Category: Uncategorized

Blood and the Circulatory System

red-blood-cells-1

Hello everyone, sorry for the delay in posting. My schedule has become tremendously hectic so my posts will be much less frequent. Regardless, I have been checking in on the statistics and I appreciate everyone who has continued to read, submit, and share this blog even as my posts have become less frequent. We are fast approaching 3000 views; I am hoping this post puts us over the top.

Today’s question comes from Jim, who asks “I came across your blog online and I was curious: How does blood work? I know it does more than just carry oxygen and the stuff they list on my blood test, but I am not really sure how it all works beyond that.”

Well Jim, this is an excellent question. Most people, I’d imagine, don’t really have a very detailed understanding of what constitutes blood, what those things do, and how blood gets from place to place.

The individual cells that make up the functional parts of the blood fall into three classes, erythrocytes (red blood cells), leukocytes (white blood cells of various types), and thrombocytes (platelets). These cells all originate in the bone marrow, from a common stem cell known as a hematopoietic stem cell (HSC). These stem cells give rise to two classes of cells, myeloid and lymphoid progenitor cells. Myeloid cells create, among other things, red blood cells, megakaryocyte (which breaks up into platelets), and a fair number of white blood cells. Lymphoid cells create a particular class of cells known as lymphocytes, which are our already familiar B cells and T cells (if you have not been reading and don’t know what these are, view this search), and a new type of T cell we have yet to mention known as a natural killer (NK) cell.

Once all of these cells are made, they have to travel in a medium of some sort. If they didn’t, they would be far too viscous to travel through even large blood vessels easily. This medium, as you might know, is known as plasma. What you might not know is that plasma is far more complex than just simply the watery substance that carries blood cells. Well balanced plasma is as essential as any other part of the blood.

There are a few essential characteristics of blood plasma that make it so important. Primary among these are the dissolved substances. Blood plasma carries a tremendous amount of things in it, from dissolved gasses to protein to hormones. Every piece is so incredibly important that four organs, the kidneys, lungs, pancreas, and liver, are devoted to maintaining this balance in every possible way.

One of the most important elements of what makes up blood plasma is protein concentration. Chief among these proteins is albumin, of egg white fame. Albumin is made in the liver and is the main protein we use to maintain what is known as oncotic pressure. Regulating this pressure maintains a proper fluid exchange between the blood and the tissues; too much albumin and fluid flows into the blood, too little and it flows into the tissues. People who have liver failure, for example, can suffer from severe generalized swelling as the liver is unable to make enough albumin and other proteins to maintain proper oncotic pressure. Albumin is also responsible for allowing some drugs to be able to travel in the blood by binding to them.

Another vital piece of the puzzle is blood pH, or level of acidity. Blood is maintained at a very narrow normal range between 7.35 and 7.45. Any severe disturbance of this range (above 7.45, known as alkalosis, or below 7.35, known as acidosis) can cause dramatic health issues, primarily due to altered or impaired enzyme activity among other physiological processes. The body regulates pH through a bicarbonate buffer system (buffers prevent rapid changes in pH), which has its roots in carbon dioxide. Without going into too much detail, increased carbon dioxide in the blood can shift the buffer balance and cause acidosis. People with acidosis, as with uncontrolled type one diabetics, have characteristic rapid, deep breathing as the body attempts to release more carbon dioxide and increase the pH. Likewise, alkalosis can cause a reduced breathing rate as the body tries to hold onto carbon dioxide.

And finally, there is a long list of substances within the blood that it carries around the body to maintain proper function. The following are a few of the major ones:

  • Electrolytes, such as sodium, potassium, calcium, and so on circulate at carefully controlled levels. Even small variations to these levels can have dramatic effects on the body.
  • As I mentioned before, gasses can also be dissolved directly in the blood. Importantly, most people think red blood cells are the only way oxygen is transported through the body. But, oxygen can also be directly dissolved in the blood.
  • Lipoproteins, which are combinations of fat and protein, travel in the blood to bring essential elements such as cholesterol around the body. These are the elements that most people refer to as “cholesterol” on a blood test. In a future post, I will likely cover the different types of lipoproteins and their effect on health.
  • Hormones: Probably the most familiar of these elements, have various sources and functions. Not important to have specifics unless you’re curious. At this level, just know that the blood is their main method of travel.

Please note that this is a very basic picture of the blood. Blood is a very complex system, so complex even that there are entirely medical specialties devoted specifically to it. So I encourage you to use this as a basic primer for further, more detailed research.

Hope this helps! As always, feel free to submit questions. Thank you for reading!

Till next time,

Justin

Sources

http://www.nsbri.org/humanphysspace/focus3/earthphys-frame.html

http://www.ncbi.nlm.nih.gov/books/NBK2263/

http://www.redcrossblood.org/learn-about-blood/blood-components

http://www.ccmtutorials.com/misc/albumin/page_03.htm

http://www.hematology.org/patients/blood-basics/5222.aspx

http://training.seer.cancer.gov/leukemia/anatomy/lineage.html

http://anthro.palomar.edu/blood/blood_components.htm

Leukemia: Symptoms and Complications

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This week’s question comes from Sarah, who asks, “A close relative of mine had leukemia years ago and recently relapsed, developing a type of leukemia known as AML. He received a bone marrow transplant from his brother a long time ago and was treated with DLI this time around. But, in the weeks that followed his chemo and DLI, he developed a potentially serious complication known as GVHD. Can you explain how leukemias happen in the first place, DLI, and GVHD/other common complications of treatment?”

Well, Sarah, before we dive into the complexities of leukemias, we should first introduce the various types and how they differ. Generally, leukemia is a cancer of the blood that specifically produces too many immature white blood cells, known generically as “blasts.” Because these white blood cells are immature, they cannot function properly and effectively take up space, eventually preventing production and function of mature, life-sustaining blood cells. This is different from the similar sounding lymphoma, which also involves immune cells but can create solid tumors that usually occur in the lymphatic tissue and organs. The difference between them is not important for this discussion, but it is important that you know they are largely discrete diseases. Leukemias, like most cancers, happen due to a genetic predisposition or mutation. Sometimes, leukemias can be caused by exposure to chemicals or radiation, but most often are a result of a natural genetic alteration (birth defect, ie. Philadelphia Chromosome translocation, or acquired via viral infection, ie. Epstein-Barr Virus).

Leukemias are divided into two major categories, acute and chronic. Acute refers to the fact that the disease comes on and progresses rapidly. Chronic, on the other hand, is the opposite. The disease may take months or years to progress fully. Either way, the abnormally high production of immature white blood cells is serious and left untreated can result in grave illness and eventually death.

Acute and chronic leukemias are further divided into lymphoblastic/lymphocytic and myelogenous. Lymphoblastic/lymphocytic leukemias specifically involve the bone marrow precursor cells that produce lymphocytes, more commonly known as B or T cells. In practice, lymphoblastic/lymphocytic leukemias can develop into lymphomas, so the diseases do have a link. Myelogenous leukemias, on the other hand, involve the bone marrow precursor cells involved in producing other parts of the blood besides lymphocytes, which include other white blood cells, platelets, and red blood cells.

So, by this classification, we end up with four major types of leukemia. Granted, these are not all the types that exist, but for the sake of brevity these are the four on which we will concentrate. The four types are:

  • Acute Lymphoblastic Leukemia (ALL)
  • Chronic Lymphocytic Leukemia (CLL)
  • Acute Myelogenous Leukemia (AML)
  • Chronic Myelogenous Leukemia (CML)

Given the brief introduction in the previous paragraph, it should be fair easy to understand generally what is involved in each of the four. If you’re curious about a more in-depth explanation of each, feel free to view the sources at the bottom. On the whole though, each presents its own dangers and are each treated differently.

On the topic of treatment, it is important that we understand that not all leukemias are created equal. Some leukemias have a nearly 100% survival rate, such as a subset of CLL known as hairy cell leukemia, while others require dramatic treatment measures to even provide a 50-50 chance at survival. Many leukemias can now be treated directly with drugs. CML, for example, is treated with a drug that targets the protein responsible for overactive production. This drug, imatinib (trade name: Gleevec), has turned CML from a slow death sentence into a chronic, manageable disease for a vast majority of patients. Likewise, chemotherapy is often successful for most AML, ALL, and CLL patients.

However, a fair number of patients after initial successful treatment relapse and a minority of patients fail first line treatments like chemotherapy, radiation, and medications. These people are then treated with bone marrow transplants, which can come from relatives or unrelated “matches” from the general population. Bone marrow transplants are tricky business, primarily because they first involve the total destruction of the patient’s own bone marrow. Without bone marrow, the patient cannot create new blood cells, including red blood cells, platelets, and immune cells. Once irradiated, they reach a point of no return, so the donor bone marrow must be as close to a “match” as possible.

I put match in quotations because no one from the general population, save for an identical twin, will ever have the same exact genetic markers necessary to prevent rejection. Interestingly and likely not surprisingly due to the genetic component, bone marrow donated from an identical twin was found to have a higher rate of relapse but lower mortality due to the lack of rejection. But for the rest of us, bone marrow must come from someone who is, by definition, genetically different. And so, rigid genetic testing is required before the marrow can be transplanted. This involves human leukocyte antigen (HLA) markers, ten of which have been identified as necessary for a true compatible donation. HLA markers are a type of major histocompatibility complex, which we have discussed before, and identify tissues throughout the body as “self.” The more matching HLA markers, the lower the likelihood of rejection or an adverse reaction. This is true regardless of transplant type, but is especially important for bone marrow transplants.

Over time, however, relapses can happen even with bone marrow transplants. Sometimes the cancer is not always completely eliminated by the new immune system. If the cancer returns in a patient who has already received a bone marrow transplant, the options are more limited. DLI, or direct lymphocyte infusion, is one of the main options available alongside standard chemotherapy and redoing the bone marrow transplant. DLI puts more of the the same donor’s T-cells directly into the blood stream to take advantage of the graft versus tumor effect, which is a fancy way of saying cancer fighting capabilities. This is often a successful treatment, given that the graft is stable.

However, there is the possibility of problems with the transplant in the first place. In this circumstance, one of two things tend to happen, graft rejection or graft versus host disease (GVHD). Graft rejection involves lingering patient immune cells recognizing the new transplant as foreign and attacking it. The risk of this can be significantly reduced with pre-treatment (chemotherapy, radiation, etc.) to thoroughly eliminate the original immune cells, but it still remains a distinct possibility following transplantation. This is a serious, often lethal, complication because the patient is left largely defenseless and without the ability to make blood products effectively.

Graft versus host disease (GVHD) is a different, and in many cases not quite so serious, complication of the bone marrow transplant. It can also be induced through DLI because of the large T-cell infusion. GVHD involves the new immune cells attacking the patient’s tissues because the new cells identify the old ones as foreign or “non-self.” Essentially, GVHD flips HLA markers on their head: instead of the body attacking the transplant, the transplant now attacks the body. It often attacks the skin, mucosa, and GI system (liver and GI tract) , which can be severely painful and debilitating. Less severe versions of GVHD can be controlled with steroids, while more severe cases have shown to be responsive to injectable antibody medications that block the signaling pathways associated with the disease. New treatments for GVHD that doesn’t respond to steroids are being developed, but by and large the use of steroids or injectable antibody medications tend to successfully manage this complication.

Hope this helped, Sarah. Thank you for sharing this deeply personal question. I highly recommend everyone join the national bone marrow registry at Be The Match. Five minutes of your time may save someone’s life.

Till next time,

Justin

Sources:

http://www.lls.org/diseaseinformation/leukemia/

http://www.mayoclinic.com/health/leukemia/DS00351

http://www.nlm.nih.gov/medlineplus/ency/article/000532.htm

http://www.cancer.gov/cancertopics/pdq/treatment/CML/Patient/page1

http://www.cancer.gov/cancertopics/pdq/treatment/hairy-cell-leukemia/Patient/page1

http://www.mayoclinic.com/health/acute-myelogenous-leukemia/DS00548

http://bethematch.org/Patient/Disease_and_Treatment/About_Your_Disease/ALL/Acute_Lymphoblastic_Leukemia_(ALL).aspx

http://www.cancer.org/cancer/leukemia-acutelymphocyticallinadults/detailedguide/leukemia-acute-lymphocytic-what-is-all

http://www.cancer.org/cancer/leukemia-acutemyeloidaml/overviewguide/leukemia-aml-overview-what-is-aml

http://www.stanford.edu/dept/HPS/transplant/html/hla.html

http://www.cancer.gov/cancertopics/factsheet/Therapy/bone-marrow-transplant

http://annals.org/article.aspx?articleid=707306

http://bethematch.org/Patient/Transplant_Process/Search_Process/HLA_Matching__Finding_the_Best_Donor_or_Cord_Blood_Unit.aspx

http://www.stjude.org/stjude/v/index.jsp?vgnextoid=791ffa2454e70110VgnVCM1000001e0215acRCRD

http://www.nlm.nih.gov/medlineplus/ency/article/001309.htm

http://my.clevelandclinic.org/services/donor_leukocyte_infusion/hic_donor_leukocyte_infusion.aspx

Addiction: The Silent Killer

addiction

Before we begin, I wanted to make sure everyone knows that this is a very special and important post, above and beyond what I normally write about. The topic’s importance cannot be understated. Most of you reading this know someone or have been personally affected by addiction. If you are currently suffering from addiction, regardless of the source, I hope that you take this opportunity to learn and seek help. Life is far too short and precious. 

This week’s question comes from B, who asks, “I recently lost my boyfriend to an overdose due to an opiate addiction. In order to be at peace with what happened, I’ve been searching for information about addiction and how specifically it affects a person’s brain. How does a person develop an addiction to opiates? What changes occur in the brain after an addiction sets in?”

Well B, sadly you are not alone in experiencing this kind of tragedy. Prescription drug overdoses, for example, kill tens of thousands of people a year and leave thousands more with permanent disability, organ damage, and/or contracted infectious diseases. Likewise, more socially acceptable drugs like tobacco and alcohol bring these numbers well into the six figure range. In total, according to the NIH’s National Institute on Drug Abuse, nearly $600 billion in lost productivity and healthcare costs are associated with addiction to alcohol, tobacco, and drugs. This makes addiction not just a pressing personal matter but also a national catastrophe both in terms of the physical harm and associated healthcare costs.

Further compounding this issue, many people still do not see addiction as a disease. Instead, addicts are labeled as maladjusted, unpredictable people seconds away from committing a crime or unspeakable violence to protect their habit. They are seen as simply out of control, that the drug takes ahold of them and they are lost forever. However, this view is dangerously incorrect. By making addiction such a stigma, addicts are pushed to the darkest corners of society; instead of helping people, we may be unwittingly contributing to their injury by forcing them into the shadows out of shame or fear.

Before we get into the specifics of opiate addiction, we should first explore how the brain becomes addicted to anything in the first place. The term “addiction” is colloquially used to describe both behavioral and chemical dependency; these are not necessarily discrete elements however addiction need not be of chemical origin. One can become addicted to basically any activity because the activity itself triggers a change in the brain over time. Many people have heard of gambling and sex addiction, which fall into this category. The brain effectively associates the given activity with being a positive and gives you a sense of reward and pleasure for accomplishing it. When competitors say they are “addicted to winning,” they are not entirely off base with their word choice, since winning in competition is a very deeply rooted trigger of this neurological process. The variation then comes with how socially acceptable it is — a person who is addicted to winning basketball games gets showered in adulation, while a gambling addict is labeled socially unacceptable for doing the same.

It is in this pleasure providing activity that we find the neurological basis for addiction. We have discussed before the role of dopamine in the brain (see here for past posts), but not yet in any particular detail. As those articles have described, dopamine is an integral neurotransmitter for, among other things, the reward-pleasure centers of the brain. This system has evolved over millions of years to make us seek out things that are beneficial to survival. We like sex, caloric foods, being active, winning, and not feeling pain because all of these things allowed us to survive longer and produce more successful offspring. Unfortunately for us, this system can be easily tricked. Drugs like amphetamines and cocaine cause a large release of dopamine in the brain directly, while drugs like alcohol and heroin indirectly cause dopamine levels to increase.

To be more specific, the area of the brain in question is known as the nucleus accumbens. Dopamine producing neurons from the ventral tegmental area of the brain terminate in the nucleus accumbens, depositing dopamine into it directly. Drugs and behaviors that affect this area can do so by multiple pathways. The nucleus accumbens is directly capable of being influenced by an increase in dopamine from these dopamine producing neurons. Drugs that cause abnormal dopamine rise can cause an actual physiological change that reinforces the value of their behavior to the brain. Over time, this modulation can cause a behavioral addiction to the act of taking drugs (“drug taking behavior”). This provides the basis for not only becoming addicted to the drug itself but also the act of taking them.

Along with reinforced behavior, the body can simply become addicted to feeling pleasure and reward stimulation. This is the basis upon which one can become addicted to behaviors that do not cause an externally sourced dopamine increase. Instead, we can look at these elements as internally sourced dopamine releases. In simpler terms, the body is rewarding you for what it believes you should be doing. This system is hard wired into all of us, but some people are more susceptible to addiction than others. There is evidence that this has a genetic basis, however the specifics of this are still undefined. Still, it remains a fact that hundreds of thousands if not millions of people in the US alone are actively addicted to something. It is in our best interest as a society to more fully understand the basis for this disease so that we can better and more comprehensively treat it.

Chemical dependency, unlike behavior based addiction, is a more complicated matter. One can only become chemically dependent on drugs, be they legal or illegal, because only drugs are capable of altering the normal physiology to the point of functional dependency. The drug alters the brain in some way that over time causes a replacement of normal function by the drug itself. For example, alcohol increases GABA receptor function (GABA reduces nerve activity) and depresses NMDA receptor sensitivity to the neurotransmitter glutamate (glutamate makes nerves more excitable). This is what is thought to cause the sedative effects. Chronic abuse of alcohol can cause these receptors to function abnormally: NMDA receptors become hypersensitive and GABA receptors become less responsive. With NMDA receptors going wild and no GABA activity to stop them, alcohol withdrawal symptoms such as the condition delirium tremens and seizures can result. Severe, untreated alcohol withdrawal can lead to death from prolonged seizures. Other drugs, such as benzodiazapines, can also cause similar withdrawal symptoms and different, non-sedative drugs, can have a variety of other withdrawal effects. In short, addiction to certain drugs isn’t just dangerous due to overdose potential but can also cause significant damage if the habit is improperly or suddenly stopped. The brain, quite literally, cannot function without them.

Specifically discussing opiates, drugs like hydrocodone (Vicodin), oxycodone (Oxycontin, Percocet), hydromorphone (Dilaudid), diacetylmorphine (heroin), and morphine are some of the most commonly prescribed drugs on the planet to treat acute and chronic severe pain. They also happen to be some of the most addictive substances available. While extremely useful in select circumstances, by and large these drugs are taken inappropriately. Many people take them to mask less than severe pain or avoid treating the underlying pathology or behavior. For example, a high school football player could either rest a sprained ankle and miss two games or take a Vicodin and play through it. For many people, these drugs are what keep them doing what they want to do when their bodies otherwise say no.

Likewise, these drugs are often over-prescribed and under-supervised. After surgery, for example, patients can be given upwards of 120 pills at a time. While the reason, to prevent unnecessary pain and suffering, is noble, ultimately it is a very sharp double edged sword. Even common pain killers like Vicodin can initiate a terrible cascade of dependency. One not need be a junkie or rebellious youth to become addicted to drugs. Sometimes something as innocuous as a broken bone or outpatient surgery can lead to a lifetime of addiction. Despite their utility in treating pain, these drugs unfortunately come at a terrible price.

Opiates can cause chemical and behavioral dependency very rapidly and this effect can grow more serious over time as the brain becomes tolerant of the drugs. Opiates operate by attaching to receptors in the brain known as opioid receptors. The body has three types of receptors (delta, kappa, and mu) and makes four of its own types of opiates, of which the well known endorphin is one (the other three are enkephalins, endomorphins, and dynorphins). Their job is to reduce the body’s response to pain signals as well as a few other functions around the body such as helping to regulate hunger and thirst. By binding to these receptors, opiate drugs take the place of these endogenous (internally sourced) opioids. However, these receptors never normally receive such a large influx of stimulation. Because of this, continuous use can cause the receptors to lose sensitivity, both reducing the value of internal opioids and forcing an ever increasing amount and strength of external opiates to keep up.

Many of the other effects, such as euphoria and sedation, are side effects related to their effect on the central nervous system, especially related to GABA receptors (the effect on which also causes the spike in dopamine that results in euphoria). Thus, opiates hit on all aspects of addiction, from dopamine release in the nucleus accumbens to opioid and GABA receptor chemical dependency. However, like with other sedative drugs, opiates can have terrible, even deadly, withdrawal symptoms as a result of their abnormal interaction with GABA.

Also, as was mentioned earlier, the dependency related to ever decreasing receptor sensitivity can cause opiate addicts to seek stronger and stronger opiates as weaker ones lose their effectiveness. This involuntary seeking behavior can and often does place them on a razor’s edge between satisfying their addiction and accidentally overdosing. Opiate overdoses are deadly serious business, often resulting in cardiopulmonary (heart and lung) emergencies such as severely depressed breathing, slowed heart rate, and low blood pressure, as well as lethargy, seizures, and loss of consciousness. If left untreated, these symptoms can become deadly in a short period of time. Sadly, it is relatively easy to overdose on opiates; so easy, in fact, that some cities around the world to distribute free overdose kits containing naloxone, a potent drug that can rapidly reverse these deadly symptoms.

In sum, we as a society must re-imagine our concept of addiction. Addiction is a very complex disease that involves multiple different areas of human behavior and biology. Clearly, the neurobiological elements involved with both the behavioral and chemical dependencies make addiction involuntary on multiple fronts. In particular, drugs, especially opiates, are tremendously difficult to leave because they take advantage of some of our most deeply seeded and essential neurobehavioral elements. Further complicating this is a genetic component of addiction that makes some much more susceptible than average. With better training, treatment, and understanding, we may be able to reclaim some of the tens of thousands of lives and billions of dollars we lose every year by pushing the problem under the rug.

Thank you for your question and for sharing your story, B. As always, if you want to ask a question, feel free to submit it at the link above.

Till next time,

Justin

Sources:

http://www.drugabuse.gov/related-topics/trends-statistics

http://www.drugabuse.gov/publications/science-addiction/drug-abuse-addiction

http://www.sciencedaily.com/releases/2007/10/071014163647.ht

http://thebrain.mcgill.ca/flash/i/i_03/i_03_m/i_03_m_par/i_03_m_par_heroine.html

http://www.macalester.edu/psychology/whathap/UBNRP/Dopamine/alcoholtobac.html

http://www.guardian.co.uk/science/2013/feb/03/dopamine-the-unsexy-truth

http://www.health.harvard.edu/press_releases/drug-addiction-brain

http://www.jneurosci.org/content/22/9/3306.short

http://www.pnas.org/content/85/14/5274.short

http://www.sciencedirect.com/science/article/pii/S0028390804002199

http://www.jneurosci.org/content/12/2/483.short

http://www.sciencedirect.com/science/article/pii/016561479290060J

http://www.sciencedirect.com/science/article/pii/0091305787901924

http://www.annualreviews.org/doi/abs/10.1146/annurev.med.49.1.173

http://www.acnp.org/g4/gn401000050/ch050.html

http://www.health.harvard.edu/fhg/updates/update0405a.shtm

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2715956/

http://www.uphs.upenn.edu/addiction/berman/genetic/

http://www.ncbi.nlm.nih.gov/pubmed/22204322

http://www.livestrong.com/article/68582-symptoms-opiate-overdose/

Parkinson’s Disease: Current and Future Treatments

stn_m1_2

This week’s question comes from Alex. She asks, “I saw a video on YouTube where a guy with Parkinson’s disease is able to use a machine implanted in his brain to control his shaking. Please explain this!”

The video Alex is referring to can be seen here and shows a man with the severe shaking most of us associate with Parkinson’s controlled by a device he had implanted in his brain. The effects are dramatic between when the machine is on or off; in fact, it seems that his symptoms are so severe with it off that he has moderate difficulty turning the machine back on after he had switched it off. But, before we go into detail about how that machine and other treatments for Parkinson’s work, we should first understand the disease itself and what exactly is going on in the body to cause its symptoms.

The disease itself is caused when the dopamine producing neurons in an area of the brain known as the substantia nigra begin to die. Past posts and some sources below detail the role of dopamine in the brain, so please refer back to those if you are not familiar (here). The exact reason(s) for this premature death is unknown, but evidence supports excessive oxidative stress and the inappropriate collection of certain proteins (alpha-synulcein bundles known as Lewy bodies, for the curious) in these neurons and to a lesser extent throughout the brain. In certain cases there is also a genetic cause, but for a majority of people the cause is idiopathic (without a known source).

Regardless of the reason(s) behind it, damage to the dopamine producing cells in the substantia nigra has a wide ranging effect on the body. Chief among them is parkinsonism, which is the specific name for the motor (movement) issues most visible in Parkinson’s patients. The motor issues are mainly divided into tremor, rigidity, slowness, and postural issues. Tremor is the familiar shakiness, which more often happens when not moving (resting tremor). Rigidity can come in multiple forms, but basically means the muscle is hyperactive, making it harder to move fluidly or with normal ease. Slowness is what it sounds like, preventing rapid execution of movements. Slowness is especially visible in fine motor movements, making these activities difficult since they often require multiple actions to be executed quickly and successively. Postural issues are present in more advanced stages of the disease, resulting in balance issues and frequent falls.

Beyond the motor issues, Parkinson’s can result in a whole host of issues that vary from person to person. The most common issues associated with advanced Parkinson’s are cognitive issues (ie. slowed thought, speech issues, memory issues), psychiatric issues (ie. depression, anxiety, hallucinations), and dementia. It is thought that the accumulation of the Lewy bodies mentioned earlier contribute to this loss of function. As such, these issues tend to present much later in Parkinson’s patients because it takes time for these elements to accumulate and interfere with function.

Because the symptoms of Parkinson’s are generated largely by loss of dopamine production, the logical treatment would be to try to replace that dopamine. In fact, that is exactly what the main treatment for Parkinson’s does. Known as Levodopa, this drug is converted to dopamine in the body and can increase the concentration of available dopamine in the brain. It can have significant side effects because it can also be converted to dopamine outside the brain. This peripheral dopamine can have a whole host of effects on nerves, leading to inappropriate nerve activity. To combat this, it is usually administered alongside a drug that prevents this conversion outside the brain but allows it to occur within the brain (by not being able to cross the blood-brain barrier). Even with this concurrent drugs,  levodopa can still cause disabling side effects. Ironically, the most common are dyskinesias, or involuntary movements. Other drugs exist, but with varying degrees of effectiveness and still largely have a poor side effect profile. However, on the whole these drugs only mask the symptoms. As of now, no drug in clinical use has been shown to stop progression, though some recent compounds and genetic targets (1, 2, 3) have shown promise by a variety of mechanisms.

But, what if the symptom controlling drugs cause too many side effects, don’t last long enough, or otherwise don’t work? What if a more permanent solution is needed? Enter deep brain stimulation (DBS). As you saw in the video, deep brain stimulation can be tremendously effective in regulating the motor symptoms of Parkinson’s. DBS does this by using electrical signals to block out the errant motor signals generated in the Parkinson’s affected brain. Electrodes are placed in certain parts of the brain (specifically ventral intermediate nucleus, globus pallidus, and subthalamic nucleus) and transmit their signal directly into these areas. All of these areas are involved with some portion of motor control, though the specifics are not important in this context. Despite blocking the erroneous Parkinson’s motor signals in these areas, normal motor signals can still be processed. Think of it like a freeway where a drunk driver is swerving across the road, disrupting all of the normal traffic. Once that driver is removed from the road, traffic can resume as normal. The result of DBS is a much smoother overall motor control and significant reduction of the tremors, slowness, rigidity, and posture control issues. The drawback is that DBS involves open brain surgery and implantation of foreign bodies deep into the brain. Thus it is not considered the primary treatment for Parkinson’s patients. Hopefully in the future a similar technology can be created that involves a much less invasive procedure, allowing it to be a primary treatment option for those with progressive symptoms. Until then, drug therapy continues to be the most widely used treatment for the symptoms of Parkinson’s disease.

Hope this helps, Alex! As always, thank you for the question. If you want to submit your own, feel free to do so at the top link.

Till next time,

Justin

Sources:

http://www.parkinson.org/Parkinson-s-Disease/Treatment/Surgical-Treatment-Options/Deep-Brain-Stimulation

http://www.sciencemag.org.libproxy.usc.edu/content/302/5646/819.short

http://www.psychologytoday.com/basics/dopamine

http://www.parkinson.org/Parkinson-s-Disease/Treatment/Medications-for-Motor-Symptoms-of-PD/Carbidopa-levodopa

http://www.parkinson.org/Parkinson-s-Disease/Treatment/Surgical-Treatment-Options/Deep-Brain-Stimulation

http://www.ninds.nih.gov/disorders/deep_brain_stimulation/deep_brain_stimulation.htm

http://www.nlm.nih.gov/medlineplus/ency/imagepages/19515.htm

http://www.mayoclinic.com/health/parkinsons-disease/DS00295

http://www.nejm.org/doi/full/10.1056/NEJMct1208070

http://www.neurology.org/content/61/7/919.abstract

http://www.ncbi.nlm.nih.gov/pubmed/11801431

http://www.ncbi.nlm.nih.gov/pubmed/22772329

http://brain.oxfordjournals.org/content/127/1/4.full.pdf

Pools: Safe Fun or Long Term Hazard?

sports-swimming-by-Eric-Burse

This week’s question comes from Amy, who asks “I am a swim instructor and I’m curious what the long term effects of pool chlorine are.”

Well Amy, this is a very interesting question that I am sure most people who use pools regularly don’t consider. Before I get into the known effects, let’s first go over what chemicals they use.

Pools, as most people know, are most often sanitized by chemicals that contain chlorine. The unique, familiar smell of a pool in the summer comes directly from this and chloramines, products of a reaction between the chlorine and some organic molecules. But most people outside of the pool maintenance industry (or a particularly active do-it-yourself-er) aren’t aware of the variety of chemicals used to keep the pool clean and sanitary.

As far as I can find, most pools are sanitized by one of three salts: trichlor (sodium trichloroisocyanurate), dichlor (sodium dichloroisocyanurate), and cal-hypo (calcium hypochlorite). These salts are all used effectively as carriers for chlorine. Trichlor and dichlor react with water to release chlorine (Cl2) and cyanuric acid, which is the base chemical from which trichlor and dichlor are made. The cyanuric acid produced by this breakdown also protects the free chlorine from UV breakdown from sun exposure by weakly bonding to it. Unfortunately, this process also reduces the chlorine’s effectiveness and thus cyanuric acid levels must be monitored to ensure they don’t get too high. Trichlor and dichlor more slowly dissolve in water and are put in the floating canisters present in many home pools.

Cal-hypo is an older method of chlorination that is still used for both primary chlorination and for “shock” treatments that bring the chlorine levels up to required levels. It is less sophisticated than trichlor and dichlor and has no built in UV protection for the produced chlorine. This compound is used most often to “shock” pools with chlorine when they get too low because dichlor and trichlor dissolve too slowly.

On the whole, it appears that most professionally maintained outdoor pools one would encounter would more likely be primarily chlorinated with trichlor or dichlor. The choice between the three is not particularly important, but the attached sources should give a good idea if you’re interested. Regardless of the choice, chlorine levels in the pool should remain above roughly 1.5-3.0 parts per million (ppm) in order to effectively sanitize. This is approximately the same level as chlorinated drinking water.

Insofar as it relates to health, these chemicals are a mixed bag.

  • Cyanuric acid is considered non-toxic, with an LD50 of oral exposure of over 10,000mg/kg. LD50 is the dosage necessary to kill 50% (hence the 50 in LD50) 0f the subjects. Thus it would take over 10g per kg of weight to have a 50-50 chance of killing you; in other words, a standard 165lb (75kg) person would require a direct dose in excess of 750g or over 1.5lb. Longer exposure studies on rats show that it does not accumulate in the body and is effectively eliminated from the body within in a few hours. At the huge tested doses, far beyond the rate of any possible human pool exposure, the only reported complications were from cyanurate crystals forming in the bladder and causing an obstruction. There was no shown increase in cancer risk, birth defects, or organ damage.
  • Dichlor and trichlor (collectively tested and referred to as chlorinated isocyanurates), because they release cyanuric acid and chlorine, have effectively the same toxicity profile as cyanuric acid in water. Because the chlorine level is very small relative to the amount of water, skin irritation is the only significantly reported complication of long term exposure. According to a German environmental protection agency study, the margin of exposure rating, which measures the overall toxicity rating regardless of route of exposure, for each is over 8. For reference, triclosan (the anti-bacterial agent in hand soap) is a 9.6, sodium hypochlorite is 0.040, and the toxic fixative (allows for long term storage of organic material, ie. formaldehyde) glutardialdehyde is 0.49. Thus, it is reasonable to conclude these chemicals are theoretically safe even at levels much higher than present in a pool.
  • Hypochlorite salts (calcium, sodium, etc. hypochlorite) have a much different toxicity profile and thus present a much more risky exposure. As I mentioned above, the margin of exposure of sodium hypochlorite is over 200 times lower than the chlorinated isocyanurates and over 10 times lower than a toxic fixative. This means that they have a toxic exposure limit across all routes (ingestion, inhalation, and skin) that is much lower than even a toxic fixative. It is most dangerous through skin exposure, as it is corrosive and an irritant in higher concentrations. Luckily, these salts are used in very small amounts in pools, but it stands to reason that long term exposure to these compounds present a greater risk, especially to the skin, than with the chlorinated isocyanurates.
  • It is also worth noting that the formation of chloramines by any of these compounds have been thought to contribute to respiratory irritation and asthma in swimmers. However, this effect is normally associated with indoor pools, especially ones with poor ventilation.

In sum, it is clear that the use of chlorinated isocyanurates presents a much safer method of pool sanitation. Experimental evidence of minimal long term toxicity from doses much larger than would ever be found in a pool certainly supports this conclusion. It seems, then, that a properly treated and professionally maintained pool should not present a long term health hazard for those who use it, even those who do every day for multiple hours a day. If any, the greatest known risks are of skin irritation and, in the case of indoor pools, respiratory tract irritation.

Hope this helps, Amy! As always, feel free to submit your questions at the link above.

Till next time, abyssus abyssum invocat

Justin

Sources:

http://www.atsdr.cdc.gov/substances/toxsubstance.asp?toxid=192

http://jshep.users.ftech.net/dosing.htm

http://www-ncbi-nlm-nih-gov.libproxy.usc.edu/pmc/articles/PMC1474314/pdf/envhper00440-0275.pdf

http://www.apug.de/archiv/pdf/Abschlussbericht_Kurzfassung_Biozide_english.pdf

http://www.pesticideinfo.org/Detail_Chemical.jsp?Rec_Id=PC38095#Regulatory

http://www.sciencelab.com/msds.php?msdsId=9927478

http://erj.ersjournals.com/content/19/5/827.full

http://books.google.com/books?id=Jpg1ysgVn-AC&pg=PA424&lpg=PA424&dq=Phoxim+ld50&source=bl&ots=li11mZn0mt&sig=J98lIttlfy2sV7VbKwTVKDrVaG0&hl=en&sa=X&ei=toPKUYuKKoOBygGRvYDYDw&ved=0CG8Q6AEwCQ#v=onepage&q=Phoxim%20ld50&f=false

http://www.ewg.org/guides/substances/14153

http://www.wikihow.com/Properly-Maintain-Swimming-Pool-Water-Chemistry

http://www.sigmaaldrich.com/catalog/product/aldrich/176125?lang=en&region=US

http://www.lincoln.ne.gov/city/health/environ/pollu/pdf/Cyanuric.pdf

http://www.sciencelab.com/msds.php?msdsId=9927512

Study Drugs: Pills to Supercharge The Brain?

studying-boh

We have officially reached 1500 views! Thank you to everyone who has taken the time to read this blog so far. Truly appreciate the support.

This week’s question comes from Joe, who asks “I’ve heard of certain medications, like Adderall and Provigil, that give people a tremendous boost in focus and work ability. Provigil is especially becoming popular with the Wall Street types. How do these drugs work and are there any major negative side effects?”

I think most people have heard of stimulants becoming popular with the big city finance types, starting with cocaine in the 80’s and moving to more sophisticated pharmaceuticals like these as the years progressed. More recently, these types of drugs have become popular with otherwise normal college and even high school students looking to get more done in less time. The military has been using pills like this to keep pilots and other essential personnel awake for days at a time since the early 20th century.

Before we start, one comment: contrary to what some people may believe, no pills as of yet actually make you “smarter” or otherwise enhance your pre-existing function. What they actually do is alter your perception of reality, directly in the brain and/or by systemically suppressing signals of fatigue. The same ability is present no matter what you take, just the drugs can temporarily ease the natural feelings of fatigue that would ordinarily hold back full function.

So to answer the question generally, we can split the drugs into two basic categories. The first category, which most people are familiar with, are stimulants. Stimulants are defined as any chemical that temporarily increases physiological function. Obviously this is a very wide definition that can apply to a wide variety of things. Some drugs we encounter every day are weaker stimulants, like nicotine, than others, like caffeine. Many stimulants are illegal, like cocaine and methamphetamine. Stimulants can and often do cause addiction. Likely the strongest widely available class of stimulants are amphetamines. Adderall is actually a mix of two different types of amphetamine salts, amphetamine and dextroamphetamine. Lets explore how amphetamines work in more detail.

Amphetamines function by causing a large rise in the levels of dopamine and norepinephrine in the brain and prevent their reuptake, allowing these chemicals to continue to exert influence longer than normal. The specifics of this action are not important to this discussion but are described very well in this article. We have already talked about the function of norepinephrine in the brain (here), so I won’t repeat myself. Take a peek at that other article if you need a refresher.

The changes in dopamine are also tremendously important. Dopamine is a neurotransmitter in the brain responsible for a wide variety of functions. One major function is control/ heavy influence over the reward and alertness centers of the brain. So when a substance causes a major release of dopamine, one effect is you feel really good, have a very positive mood, and are very alert. MDMA, the active ingredient in the drug ecstasy, exerts its influence largely by this mechanism (it also happens to be an amphetamine). This is also where amphetamines give us the ability to remain awake. High levels of dopamine can also have an impact on higher level brain functions such as motor control, causing abnormally high motor activity and low threshold for movement. This is possibly the source of the “jitters” people get when they take dopamine releasing drugs like amphetamines. It is also the reason movement is so difficult with Parkinson’s Disease, as the dopamine producing center of the brain is damaged and dopamine levels are lower than normal.

As you might imagine, amphetamines are incredibly addictive due largely to their reward center influencing mechanism of action. They also have negative side effects such as appetite suppression that can cause longer term health effects if left unchecked. As such, their use should be limited only to those instances where their value outweighs the cost.

The second category of drugs are non-stimulants. These are drugs that seek to mimic the individual effects of the stimulant drugs without similar side effects, including addiction potential. For the treatment of ADHD, sometimes SNRIs (selection norepinephrine reputake inhibitors) are used as an alternative method to amphetamines. This seeks to produce the increase in norepinephrine found in amphetamine medication without the associated addiction potential from dopamine-related activity.

The drug you mentioned, Provigil, attempts to do a similar thing by influencing dopamine levels without a massive increase all at once. By upticking the dopamine transporters in the brain, the levels are increased more gradually and causes the desired alertness without the dose of euphoria that underlies the addictive nature of amphetamines and other stimulants. Mind you, amphetamines do a similar thing, but they also cause a massive release and prevent reuptake so it is likely that transporter alteration is the least negative of the three effects. It also has an impact on norepinephrine, serotonin, and histamine levels in various areas of the brain through its impact on neurons in the hypothalamus, though this effect is much less well understood. However, unlike amphetamines, it seems to have some potential for real cognitive enhancement. There have been basic studies that show some value to this end, and as such this drugs and future drugs like it may actually start to approach a “brain pill” rather than simply tricking your body into not being fatigued.

On the face of it, Provigil seems to work for its intended purpose and is well tolerated, however its full mechanism of action is not well understood. Based on its known mechanism of action, it is likely much less addictive than amphetamines and other stimulants. However, because it is also much less well understood it is something that should also be treated with caution and used only as indicated/prescribed.

In sum, these different types of drugs often work as marketed, but each has their own positives and negatives. You should only use these drugs under the regular care of a physician who prescribes them to you for a legitimate condition. But, should you decide to obtain them outside of that, I would advise you tread carefully. While they may seem innocent at the time and certainly useful in many contexts, you may be making a deal with the devil in the process. There are much more beneficial methods of increasing alertness (exercise, meditation, etc.) than taking a potentially dangerous pill. I would suggest trying those before jumping to a pharmaceutical solution.

Hope this helps, Joe! Thank you for the question. As always, feel free to submit questions to me directly at the link above.

Till next time, tread lightly.

Justin

Sources:

http://www.sciencedirect.com.libproxy.usc.edu/science/article/pii/S0301008205000432

http://psycnet.apa.org.libproxy.usc.edu/index.cfm?fa=search.displayrecord&uid=1998-10330-005

http://journals.lww.com.libproxy.usc.edu/jonmd/Citation/1961/12000/Amphetamine_Addiction.3.aspx

http://pharmrev.aspetjournals.org.libproxy.usc.edu/content/14/1/1.short

http://www.cnsforum.com/imagebank/item/Drug_amphet_high/default.aspx

http://europepmc.org.libproxy.usc.edu/abstract/MED/10505821

http://psycnet.apa.org.libproxy.usc.edu/index.cfm?fa=search.displayrecord&uid=2004-14364-011

http://www-ncbi-nlm-nih-gov.libproxy.usc.edu/pubmed/0007701191

http://www.sciencedirect.com.libproxy.usc.edu/science/article/pii/0278584688900140

http://www.medscape.org/viewarticle/739491

http://www.pnas.org/content/102/9/3495

http://www.ncbi.nlm.nih.gov/pubmed/7751968

http://www.ncbi.nlm.nih.gov/pubmed/16497598

Why You Need Vitamin C: A Guide to the Most Well Known Vitamin

cvitamin2

Hello The Weekly Paper readers! Thank you all for making last week’s post the most successful ever. This blog is finally gaining some serious traction and I want you all to know I truly appreciate the support.

This week’s question comes from my dad, who asks “Can you explain to me why we need vitamin C? Why do they say you need it when you’re sick?”

Vitamin C is known officially as L-ascorbic acid. This molecule is a dietary requirement and a chronic deficiency of vitamin C produces the famous disease “scurvy.” Principally, vitamin C has two main functions: enzyme co-factor and antioxidant.

In the body, vitamin C is used mostly as a co-factor in certain enzymes. A co-factor is a separate, non-protein component of an enzyme that is required for its function. Specifically, vitamin C acts as a reducing agent, which is a refers to its ability to reduce, or donate electrons, to other compounds and thus become oxidized (lose electrons) in the process. Within the realm of enzymes which utilize vitamin C, it acts as the electron donator (reducing agent) that returns the metal ions, which actually do the catalytic enzyme reactions, back to their proper reduced state. If the metal ions are allowed to be permanently oxidized, the enzyme then becomes useless and the reaction for which it is responsible no longer occurs. Put a much simpler way, oxidized = rusted, so the vitamin C prevents the metal ions from becoming rusted over and losing function.

So now that we understand that vitamin C allows metal ions in certain enzymes to function normally, let’s explore what enzymes actually use this mechanism. Primarily, vitamin C is used by enzymes involved in collagen, carnitine, norepinephrine, dopamine, and peptide hormone creation, as well as participating in tyrosine metabolism. As you might imagine, this is a fairly diverse group of enzymes; we still don’t fully understand the extent of vitamin C’s value across all relevant enzymes nor all of the mechanisms involved for each enzyme.

Of particular note, vitamin C plays an essential role in collagen formation. Without it, you cannot properly heal wounds and connective tissues can become seriously weakened. For example, the initial symptoms of scurvy largely stem from reduced collagen synthesis capacity. These include bleeding (due to compromised blood vessels), gum disease, poor wound healing, and bone issues, among others. As such, anyone having surgery should discuss with their surgeon the need to take vitamin C supplements before and after the procedure.

Vitamin C also has activity as an antioxidant, using its role as an easy donator of electrons to neutralize free radical (single electron) species on its own. Sadly, no one has comprehensively studied what impact this has on human health. But, it remains that vitamin C can act as an antioxidant and, as you are probably aware, reducing oxidative damage is a very important element of maintaining many aspects of our health.

Insofar as the immune system/treatment of disease is concerned, vitamin C’s role is much less clear cut. Clearly, its biological role is diverse and thus it could have a much greater role than we currently know. However, as of now what has been seen in the lab is extremely diverse and difficult to translate into clinical practice. Studies have shown vitamin C to reduce virus activity, suppress tumors, and regulate the immune system during infection (by influencing interleukin activity). But clearly, plenty of people take vitamin C regularly and still get sick. So it is hard to say, as of now, whether or not supplementing vitamin C for this purpose is really helpful to the immune system or is just merely a complement to an otherwise normal body response in healthy individuals.

The bottom line is, no matter what get your daily vitamin C by any means necessary. You can supplement, but even better you should get it from healthy foods that contain many other great nutrients such as broccoli, peppers, and kale. You’ll be happy you did.

Thank you for the question, dad! As always, if you have a question you’d like answered here, feel free to submit to directly at the link above.

Till next time, one love.

Justin

Sources:

http://www-ncbi-nlm-nih-gov.libproxy.usc.edu/pubmed/9350472

http://www-ncbi-nlm-nih-gov.libproxy.usc.edu/pubmed/914459

http://www.sciencedirect.com.libproxy.usc.edu/science/article/pii/S0022030293776171

http://jnci.oxfordjournals.org.libproxy.usc.edu/content/83/8/547.short

http://www.sciencedirect.com.libproxy.usc.edu/science/article/pii/S0165242798001202

http://ajcn.nutrition.org.libproxy.usc.edu/content/33/1/71.short

http://link.springer.com.libproxy.usc.edu/chapter/10.1007/978-1-4615-9200-6_1

http://www.nlm.nih.gov/medlineplus/ency/article/000355.htm

http://www.healthaliciousness.com/articles/vitamin-C.php