Dangerous exercise: lessons from dysregulated inflammatory responses to exercise 2007

Dolphin

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(I had to abbreviate the title slightly to get it to fit)

Dangerous exercise: lessons learned from dysregulated inflammatory responses to physical activity

Dan Michael Cooper, Shlomit Radom-Aizik, Christina Schwindt, and Frank Zaldivar, Jr.

J Appl Physiol 103: 700-709, 2007.
First published May 10, 2007;
doi:10.1152/japplphysiol.00225.2007

Pediatric Exercise Research Center, Department of Pediatrics, University of California, Irvine, California

Exercise elicits an immunological "danger" type of stress and inflammatory response that, on occasion, becomes dysregulated and detrimental to health.
Examples include anaphylaxis, exercise-induced asthma, overuse syndromes, and exacerbation of intercurrent illnesses. In dangerous exercise, the normal balance between pro- and anti-inflammatory responses is upset. A possible pathophysiological mechanism is characterized by the concept of exercise modulation of previously activated leukocytes. In this model, circulating leukocytes are rendered more responsive than normal to the immune stimulus of exercise. For example, in the case of exercise anaphylaxis, food-sensitized immune cells may be relatively innocuous until they are redistributed during exercise from gut-associated circulatory depots, like the spleen, into the central circulation. In the case of asthma, the prior activation of leukocytes may be the result of genetic or environmental factors. In the case of overuse syndromes, the normally short-lived neutrophil may, because of acidosis and hypoxia, inhibit apoptosis and play a role in prolongation of inflammation rather than healing. Dangerous exercise demonstrates that the stress/inflammatory response caused by physical activity is robust and sufficiently powerful, perhaps, to alter subsequent responses. These longer term effects may occur through as yet unexplored mechanisms of immune "tolerance" and/or by a training-associated reduction in the innate immune response to brief exercise. A better understanding of sometimes failed homeostatic physiological systems can lead to new insights with significant implication for clinical translation.

inflammation; innate immunity; leukocyte; asthma
Free full text at: http://jap.physiology.org/cgi/content/full/103/2/700
And
http://jap.physiology.org/cgi/reprint/103/2/700

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tomk: Somebody summarised this to me with the following "take-home" points:
- exercise is a major stimulus of the immune system
- very little research done on exercise in chronic inflammatory states (p.705) (which CFS likely has some components of)
This person said: The intro and page 705 are pretty readable for the lay public.
 

PoetInSF

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Dangerous exercise demonstrates that the stress/inflammatory response caused by physical activity is robust and sufficiently powerful, perhaps, to alter subsequent responses. These longer term effects may occur through as yet unexplored mechanisms of immune "tolerance" and/or by a training-associated reduction in the innate immune response to brief exercise. A better understanding of sometimes failed homeostatic physiological systems can lead to new insights with significant implication for clinical translation.
Thanks for posting, this is very interesting. CFS could be a damage to homeostatis/ANS system caused by a traumatic exercise/stress in some individuals, and PEM could be the body's false/exeggerated attempt to restore homeostasis by invoking abnormal immune response after a subsequent brief exercise. Even though CDC study of orthostatic instability calls for rethinking of CFS as a dysautonomia because OI is not prevalent among CFS patients, we still have NMH and HPA axis dysfunction prevalence for which ANS dysfunction is suspected. I think it is a furtile ground for further research. Hopefully, they'll shovel more moeny into it once the dead retrovirus horse is buried for good.
 

Sunday

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OI isn't prevalent among CFS patients? It's certainly not universal, as PEM seems to be, but judging by my talks with CFSers in person and what I've seen on this forum, I would judge it to be one of the more common symptoms. In fact this forum is where I learned what OI was (never had a name for it before, just the frequent experience); apparently it's related to CFS inability for blood pressure to go up when we stand up. In normal people this is automatic. I haven't read anything more than an abstract of the CDC study, so I'm not sure what they say about it.

But these are interesting thoughts, worth pondering. The damage-to-homeostatic/ANS system does make sense; so many of us seem to come to this disease from different directions, but all of them involve some form of trauma on the body.
 

Dolphin

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Slightly OT: Orthostatic intoleance

Thanks for that.

Re:
Even though CDC study of orthostatic instability calls for rethinking of CFS as a dysautonomia because OI is not prevalent among CFS patients, we still have NMH and HPA axis dysfunction prevalence for which ANS dysfunction is suspected.
That CDC study was done using the Wichita 2003 two-study cohort.
It is kind of an odd one as they dont use the empiric definition for it.
What they seemed must have done class people as having CFS if they once had CFS between 1997 and 2000. Because by 2003, only 10 had Fukuda CFS (or 16 if you only exclude people with Major Depressive Disorders with melancholic features) or 43 with the empiric definition but the numbers are even higher than 43. So basically most of the people who they claimed had CFS couldnt have had at the time of testing.
I only spotted this in 2008 or I would have sent a letter.
Anyway, basically I dont think that paper (CDC OI study) is of value unfortunately.
 

Dolphin

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Another exercise and inflammation paper

I've been making my way through the first paper I highlighted. Its interesting to see the points raised about other conditions and that its not all exercise has to be good for you. Dont ask me to try to repeat what it says!

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Anyway, somebody sent me the following which might be of interest.

=============

Hi Tom,

I've attached the Cooper paper. I've only had a brief look but it looks interesting. Good for knowing more about the background of exercise physiology...... Also the Gleeson paper is probably of interest.

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Full free text: http://jap.physiology.org/cgi/content/full/103/2/693 or http://jap.physiology.org/cgi/reprint/103/2/693

J Appl Physiol 103: 693-699, 2007. First published February 15, 2007; doi:10.1152/japplphysiol.00008.2007
8750-7587/07 $8.00

INVITED REVIEW

Exercise and Inflammation
Immune function in sport and exercise
Michael Gleeson
School of Sport and Exercise Sciences, Loughborough University, Loughborough, United Kingdom

Regular moderate exercise is associated with a reduced incidence of infection compared with a completely sedentary state. However, prolonged bouts of strenuous exercise cause a temporary depression of various aspects of immune function (e.g., neutrophil respiratory burst, lymphocyte proliferation, monocyte antigen presentation) that usually lasts 324 h after exercise, depending on the intensity and duration of the exercise bout. Postexercise immune function dysfunction is most pronounced when the exercise is continuous, prolonged (>1.5 h), of moderate to high intensity (5575% maximum O2 uptake), and performed without food intake. Periods of intensified training (overreaching) lasting 1 wk or more may result in longer lasting immune dysfunction. Although elite athletes are not clinically immune deficient, it is possible that the combined effects of small changes in several immune parameters may compromise resistance to common minor illnesses, such as upper respiratory tract infection. However, this may be a small price to pay as the anti-inflammatory effects of exercise mediated through cytokines and/or downregulation of toll-like receptor expression are likely mediators of many of the long-term health benefits of regular exercise.

cytokines; leukocytes; infection; inflammation; Toll-like receptors
I haven't read this yet and may well not get to. It looks like it might be trying to justify exercise while the other paper does not.
 

PoetInSF

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However, prolonged bouts of strenuous exercise cause a temporary depression of various aspects of immune function
The temporary suppression of immune function by strenuous exercise is well known/understood. (I've caught colds more than once after strenuous week of skiing in my previous life.) The first paper was talking about longer term effect on immune "tolerance" by a dangerous exercise, and subsequent dysfunctional response to brief exercises, which I think is more germane to CFS.
 

Dolphin

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(Not important) e-letter posted

I just had this e-letter posted. It's not very exciting. I'm hoping that others interested in the issue might get interested in ME/CFS.

Editor said:
We have sent your commentary to the authors and invited them to submit a response.
http://jap.physiology.org/cgi/eletters/103/2/700

Numerous exercise abnormalities been found in Chronic Fatigue Syndrome (CFS)

One curious omission from this interesting review[1] is Chronic Fatigue Syndrome (CFS), which is also sometimes known as Myalgic Encephalomyelitis (ME). An abnormal response to physical activity is an essential part of widely used ME/CFS clinical criteria for adults[2] and children[3]. The most frequently used research criteria for CFS [4] require that patients, along with suffering from chronic debilitating fatigue lasting at least 6 months, have at least 4 out of a list of 8 symptoms, one of which is “postexertional malaise lasting more than 24 hours.”

There is a growing body of research on abnormal responses to exercise in CFS. A recent review[5] covers the issue in a fairly comprehensive manner - here's a summary: “Exertion induces post-exertional malaise with a decreased physical performance/aerobic capacity, increased muscoskeletal pain, neurocognitive impairment, "fatigue", and weakness, and a long lasting "recovery" time. This can be explained by findings that exertion may amplify pre-existing pathophysiological abnormalities underpinning ME/CFS, such as inflammation, immune dysfunction, oxidative and nitrosative stress, channelopathy, defective stress response mechanisms and a hypoactive hypothalamic-pituitary-adrenal axis.”

High rates of adverse reactions to graded exercise programs have been reported in patients with CFS – sometimes 50% or greater[6].

CFS remains a fairly poorly understood condition. There is increasing evidence that CFS is heterogeneous and this heterogeneity could be of relevance to therapeutic programs involving exercise [7,8]. Those interested in researching abnormal responses to physical activity, including dysregulated inflammatory responses, could find much of interest if they chose to study CFS.

References:

1) Cooper DM, Radom-Aizik S, Schwindt C, Zaldivar F Jr. Dangerous exercise: lessons learned from dysregulated inflammatory responses to physical activity. J Appl Physiol. 2007 Aug;103(2):700-9. Epub 2007 May 10.

2) Carruthers BM, Jain AK, De Meirleir KL, Petersn DL, Klimas MD, Lerner AM, Bested AC, Flor-Henry P, Joshi P, Powles ACP, Sherkey JA, van de Sande MI (2003). "Myalgic encephalomyelitis.chronic fatigue syndrome: Clinical working definition, diagnostic and treatment protocols". Journal of Chronic Fatigue Syndrome 11 (1): 7-36.

3) Jason LA, Porter N, Shelleby E, Bell DS, Lapp CW, Rowe K, & De Meirleir K. (2008). A case definition for children with Myalgic Encephalomyelitis/ chronic fatigue syndrome. Clinical Medicine: Pediatrics, 1, 53-57.

4) Fukuda K, Straus SE, Hickie I, Sharpe MC, Dobbins JG, Komaroff A. The chronic fatigue syndrome: a comprehensive approach to its definition and study. International Chronic Fatigue Syndrome Study Group. Ann Intern Med. 1994 Dec 15;121(12):953-9.

5) Twisk FN, Maes M. A review on cognitive behavorial therapy (CBT) and graded exercise therapy (GET) in myalgic encephalomyelitis (ME) / chronic fatigue syndrome (CFS): CBT/GET is not only ineffective and not evidence-based, but also potentially harmful for many patients with ME/CFS. Neuro Endocrinol Lett. 2009;30(3):284-99.

6) Kindlon T, Goudsmit EM. Graded exercise for chronic fatigue syndrome: too soon to dismiss reports of adverse reactions. J Rehabil Med. 2010 Feb;42(2):184; author reply 184-6.

7) Jason LA, Corradi K, Torres-Harding S, Taylor RR, & King C. Chronic fatigue syndrome: The need for subtypes. Neuropsychology Review 2005, 15, 29-58.

8) Kindlon T. Stratification using biological factors should be performed in more CFS studies. Psychol Med. 2010 Feb;40(2):352. Epub 2009 Oct 12.
 

MEKoan

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So interesting, Tom.

I have had exercise induced asthma since childhood and have carried an inhaler around with me for >40 years. You'd think I would have made this connection before now but I never did.

Many thanks for another really interesting post and thread.
 

Dolphin

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So interesting, Tom.

I have had exercise induced asthma since childhood and have carried an inhaler around with me for >40 years. You'd think I would have made this connection before now but I never did.

Many thanks for another really interesting post and thread.
Thanks Koan. :Retro smile:

I don't think this general issue of exercise causing problems with other conditions has been picked up much.

There are lots of aspects to the exercise debate that can be added to. For example, the different safety rules that appear to apply to drugs rather than exercise programs - adverse reactions are taken seriously with drugs and these don't have to happen in clinical trials.
 

Dolphin

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Exercise-induced migraine

I happen to turn on a programme today (to read teletext) and they had on who they described as the "leading neurologist in Ireland" or something like this. She is into mainstream medicine (I know from other situations) and was pooh-poohing the idea that, for example, avoiding certain foods could help migraines.

Anyway she happened to mention that exercise can induce migraines. I'd never heard this (but then I'm not a doctor) and it isn't mentioned in the original article. But if one does a Google search for "exercise induced migraine", 27200 results show up (including plenty from peer-reviewed journals) and there are probably many more results that don't use that term. Don't have time to look into the issue but thought I'd mention it - exercise is so often presented as only leading to feeling good (and, indeed, that was my experience before I got ME/CFS when I used to love exercising and playing sports).
 

PoetInSF

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I know a woman who went to the emergency after a heavy practice thinking that she was having a stroke. It turned out she had a migraine. I wonder if people prone to exercise induced maladies are also prone to CFS. I myself have an exercise induced asthma.

As far as exercise go, I think it is closest thing to panacea. If done within the limit that is.
 

Dolphin

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As far as exercise go, I think it is closest thing to panacea. If done within the limit that is.
I haven't seen much evidence of that e.g. Belgian rehab clinics - over 600 with CFS (Fukuda) finished (average of 41 sessions at centres). Recovery rate was negligible. I don't see it in others I know better. If and when you're back at work full-time and have a good life outside work, I'll be more interested. Hoping it's the answer is different.
 

parvofighter

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Exercise & heart inflammation in elite athletes

Tomk, thanks for another fascinating thread.

Exercise in Elite Athletes, Inflammation, Heart complications
Here's another angle on potentially the same issue: elite athletes, exercise-exacerbated inflammation/immune problems, and myocarditis. I believe these are simply one end of the spectrum in our ME pathology... athletes who have a latent virus, with inflammation and immune dysfunction spiking as a result of exercise.

This is just one of many, many examples from PubMed: http://www.ncbi.nlm.nih.gov/pubmed/19575161. http://www.ncbi.nlm.nih.gov/sites/entrez

Herz. ("Heart" in German) 2009 Jun;34(4):299-304.
[Myocarditis and sudden cardiac death in athletes. Diagnosis, treatment, and prevention]
[Article in German]
Frick M, Pachinger O, Plzl G.
Universittsklinik fr Innere Medizin III - Kardiologie, Medizinische Universitt Innsbruck, Anichstrasse 35, 6020 Innsbruck, Osterreich. Matthias.Frick@i-med.ac.at
Myocarditis is the reason for sudden cardiac death in 5-22% of athletes < 35 years of age. Actually, parvovirus B19 and human herpes virus 6 are the most important pathogens.(NOTE: I wonder if XMRV is involved?) MRI is not able to assess viral persistence. Therefore, endomyocardial biopsy (EMB) remains the gold standard in diagnosis of myocarditis. (Note: I think they might be able to get away with a less risky gut biopsy as a proxy measure). Clinical presentation of myocarditis is heterogeneous, with all courses between asymptomatic and fulminant reported. Especially in athletes it is important to take subtle discomforts seriously and initiate further evaluation. Electrocardiogram, laboratory parameters, serologic markers, and echocardiography are helpful in diagnosis of myocarditis, but are not specific. Magnetic resonance imaging (MRI) of the heart has become an important tool in the evaluation of patients with myocarditis and allows noninvasive appraisal of myocardial inflammation using late enhancement. However, When considering EMB in these athletes one should not ignore spontaneous healing in 50% of patients with myocarditis. Contrariwise, specific therapy (e.g., immunosuppression, interferon, immunoglobulins) for myocarditis is only feasible after getting results of EMB. When myocarditis is verified, athletes have to withdraw from sport for at least 6 months. Before restarting physical activity, a detailed examination is necessary and most of the patients will undergo another EMB. For prevention of myocarditis and sudden cardiac death it is recommended to stop elite sport for 4 weeks after an unspecific infection. Whether moderate sport can be started earlier is unclear.
For more, just do a keyword search of "Myocarditis, athlete" at http://www.ncbi.nlm.nih.gov/sites/entrez
 

justinreilly

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Tomk, thanks for another fascinating thread.

Exercise in Elite Athletes, Inflammation, Heart complications
Here's another angle on potentially the same issue: elite athletes, exercise-exacerbated inflammation/immune problems, and myocarditis. I believe these are simply one end of the spectrum in our ME pathology... athletes who have a latent virus, with inflammation and immune dysfunction spiking as a result of exercise.



Overtraining can result in ME, at least in part by altering cortisol and immune function. My cousin was an elite runner and has ME. There was something to the effect of 5% of elite cyclists got ME in Osler's Web.

I'll just throw out that David Bell mentions in his latest book about Dr. Pall's theory that there is a type of 'all body' I think it's called migrane that doesn't involve primarily the head and that this is basically ME.
 

Dolphin

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Tomk, thanks for another fascinating thread.]

Thanks. :Retro smile:

Exercise in Elite Athletes, Inflammation, Heart complications
Here's another angle on potentially the same issue: elite athletes, exercise-exacerbated inflammation/immune problems, and myocarditis. I believe these are simply one end of the spectrum in our ME pathology... athletes who have a latent virus, with inflammation and immune dysfunction spiking as a result of exercise.

This is just one of many, many examples from PubMed: http://www.ncbi.nlm.nih.gov/pubmed/19575161. http://www.ncbi.nlm.nih.gov/sites/entrez

<snip>
[/I][/INDENT]For more, just do a keyword search of "Myocarditis, athlete" at http://www.ncbi.nlm.nih.gov/sites/entrez.
Thanks.

It's disappointing that more doctors aren't interested in heart infectons in ME/CFS - Lerner is the main one it seems.

Around 20 years ago, in the UK, heart symptoms in ME were often seen as connected to Coxsackie B viruses/enteroviruses.

For prevention of myocarditis and sudden cardiac death it is recommended to stop elite sport for 4 weeks after an unspecific infection. Whether moderate sport can be started earlier is unclear.
That's interesting. Rugby was the main sport in the school I went to. Concussion and concussion-type knocks were taken seriously and I think you were told not to take part for 3 weeks. While I remember a couple of times having colds and it was almost looked down on that you wouldn't take part at the same time. And of course Brian O'Driscoll (captain, Irish rugby team) said for the England vs Irish rugby match recently he had a virus so others did most of the team talks.
 

Dolphin

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I'll just throw out that David Bell mentions in his latest book about Dr. Pall's theory that there is a type of 'all body' I think it's called migrane that doesn't involve primarily the head and that this is basically ME.
The neurologist today said you can have migraine without a headache - you get an aura. Other symptoms were mentioned as part of migraine e.g. pins and needles.
 

Mithriel

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Interesting thread but we must remember that the "exercise" that causes problems in ME is the often just the normal activities of living.

My original diagnosis, long before CFS was invented, was "migraine with more of the funny symptoms less of the headaches". I once mentioned this to Nigel Speight and he said that it would have been his diagnosis at the time, but I never got the chance to ask him any more.

My symptoms were pain and muscle spasms and things I now know are related to the autonomic nervous system, like temperature problems and and an inability to stand without feeling ill.

I also had a lot of neurological problems, sudden loss of speech, blindness, paralysis and absences with stranger things like forgetting how to get home and perception problems where the world became distorted.

I never missed much school, I had a Saturday job and I went out dancing four nights a week. But I carried a card that told me how to get home, a biscuit for sudden hypoglycaemia and had to wear tight straps on my wrists to keep the pain tolerable.

I have never related much to the symptoms of CFS - I was ill and diagnosed with ME by a neurologist who had been at the Royal Free years before CFS came on the scene.

I had always been told "you'll know what tiredness really is when you grow up" so it is possible I never recognized fatigue. I took it for granted that I had to drag myself up stairs on my hands and knees after weeding the garden because everyone else was better than me and didn't give in. I was very ashamed and hid it. It is one of the problems of getting ill at fourteen and I wonder how many teenagers out there are suffering the way I did.

I suspect that pushing on caused the continual deterioration to the severe disease I have today.

Mithriel
 

willow

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I have never related much to the symptoms of CFS - I was ill and diagnosed with ME .......years before CFS came on the scene.
Yes me too Mithriel, though I was diagnosed by a microbiologist. My GP sent me up to see her because he knew her outside of his work and she'd dx'ed 2 others with it in the previous months.

She was particularly looking for high Coxsackie titres, one of mine was the upper limit of range the other ok. She was very matter of fact that my body might be too depleted to produce a more vigourous immune response.... Aah those were the days, open minds if no cures... Well my GP offered me steroids which I declined.

I had weird neuro symptoms too, some of which I also was very ashamed and managed to hide by avoiding doing things that made them intolerable to me or obvious to others. Aged about 13 and based mainly on my worsening PEM the medics ran a lot of tests on me which all came back negative, so to them and my family I was healthy. I also forced myself to do physical things both believing I was lazy and to avoid arguements. As a lucky co-incidence around the time my physical fatigue, air hunger etc markedly increased our school dropped its sports focus so the physical demands decreased, and as best i could I blagged my way through the academic ones.

I suspect that pushing on caused the continual deterioration to the severe disease I have today.
Yes, me too, I think I've pushed myself to a really nasty disease which seems pretty different to most with the ME dx.

Have you had improvements with any treatments? Or any ideas what your main pathogens, toxins or sick organs might be? My adrenals and thyroid seem to be in a relatively good state, but brain, CNS, ANS etc are my weak points.
 

Mithriel

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That is so interesting Willow. I, too, had the highest titre to Coxsackie B.

I have lots of neuro symptoms. I wonder if I would be classed in the US as atypical MS. I look as if I have MS but all my symptoms are made worse by any exertion beyond whatever limit I have that day.

Since reading about the heart problems I think I have that so when I feel I must lie down I do and don't try to push on.

Like you, it is mainly CNS, brain etc, though I have constant pain muscle and neuropathy. I have had paroxysmal dyskinesia for the last twenty years which I control with baclofen. I also go to hyperbaric oxygen therapy which slowed the neuro problems.

I think my mitochondria don't work properly because of a continuing coxackie B infection though XMRV could be behind that and causing damage too. I hope so because then there might be a treatment :Retro smile:

Dr Bell said in an article that when children have ME they will accept that they are not ill and push themselves in a way that adults would not. It is so true.

I would love to have some of the tests they talk about but after some awful experiences - everything went downhill after CFS and SW muddied things up - I feel lucky to be getting symptomatic relief an don't want to rock the boat. Fifteen years ago, during a spell in hospital, the neurologist said I didn't need baclofen or painkillers and referred me to a psychologist. I have just kept on handing in the repeat prescriptions and no one has ever said anything :Retro smile:

The psychology referral was a disaster. She said my problems were caused by anxiety and assured me that their was no need to feel ashamed and deny it, she felt anxious at times. I asked her why I was in a wheelchair and she wasn't and she said "I don't think this is working out" and discharged me :D

Mithriel