebook message. I couldn’t say for sure if I’d keep using this product until I could see how it compares to the actual lab tests.

The Big Showdown

The experiment that uses this data will be a much bigger, more involved post. But this one component of it I can share now and it’s quite interesting. Below are three of the blood draws and the glucometer readings right afterward.

For the fourth test, I decided to go all out. I actually did four tests from the Xtra, four from the Mojo. Each of these pairings were from different fingers (right-hand index, pinky, then left-hand index, middle finger).

Okay, so let’s get this into a table to compare:

To be sure, this is a pretty small sample size at just seven data points. But that said, it’s a pretty strong endorsement for glucose accuracy on the Mojo side of the fence. The Xtra did have a couple spots where it beat out the Mojo against the lab results, but the two tests where it was off by -9 and -10 were certainly not encouraging by comparison.

Again, I’ll happily concede I was pulling for the Mojo as I hoped it would have comparable or better readings than the Xtra. But data is data. If these columns were reversed, I’d feel compelled to keep sticking with the Xtra on glucose testing. Fortunately, the Mojo delivered.

What Isn’t Covered

While this article ultimately compared the Xtra and Mojo regarding glucose testing, it didn’t touch on the other main front of ketones. Unfortunately, I don’t have an easy way to test this with my existing blood draw labs given their ketone readings aren’t very precise (I often get a “high” reading instead of a number). However, while not shown, I’ve found the Xtra and Mojo are generally within 0.1 of each other on ketone testing (in fact, just this morning it was 0.9 and 0.8, respectively). So overall, this is probably an avenue I won’t be pursuing much.

 

 

Oct 23

New Adventures in Carbland – Parts II and III

As mentioned in Part I, I haven’t had the best time with this experiment.

However, as I’ve said time and time again – mine is a journey of science, not of advocacy. So you might find it interesting that I’ll have a few more positive things than last time to say from Carbland… even if I can’t wait to return to Fatland. (I should find a better name for the latter location :D)

Updates from the Last List

GI Stress. This has gotten better. Since my last posting, I’ve had it just once in the morning. This could be due to my current phase having only 1155 calories / day, of course.

Postprandial drowsiness. This is likewise improved. But as above, this isn’t too surprising given each of my meals are just 385 calories during this last sprint.

Broken circadian rhythm. Also improved. Very close to how I was sleeping in keto.

Weight gain. So I found out my scale wasn’t giving me accurate numbers. After trying a few tear aways by holding specific weights while on it, then without, I found it was extremely inconsistent. I changed the batteries, reset it, and afterward, it appeared to work better. At that point it displayed I was 183lb and I was one day into this lower calorie phase.

In short, I now don’t trust my original weight readings mentioned earlier and thus I can’t say for sure on that metric. It’s just as possible I didn’t gain much weight, even if more was showing in my waistline — however, even in this case, it was likely more water weight than anything else. (My hope is that it is 100% water weight. :D)

Transient Symptoms or Just Lower Calories?

As mentioned above, I’m now in a phase where I’ve been lower calorie overall, yet still having around 108g of carbs a day. It could be some of the previous symptoms were due to the transition to having carbs back, and to some degree, it could be having lower energy load overall. My guess is that it is a little from Column A and a little from Column B.

And hey, while I’m on this pro-carb-just-lower-calorie promotion train, I have a uniquely special circumstance that is worth mentioning. In all my experiments, I’ve always had a very difficult time eating below 1200 calories as I feel generally hungry, keto or not. Yet, this current low-calorie phase has been easier relative to the others in that I don’t crave larger helpings of the food I’m eating. Yes, it does help that I really, really dislike this diet (as Siobhan called it, “prison food”), but even so, I’m finding less physiological hunger to eat more.

Aside from the physiological cravings, however, my mind has been filled with the delicious, juicy cuts of fatty meat I plan to eat when this is all done. As experiments go, this one has been one of the toughest. I miss my keto diet terribly and I’m excited to get back soon.


A Very Unexpected Part III

I’ve been planning to post the above for Monday morning, Oct 23rd, which is tomorrow as of this writing.  Everything there was written in the late morning today and I presumed nothing more would change.

But something very odd happened that I feel I should make note of…

Around 2 pm I was doing monotonous work with my spreadsheet and nothing about it was unusual. Weirdly, I felt a kind of acute mood shift. It was like a wave of both exhaustion and general pessimism. What made this particularly noticeable was how fast the trend was. One moment I was trucking along with some code and the next I felt heavy malaise.

I happened to have a Skype meeting with Siobhan a few hours later and was trying to describe what it was like. “I feel strangely pessimistic about everything now.” Indeed, I was feeling gloomy about my experiment and at how valuable the data might be. I have a family member I’m working with and had new and less optimistic thoughts about this outcome of this as well. I tried to take a break and browse Netflix, but felt unusually anxious and annoyed at their selection. It was as though I had just gotten some terrible news about something and it was affecting me in a very profound way… but without the actual news.

Everything I thought about seemed to have a greater negative spin to it.

Being the scientist I am, I actually started ranking my mood on a 1-10 scale on the hour (1 being miserable, 10 being very happy). How long would this last?

1pm 2pm 3pm 4pm 5pm 6pm 7pm 8pm 9pm 10pm 11pm
8 2 2 2 3 4 2 2 4 4 4

Right now it is 11:30pm as I write this and I think I’m still at a 4. I just can’t seem to shake this odd episode. I’d say it gives me all the more reason to look forward to the experiment’s end tomorrow following the blood draw, but even that doesn’t seem as exciting as it should be. Truly, I can’t recall ever having experienced anything like this before.


Morning Update

My mood is closer to a 7 now, but I woke up exhausted – and I mean really exhausted. Like I pulled an all-nighter with work and I could head back to bed and sleep five hours. Why?!?

This is one of those moments I truly wish I just had a lot more money to put down on a per-test basis. I’d add more tests to my blood draw like a thyroid panel and hormones (such as Cortisol), which I used to do when I was more flush with savings. If this is some strange biochemical episode, I’d love to catch its origin better.

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