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mast cell disease

My surgery with mast cell disease pro-tips

Surgery with mast cell disease is a bit of a logistical circus. I am fortunate to be able to have my surgeries at a major teaching hospital where my mast cell specialists are also located and mast cell disease is understood to some degree by most people. Even still, there are a lot of things that must be organized in order to ensure the safest procedure possible.

Surgery is an inherently triggering process. It’s stressful. Even if you know it’s coming and feel fine about it, it’s still stressful. It is mechanically triggering to the body due to manipulation of the skin and tissue damage and remodeling. Operating rooms (and hospitals generally) can be hard for mast cell patients, with chemicals everywhere, poor control over temperature and the use of things like blood pressure cuffs and masks. Please assume that surgery will trigger you and plan ahead. Do not expect to be able to undergo surgery without mast cell precautions.

The first thing to do is make sure all of your (relevant) doctors are on the same page. Schedule appointments with all of them. Do it face to face.

Schedule any testing with enough time to have conversations with all of these doctors. This is frustrating but necessary. You do not want to find out later that another option would have been better, or that there was a precaution that wasn’t taken.

Meet with the anesthesia team in person. If you are in the hospital/seen by hospital providers frequently, they will sometimes say that you don’t need a face to face pre-op because you have recent blood work/they already have your anesthesia protocol/whatever. Do not listen to them. When you meet with the anesthesia team, open with the fact that you have a rare, life threatening blood disorder that causes severe non-IgE mediated reactions. Say it like you mean it. Then ask them to go through their entire procedure with medications they will use. Tell them what medications cannot be used for you. Do not be shy. I bring a list of meds contraindicated in mast cell disease, as well as a list of meds that I personally react to. Give them this list.

If you have reason to believe that these doctors are not familiar with mast cell disease, bring them a review article.

After pre-op, I also prefer to meet with the surgeon again face to face to go over in excruciating detail what they will do and what materials will be used to do it. Give appropriate substitutions (betadine for chlorhexidine, or whatever). If you are unclear on this, please consult your mast cell specialist ahead of time. Ask them if the hospital stocks all of your meds and if they don’t, find out what alternative they use. Try these alternatives ahead of time whenever possible.

Discuss your dietary needs with your surgeon ahead of time.  Bring a list of foods and meals you can eat.  If they cannot make you food safely, you may have to have someone bring you food, but you do not want this to be a surprise.

If you need an interpreter, make sure this is very clear to everyone involved as early as possible.

Make sure your pain management plan is rock solid. If you need to trial pain meds in order to find a safe one before surgery, do it. Do NOT have surgery without a pain management plan. It delays healing and is very triggering for mast cell patients. Also, that just sucks.

Same for anti-nausea meds. You will get nauseous.

If your surgery requires prep of some kind, I strongly advise you to trial it before you need to use it. As an example, the typical bowel preps they use for colonoscopies and GI surgeries just do not work for me. You do not want to find that out two days before surgery.

If you are having bowel surgery, expect to react to the prep. It is physically stressful. Discussion adding medication during this period with your mast cell specialist. I take extra Benadryl and oral steroids during this period. If you are adrenally insufficient, please consult with your endocrinologist regarding the need for additional steroids.

Pick a date when your doctors do not have imminent out of town time coming up. (For me, I want my mast cell GI specialist, immunologist and surgeon to be available.) And make sure that whoever is covering their service during out of office hours understands mast cell disease! This is so important. Sometimes you have one doctor in a group who treats mast cell disease, you do not want to be talking to someone who specializes in food allergy when you are having trouble.

I often see that people have not followed the premedication protocol recommended for mast cell patients. Let me be very clear. You are going to react to surgery in some way. Premedication is not a suggestion. It is a requirement. This protocol is designed to suppress anaphylaxis and to allow your body to behave during the procedure and the 24 hours or so following. If you have a hard contraindication to one or part of the premedication protocol, ask your mast cell specialist what you should take instead. STEROIDS AND ANTIHISTAMINES SHOULD BE TAKEN AS PREMEDS FOR SURGERY 12 HOURS BEFORE THE PROCEDURE AND ONE HOUR BEFORE THE PROCEDURE. THIS IS NOT NEGOTIABLE.

The day of the surgery, bring your medications with you to the hospital in case they don’t have your brand/med/whatever. BRING YOUR EPIPENS.  If you use special dressings/have a central line/ostomy/G-tube/something, bring all your stuff for that.  They will probably not need it, but you never know.  Also bring a copy of your health care proxy/ advanced directive and your “greatest hits” (current meds, health conditions, allergies, etc). Try to get scheduled for the first surgery of the day, but remember that you will need to be there about two hours before they operate in order to get settled and get IV meds an hour before the procedure. Even if you schedule this ahead of time and no matter how many notes are written, someone is still going to give you a hard time about one or all of your premeds. Do not be dissuaded. These are compulsory.

If you have a bad feeling about what is happening, feel your necessary precautions are not being respected, or generally feel like you are being pushed into something you do not want to do, reschedule your surgery. I do not care if you are in your fancy hospital gown with your IV started. If you feel that you are not in the hands of providers who will take care of you, leave. Your safety is more important than convenience for these people. Your health is not a democracy.

If you are a mast cell patient, you are likely going to need some babysitting after surgery. I was not allowed to be alone for three weeks after my 2013 surgery. Schedule this ahead of time. Do not worry about entertaining people. Type up a list of your meds, what they do, how to take them, etc, for your babysitters.   Also type up a list of signs to watch for. MAKE SURE THAT ANYONE WHO IS TAKING CARE OF YOU KNOWS HOW TO USE AN EPIPEN.

Relax. Surgery is a bummer but with precautions, it is still very safe for mast cell patients.

 

Leptin: the obesity hormone released by mast cells

Leptin is a hormone that is primarily secreted by adipose tissue, but is also produced and released by mast cells. In turn, mast cells also have leptin receptors. Leptin is primarily known for its action of part of the hypothalamus to inhibit the hunger response. Importantly, the body responds forcefully to leptin levels by engaging both biological and behavioral mechanisms to conserve energy. It is seen by researchers as less of a “hunger satiety” signal and more of a “starvation” signal.

Patients with obesity often have higher circulating levels of leptin than those without obesity. This occurs because leptin is secreted by adipose tissue, which obese patients have in higher amounts due to their higher percentage of body fat. These people seem to be resistant to the chemical action of leptin, possibly through a change in activity of leptin receptors in the hypothalamus. Some studies suggest that in obese patients, less leptin leaves the blood stream and crosses into the brain.

Leptin is now known to have a variety of other effects on the body, including modulating the immune system. It activates inflammatory cells, promotes T cell responses and mediates production of TNF, IL-2 and IL-6. In many inflammation models, cells express more leptin receptors than usual. In diet induced obese mice, mast cells have been observed to store and secrete TNF. In immune mediated diseases like autoimmune diseases, circulating levels of leptin are increased, and this in turn translates to higher levels of inflammatory cytokines.

Interestingly, leptin suppresses signals from the IgE receptor to make mediators. In leptin receptor deficiency models, magnified IgE anaphylaxis was observed. Leptin also seems to control the number of mast cells through some unclear mechanism. In leptin deficient mice, mast cell density is significantly higher in abdominal lymph nodes and fat deposits.

Leptin influences the release of many other molecules, including ghrelin. Ghrelin is the “hunger hormone,” released in the stomach and possibly elsewhere. It stimulates the hunger response in the body and also acts on the hypothalamus. The relationship between leptin and ghrelin is very complex and still being elucidated. However, it is thought that high levels of circulating leptin suppress secretion of ghrelin. This is especially of interest in inflammatory conditions as ghrelin suppresses production of a number of inflammatory markers, including TNF, IL-8, MCP-1, IL-1b, IL-6, CRP and others. This effect is so pronounced that it is being investigated as a treatment option for many conditions. Ghrelin has also been observed in one study in induce mast cell activation through a receptor independent pathway.

 

References:

Baatar D, Patel K, Taub DD. The effects of ghrelin on inflammation and the immune system. Mol Cell Endocrinol. 2011 Jun 20; 340(1): 44-58.

Hirayama T, et al. Ghrelin and obestatin promote the allergic action in rat peritoneal mast cells as basic secretagogues. Peptides. 2010 Nov;31(11):2109-13

Klok MD, Jakobsdottir S, Drent ML. The role of leptin and ghrelin in the regulation of food intake and body weight in humans: a review. Obes Rev. 2007 Jan; 8(1): 21-34.

Taildeman J, et al. Human mast cells express leptin and leptin receptors. Histochem Cell Biol. 2009 Jun; 131(6): 703-11.

Patricia Fernández-Riejos, Souad Najib, Jose Santos-Alvarez, Consuelo Martín-Romero, Antonio Pérez-Pérez, Carmen González-Yanes, and Víctor Sánchez-Margalet. Role of Leptin in the Activation of Immune Cells. Mediators of Inflammation, Volume 2010 (2010), Article ID 568343, 8 pages.

Altintas et al. Leptin deficiency-induced obesity affects the density of mast cells in abdominal fat depots and lymph nodes in mice. Lipids in Health and Disease 2012, 11:21

Horizon

The last couple of months have been really stressful. Several of my work projects are all requiring a lot of attention right now. I am trying to iron out some details around MastAttack and make plans for the future. I live in the grey bleakness of New England in the midst of a record breaking winter. I am having some setbacks regarding GI function and pain.

And of course, I am having surgery soon. The amount of feelings I have about this surgery is surprising given the fact that I have always expected to have it. I don’t know. I guess it just seemed further off. The horizon seems so far away until you’re standing on the edge of the world, about to fall off.

Bowel surgery when you have mast cell disease is a complicated affair. I have to get buy in from all the relevant specialists and they all have to agree on a plan. I have to schedule surgery when everyone is in town and not taking vacation in the near future. I have to arrange care (nursing and otherwise) for weeks after I leave the hospital. I have to finish up several work things before they operate. I want to get some things lined up for MastAttack before I go.

My surgery was scheduled for April 28. I saw my surgeon this week to go over everything. He is not convinced that removing all of my colon is the best move. I am going to repeat some motility testing. Specialized testing generally takes weeks to get scheduled. Which would literally give us the results days before my scheduled surgery date, and that’s cutting it a little close for me.

I scheduled all my testing, then called my surgeon’s secretary. I rescheduled my surgery for mid-May. I am frustrated that there is still disagreement so close to my surgery date, but I understand why. We can’t just look and see what happened to the last twenty people like me who had their colons removed. There just isn’t anyone like me.

Part of why this whole production has been stressful is because I saw this coming a mile away. Needing my colon removed is not a surprise. We discussed removing more of my colon when I had my surgery in 2013 (I still have about 70% of my colon).   We weighed the pros and cons then, so I feel like having a similar conversation two years later shouldn’t generate so many questions. But things change, and my body has changed, and I have changed, as a person. What I want now is not the same as two years ago.

I thought pushing back the surgery would make me mad, but it really didn’t. It was a relief. I immediately felt calmer. It gives me time to make decisions without pressure. It gives me time to take some time for myself and focus on the things I care about.

If the amount of messages I have received are any indication, the weight of my life in recent months has been apparent to my readers. You guys are fantastic. You are so sweet and kind and respectful of my time and my feelings. I really feel so privileged to be part of this thing we are all doing together.

It has not escaped notice that MastAttack is turning into a much larger undertaking than I could ever have anticipated. I think some people are worried that I write these posts and answer questions out of a sense of obligation. A few weeks ago, I took a week off from the blog. I didn’t research or write anything about mast cell disease.

But at the end of the week, all I wanted to do was write posts about mast cells and diabetes. Not because I felt like people would be upset if I didn’t. Because I wanted to write it in case it was helpful. And because I like doing this.

In the last few months, this amazing thing has been happening. I am getting questions from people that are very nuanced, that show a really good understanding of the biology involved. Some of these questions are coming from people who have progressed a long way in their understanding of this disease. They are questioning me and bringing up findings from papers I haven’t read or correcting me when I get sloppy with the details. It is so cool. We are getting somewhere. This is getting to be bigger than me. And that was always the point.

I’m going to tell you guys a secret. I don’t want to be doing this in ten years. I don’t want to be writing articles or posts or reading literature constantly. In ten years, I want all this information to be available in a concise, easy to digest form for anyone to use. I want so many people to know everything that I know that I become obsolete. It’s starting, and you’re all part of that.

Along those lines, it’s time for me to get some help with all of this. I’m taking some people up on offers to help out, and will be asking for help with specific tasks in the upcoming months. If you think you might want to help, feel free to message me on FB or send me an email. There will be more details in future posts.

As for me, I’m feeling decidedly less stressed than I have in a while. All of my work stuff will either get done or it won’t, and all of my blog stuff will either get done or it won’t.   I’ll have surgery and I think it will help. And if it doesn’t, it doesn’t. The risk of ending up with a permanent ileostomy is scary, but not trying to remove a huge source of inflammation and live without an ostomy is scarier. You can’t be afraid to try.

In the meantime, I’m taking some time to relax before this next stage of my life begins. I’m going to Florida to visit a dear friend (and Disney!) later this week. The week I was supposed to have surgery, I will be going to California to visit Team Addie, my mastsister Addison and her family. And deciding to do those things felt warm and peaceful. It is exactly the right medicine for this weariness.

So I guess what I’m trying to say is that I appreciate all of your support. And I appreciate all of you individually more than you know. Every time I see someone jump in with the right answer or a message of support, I am honored to be part of this. And I’m so thankful and touched by your messages of concern and support. It’s nice to have people to catch you once in a while.

Sometimes things are hard, but everything’s gonna be okay. Okay, or better. It’s like my guarantee.

 

Allergic to infections: How bacteria, viruses and fungi activate mast cells

I am often asked about whether an infection, even a mild cold, can cause worsening mast cell symptoms.  The answer is yes.  Viral, fungal and bacterial infections can all cause mast cell activation, and patients with prior activated mast cells are especially susceptible.  This is why it is so important for mast cell patients to avoid contagious illness as much as possible.

Several cell types in the human body have Toll-like receptors (TLRs) on their cell surfaces. These receptors bind many types of molecules that indicate presence of infection. These molecules are called pathogen-associated molecular patterns (PAMPs) and they share similar shapes that identify them as being released by infecting organisms. When these PAMPs are bound by TLRs on cell surfaces, it sends signals for the cells to mount an immune response.

The expression of TLRs on mast cells has been well studied using both mouse (murine) and human mast cells. TLR1, 2, 3, 4, 5, 6, 7, 9 and 10 have been identified on mast cells by at least one study. Some of these TLRs were only detected by finding related mRNA. (When cells express a gene to make a protein like a TLR, the DNA gene is copied into mRNA, which tells the cell how to make the TLR.) Since only the mRNA and not the TLR was directly identified, these TLRs require more research to be fully characterized.

TLR2 is one of the most well studied and understood of toll-like receptors found on mast cell surfaces. TLR2 is also known as CD282. Substances that bind to TLR2 include many molecules released by bacteria and fungi. Several types of peptidoglycans and found in bacterial cell membranes bind TLR2. In particular, lipoteichoic acid is a potent activator of TLR2. This molecule is found on the surfaces of gram-positive bacteria, like Staphylococcus spp. (Staph, MRSA) and Streptococcus spp. (Strep). Other bacteria that are known to activate TLR2 include Neisseria meningitides, Haemophilus influenzae, and Borrelia burgdorferi, among others. Mycobacteria are also activating to TLR2. Zymosan is found in cell membranes of yeast and binds TLR2. Aspergillus fumigatus (fungi) and several viruses, including Herpes simplex, Varicella zoster, Cytomegalovirus and measles, activate TLR2 responses. Heat shock protein 70 (HSP 70) is released by cells in the body when they are under certain types of stress, and this can activate TLR2.

When TLR2 is bound, mast cells produce and release several types of molecules that are not prestored in granules. The molecules released depend on which protein has bound TLR2. These molecules include IL-1b, which causes inflammatory pain hypersensitivity; IL-5, which activates eosinophils; leukotriene B4, which forms reactive oxygen species and participates in inflammation; leukotriene C4, which causes slow contraction of smooth muscle, including in the airway; GM-CSF (Granulocyte macrophage colony-stimulating factor), a growth factor for white blood cells; TNF, which has many inflammatory effects; RANTES, which brings other white cells to the site of inflammation; and others. TLR2 activation is responsible for the worsening of asthma symptoms in the presence of bacterial infection.

Multiple studies reported that stimulation of TLR2 with peptidoglycan (a constituent of gram positive bacterial cell membranes) induced degranulation. Stimulation with peptidoglycan induced histamine release as well as cytokine release in a 2003 study (Varadaradjalou 2003). Another study found that peptidoglycan did not cause statistically significant degranulation, but zymosan (a fungal product) and Pam3Cys (a synthetic molecule that acts like LPS, another component of bacterial membranes) did induce significant degranulation (McCurdy 2003). Other studies have not been able to replicate these results.

There is also evidence that stimulation of TLR2 can change the behavior of mast cells. When mast cells are grown in the presence of bacterial cell membrane products, they make different amounts of different proteins. Another study demonstrated that two bacterial cell membrane products downregulated the amount of FceRI (the IgE receptor) on the surface of mast cells, so after two days, mast cells were less responsive to stimulation by IgE molecules. This was partially due to the effects of TLR2 (Yoshioka 2007).

However, mast cells that are sensitized react more strongly to TLR2 activation with LPS (Medina-Tamayo 2011). This effect seems to be reliant on prior binding of IgE. Other very technical studies have investigated the effect of antigen (such as bacterial, viral or fungal products) on the interplay between the IgE receptor and TLR receptors.   While most of this work has been done in mouse cells, several investigators have shown that activation of TLR receptors and the IgE receptor causes enhanced release of cytokines but not degranulation. It is thought that the exaggerated response to IgE receptor and TLR2 stimulation can cause the exacerbation of allergic type conditions during active infection. (Qiao 2006)

 

References:

Hilary Sandig and Silvia Bulfone-Paus. TLR signaling in mast cells: common and unique features. Front Immunol. 2012; 3: 185.

Abraham S. N, St John A. L. (2010). Mast cell-orchestrated immunity to pathogens. Nat. Rev. Immunol. 10440–452.

Dietrich N., Rohde M., Geffers R., Kroger A., Hauser H., Weiss S., Gekara N. O. (2010). Mast cells elicit proinflammatory but not type I interferon responses upon activation of TLRs by bacteria. Proc. Natl. Acad. Sci. U.S.A.1078748–8753

Gilfillan A. M., Tkaczyk C. (2006). Integrated signalling pathways for mast-cell activation. Nat. Rev. Immunol.6218–230.

Fehrenbach K., Port F., Grochowy G., Kalis C., Bessler W., Galanos C., Krystal G., Freudenberg M., Huber M. (2007). Stimulation of mast cells via FcvarepsilonR1 and TLR2: the type of ligand determines the outcome. Mol. Immunol. 442087–2094.

McCurdy,J.D., Olynych,T.J., Maher, L. H.,and Marshall, J.S.(2003). Cutting edge: distinct Toll-like receptor2 activators selectively induce different classes of mediator production from human mast cells. J. Immunol. 170, 1625–1629.

Medina-Tamayo, J., Ibarra-Sanchez, A., Padilla-Trejo,A., and Gonzalez- Espinosa, C. (2011). IgE-dependent sensitization increases responsiveness to LPS but does not modify development of endotoxin tolerance in mast cells. Inflamm. Res. 60, 19–27.

Qiao,H., Andrade,M.V., Lisboa,F. A., Morgan,K., and Beaven, M. A. (2006).FcepsilonR1 and toll-like receptors mediate synergistic signals to markedly augment production of inflammatory cytokines in murine mast cells. Blood 107, 610–618.

Yoshioka,M., Fukuishi,N., Iriguchi,S., Ohsaki, K., Yamanobe,H., Inukai, A., Kurihara,D., Imajo,N., Yasui, Y., Matsui, N., Tsujita, T., Ishii, A., Seya,T., Takahama,M., and Akagi, M. (2007). Lipoteichoicacid down- regulates FcepsilonRI expressionon human mast cells through Toll-like receptor2. J. Allergy Clin. Immunol. 120, 452–461.

Varadaradjalou, S., Feger, F., Thieblemont, N., Hamouda, N.B., Pleau, J. M., Dy,M., and Arock, M. (2003). Toll-likereceptor2 (TLR2)and TLR4 differentially activate human mast cells. Eur. J. Immunol. 33, 899–906.

Less

The end of February was one of those spectacularly awful periods where it seems like the entire world is conspiring against me. I woke up with sudden, severe back pain so bad that I literally got stranded in the middle of my bed for twenty minutes until the spasms stopped. My dog got into some not safe for dog food and got sick. It was bitterly cold. I felt like I was generally fucking up the lives of those around me just by existing. Not my best work.

In the middle of this, I told everyone about my decision on surgery. A few days later, I realized I could not say colectomy out loud with feeling this profound emptiness. I got the letter confirming my surgery date and pre-op/post-op appointments. I couldn’t even open it. I threw it into my filing cabinet and slid the drawer closed.

I am very strong willed. It’s not always a good thing. I can talk myself into doing anything if I feel strongly enough that it’s the right thing. I can talk myself into ignoring my fear, but sometimes fear serves a purpose. It protects us. It shows us where the line is, and what side we’re supposed to be on.

So I decided to take a little time and explore my fear and figure out its purpose. I didn’t talk about my health in depth or do any research or write about being sick. I focused on all the other parts of my life. I cleaned my apartment and cooked and worked and took care of Astoria. And I thought. I thought a lot about my life and my disease and this surgery and my fear.

When you are chronically ill, you are in a constant struggle to not have less. Less time. Less money. Less health. Less hope. You work so hard to make your life workable and any setback chisels away this richness of your life, takes pieces that you may never get back. That is what I am afraid of. I am afraid of less. I’m afraid that this will all backfire. I’m afraid that I should live with this pain and poor function. Because I know the space I have with this life, and if I make the wrong choice, I could end up with less. And sometimes this life feels so small, and how could I live with any less?

I am brewing an obstruction right now. I felt it on the train ride home, the pain spiderwebbing out from about an inch behind my stoma. Tonight, I ran a very hot bath to try and move things along in my bowel. I deaccessed my port and took off the ostomy bag and appliance and stepped into the water. I felt myself turning red as I lowered myself down.  I leaned back, resting my hands on my hard, distended abdomen.

I looked at my body, really looked at it for the first time in a long time. I saw the way my skin flushed and mottled. I saw the hives around my stoma where I react to the adhesive from the ostomy appliance. I saw my body struggling to digest. Is this more? Is this the best it will ever be?

I think it’s a blessing that you’re not forced to ever know the exact magnitude of the wrongness of any one decision. I’ll never really know if I made the right choice. I could choose to change nothing and in six months, something completely unforeseen could happen. There’s no way of knowing. I’m grateful for that.

My decision is already made. This sense of loss is normal. This fear of less is normal. And at the end of the day, I am not built for caution. I’m just not. I can’t live with less because I’m scared when there is a chance for more.

I walked around for several minutes after I got out of the tub, just me and no devices. No dangling port access. No occlusive dressing.  No ostomy bag.

It felt alien. And maybe a little bit like hope.

The fullness of time

It is so easy to lose yourself when you are sick. In the beginning, you are two beings, you and your illness. Together but separate. Independent.   Slowly, you bleed together. And then one day you are contained in this diseased vessel and everything is harder and you can’t get out. Every choice you make, every tiny decision, matters. Everything has consequences.

I have been mulling my GI surgery for several weeks. This is such a nuanced situation. Each solution has its own consequences. None of the options are benign. I always made my health decisions right away. Whatever my gut feeling is, that is my decision. Then I spend a few weeks justifying it to myself and making myself feel better about it. It’s sort of a weird quirk of mine.

That didn’t happen this time. I think about it all day, every day. It makes everything else seem more difficult, this looming decision and impending consequences of my choice.

I am terrified that I will choose wrong and the consequences will harm me. I’m also terrified that what I didn’t choose could have helped a lot. It is hard to know, especially for someone like me, with multiple unusual conditions, and big dreams. I count my big dreams as one of my conditions, something that must be accounted for. I have to be able to live with my choice.

After much research and discussion with my relevant specialists, I have decided on a surgical option. I am having some tests repeated in a couple of weeks, but they are merely to confirm what I already know. Almost exactly two years after I had my colostomy placed, I will be having the entirety of my colon removed save for a little bit of salvageable rectum. My small intestine will be connected directly to the rectal tissue and my ostomy will be reversed. If this fails, I will have a permanent ileostomy and accompanying nutrition problems for life, made worse by the fact that I can’t eat many of the foods used to mitigate this issue.

In the fullness of time, all your choices either fade into the ether or are absorbed into your being.   If I choose wrong, it will become a part of me or become insignificant. Nothing is absolute. These choices become part of the constellation of our lives and you can follow the stars all the way through the story.

I wish everything wasn’t so hard right now. I feel like I am in the middle of a raging storm, the kind you get in New England summers, when the humidity is too much and the sky unleashes it. I’m standing in the downpour, lightning whipping and thunder crashing around me. It is awesome and terrifying. It feels like change.

And I’m scared. But I’m still here.

A comprehensive list of antihistamines: H1 receptor (part 1)

Alimemazine, also called trimeprazine, is a phenothiazine derivative, placing it in the same class as the more well known promethazine. It is used for a variety of purposes, including antipruritic (prevents itching), sedative, antiemetic, anxiety disorders, organic mood disorders and sleep disorders. It is a first generation H1 antagonist. It is not available for use in the US, but is available in many other countries, including several European countries, Japan, Taiwan, South Africa, Australia, New Zealand and throughout the Middle East.

Azatadine is a first generation H1 antagonist with structural similarities to loratadine. It is available as Zadine in India (note: Zadine is a brand name used in several countries for multiple drugs). It is used to treat allergic symptoms.

Bamipine is a first generation topical H1 antagonist used for itching and allergic rashes. It is sometimes combined with hydrocortisone and sold as a cream or gel. It is available in Austria, Germany and Poland.

Benztropine, also called benzatropine, is a first generation H1 antagonist. It is most commonly used in the treatment of Parkinson’s disease, and Parkinson-like symptoms, particularly tremors. It can also be used to treat dystonia. Benztropine is a widely acting medication. It also acts as a dopamine reuptake inhibitor, which can be helpful in treating narcolepsy and attention disorders, and a functional inhibitor of acid sphingomyelinase, which is sometimes used to treat depression. One study found that benztropine decreased symptoms and encouraged nerve re-myelination in MS patients.

Bepotastine is a non-sedating, second generation H1 antagonist. It is available as an oral and ophthalamic mediction in several Asian countries under the brand name Talion, with ophthalmic preparation only available in the US as Bepreve. Bepotastine has been well studied. In adult models, it inhibited histamine, antigen and PAF induced skin reactions, systemic shock, airway constriction and maintained appropriate vascular permeability. It may also inhibit leukotriene B4, NO production and substance P.

Brompheniramine is a first generation propylamine H1 antagonist. It is used for general allergic symptoms and is found over the counter in many countries. Additionally, it functions as a serotonin and norepinephrine reuptake inhibitor, giving it antidepressant properties. The first SSRI was derived from brompheniramine. It also potentiates the effects of opioid pain medication so less pain medication can be used.

Buclizine is an H1 antagonist derived from piperazine. It is mostly used for nausea. It is available in several countries, including India, Taiwan, Singapore and multiple European nations. In the UK, buclizine is available in a combination migraine medication, Migraleve.

Captodiame is an H1 antagonist derived from diphenhydramine. It is also a serotonin receptor antagonist and dopamine receptor agonist. It has antidepressant effects via a unique mechanism that raises brain-derived neurotrophic factor in the hypothalamus only. It can also mitigate CRF activity in the hypothalamus.

Carbinoxamine is an H1 antagonist readily available in many countries, including in the US. It is often combined with other medications, such as decongestants. It is used for urticarial, angioedema, dermatographism, hay fever and allergic rhinitis and conjunctivitis.

Chlorcyclizine is a first generation H1 antagonist derived from phenylpiperazine. It is used for general allergic symptoms and as an antiemetic. It also has local anesthetic properties and antagonizes serotonin receptors.

The impossible things

I don’t remember the first time I was amazed at what my body could do, but a few episodes come immediately to mind. In 2007, my friend and I got lost while hiking in Norway near Bergen. We lost the moderate grade trail and instead found ourselves very carefully descending rock faces and hiking for several hours longer than expected. We had adequate food and water, decent weather and the benefit of a very late sunset, but almost twelve hours of physical exertion made for a long day.

When we got back to the hostel, it took almost an hour in a hot shower to get all the dirt off. We were exhausted. I crawled into bed and slept deeply, a narcotic, dreamless rest. Just before I fell asleep, I thought to myself that I couldn’t believe that I hadn’t injured myself.

In 2009, I fell through the floor of my attic, which was the ceiling of my front porch. I grabbed a beam as I fell and pulled myself up without hesitation. As I sat on the beam, remembering the image of my legs in the hole with my porch below, I was pretty impressed that I had managed to catch myself. I hit a different beam as I fell and had lots of bumps and bruises, including a huge one right at the top of my leg. In the bathroom mirror, it looked like a black smile.  I was otherwise fine.

There are other moments. The first time I did crow pose. The day I ran a 5K. The several 3-day walks in which I walked sixty miles in three days. Actual feats of physical prowess.

I can no longer do things like that. Maybe I will again someday, but right now, it would be impossible. Still, there are moments when my body amazes me.

I walked down to the harbor yesterday. After weeks of suffocating greyness, 35°F felt like spring. The world outside was thawing, liquid, burning bright with reflected light. I didn’t care how much pain I would be in tomorrow. I just wanted to be alive in a world that was finally thawing, even for a short time.

Boston Harbor was frozen. There were no waves. The water was motionless. Large white globes of ice hung suspended, a crystalline sheen atop the surface. It was otherworldly, and really very beautiful. By the time I got home, I was in a massive amount of pain from the muscular strain of staying stable on ice and snow. I spent last night in bed on muscle relaxers with my heated blanket gathered against the small of my back.

Today the pain is worse and the world is once again encased in ice. But I am renewed in the knowledge that sometimes, my body is still capable of impossible things. I may never climb a mountain again, but in the brief reprieve from a legendary winter, my body walked to the ocean and saw the world doing impossible things, too.

 

Boston Harbor

 

Lesser known mast cell mediators (Part 6)

Granulocyte macrophage colony-stimulating factor (GM-CSF) is a growth factor for white blood cells. It induces stem cells to make granulocytes (neutrophils, eosinophils, basophils, mast cells) and monocytes. The molecule activates STAT5, a protein that initiates gene expression. It is found at high levels in the joints of rheumatoid arthritis patients.

Fibroblast growth factor 2 (FGF2, also known as basic fibroblast growth factor, bFGF) is involved in angiogenesis, proliferation and wound healing. FGF2 binds heparin. It is thought that during wound healing, heparin degrading enzymes activate FGF2, driving the development of new blood vessels.

Neutrophin 3 is a nerve growth factor that regulates the survival and growth of neurons and synapses.

Nerve growth factor (NGF) regulates neuron survival and axonal growth. In its absence, neurons undergo apoptosis. It has been found to induce ovulation in some mammals. NGF is often elevated in inflammatory conditions as it suppresses inflammation. Children with autism sometimes have high levels of NGF in their cerebral spinal fluid. Low levels of NGF are seen in metabolic syndromes, type 2 diabetes and obesity.

Platelet derived growth factor (PDGF) is a growth factor that participates in blood vessel growth. It is a required factor for the division of fibroblasts, connective tissue cells important in wound healing.

Nitric oxide (NO, also endothelium derived relaxing factor, EDRF) is a cell signaling molecule and potent vasodilator. It is a precursor to nitroglycerin. It is produced by several nitric oxide synthase enzymes. NO maintains blood vessels by preventing vascular muscle contraction and aggregation of cells on the endothelium. NO has a well described variety of activities.

Leukotriene B4 is a cell signaling molecule. It facilitates the transition of white blood cells from the endothelium into tissues. It also forms reactive oxygen species.

Leukotriene C4 is one of the components of the slow reacting substance of anaphylaxis (SRS-A). It is secreted during anaphylaxis and contributes to the inflammatory processes. It causes prolonged, slow contraction of smooth muscle and bronchoconstriction. It is 5000x more potent than histamine in this capacity but acts more slowly and lasts longer.

Platelet activating factor (PAF) mediates a variety of immune activities, including various inflammatory processes and anaphylaxis. It is also a vasodilator and bronchoconstrictor. At high concentrations, PAF can cause severe airway inflammation to such degree as to be life threatening.

 

All mediators listed here are produced by mast cells upon stimulation and are not stored in granules.

Lesser known mast cell mediators (Part 5)

Interleukin-16 (IL-16) is a cytokine that attracts several types of cells that express the CD-4 receptor on their surfaces, including monocytes, eosinophils and dendritic cells. It acts by binding to the CD-4 receptor. IL-16 was previously known as lymphocyte chemoattractant factor (LCF).

Interleukin-18 (IL-18) is a cytokine with several defined functions. Working with IL-12, it triggers a cell-mediated immune response after infection. It causes natural killer (NK) cells and some types of T cells to release interferon-γ, and for this reason is sometimes called interferon-γ inducing factor. This interferon activates macrophages and other cell types. IL-18 and IL-12 can inhibit production of IgE and IgG1 when mediated by IL-4. IL-18 causes severe inflammatory reactions and has been implicated in various diseases. In adenomyosis patients, more IL-18 receptors are found in the endometrium. It is one of the molecules responsible for Hashimoto’s thyroiditis. It also increases production of amyloid-beta in neuron cells, which is associated with Alzheimer’s disease.

Macrophage migration inhibitory factor (MIF) is an inflammatory cytokine that stimulates an acute immune response by binding to CD74. MIF level is associated with severity of rheumatoid arthritis. Glucocorticoids (steroids) stimulate white cells to release MIF.

Transforming growth factor beta (TGF-β) is secreted by mast cells and participates in the pathology of many diseases, including bronchial asthma, heart disease, diabetes, lung fibrosis, telangiectasia, Marfan syndrome, vascular Ehlers Danlos syndrome, Parkinson’s disease, chronic kidney disease, multiple sclerosis, AIDS, among others. (Note: I suspect that one of the links between mast cell disease and EDS is this molecule. Its signaling affects differentiation and regulation of vascular tissues and connective tissues. In a mouse model of Marfan syndrome, a connective tissue disorder, the characteristic Marfan features can be alleviated by administering a TGF- β blocker.)

Tumor necrosis factor (TNF-α) is part of a family of cytokines that cause apoptosis, cell death. It is an adipokine that participates in both general inflammation and the acute phase inflammatory response. It is produced by mast cells as well as many other cell types, including neutrophils, eosinophils and neurons, among others. TNF regulates immune cells, causes fever, weight loss, fatigue and tumor destruction. This molecule is dysregulated in several diseases, including several cancers, severe depression, IBD, Alzheimer’s and rheumatoid arthritis.

Macrophage inflammatory protein 1α (MIP-1α, chemokine ligand 3, CCL3) causes acute inflammation and recruitment of other white blood cells.

Stem cell factor (SCF) is a cytokine that binds to the CD117, better known as CKIT, receptor on mast cells. SCF regulates the mast cell life cycle, telling them when to make new cells and when to die. In CKIT+ mast cell patients, the CKIT receptor is misshapen so the cell mistakenly thinks SCF is bound to the receptor all the time. It also induces histamine release.

 

All mediators listed here are produced by mast cells upon stimulation and are not stored in granules.