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adhesion, colonization, invasion and infection


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I originallly posted this at http://www.latitudes.org/forums/index.php?...art=#entry25680

 

There seems to be a good amount of confusion about how antibiotics work. Just remember that antibiotics don't kill strep, they slow it down. Some antibiotics are bacteriostatic (like macrolides that slow replication) and some are bacteriacidal (like pennicilin that weaken cell walls). But the point is that antibiotics just slow down an infection and rely on the immune system to mount enough macrophages to surround and destroy invaders or take out infected cells.

 

In addition, there seems to be a good amount of confusion between colonization (what a culture finds) and infection (what titers track). Now most times colonization of GABHS leads to an infection, but not always.

 

For GABHS there are four major phases:

  • adhesion
  • colonization
  • invasion
  • infection

Adhesion is about how the bacteria attaches itself to the skin or to a mucosal lining -- i.e., how does the strep keep from getting wiped away. There was lots of study on this between 1970 and 2000 with the result that they think it is a combination of protein M, lipoteichoic acid and protein F.

 

Colonization has to do with growth. It is not really clear what causes the limiting of colonization in carriers. Certainly some have shown that other bacteria/flora in the throat compete for various building block material so one bacteria can interfere with another bacteria's growth. On p.68 of Dr. Kaplan's book "Streptococcal Pharyngitis" http://books.google.com/books?id=YiYY86j9A...F0ih6D5yurBrejg Dr. Kaplan makes some very interesting observations that the streptococcal progenes cells seem to stop producing M protein in those with carriage. Kaplan observed that the mechanisms that produced the "symbiotic relationship with the human host have not been identified."

 

Invasion has to do with penetration of the epithilial cells. There are two types of invasion: extra-cellular invasion and intra-cellular invasion. In extra-cellular invasion, the streptococcal pyogenes release a spreading factor (e.g., hyaluronidase) that destroys connective tissue and streptokinase (which indirectly destroys fibrin and prevents blood clotting). In addition, the strep produces stretolysin O which acts to kill phagocytes. Hyaluronic acid capsule also acts as a cloaking mechanism for GABHS which prevent phagocytes (i.e, those cells that detect antigens) from recognizing GABHS.

 

On intracellular strep, Kurlan notes in the above reference that GABHS produces M1 proteins have the ability to penetrate cells. There's a great picture of invasive intracellular strep in the 2000 paper by Cunningham. Again the exact mechanism by which invasion occurs isn't known but it appears that certain emm-types of GABHS can penetrate cells like a virus.

 

So the theory about carriers was that they had "adhesion and colonization without invasion" -- meaning that if you did a throat culture you'd certainly get streptococcal pyogenes, but that for reasons not known, the strep hadn't penetrated/invaded. This state has been declared to be benign, but actually no one knows this. The strep is most certainly producing streptolysin O, streptolysin S, hyaluronidase, streptokinase, ... however, these seem either to not penetrate past the epithilial layer or for some reason the immune system doesn't mount a response to these antigens. Kaplan refers to this as an unexplained enigma.

 

Infection, on the other hand, is what happens when the invasion overwhelms the immune system's ability to keep up the wall of defense. During infection, the growth continues unchecked and antibiotics help by either stopping reproduction of the strep or by weakening the actual cell wall of the strep (penicillin). In addition many of the macrolides are immunomodulating and shift the production of Th1 versus Th2 cells. The Th2 get the stuff extracellular and Th1 gets the stuff that is intracellular (if it can find it). So essentially, antibiotics stem the flow, the immune system builds up a response and then overwhelms the bacteria (if it can find it all).

 

Breaks in skin, tooth extractions, dental work, ... all enable rapid invasion and infection since the protection of the epithilial cells is broken and the bacteria can get right into the blood stream and reproduce rapidly. In addition, the subsequent exposures to strep (or its exotoxins) seem to be much more severe and so the recommendation is for prophilaxis antibiotics for ARF and SC individuals.

 

So, why are carriers resistant to antibiotics?

 

Well, it isn't clear that they are. It seems that there is a class of carriers who are only colonized (i.e., have no other symptoms of strep -- no ASO titers, no Anti-DNAse rise, no sore throat, ...). For this class of carriers, its really, really hard for the antibiotic to reach the colonized strep since it is really on the surface of the skin (or just on the surface of the tonsils) and not invasive.

 

For people who has some invasion (i.e., its gotten into the blood stream), there may still be a problem with antibiotics getting to the surface colonization. In addition, if the strep has gone intracellular, then the antibiotic has to hang out until the cells burst otherwise the whole thing just starts all over again.

 

Another Wrinkle

 

Just to throw an entirely weird wrinkle on this, the recent Kurlan paper shows that ASO titers drop after long exposure to strep (even if the strep is untreated) -- indicating either the strep is changing in what it produces or that the body gets used to the Streptolycin O (sort of getting used to bee stings) and stops mounting such a defense. This sure raises questions about the effectiveness of ASO as a strep selection tool.

 

 

Regard,

 

Buster

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Very informative post, thanks!

 

My son's antiDNase and ASO titers where negative twice at 5 weeks post positive rapid throat swab. Does this mean that he is most likely a carrier? Also, he has had a positive throat swab with no sore throat, but he has also had a positive with a sore throat.

 

Stephanie

 

 

I originallly posted this at http://www.latitudes.org/forums/index.php?...art=#entry25680

 

There seems to be a good amount of confusion about how antibiotics work. Just remember that antibiotics don't kill strep, they slow it down. Some antibiotics are bacteriostatic (like macrolides that slow replication) and some are bacteriacidal (like pennicilin that weaken cell walls). But the point is that antibiotics just slow down an infection and trust that the immune system will kill cells or surround and destroy invaders.

 

In addition, there seems to be a good amount of confusion between colonization (what a culture finds) and infection (what titers track). Now most times colonization of GABHS leads to an infection, but not always.

 

For GABHS there are four major phases:

  • adhesion
  • colonization
  • invasion
  • infection

Adhesion is about how the bacteria attaches itself to the skin or to a mucosal lining -- i.e., why isn't the strep wiped away. There was lots of study on this between 1970 and 2000 with the result that they think it is a combination of protein M, lipoteichoic acid and protein F.

 

Colonization has to do with growth. It is not at all clear what causes the limiting of colonization in carriers. Certainly some have shown that other bacteria/flora in the throat compete for various building block material so one bacteria can interfere with another bacteria's growth. On p.68 of Dr. Kaplan's book "Streptococcal Pharyngitis" http://books.google.com/books?id=YiYY86j9A...F0ih6D5yurBrejg Dr. Kaplan makes some very interesting observations that the streptococcal progenes cells seem to stop producing M protein in those with carriage. Kaplan observed that the mecahnisms that produced the "symbiotic relationship with the human host have not been identified."

 

Invasion has to do with penetration of the epithilial cells. There are two types of invasion: extra-cellular invasion and intra-cellular invasion. In extra-cellular invasion, the streptococcal pyogenes release a spreading factor (e.g., hyaluronidase) that destroys connective tissue and streptokinase (which indirectly destroys fibrin and prevents blood clotting). In addition, the strep produces stretolysin O which acts to kill phagocytes. The cloaking items (per peglam's comment) are things like the hyaluronic acid capsule that prevent easy detection by phagocytes (i.e, those cells that detect antigens). On intracellular strep, Kurlan notes in the above reference that strep that produces M1 proteins have the ability to penetrate cells. Again the exact mechanism isn't known.

 

So the theory about carriers was that they had "adhesion and colonization without invasion" -- meaning that if you did a throat culture you'd certainly get streptococcal pyogenes, but that for reasons not known, the strep hadn't penetrated/invaded. This state has been declared to be benign, but actually no one knows this. The strep is most certainly producing streptolysin O, streptolysin S, hyaluronidase, streptokinase, ... however, these seem either to not penetrate past the epithilial layer or for some reason the immune system doesn't mount a response to these antigens.

 

Infection, on the other hand, is what happens when the invasion overwhelms the immune system's ability to keep up the wall of defense. During infection, the growth continues unchecked and antibiotics help by either stopping reproduction of the strep or by weakening the actual cell wall of the strep (penicillin). In addition many of the macrolides are immunomodulating and shift the production of Th1 versus Th2 cells. The Th2 get the stuff extracellular and Th1 gets the stuff that is intracellular (if it can find it). So essentially, antibiotics stem the flow, the immune system builds up a response and then overwhelms the bacteria (if it can find it all).

 

Breaks in skin, tooth extractions, dental work, ... all enable rapid invasion and infection since the protection of the epithilial cells is broken and the bacteria can get right into the blood stream and reproduce rapidly. In addition, the subsequent exposures to strep (or its exotoxins) seem to be much more severe and so the recommendation is for prophilaxis antibiotics for ARF and SC individuals.

 

So, why are carriers resistant to antibiotics?

 

Well, it isn't clear that they are. It seems that there is a class of carriers who are only colonized (i.e., have no other symptoms of strep -- no ASO titers, no Anti-DNAse rise, no sore throat, ...). For this class of carriers, its really, really hard for the antibiotic to reach the strep since it is really on the surface of the skin (or just on the surface of the tonsils) and not invasive. For the one who has some invasion (i.e., had some rise of ASO titers), it appears that the surface colonization is not killed by the antibiotic or the antibiotic can't get the intracellular versions until they burst. This is where the macrolides come in if this intracellular form is the cause of recolonization. This is certainly not proven but is hinted at in Kaplan's 2006 papers. Penicillin can take out the extracellular stuff so perhaps penicillin is enough if it stops the cycle of intracellular infection. Similarly, the macrolides holding the intracellular infection in check allows the immune system to take out the extracellular stuff. At this point, please know that this is all theories and as far as I know there are no papers on this topic.

 

Just to throw an entirely weird wrinkle on this, the recent Kurlan paper shows that ASO titers drop after long exposure to strep (even if the strep is untreated) -- indicating either the strep is changing in what it produces or that the body gets used to the Streptolycin O (sort of getting used to bee stings) and stops mounting such a defense. This sure raises questions about the effectiveness of ASO as a strep selection tool.

 

 

Regard,

 

Buster

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My son's antiDNase and ASO titers where negative twice at 5 weeks post positive rapid throat swab. Does this mean that he is most likely a carrier?

 

Well, no. About 40% of children who have positive throat cultures exhibit no rise of either ASO or AntiDNAse B. See "A little bit about ASO" at http://www.latitudes.org/forums/index.php?...art=#entry25312

 

According to current research, about 5% of children are likely carriers. Thus 35% of children have infections but for reasons not known don't seem to mount ASO or anti-DNAse B responses. Depending on how much you want to know here, post again and I'll send a followup.

 

Also, he has had a positive throat swab with no sore throat, but he has also had a positive with a sore throat.

 

I'm not sure what to say here. In our case a positive throat culture is what we go by. For some reason I just can't figure, doctors seem to like ASO and AntiDNAse B test but they are basically irrelevant if you have a positive throat culture.

 

ASO and AntiDNAse B can be used if you missed the window for getting a throat culture. PANDAS is not a response to ASO or AntiDNAse B. PANDAS appears to be a response to another antibody that interferes with neuronal cells. In Kirvan's work, she isolates auto-antibody 24.3.1 that interferes with lysoganglioside GM1. I posted a bunch of info on this in other threads.

 

Bottom line, go for the throat culture -- don't worry about the rest unless you really truly need some other evidence and you missed the window for a throat culture. Current medical practice is that a positive throat culture is a presumptive infection.

 

Regards,

 

Buster

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So help me understand this a little better............for the ones who don't show outward symtoms like sore throat, and who have had low titers, does this suggest 'colonization'?? and if so, that means abx won't necessarily work for them? this seems to be in line with us. .... we've only had success once on abx when he WAS symptomatic for strep and WAS diagnosed. but the following times, I just asked our ped to let me try again when my son was waxing with tics (no outward illness) but it did not seem to help. so this does seem to correlate with us. Does this mean that no antibiotic of any kind would probably not work for us? we havn't had any recent illness and havn't tried abx in about two years.........so what happens with us in this type category? I'm still trying to figure where we fit in.

 

Faith

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I'm not sure what to say here. In our case a positive throat culture is what we go by. For some reason I just can't figure, doctors seem to like ASO and AntiDNAse B test but they are basically irrelevant if you have a positive throat culture.

 

ASO and AntiDNAse B can be used if you missed the window for getting a throat culture. PANDAS is not a response to ASO or AntiDNAse B. PANDAS appears to be a response to another antibody that interferes with neuronal cells. In Kirvan's work, she isolates auto-antibody 24.3.1 that interferes with lysoganglioside GM1. I posted a bunch of info on this in other threads.

 

Bottom line, go for the throat culture -- don't worry about the rest unless you really truly need some other evidence and you missed the window for a throat culture. Current medical practice is that a positive throat culture is a presumptive infection.

 

I should add that the "window for a throat culture" could be pretty big. Some kids (carriers?) can continue to culture positive for months or years (this is from the June 2008 Pediatrics paper by Kurlan/Kaplan). The usual expectation would be that you would only culture positive for a couple of weeks...but this isn't always the case! (Our dd cultured positive 2mo. after FEVER/onset of behavior change.)

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Faith, let me see if I can clear this up...

 

So help me understand this a little better............for the ones who don't show outward symtoms like sore throat, and who have had low titers, does this suggest 'colonization'?? and if so, that means abx won't necessarily work for them? this seems to be in line with us. .... we've only had success once on abx when he WAS symptomatic for strep and WAS diagnosed. but the following times, I just asked our ped to let me try again when my son was waxing with tics (no outward illness) but it did not seem to help. so this does seem to correlate with us. Does this mean that no antibiotic of any kind would probably not work for us? we havn't had any recent illness and havn't tried abx in about two years.........so what happens with us in this type category? I'm still trying to figure where we fit in.

 

Faith

 

Look for an episodic course

As far as we know, PANDAS seems very similar to Sydenham Chorea and is looking less and less like chronic tic disorders or Tourette Syndrome. What I'm getting at is that tics that are there relatively constant without cessation probably are not the episodic course characteristic of PANDAS and Sydenham Chorea. I say probably, because we don't really know.

 

It's auto-antibodies and a breach of the BBB

The best research I've found is Kirvan's 2006 work where she isolated antibody 24.3.1 and found that this antibody cross-reacted with lysogangliosides and appears to interfere (through CaM Kinase II activation) with neuronal signalling in the brain. 24.3.1 seems to get produced by the B-cell/T-cells in some kids in response to a strep infection -- however, what is odd about 24.3.1 is that it targets GlcNAc (a carbohydrate that is exposed on the surface of the GABHS cell wall).

 

The only problem with this is that GlcNAc is also exposed on other cell walls so this little antibody can cause some problems and attach where it shouldn't -- particularly if it attached to the basal ganglia. Now the good news is that it doesn't look like it causes any cell death or demylination -- yeah. But it does seem to interfere -- like a cellphone interfering with the radio.

 

So now, what about colonization, infection ....

 

I have no idea if your kid has PANDAS... if you are seeing a correlation of really severe exacerbations and when that happens your kid has a positive throat culture -- and then during quiescence your kid has a negative throat culture, then this is a good indication of PANDAS. If instead you have slow waxing and waning of symptoms (i.e., no abrupt onset or symptom remission) then that probably doesn't meet Swedo's criteria.

 

If it is PANDAS, then all that is technically required is elevated auto-antibodies in the blood stream (such as 24.3.1) and some break down in the blood brain barrier. Intense fear or stress, infection (viral or bacterial) or high blood pressure are all capable of causing a breach of the BBB. Once the auto-antibodies cross, then it is thought that they interfere with the basal ganglia.

 

So what does antibiotics have to do with the above...

 

Well, the auto-antibodies have a half-life (i.e., they seem to dissipate at around 4-6 weeks after GABHS is treated). Now for most kids, they can overcome strep on their own (14 days without antibiotics) however, some kids are able to stay colonized for a while. This means that the B-cells stay activated producing more antibodies until eventually the B-cells stop and the whole cycle stops.

 

The benefit of antibiotics is that they stop the GABHS sooner (i.e., 2 days versus 14 days) and thus there's less antigens and thus less antibodies.

 

So now all the way back to your child....

 

Being on antibiotics doesn't "do" anything except make it harder for the GABHS to get a foothold. Antibiotics don't stop tics or stop antibodies. The antibodies are there in response to the antigen. When the antibiotics slow the antigens the immune system comes along and wipes out the antigens -- but still there will be left over antibodies that will hang out for a while (again typically 4 weeks).

 

Once again, if you aren't seeing that correlation (i.e., you don't see a postiive throat culture correlated with a very explosive or high ramp in symptoms) then it is certainly possible that something other than SC or PANDAS is going on. It is this episodic nature that is the hallmark of PANDAS.

 

Is colonization enough?

 

Now there's been considerable debate about whether colonization is enough to set off a PANDAS kids' immune system or whether infection is actually required. I don't know. All the studies are being conservative and so are checking correlation with infection demonstrated with rising titers or with sore throats -- but this undoubtedly is too conservative and is missing a number of cases. In our case, our daughter ramping symptoms meant to take her sister to the doctor for a throat culture. 7/8 times her sister was positive for strep. She was a canary for us. So for us, it sure seemed that colonization was all that was necessary -- not all out infection.

 

We ended up plotting symptoms daily for 75 weeks while we tried to figure out this crazy thing.

 

Hope this helps -- the point is that episodic course of symptom severity is key. Correlation with a positive throat culture is great as a diagnostic tool. Getting cunningham tests sure seems to help as a puzzle piece (although it is not a diagnostic test).

 

Best regards,

 

Buster

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I have no idea if your kid has PANDAS... if you are seeing a correlation of really severe exacerbations and when that happens your kid has a positive throat culture -- and then during quiescence your kid has a negative throat culture, then this is a good indication of PANDAS. If instead you have slow waxing and waning of symptoms (i.e., no abrupt onset or symptom remission) then that probably doesn't meet Swedo's criteria.

 

If it is PANDAS, then all that is technically required is elevated auto-antibodies in the blood stream (such as 24.3.1) and some break down in the blood brain barrier. Intense fear or stress, infection (viral or bacterial) or high blood pressure are all capable of causing a breach of the BBB. Once the auto-antibodies cross, then it is thought that they interfere with the basal ganglia.

 

However, IMO things can start to get murky when PANDAS has gone on long enough. It not longer takes a strep infection to trigger an exacerbation, but any illness or stress (or colonization). Our dd's PANDAS got to the point were she had chronically elevated auto-antibodies (her CAM kinase was in the high PANDAS range when she wasn't in an exacerbation, after 1 year of antibiotics, positive for anti-neural antibodies) and got worse when she was in an exacerbation (after the flu, CAM kinase ll high SC range, still on treatment strength azith). So, it is my belief that if this illness goes on long enough, you might not have really obvious exacerbations and periods of quiescence ("episodic" like Swedo talks about.). You get a baseline change where the child never gets back to "normal" (without PEX or IVIG at least) b/c the anti-neural antibodies are always there....they become chronically ticky (or have other chronic mood/adhd/ocd issues).

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I have no idea if your kid has PANDAS... if you are seeing a correlation of really severe exacerbations and when that happens your kid has a positive throat culture -- and then during quiescence your kid has a negative throat culture, then this is a good indication of PANDAS. If instead you have slow waxing and waning of symptoms (i.e., no abrupt onset or symptom remission) then that probably doesn't meet Swedo's criteria.

 

If it is PANDAS, then all that is technically required is elevated auto-antibodies in the blood stream (such as 24.3.1) and some break down in the blood brain barrier. Intense fear or stress, infection (viral or bacterial) or high blood pressure are all capable of causing a breach of the BBB. Once the auto-antibodies cross, then it is thought that they interfere with the basal ganglia.

 

However, IMO things can start to get murky when PANDAS has gone on long enough. It not longer takes a strep infection to trigger an exacerbation, but any illness or stress (or colonization). Our dd's PANDAS got to the point were she had chronically elevated auto-antibodies (her CAM kinase was in the high PANDAS range when she wasn't in an exacerbation, after 1 year of antibiotics, positive for anti-neural antibodies) and got worse when she was in an exacerbation (after the flu, CAM kinase ll high SC range, still on treatment strength azith). So, it is my belief that if this illness goes on long enough, you might not have really obvious exacerbations and periods of quiescence ("episodic" like Swedo talks about.). You get a baseline change where the child never gets back to "normal" (without PEX or IVIG at least) b/c the anti-neural antibodies are always there....they become chronically ticky (or have other chronic mood/adhd/ocd issues).

 

 

A very big "Amen" to your opinion! Like our son, so many of these kids get alphabet diagnoses until (if fortunate) an on the ball doc (in our case, a child psychiatrist) starts connecting the dots. We've had over 8 years of this (7, before being dx'd a year ago). We always said that we were missing a puzzle piece--we think we've found it. Very well put, EAmom!

 

Six days post-IVIG,

Dawn

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So, it is my belief that if this illness goes on long enough, you might not have really obvious exacerbations and periods of quiescence ("episodic" like Swedo talks about.). You get a baseline change where the child never gets back to "normal" (without PEX or IVIG at least) b/c the anti-neural antibodies are always there....they become chronically ticky (or have other chronic mood/adhd/ocd issues).

 

Totally agree! (of course I better since EAMom is my dw) :wub:

 

We still did, however, have the episodes and escalations even with the baseline change. The problem wasn't the recognition of the exacerbation, the problem was that the remission never got back down. I don't know if over the prior year it was just the frequency of exposure (since her sister had 5 strep infections plus the one you had) or whether her immune system just got more sensitive or that the CaM Kinase II just never dissipated.

 

For some strange reason, in our dd the antibodies didn't seem to just disappear after 4-6 weeks -- they most certainly went down but a basic baseline kept creeping up. With IVIG, the baseline reset to 0 again.

 

Buster

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So, it is my belief that if this illness goes on long enough, you might not have really obvious exacerbations and periods of quiescence ("episodic" like Swedo talks about.). You get a baseline change where the child never gets back to "normal" (without PEX or IVIG at least) b/c the anti-neural antibodies are always there....they become chronically ticky (or have other chronic mood/adhd/ocd issues).

 

Totally agree! (of course I better since EAMom is my dw) :wub:

 

We still did, however, have the episodes and escalations even with the baseline change. The problem wasn't the recognition of the exacerbation, the problem was that the remission never got back down. I don't know if over the prior year it was just the frequency of exposure (since her sister had 5 strep infections plus the one you had) or whether her immune system just got more sensitive or that the CaM Kinase II just never dissipated.

 

For some strange reason, in our dd the antibodies didn't seem to just disappear after 4-6 weeks -- they most certainly went down but a basic baseline kept creeping up. With IVIG, the baseline reset to 0 again.

 

Buster

 

Thank you dear. It is always a good idea to agree with your wife.

 

Can you imagine what would have happened if this had gone on for 5 or 10 more years? What happens to the baseline then? Like Dawn said...a bunch of alphabet until someone eventually is able to fit all of the pieces of the puzzle together.

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Can you imagine what would have happened if this had gone on for 5 or 10 more years? What happens to the baseline then?

 

This has been happening to my daughter in excess of 10 years. Her CamK level while she was in "remission" was 242%. Its hard to realize she's in remission til we see exacerbation... Hoping to do IVIG soon.

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Thank you. Just the very beginning of your post, explaining how antibiotics work made a light go off for my husband and me. I didn't understand how they work at all. I thought that they killed the bacteria, and now that we are finding out our daughter's immune system is compromised via the blood work we just had done, it makes more sense why people have to go the ivig route. If we don't have enough of the good cells to fight the strep, the antibiotics aren't ever going to work. We have been testing positive for strep almost monthly. I would guess that we really haven't been able to eradicate it. Again, thank you. This will help us tremendously with our Doctor's appointment next week.

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