Old Men Throwing a Football…

 

Three days ago – I drove up to my hometown on Lake Superior to visit relatives and some friends that I have had since childhood.  From about 1963 to 1973 we played football primarily but also several other sports in and around the only park we had as kids.  For a few months in the winter, it was a skating rink.  The rest of the time it was an abandoned field.  For about half of those years, the field was next to a ravine with a small swamp at the bottom of it.  Eventually the ravine was filled in and it was an even rougher field to play one.  We stuck to the rink surface, an abandoned lot across the street and in the wintertime the streets lined by snowbanks.  Of course, in the fall and winter we typically played in the dark after school.

And we played every night – in the rain, snow, and subzero weather.  There was no formal start time. Sometimes I would hear a pebble bouncing off my bedroom window and look out and the boys were all there waiting.  Other times I would step out into the alley and two blocks away see one of my friends waving his arms in a crossing motion over his head.  I would reply with the same motion, and we would head to the field. People would filter in when they saw us there warming up.  Quitting time, was highly dependent on when the neighborhood store closed (usually 8:30 PM).  The winner was often determined by that quitting time: “Whoever gets to this score or 8:15 PM”.  Our post game ritual was consuming 16 oz RC Colas at the store, and we couldn’t miss it.  

Most of these games were 2 on 2 or 2 on 3 passing games.  As a result we could all throw well and learned to catch a football very well. What was remembered three days ago was learning how to catch a ball that disappeared above the streetlights in the extreme dark cold of winter when it suddenly reappeared under the lights.  We would say “it came out of nowhere” – but we would catch it. On this day we did not do any kicking or punting, but I also remembered the guy in our group who taught himself to punt a perfect spiral.  It was amazing to see and that disappeared above the streetlights for a very long time before it came into view.

Today we were focused on short passes of 10-30 yards and throwing flat minimal arc spirals. I still recall my high school coach showing us how to throw a spiral with the nose of the ball slightly elevated for more distance and that was what I was going for.  I wondered if we were going to throw for distance like we used to do but that never happened.  The focus was on these short passes and catching the ball in the hands.  The fall detection on my watch was set off by catching a few of these passes. These passes still had a little heat on them. One of my friends talked about having "$1,000 hands" based on what he caught at work and telling the story of how he developed that ability. 

Only a couple of us played organized sports.  I wrote about that in another post. But the caliber of play was high.  Playing a sport every day for 10 years brings with it a high degree of athleticism both in terms of conditioning and coordination.  And it seems hard to believe these days but the only diversions available to us was very mediocre black and white television transmitted through the air and reading. Technical problems were common with the TV and to see a show you had to be there. It seems hard to believe now - but there was no on-demand viewing or recording.  Reading was limited by what you could buy or borrow from the library. At the same store where we drank the RC Colas – a bookmobile showed up every Saturday.  I remember borrowing and reading When Worlds Collide - a novel written in 1933 - and being fascinated by it.  Toward the end of my football period I worked for the library and mailed books out to other bookmobile locations.

That lack of diversions – technical and otherwise may have kept us focused on our game.  Several people commented to me that nobody ever plays in that field anymore.  On some days we had 10 or 20 additional players.  But these days nobody ever shows up and plays every day.  The city baseball and softball leagues have also been decimated far beyond what could be accounted for by a population decrease. It seems that in small town America not many people are playing sports anymore.

As we were throwing the ball around. One of my friends reminded me of a time when I threw him a pass and he dropped the ball.  I told him to take his gloves off so he could catch it the next time and it was 17 degrees below zero at the time. I am certainly not the same guy I was back then – you become a better person with age.  I asked him what he made of that today and he summed it up: “That’s just the way it was back then.”  There were definite periods where we were unnecessarily rough and angry. But I don’t recall any out and out fights.  The roughness of the game when you are a kid is a source of pride.  We were all from the East End and we had a shared "wrong side of the tracks" blue collar mentality. To this day – one of my friends in the photo gives West Enders a rough time.  He told me that he recently asked one of them: “Did you even play outside when you were kids?”  Trash talking is not a new invention.

The shared experience is something I never thought about at the time. I heard a recent piece on This American Life about the importance of camping to some people and how there were campers and non-campers and the non-campers would never understand the emotional importance of camping.  The same thing was true of our football games.  It gave us all meaning at a time in our lives where there wasn’t much. It gave us a chance for intense emotional expression and eventually being able to control that expression.  It helped us through some pretty bad times. I still remember hearing the pebble bounce off my window and telling the guys: “I can’t play today – my Dad died last night.”  I remember the expression on their faces when they heard that news. I remember it as clearly as if it happened yesterday.  All of the homilies that I heard at various sports banquets about the importance of teamwork - rings hollow. It is more important just to be there and share the experience.  Nobody ever tells you that when you are a kid beating yourself up for losing a game. It really doesn't matter who wins or loses.  It doesn't matter how you play either. It just matters that you show up and keep showing up.

This day - it was happier times.  We had all just finished working - as in retired.  School, work, and in some cases military service were all necessary distractions from our game. One of my friends has just completed 41 years of work without missing a day and for some of those days he was working 7 days a week. We had all dodged severe medical problems of one form or another.  We had all survived COVID so far and had the vaccinations. It was a good day to be alive on our childhood playing field.   

We may have lost a step or two but old men can still throw and throw quite well.  But there were no diving catches.

 

George Dawson, MD, DFAPA

Happy Labor Day

 

Happy Labor Day

 

“It should be evident to all students, residents, and practicing physicians that the enormous investment in time, money, and commitment typically necessary to become a physician makes no sense if practicing medicine frequently fails to be interesting and enjoyable.”  Samuel B. Guze, MD 1992 (1)

 

Every year I try to post something about my impression of the physician work environment. That has been a progression of depressing posts as the work environment deteriorates every year largely due to micromanagement by managed care companies and various governments that has resulted in a trillion dollar overhead, quality as an advertising meme rather than a clinical reality, poorer reimbursement for physicians, massive numbers of wasted hours for the bureaucracy and its documentation requirements, and the negative feedback loop of using the healthcare system as a jobs program for business administrators.  Each of those iterations moves use farther and farther from Dr. Guze’s reality of an enjoyable and intellectually stimulating career in medicine.  Interestingly – enjoyability is not an obvious factor in the most frequently used scale to detect burnout in medical staff.  Those scales tend to be focused on a learned helplessness/loss of personal efficacy model.  Lack or loss of enjoyability is probably the first step toward that extreme conclusion.

It is equally frustrating for patients who have seen access get markedly worse.  Just this month I tried to assist a friend in finding a therapist either inside or outside of her insurance plan. And there were none. I am not talking about a waiting list and an appointment 2 or 3 months out.  I am talking about no access at all.  The clinics would not even place her on a waiting list.  I saw a consultant myself back in January who told me he was referring me to another specialist to be seen this August.  When that did not happen, I called and my calls were not returned. Eventually by sending enough messages to my primary care MD they called me and set up an appointment on September 2.  I was called yesterday and told that appointment was cancelled.  They gave me another appointment in mid-November with the qualifier: “We have you penciled in but there is no guarantee that this won’t change again”.

I am very aware of the strain the pandemic and its mismanagement has put on the system.  Also aware of physicians and nurses resigning in droves (2). In the case of primary care specialties and psychiatry there was a serious shortage before the pandemic hit.  The pandemic itself is an insufficient explanation for what has happened over the past three years. The lack of an adequate pre-existing public health infrastructure had a lot to do with it (4).  Inadequate protection for front line workers and an inability to scale as the morbidity and mortality increased in some cases exponentially. In the case where public health officials were doing what they could they often found themselves threatened and attacked by pandemic deniers, anti-vaxxers, and let’s face it various elements of the right wing (3). The same people basically responsible for building out America’s immense for-profit and inefficient health care system. What could be more depressing than to try to treat a pandemic while a political party is basically denigrating standard public health measures and either verbally attacking or threatening public health officials to the point that many had to get security personnel for protection. When you have a big enough platform – I consider acts of omission-like not taking a stand firmly against political violence as bad as the people making the threats. I also don’t make any distinction between threats from the average man or woman on the street and members of Congress making clear threats.  Many seem to act like they have immunity in those situations.

The politically designed medical systems of care that is basically run by unqualified business people was ramped up to even worse performance by the associated political anarchy. That anarchy continues. Who could blame physicians for bailing out in those circumstances?  I think there is a legitimate concern about whether the system will every get back to its baseline prepandemic inefficiency.

Some have considered the increased use of telemedicine and telepsychiatry to be a positive correlate of the pandemic. I gave a continuing medical education presentation on it in November of 2021. For various reasons – I think the eventual outcome of telemedicine is uncertain. The main reasons have to do with businesses taking over and managing the visits for profit and to the detriment of any therapists or physicians involved. A review of what can happen was published in the New York magazine (5). I see television ads all the time for rapid access to all kinds of prescriptions just by calling a business running a specialty telemedicine site. Some of these sites are already controversial and there appears to be very little transparency when it comes to comparing these sites to the even meager quality of care offered by in-person managed care.  Payer gaming at all levels is another possibility. During the pandemic reimbursement for care delivered was at the standard rate.  We are just starting to see decreased reimbursement or no reimbursement for televisits. I have also seen very disadvantageous contracts for physicians and therapists attempting to do televisit work at the levels of reimbursement, risk, and required access. That is consistent with the decade’s old observation that medical practice environments deteriorate in quality with increasing business involvement.

On a positive note this year – the main alternative to maintenance of certification by  American Board of Medical Specialties (ABMS) is the National Board of Physicians and Surgeons (NBPAS). This year the NBPAS was given recertification status by the Joint Commission and hospital accrediting agencies. The NBPAS model is the original “life long learning” model proposed for all physicians since the Flexner era. I have personally been recertified every two years by the NBPAS, but until this year realized that most younger physicians were not in a position where they could abandon much more costly and some would say overly involved ABMS recertification procedures.  The change this year apparently makes it easier to make that transition, but a lot will depend on hospital committees and local accreditation procedures. ABMS recertification is onerous enough to tip the balance in favor of leaving the field for retirement of a different occupation so that this change may also lead to physician retention.  But a lot will depend on how all of this unfolds.

I can still recall reading about why Paul Tierstein, MD came up with the original idea for NBPAS. He noticed a colleague who was an electrophysiologist cramming for a recertification examination and learning details he would never use in his day-to day practice.  Most physicians – even within their own specialty or subspecialty develop a knowledge base for that practice.  That knowledge base is not consistent with a preparatory based knowledge learned in medical school or as a resident. Relearning irrelevant material for the sake of taking an examination is another unnecessary drain on a physician’s time and finances. Life long learning is a better way to acknowledge that physician’s highest level of certification and ongoing efforts to maintain that specialized knowledge.

All things considered it has been another very stressful year for physicians. There is a glimmer of hope on the recertification front that will hopefully alleviate a lot of unnecessary stress.      

We still have a very long way to go to reach Dr. Guze’s suggested practice environment that is both fun and intellectually stimulating.  Like he says in his book – I was taught about that is medical school and experienced it only in the very first years of practice. We need to make medicine interesting and enjoyable again and that’s a very tall order.

 

George Dawson, MD, DFAPA

Supplementary:

 Explanation of the graphic: sometime ago I posted that heavy lifting is a metaphor for what has happened to medical practice in the US. This is another example. 

References:

1:  Guze SB. Why Psychiatry Is a Branch of Medicine. New York; Oxford University Press: 1992: p. 118.

2:  Abbasi J. Pushed to Their Limits, 1 in 5 Physicians Intends to Leave Practice. JAMA. 2022;327(15):1435–1437. doi:10.1001/jama.2022.5074

3:  Ward JA, Stone EM, Mui P, and Resnick B, 2022:Pandemic-Related Workplace Violence and Its Impact on Public Health Officials, March 2020‒January 2021.American Journal of Public Health 112, 736_746, https://doi.org/10.2105/AJPH.2021.306649

4:  Bishai DM, Resnick B, Lamba S, Cardona C, Leider JP, McCullough JM, Gemmill A. . Being Accountable for Capability—Getting Public Health Reform Right This Time. American Journal of Public Health 0, e1_e5, https://doi.org/10.2105/AJPH.2022.306975

5: Fischer M.  The Lunacy of Text Based Therapy (And other technological solutions for a nation in trauma).  New York Magazine March 29-April 11, 2021.

Image Credit:

National Archives and Records Administration, Public domain, via Wikimedia Commons https://commons.wikimedia.org/wiki/File:Girls_deliver_ice._Heavy_work_that_formerly_belonged_to_men_only_is_being_done_by_girls.

Heavy work that formerly belonged to men only is being done by girls. The ice girls are delivering ice on a route and their work requires brawn as well as the patriotic ambition to help. - NARA - 533758. https://upload.wikimedia.org/wikipedia/commons/0/0a/Girls_deliver_ice._Heavy_work_that_formerly_belonged_to_men_only_is_being_done_by_girls._The_ice_girls_are_delivering_ice_on_a_route_and_their_work_requires_brawn_as_well_as_the_partriotic_ambition_to_help._-_NARA_-_533758.gif

Has The Mechanism of General Anesthesia Finally Been Discovered?

 

General anesthesia is one of the greatest innovations of modern medicine.  Even within  the history of that innovation there have been tremendous improvements ranging from the administration of ether in the 1960s to very closely monitored combinations of opioids, benzodiazepines, and inhaled anesthetics in more modern times. The mechanism of action of opioids and benzodiazepines at the receptor level are known, but the effects of inhaled anesthetics have been more of a source of speculation.  I first became aware of this as an undergraduate taking physical chemistry (1) when I read about Linus Pauling’s hypothesis (2).  He suggested that microcrystalline hydrates form from the reaction of anesthetic gases and water molecules at the membrane surface. Those microcrystalline hydrates then interfere with synaptic transmission leading to loss of consciousness. Pauling was a physical chemist who was awarded the Nobel Prize for his work on the hydrogen bond and wrote about many general anesthetics as not working through hydrogen bond mechanisms.  He was also very optimistic about the role of physical chemistry in biological systems. Interestingly he briefly discusses how general anesthesia and the mechanism are important for psychobiology (2):

“The progress that has been made in the field of molecular biology during this period has related in the main to somatic and genetic aspects of physiology, rather than to psychic. We may now have reached the time when a successful molecular attack on psychobiology, including the nature of encephalonic mechanisms, consciousness, memory, narcosis, sedation, and similar phenomena, can be initiated. As one of the steps in this attack I have formulated a rather detailed theory of general anesthesia, which is described in the following paragraphs.” (p. 15)

He provides an elaborate physical chemistry rationale for the hydrate-microcrystal theory of anesthesia in this paper.  Pauling’s work comes on the cusp of the era of molecular biology – a field that he is credited with creating.  In his original explanation he discussed x-ray crystallography of crystals and new biologically active protein structures continue to undergo this analysis when they are isolated and purified.

Fast forward to a paper I just read in Current Biology a few days ago (3). It is written in the context of no clear mechanism of action for volatile inhaled anesthetics since their first observed effects noted over a century ago despite numbers speculative papers including papers from the past decade in this same journal.  The authors suggest that a disruption in electron transport in the mitochondria specifically Complex I  of 4 transport proteins is the area responsible for the effects of general anesthesia. Before getting to their experiment, a few words about this system.

Electron transport, oxidative phosphorylation, and ATP synthesis are all tightly coupled processes occurring over 5 proteins known as mitochondrial complexes (Complexes I-V).  Before the era of molecular and structural biology, these processes were partially deduced using in vitro methods looking at chemical reactions in mitochondrial preparations and specific reactions that affect each step. The cofactors were determined along with the overall stoichiometry of the process. With greater emphasis on structural and molecular biology there have been additional hypotheses about the specifics of electron transfer across the complexes and how ATP synthesis occurs.  Although there is much evidence to support various hypotheses about how all of these processes occur – in all of my reading it does not appear to be settled science.  In fact, some authors talk about emergent properties of this system that cannot be defined by what is known about the current components (10).  The discussion of emergent properties is interesting on at least a couple of levels. First, that kind of discussion is routine in consciousness research. There are no clear-cut biological mechanisms that generate a conscious state and it is discussed as an emergent property of the brain. Second, the minimum requirements of a biological system to create emergent properties is never really discussed. Does the mitochondrial system of electron transport, generating a proton gradient, ATP synthesis, and tightly couple oxidation and phosphorylation qualify?

This mechanism may have implications for the science of consciousness. In humans who are in good health and have no known brain diseases - general anesthesia and non-REM (NREM) sleep are considered to the the only states of unconsciousness. During that time the thalamus appears to be inactivated (13).  There have been several studies showing that some people dream during NREM sleep so that is not a clear boundary. But in the case of this mechanism questions would include considering the synaptic mechanisms as well as the global neuroanatomical mechanisms as well as the issue of emerging properties of biological systems of varying complexity.  What does it mean if a smaller system with emergent properties can turn off a larger system with emergent properties? What is the relationship of the emergent properties between systems?  

Moving on to the paper – the authors start by pointing out that neurotransmitter recycling in neurons is dependent on ATP and endocytosis.  Further - that Complex I of the mitochondrial electron transport chain (ETC) is the rate limiting step in this process and that disrupting it causes sensitivity to volatile anesthetics (VA). Knockout mice (for a protein in Complex I) were physiologically normal but much more sensitive to VA. The authors hypothesized that VAs decrease presynaptic ATP production by the ETC (oxidative phosphorylation) leading to decreased endocytosis and neurotransmitter cycling, and that the inhibition of Complex I was the primary mechanism.  They conduct a number of experiments to illustrate the effects of VA (isoflurane) on the ETC chain looking at perturbations would increase the effect and decrease the effect and conclude that their hypotheses are supported by the data.  They conclude that Complex I inhibition may be the mechanism of action of isoflurane. If supported by other studies the mystery of the mechanism of action of VA may be solved after 170 years.

I continue to be astonished at the trajectory of brain science and all of the factors that are needed for these advancements.  Even at the level in this paper the suggestion is that the proposed hypothesis will require additional work.  This research occurs at the intersection of a series of historical hypotheses about the mitochondrial ETC and parallel hypotheses about the mechanism of action of volatile anesthetic gases. The scientific work and hypothesizing was built both on previous discovery and advances in technology.  In this area advancement was slow and is still not completely settled in either research area. A lot of science discussed in the press seems to suggest that there are arbitrary time frames or amounts of investment for advances and that is obviously not true.

George Dawson, MD, DFAPA

 

References:

1:  Moore WJ.  Physical Chemistry, Fourth Edition. Englewood Cliffs: Prentice-Hall, Inc; 1972: p. 241-243.

2:  Pauling L. A molecular theory of general anesthesia. Science. 1961 Jul 7;134(3471):15-21. doi: 10.1126/science.134.3471.15. PMID: 13733483.

3:  Jung S, Zimin PI, Woods CB, Kayser EB, Haddad D, Reczek CR, Nakamura K, Ramirez JM, Sedensky MM, Morgan PG. Isoflurane inhibition of endocytosis is an anesthetic mechanism of action. Curr Biol. 2022 Jul 25;32(14):3016-3032.e3. doi: 10.1016/j.cub.2022.05.037. Epub 2022 Jun 9. PMID: 35688155; PMCID: PMC9329204.

4:  Sharma LK, Lu J, Bai Y. Mitochondrial respiratory complex I: structure, function and implication in human diseases. Curr Med Chem. 2009;16(10):1266-77. doi: 10.2174/092986709787846578. PMID: 19355884; PMCID: PMC4706149.

5:  Wikström M, Hummer G. Stoichiometry of proton translocation by respiratory complex I and its mechanistic implications. Proc Natl Acad Sci U S A. 2012 Mar 20;109(12):4431-6. doi: 10.1073/pnas.1120949109. Epub 2012 Mar 5. PMID: 22392981; PMCID: PMC3311377.

5:  Jones AJ, Blaza JN, Varghese F, Hirst J. Respiratory Complex I in Bos taurus and Paracoccus denitrificans Pumps Four Protons across the Membrane for Every NADH Oxidized. J Biol Chem. 2017 Mar 24;292(12):4987-4995. doi: 10.1074/jbc.M116.771899. Epub 2017 Feb 7. PMID: 28174301; PMCID: PMC5377811.

7:  Toda C, Diano S. Mitochondrial UCP2 in the central regulation of metabolism. Best Pract Res Clin Endocrinol Metab. 2014 Oct;28(5):757-64. doi: 10.1016/j.beem.2014.02.006. Epub 2014 Mar 7. PMID: 25256770.

8:  Giorgio V, Fogolari F, Lippe G, Bernardi P. OSCP subunit of mitochondrial ATP synthase: role in regulation of enzyme function and of its transition to a pore. Br J Pharmacol. 2019 Nov;176(22):4247-4257. doi: 10.1111/bph.14513. Epub 2018 Nov 28. PMID: 30291799; PMCID: PMC6887684.

9:  DiMauro S, Garone C. Historical perspective on mitochondrial medicine. Dev Disabil Res Rev. 2010;16(2):106-13. doi: 10.1002/ddrr.102. PMID: 20818724; PMCID: PMC3839238.

10:  Voet D, Voet JG. Electron Transport and Oxidative Phosphorylation. In: Biochemistry, 2^nd Edition. New York: John Wiley & Sons, Inc;1995: 563-598.

11:  Kurz FT, Aon MA, O'Rourke B, Armoundas AA. Functional Implications of Cardiac Mitochondria Clustering. Adv Exp Med Biol. 2017;982:1-24. doi: 10.1007/978-3-319-55330-6_1. PMID: 28551779; PMCID: PMC7003720.

12:  Deshpande OA, Mohiuddin SS. Biochemistry, Oxidative Phosphorylation. [Updated 2021 Aug 3]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2022 Jan-. Available from: https://www.ncbi.nlm.nih.gov/books/NBK553192/

13:  12:  Vacas S, Kurien P, Maze M. Sleep and Anesthesia - Common mechanisms of action. Sleep Med Clin. 2013 Mar;8(1):1-9. doi: 10.1016/j.jsmc.2012.11.009. PMID: 28747855; PMCID: PMC5524381.

Graphics Credit:

 Mitochondria graphic is my modification of a VisiScience slide per their user agreement for non-commercial use.

Supplementary:

1:  The Krebs cycle, citric acid cycle, or tricarboxylic acid cycle occurs only in the mitochondrial matrix basically converting chemical energy into the reducing power of NADH for ATP synthesis from electron transport.

2:  Additional review on mitochondrial dysfunction and Alzheimer's Disease:

Misrani A, Tabassum S, Yang L Mitochondrial Dysfunction and Oxidative Stress in Alzheimer’s Disease.  Front. Aging Neurosci. 2021; 13:617588. doi: 10.3389/fnagi.2021.617588

Rosacea Is A Complex Illness – And Here Is Why That Is Important

 

Pathophysiology of Rosacea from Ref 2 via-Noncommercial 4.0 International (CC BY-NC 4) 0)

    (click to enlarge)

 

This post is part of my apparent never-ending quest to get complex illnesses and blog about them.  About 15 years ago, I saw my primary care physician and described some dermatology problems that I was having.  I won’t get too deep into the weeds about my symptoms, but somewhere along the line I also recalled that my father had similar symptoms. In those days back in the 1950s and 1960s he really did not get any formal diagnosis.  He was told instead that the somewhat matted lesions he had on his face should be “drained” and his physician cut into them with a scalpel.  Eventually they cleared up on their own. In my case I was given some topical metronidazole that seemed to work for local outbreaks and have been using it ever since. It seems good for focal lesions but it does not seem to do much for more global symptoms such as a burning and stinging sensation of the more recently discovered ocular symptoms of rosacea. 

I first started to diagnose it and refer it for treatment when I was seeing patients in acute care psychiatric units.  I acquired a text that was considered state-of-the art in the late 20^th century (1) to assist me in describing rashes and diagnosing dermatology diseases.  The definition of rosacea was: “Papules and papulopustules occur in the center of the face against livid erythematous background with telangiectasias. There is also quite often diffuse connective tissue and sebaceous gland hyperplasia and sometimes hypertrophy of the nose (rhinophyma)” (p. 730).  The disease was described as progressive stages rather than discrete phenotypes and the pathology of each stage was described and as a chronic inflammatory condition.

Little was known about the pathophysiology at the time but the usual suspects of genetic predisposition and relationships to diet and other potential irritants. The mite Demodex folliculorum was suspected.  Various irritants like sun, mechanical irritation, heat, cold, hot drinks, alcohol, and caffeine increased the erythema (redness).  The authors described progressive stages rather than distinct phenotypes. Eye involvement was known at the time including complications like blepharitis, conjunctivitis, iritis, and in some cases keratitis of the cornea leading to blindness.  Associated symptoms were eye pain and photophobia.  The main treatment described was systemic and topical antibiotics, sunscreen and avoiding other irritants.

Today like many diseases there are clearer diagnostic criteria and there is also accumulated knowledge on possible pathophysiology. The American Rosacea Society proposed the criteria listed in the following table. Currently 2 or more major features are diagnostic.  The criteria are controversial because they include a number of features with low predictive value.  A subsequent update by the Global ROSacea COnsensus Panel (ROSCO) modified the criteria and expanded to 6 phenotypes. Note that there are no formal biomarkers for the phenotypes just very approximate clinical descriptions.

 

Primary Features	Central distribution of:   Transient erythema (flushing) Permanent erythema Papules/pustules Telangiectasia
Secondary Features	Burning or stinging sensation Ocular involvement Edema Dryness Plaque formation Peripheral location Phymatous changes
Phenotypes	Subtypes:   Erythematotelangiectatic Papulopustular Phymatous Ocular   Variant: Granulomatous

 

 

ROSCO Phenotypes

Flushing

Persistent Erythema

Telangiectasia

Papules/pustules

Phymatous changes

Ocular manifestations

 

This post is not about how to make the diagnosis or treat this disorder, although every physician including psychiatrists should be able to recognize the condition. I am hoping to convey some diagnostic imperatives and discuss disease complexity that underlies fairly basic diagnostic categories. It will also be apparent that basic science research has added quite a lot in terms of the treatment or this disorder, but that a lot of uncertainty remains.

Let me start with pathophysiology. There is always plenty of controversy about pathophysiology despite the fact that not much is known about it – even in common complex diseases.  That includes psychiatric diseases and yet people seem to suspend their critical thinking when it comes to psychiatry – and claim that the lack of pathophysiological mechanisms and medications specific for that pathophysiology represents something unique. In the case of rosacea since it is considered a complex inflammatory disease there are a couple of approaches to looking at pathophysiology. The first is to consider the two main types of immunity and how they are modified.  The first general type in innate immunity basically comprised of various barriers to pathogens like skin and mucous membranes, non-specific immune cells, and inflammatory proteins like interferons.  Local chemical environments can also produce a number of physical and chemical conditions that can kill potential pathogens.  Adaptive immunity is more specific and it depends on recognitions on antigens on pathogens and the resulting reactions with antibodies and immune cells. In the case of rosacea there are different theories involving both types of immunity.

One theory suggests that there is increased production of cathelicidin antimicrobial peptide (CAMP) – a component of innate immunity that leads to the inflammatory process associated with rosacea.  CAMP gene expression is regulated by VDR (a Vitamin D dependent transcription factor) and C/EBPα (a Vitamin D independent transcription factor). During winter months there is not enough UV light to produce CAMP by the Vitamin D dependent process. This theory suggests there is a mutation that allows for C/EBPα activation leading to toll-like (TLR) receptor mediated immune responses and upregulation of endoplasmic reticulum (ER) stress responses.  Although this sequence of events leads to increased inflammation due to a number of end products [sphingosine-1-phosphate (S1P), LL-37 the active cleavage product of CAMP, interleukin-1β (IL-1β), IL-17, IL-18, as well as associated T-helper (Th) cells and chemokines.  This process is depicted in the graphic at the top of this post (click on it to enlarge).  The activation of this inflammatory reaction can be verified by measuring end products in both the epithelium and the ocular surface.  Dry eye clinics have the capacity to check for tear osmolarity and inflammatory markers like matrix metalloproteinase-9 (MMP-9) – an enzyme.  MMP-9 can be done as a point-of-care test so that the results are available within minutes.

A logical question to ask is whether widespread activation of the inflammatory response associated with rosacea can affect organ systems other than skin. The degree of inflammation is also a factor. It is common to see patients with diverse findings ranging from mild erythema on the cheeks to intense erythema of the eyelids and central facial areas. The question of other organ systems has been examined with interesting findings. Cardiac, neurological, and psychiatric conditions are all more likely in patients with rosacea (6-15).  In terms of cardiac conditions that includes a modest increased risk for atherosclerotic heart disease.  There is less evidence of increased risk for arrhythmias but that increased risk has been demonstrated for other inflammatory dermatological conditions like atopic dermatitis and psoriasis (14). In the papers where the authors comment on possible pathophysiology the suggested mechanisms are innate immunity, adaptive immunity, or both.

Rosacea is a complex inflammatory disease that can lead to significant ocular and dermatological complications. According to one theory the pathophysiology of the illness may have been caused by an adaptive mutation in Nordic populations that preserved innate immunity when Vitamin D dependent factors were not available due to decreased photoperiod and UV light. The general consensus is that there is no agreed up theory to explain the underlying pathophysiology and like the immunological literature in psychiatry different authors have differing hypotheses.

Psychiatrists need to be aware of the condition because about 5% of the population has it, it is readily diagnosed based on visual inspection but the ocular phenotype may require referral to a specialized dry eye clinic. The dry eye disease untreated can lead to significant eye complications. From a theoretical perspective there are direct parallels with the psychiatric process including the categorial diagnoses, theoretical pathophysiology, and a number of treatments that may or may not address that pathophysiology.  Current clinical and future research questions include:

1:  Are there immunological mechanisms common to both rosacea and common psychiatric disorders?  Immune etiopathophysiological hypotheses for psychiatric disorders have been proposed since 1985 (16) and their complexity and the number of disorders covered have only increased since that time.  Over the same time frame much more has been discovered about the basic science of immunology. Do the proposed immune mechanisms of rosacea affect other organ systems in the same way that the skin is affected?  Are these mechanisms responsible for some of the early observations about PET imaging of the brain (15) in rosacea?

2:  What about the immunological products of rosacea?  Is it possible that they are contributing to what are considered symptoms of general disorders like anxiety and depression?  Cytokines like IL-17 can lead to flu-like symptoms and a general feeling of malaise – could this lead to the appearance of a treatment resistant anxiety or depressive disorder?  Could it lead to the misdiagnosis of a psychiatric disorder?

3:  Even if there is no direct physiological connection between rosacea and anxiety and depression can pathophysiological processes lead to psychiatric complications especially with pre-existing anxiety and depression. For example- rosacea leads to neurovascular hyperactivity in the form of facial flushing and skin sensitivity to a variety of physical and chemical irritants. If you have a pre-existing concern about embarrassment, humiliation, and obvious physical signs of anxiety rosacea compounds that.  It also can lead to sleep problems due to skin sensitivity that will compound any associated psychiatric disorder.

4:  Dealing with the stress of a chronic disorder activates additional processes that can either exacerbate or precipitate anxiety or depression. There is an inherent bias to see conditions like rosacea as a minor problem rather than a potentially very stressful problem with considerable morbidity that can actually lead to physical disability.

That is what I have found to be interesting about rosacea and dealing with it at an individual level.  I hope there is more research focused on it in the future from the combined perspectives of psychiatry, dermatology, and immunology.  There is much more to be learned.

 

George Dawson, MD, DFAPA

 

References:

1:  Braun-Flaco O, Plewig G. Wolff HH, Winkelmann RK.  Dermatology.  Springer-Verlag, Berlin 1991: 730-731.

2:  Melnik BC.  Rosacea: the blessing of the Celts – an approach to pathogenesis through translational research.  ACTA Derm Venerol 2016; 96: 147-156.

3:  Ratajczak MZ, Pedziwiatr D, Cymer M, Kucia M, Kucharska-Mazur J, Samochowiec J. Sterile inflammation of brain, due to activation of innate immunity, as a culprit in psychiatric disorders. Frontiers in psychiatry. 2018 Feb 28;9:60.

4:  Salam AP, Borsini A, Zunszain PA. Trained innate immunity: A salient factor in the pathogenesis of neuroimmune psychiatric disorders. Molecular Psychiatry. 2018 Feb;23(2):170-6.

5:  Zengeler KE, Lukens JR. Innate immunity at the crossroads of healthy brain maturation and neurodevelopmental disorders. Nature Reviews Immunology. 2021 Jul;21(7):454-68.

6:  Garrett ME, Qin XJ, Mehta D, Dennis MF, Marx CE, Grant GA, VA Mid-Atlantic MIRECC Workgroup, PTSD Initiative, Injury and Traumatic Stress (INTRuST) Clinical Consortium, Psychiatric Genomics Consortium PTSD Group, Stein MB. Gene expression analysis in three posttraumatic stress disorder cohorts implicates inflammation and innate immunity pathways and uncovers shared genetic risk with major depressive disorder. Frontiers in Neuroscience. 2021 Jul 29;15:678548.

7:  Pape K, Tamouza R, Leboyer M, Zipp F. Immunoneuropsychiatry—novel perspectives on brain disorders. Nature Reviews Neurology. 2019 Jun;15(6):317-28.

8:  Bekkering S, Domínguez-Andrés J, Joosten LA, Riksen NP, Netea MG. Trained immunity: reprogramming innate immunity in health and disease. Annual review of immunology. 2021 Apr 26;39:667-93.

9:  Dounousi E, Duni A, Naka KK, Vartholomatos G, Zoccali C. The innate immune system and cardiovascular disease in ESKD: monocytes and natural killer cells. Current Vascular Pharmacology. 2021 Jan 1;19(1):63-76.

10:  Scott Jr L, Li N, Dobrev D. Role of inflammatory signaling in atrial fibrillation. International journal of cardiology. 2019 Jul 15;287:195-200.

11:  Zhou X, Dudley Jr SC. Evidence for inflammation as a driver of atrial fibrillation. Frontiers in cardiovascular medicine. 2020 Apr 29;7:62.

12:  Bellocchi C, Carandina A, Montinaro B, Targetti E, Furlan L, Rodrigues GD, Tobaldini E, Montano N. The Interplay between Autonomic Nervous System and Inflammation across Systemic Autoimmune Diseases. International Journal of Molecular Sciences. 2022 Feb 23;23(5):2449.

13:  Choi D, Choi S, Choi S, Park SM, Yoon HS. Association of Rosacea With Cardiovascular Disease: A Retrospective Cohort Study. J Am Heart Assoc. 2021 Oct 5;10(19):e020671. doi: 10.1161/JAHA.120.020671. Epub 2021 Sep 24. PMID: 34558290; PMCID: PMC8649155.

14:  Schmidt SAJ, Olsen M, Schmidt M, Vestergaard C, Langan SM, Deleuran MS, Riis JL. Atopic dermatitis and risk of atrial fibrillation or flutter: A 35-year follow-up study. J Am Acad Dermatol. 2020 Dec;83(6):1616-1624. doi: 10.1016/j.jaad.2019.08.039. Epub 2019 Aug 20. PMID: 31442537; PMCID: PMC7704103.

15:  Liu Y, Xu Y, Guo Z, Wang X, Xu Y, Tang L. Identifying the neural basis for rosacea using positron emission tomography-computed tomography cerebral functional imaging analysis: A cross-sectional study. Skin Res Technol. 2022 May 29. doi: 10.1111/srt.13171. Epub ahead of print. PMID: 35644027.

16:  Knight JG.  Possible autoimmune mechanisms in schizophrenia.  Integrative Psychiatry 1985; 3: 134-143.

The Umbrella Review of Serotonin

Over the past week a review was published in Molecular Psychiatry that claimed to discredit nearly all of the previous work on serotonin hypotheses of depression (there are far more than one).  Ron W. Pies, MD, and I wrote a rejoinder to this review. Whenever you consider a commentary about a published paper the level needs to be considered.  For example, if the paper is a polemic – responding to the rhetoric is one approach.  For those not familiar with the rhetoric around this issue take a look at this previous post on Chemical Imbalance Theory and you will be brought up to speed.  If you need additional information here is a second, more recent post.  If the paper is primarily scientific then responding to the science and measurements in the paper is another. These days, responding to the statistics is a third option and in the case of specialized reviews like an “umbrella review” commentary on the methodology is a third.  For our initial effort we made a conscious decision not to go “to far into the weeds” of science or statistics.

On that basis, we respond to a fair amount of rhetoric and science. I refer interested readers to our paper published this morning on the Psychiatric Times.  On that page the study I am referring to is reference 1, The serotonin theory of depression: a systematic umbrella review of the evidence.  The serotonin theory of depression is just like Fight Club – there is no serotonin theory of depression and that is one of the first points we make in the paper.

As far as the science of serotonin goes – it is fairly intense. Since 1957 when there were only 2 known serotonin receptors types, we have developed a lot of knowledge about this system.  With that knowledge there has been a mind-boggling amount of system complexity that nobody has been able to explain to date. We are basically getting glimpse of how the entire system works. It is highly likely that there are behavioral, cognitive, and autonomic correlates of these systems – but we have a way to go.  Back in the day when I was a research fellow in neuroendocrinology I tried (in vain) to find out how serotonin signaling affected the HPA axis. Practically all researchers at the time considered monoaminergic hypotheses of mood disorders to have heuristic value (see the quote below). The intervening 30 years of advanced research proved them correct. The authors of the umbrella review conclude that it is time to acknowledge that the serotonin theory of depression is unsubstantiated despite a large research effort and that this should be acknowledged.  That is difficult to do when they seem to be the only people promoting this theory.

For those interested in excellent summaries of current serotonin research I suggest the following volumes written by 41 and 128 scientists respectively.

At some point, I will take a much closer look at the methodology used in this study. Just looking at the PRISMA diagram and 360 reviews being pared down to 17 with just a few in some categories – suggests that the umbrella has collapsed.

 

George Dawson, MD, DFAPA

Reference:

Ron W. Pies, George Dawson.  The Serotonin Fixation: Much Ado About Nothing New, Psychiatric Times. August 3, 2022

https://www.psychiatrictimes.com/view/the-serotonin-fixation-much-ado-about-nothing-new

Supplementary Graphic:

When I first started to respond to the chemical imbalance theory rhetoric - I took all of the psychopharmacology books off my shelves from the past 35 years to illustrate that in all of those texts on the subject there were no references to a chemical imbalance theory and that I had never been taught such a theory by my professors (many of whom were leading psychopharmacologists).  Since the original photo, my stack of psychopharmacology journals has increased about 3/4 of a foot and that would bring the stack up to about 5 feet. I am not going to pull them all down to remeasure so I just made this graphic.

Graphics Credit:

The iceberg graphic at the top of this post was done by the following authors and I added the text only.  Full credit is listed below per Wikimedia and CC licensing:

Created by Uwe Kils (iceberg) and User:Wiska Bodo (sky)., CC BY-SA 3.0 , via Wikimedia Commons 

More On Disease-Modifying

                                        See reference 6 and graphic credit for source.

 

My last post was not satisfactory after I read thorough it several times.  I decided to diagram the concepts of symptomatic and disease modifying with the suggested parameters and cite a few specific examples in the diagram.  An obvious problem with the definitions as used by Professor Ghaemi is that it involved a lot of inductive reasoning on the pathophysiology side of the equation. 

How can you say a medication is affecting underlying pathophysiology if it is unknown?  Much pathophysiology of complex disease is at the hypothetical rather than theoretical level. The hypotheses are restated over time, but there are no widely accepted theories. That has resulted in measurable proxies for pathophysiology being used like serum biomarkers for rheumatological disease and brain plaques for active disease and remissions in multiple sclerosis.  

The problem with that approach is highlighted with the recent controversy in the FDA approval of aducanumab ( an anti-beta~amyloid antibody) for Alzheimer’s Disease or mild cognitive impairment.  The biomarker of PET visualized beta~amyloid plaques were significantly improved in two clinical trials relative to placebo.  Both of these trials were terminated early when it became apparent, they would not reach primary efficacy endpoints. In this case, the drug did not reach clinical efficacy as a disease-modifying drug and it is effective against a biomarker that may not be a true marker of the pathophysiology of Alzheimer’s Disease.  Additionally, the drug was associated with amyloid-related imaging abnormalities (ARIA) at a significantly higher rate than placebo.  These lesions were thought to represent vasogenic edema and microhemorrhages and necessitate careful screening at baseline for preexisting vascular disease.

There are biases in the literature on where the term was used.  Disease-modifying seems to be associated primarily with rheumatological and some specific illnesses like multiple sclerosis.  In other areas it is mentioned primarily as an absence as in: “there are no disease-modifying drugs for this condition”.

 

What are the main points that I tried to incorporate into the diagram?

1.  Neither the disease-modifying or symptomatic interventions are 100% effective.  With any complex, polygenic illness there will be non-responders, partial responders, and optimal responders.  In many studies the optimal responders will meet study criteria for remission – but that also happens in clinical practice.  For example, it is common to assess people undergoing antidepressant treatment and find that from a subjective standpoint their depressive symptoms are gone and they feel like they are back at their baseline.  Of course, in randomized clinical trials there is an intent-to-treat analysis that counts study drops outs in the denominator no matter what the cause. In clinical practice that group would be provided with an alternate treatment.

2.  There can be overlap between disease-modifying and symptomatic treatment. There are a few examples in the graphic, but prednisone for rheumatoid arthritis is probably the best example.  It treats acute joint and systemic inflammation while preventing bone erosion early in the course of illness.  There are many drugs that are either symptomatic or disease-modifying.

3.  Many of the outcomes are not cleanly separable.  Symptom ratings and symptom defined remission can be associated with hospitalizations, disease markers, and composite outcomes. Measurable disease markers or biomarkers are certainly preferable, but as noted in the case of aducanumab there may be unexpected findings suggesting other important underlying pathophysiology.  In the case of complex diseases we are learning more and more that many genes and many gene networks are potentially involved.  In that case – a final common pathway or a parsimonious analysis should not be expected.  We appear to be at the very early stages of being able to analyze these complex interactions.

No matter how you parse it – the definitions considered above do not allow for a very clearly defined category of disease-modifying and symptomatic.  Does regulatory language from the US Food and Drug Administration (FDA) or the European Medicines Agency (EMA) help?  The standard for disease-modifying approvals apparently changed before 2019 (2).  Up until that time the standards were largely descriptive like delaying disability or slowing the progress of illness.  The authors note an uneven approach to the term disease-modifying with a tendency to use it in rheumatic diseases but less so in neurodegenerative diseases. They attribute that to disease-modifying being an inferential concept because “changes in the brain cannot be directly observed”.

This is an important concept because it applies to all of the hypothetical mechanisms of action of most drugs that exist.  In the previous post I pointed out that all of the disease modifying drugs for multiple sclerosis have no widely accepted theories about their mechanism of action.  The hypotheses may be listed but more commonly are listed as unknown or not fully understood.  The same is true for the disease-modifying drugs in psychiatry listed by Ghaemi in his recent paper (4).  Various signaling systems are cited, but the reality is there is no widely accepted mechanism of action and more importantly no mechanistic way to explain lithium nonresponse.  

The best way to approach disease-modifying drugs in general and more specifically in psychiatry is to discuss the hypothetical mechanisms of action and the implications of those mechanisms.  That is the focus of research and the basis for many purported biomarkers of disease in psychiatry but clearly in many other fields of medicine. With the advent of genomics we are also witnessing a necessary paradigm shift away from simple explanations.

 

George Dawson, MD, DFAPA

 

References:

1:  Rabinovici GD. Controversy and Progress in Alzheimer's Disease - FDA Approval of Aducanumab. N Engl J Med. 2021 Aug 26;385(9):771-774. doi: 10.1056/NEJMp2111320. Epub 2021 Jul 28. PMID: 34320284.

2:  Morant AV, Jagalski V, Vestergaard HT. Labeling of Disease-Modifying Therapies for Neurodegenerative Disorders. Front Med (Lausanne). 2019 Oct 17;6:223. doi: 10.3389/fmed.2019.00223. PMID: 31681780; PMCID: PMC6811601.

3:  Schubert, K.O., Thalamuthu, A., Amare, A.T. et al. Combining schizophrenia and depression polygenic risk scores improves the genetic prediction of lithium response in bipolar disorder patients. Transl Psychiatry 11, 606 (2021). https://doi.org/10.1038/s41398-021-01702-2

4:  Ghaemi SN. Symptomatic versus disease-modifying effects of psychiatric drugs. Acta Psychiatr Scand. 2022 Jun 2. doi: 10.1111/acps.13459. Epub ahead of print. PMID: 35653111

5:  Alda M. Lithium in the treatment of bipolar disorder: pharmacology and pharmacogenetics. Mol Psychiatry. 2015 Jun;20(6):661-70. doi: 10.1038/mp.2015.4. Epub 2015 Feb 17. PMID: 25687772; PMCID: PMC5125816.

6:  Kerr F, Bjedov I and Sofola-Adesakin O (2018) Molecular Mechanisms of Lithium Action: Switching the Light on Multiple Targets for Dementia Using Animal Models. Front. Mol. Neurosci. 11:297. doi: 10.3389/fnmol.2018.00297

 

Graphic Credit:  Reference 6 and the following copyright and Open Access license:

Copyright © 2018 Kerr, Bjedov and Sofola-Adesakin. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.