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Thursday, 28 June 2018

Tail Docking - Again!

I was, with respect (as they say), very disappointed to read this recent tail docking monologue. OK, Prof Mellor accepts that there is no behavioural substitute for a dog-mounted tail, that tail docking is likely to result in chronic inflammatory pain and chronic neuroma pain..., but, he contests, that a puppy up to a few days old is incapable of feeling pain because they lack consciousness. He says that this is what the "science says", but I am sorry, but I think the science says no such thing.  I think the most straightforward uncontestable fact is that we don’t know, and maybe that we can’t possibly know.  
So what evidence does Prof Mellor present in this paper, to assuage us of the idea that neonates feel pain.  Well, this is a little embarrassing, because the paper is quite difficult to read from a critical perspective, it is written in many ways like a blog.  Whilst it includes about 25 self-citations these are kind of mostly references to the fact that he has argued previously that puppies don’t feel pain (or that different species attain consciousness at different times).  
At one point there is a line with 8 references followed by several sentences of the main argument (that puppies don’t have consciousness for several days)... but few specific facts in this section have their own citation! I am embarrassed to say this of someone so eminent, really, but that is no way to write a scientific paper. We want, in the main body, fact citation, fact citation et seq.  
I made the effort to try and track down those 8 references.  Most are simply self-citations of reviews. Not good enough. Mark = D- (not a U/E... because there was an attempt to use referencing). Whilst most are reviews, others were original scientific papers.  These were 1967 EEG papers showing that neonates have far less complex EEG than more developed puppies. Largely in the sleep state.  In fact, they DO SHOW that the EEG changes on nociceptive stimulus, but not as much as the adult.  It would be over-reaching to therefore state that they feel less pain (because we do not know categorically with old studies like that what the actual markers of pain would be except.. different to no pain), but that would be the most you could possibly say, from that data.  So cutting a puppy’s tail off would be, what 25% as painful as cutting an adult leg off? 15%? 30%? Still sounds pretty painful.

The main body does two things; one half attests that the reason we think they do feel pain is by ill-founded analogy with other species, and then... the other half rebuts this with, largely, analogy with rats.  
Unless you are prepared to read all the previous REVIEWS I didn’t feel there was any useful new information in this one paper. The basic mantra is: They don’t have consciousness, as evidenced by the fact that I have previously stated that they don’t have consciousness. 
So there’s a quoted paper (much more specific) showing the average yelps during the procedure is about 20.  Feeble-minded sorts like myself may assume that this is because it hurts, but of course the old argument is used that this a subcortical behaviour to signal the need for assistance from the mum. Clearly, as stated in this piece, nociceptive (pain) signal has traversed to the spinal cord and up to the sub-cortical yelp centres [partly agree], but it doesn’t reach the cortex because ...because he says so on the basis of previous reviews.  Why “partly” agree above?  Because studies have not even successfully located where the yelp centre is and how it is controlled even in adult dogs.  Big damage to pretty much any part of the cortex can suppress this “reflex” (reference: I say so - gosh isn’t academic writing easy once you can just quote yourself). 
So can I prove that puppies feel pain? Nope. I cite Occam's Razor (“the starting hypothesis should be the simplest”).  Now, this creates a problem.  If you really are deeply religious in a literal and creationist way you believe that man was created, then woman then animals. OR was it the other way around (Sunday School quite a while ago)? Anyway, they were created separately. Animals are sort of machines created for our entertainment.  So Occam's Razor could be that only humans feel pain.  In fact, I think some people believe that only they themselves feel pain! standpoint is that of evolution as a proven fact.  In that case, I would say that Occam's Razor is that all those responses that look the same are the same.  And you need an experiment to disprove it.  What experiment could you do? ...well it is tricky!! ...Maybe we should think about FRMI or something at least... are there cortical changes in the cortex of a puppy with pain... but even that means that we feel we really know where consciousness lies and we are not that sure.....  and anyway, those 1967 papers already showed that there is a cortical change on painful stimulus in a puppy.  So why would anyone be soooo desperate to dock a puppy that they would need to do those type of experiments just to shed light on whether the well recognised screaming really represents pain or not.... when we already no about the chronic pain, the neuroma and the tail’s central role in canine behaviour?

Sunday, 29 April 2018

OARSI - Is pseudoscience making a come-back?

OARSI 2018, the international osteoarthritis conference is over, so what did I really think? 

What I liked:
  • Friendly and lovely people, 
  • Commitment to ultimately delivering improved patient care.  
  • Enthusiasm from so many people.
And what I didn’t like:
  • Food (lack of lunches!)
  • Sending hundreds of tweets from the official OARSI account without being able to give my own opinion (I'm way too professional :-).
  • An apparently general acceptance of “placebo”, “contextual response” and “clinical opinion”.

“Placeboists” & “Contextual Response”
Once upon a time, there were pretty much no effective medicines.  Gangrenous limbs could be chopped off and the joints cauterised, but that was virtually it. But plenty of “medicines” were still sold, mercurials, cupping, various charms and snake oils. These were all beneficial due to their placebo effect. …and when I was a child I was taught the purveyors were called “quacks” and charlatans.  
Remember Moniz’s leucotomy (pre-frontal lobotomy treatment of mental illness) and his Nobel Prize?

The leucotome, device invented by Moniz

Then these foolish things all started to lose out as science an medicine started to take over. We got water sanitation, antibiotics, anaesthetics, aspirin, opioids; wonderful painkillers, aspirin, the understanding of infection and the role of sterility in surgery, vaccinations… then antihypertensives, insulin injections, chemotherapy, antihistamines for acid, others for hay-fever, adrenaline AND anti-histamines for real bad allergies.  AND countless more.  The term placebo was then coined and we all knew what it meant: “patients were tricked into saying they felt better when really they didn’t”.

But osteoarthritis? Well sadly, there aren’t really any great treatments.  There are painkillers and surgery; in fact, physiotherapy and exercise seem to be best if patients can manage it. Hopefully, soon there will be new and effective treatments.  …but now it is pretty poor.
A side-effect of the paucity of treatments….. placebo is making a remarkable comeback.
So question: Why might an osteoarthritis patient report that their symptoms have improved?
  1. Well, it may be because they have.
  2. It might be because they are reeeaaaally bad at judging their own pain.
  3. It may be because they are embarrassed about how much trouble they are being and how much they have just cost/spent.
  4. It may be that they so desperately want the treatment to work they kid themselves, even though their pain is unchanged.
  5. It might be because they didn’t really have real osteoarthritis, but aches and pains to some other cause and these were now less bad; their chronic pain had “regressed to the mean”.
  6. It may be because they have given up, and accept there is nothing that can be done and decide to move on.
  7. It may be because the treatment was so unpleasant they say they feel better to avoid further treatment.
  8. The degree of pain prior to treatment is so variable, either intensity or frequency (or both) that is is literally impossible for patients to report accurately and they throw a bone to the investigator and guess on the low side after they have received treatment from an obviously well-meaning and earnest person.

All these things are possible, but it would seem that some investigators ONLY consider (1) is viable.  Then, since placebo clearly leads a number of patients to report less pain, these investigators extrapolate that placebo has actually made their pain decrease.  …and, therefore, there are now investigators, “placeboists”, actively promoting the treatment of patients with placebo.  Sometimes they call it other things “contextual response” is another way of putting it; if you give a nice painful injection with a kind and persuasive caregiver in a very posh looking hospital they are more likely to tell you that their pain is less.

These other factors also all help to persuade patients to report less pain; the pain of treatment, injection, price, the novelty of treatment, the authority of the administrator of the “treatment”.  

So does it matter that investigators are promoting consideration of placebo as a viable treatment? Hell yes!  It brings snake oil, crystal charming etc all back into play.  Things that were marginalised in bygone days will return.  Now presumably, once a really genuine treatment for osteoarthritis, that really works is invented these placeboists will either change their spots or be themselves marginalised.
But currently, the law kind of makes it difficult for people to treat with anything that doesn’t beat placebo. At this OARSI, however, there was an increasing volume of calls for “contextual treatment”.  
So spelling out contextual once more.. it means all those factors that persuade a patient to report lower pain OTHER than a placebo (or something that does decrease pain). So, it has been discovered that patients are so suggestible that not only can you trick them to reporting lower pain with a big fancy pill (placebo), you can do it with the environment, consultations, appearance of care or just kind consideration.  

Clinical Opinion
Feeding into this, is my second bĂȘte noire (or third maybe?): “Clinical opinion”. There have been several calls at OARSI for decisions over licensing of treatments to include not just clinical trials… but also to include “clinical opinion”.  In other words, calls to unpick the very standard which has been developed (double-blind random control trials).  Why?? Well because this happens; someone treats loads of patients with X.  The experience of a clinician is that they seem to be better, but the clinical trial says they are actually no better than placebo.  So what is happening is that placeboists are starting to say that just the fact that a clinician feels that a patient got better should be enough (or more fairly, a part of the equation) to decide whether or not to adopt X as a standard treatment.  Now to a non-scientist or statistician, that kind of logic probably seems fine. But to me it is horrific.  It is EXACTLY the same logic that was used by Moniz and the snake oil salesmen of centuries past.  

….now all this is understandable; it must be so depressing to see patients for year after year of your entire career and never really be able to help them.  So any suggestion that they may be slightly better is clutched at like a drowning man/woman clutching at an undersized life buoy.  Whilst some people pillory Moniz and his “brutal” leucotome, others accept that this was a genuine and desperate attempt to treat a then intractable mental illness. Anyone looking for a big pharma conspiracy theory can take a long walk on a short pier because placeboists are really nice genuine people who sincerely want to help.

But, some would argue, placebo causes real biological changes in the brain so it must be working? Nonsense. EVERYTHING causes biological changes in the brain. Standing up, thinking, walking; the brain is a bag of swirling chemicals and there is nothing you can do or not do that won’t change chemicals. Thought and love are just chemical and electrical activity changing.  Increases in endorphins??  Causing stress or inflicting pain itself increases the endogenous release of endorphins, so that is a particularly bad argument to use.

And does any of this matter? Oh yes, it matters, because when you treat with placebo and context you are with-holding real treatments however poor they are.  And if you end up treating with, for example, steroids which clinical trials show to not work (long term - they may help a bit over the first few weeks), you will do actual damage. Steroids for example do all sorts of awful things to people including weakening bones just for starters.

So what can be done: Well I could stop going to OARSI …. but to be honest, I firmly believe that once really effective treatments arrive it will be game over for “contextual treatments” and placebo.  Science and medicine will be able to fight back and I long for that as should patients and other investigators!!

Monday, 12 March 2018

Novichok/sarin/VX: The Science bit

The BBC report that comrade Sergei Skripal was poisoned with a nerve agent VX, and now we hear this is novichok and that “technically this is a nerve toxin”. Shocking. Shocking that the Science coverage can be so bad. For goodness sake “nerve toxin” is the “technical” term?? Seriously that is a classic case of the science bit having ….no science it. ….like a VSCI200 lecture. Shocking. This is, literally, the BBC’s full explanation: ”What are nerve agents? They are highly toxic chemicals that prevent the nervous system from working properly, and can be fatal:” Anyway, some waffle; then some science from me:
Russia must be a great place to be a pharmacologist. Not only are they making pharmacology a sport they are making sport, basically, pharmacology. Russian sports stars seem to dine on nothing but drugs; who needs milk and sugar on their cereal when they could have vodka and meldromium?

AND of course, the Ruskies have a long proud history of exotic poisoning…. That Bulgarian (Markov) killed with a ricin-tipped umbrella on London bridge, Hugh Gaitskill also to make way for Harold Wilson, and of course, poor Mr Litvinenko; Wall Street Journal and Business Insider lists a load of others too (they would).
Now Sergei Skripal. So questions: Why did they use novichok? and how does it work? How is it treated? What are the biological unknowns?

Why novichok? Well there is the political interpretation of which I am not qualified to answer. I am guessing they didn’t like him much (!) and wanted to make a very public statement that the KGB NEVER forgets. …but pharmacologically, novichok is very similar to VX and the magic of that, over say, sarin, will be it’s so-called ”*logP*” that’s a measure of how fat soluble a drug is. It’s one of the foremost chemical properties you think about when using drugs (medically). The point being that the more fat-soluble a drug is, the better it absorbs through the skin. VX itself has a much greater logP than good old fashioned sarin. Sarin would need to get in the body through mouth etc, but VX ought to absorb straight through the skin. That’ll be why. The next level of “why“ is why this family of drugs (organophosphates)? So many poisons,so little time. I don't have a crisp answer for this, but a guess: This family of drugs, the “organophosphates” were originally developed as pesticides. Most neurotoxic drugs are developed for research in minute quantities and quite tricky to deal with. The organophosphates were originally developed by the absolute bucket load and even dropped from planes. So it stands to reason that it must pretty easy to make in the large quantities you would also need for warfare. Yuk. What a thought.

How do novichok/VX/sarin work? Well that’s widely reported. Nerves communicate (signal to one another and to muscle) by release of “neurotransmitter” chemicals. …and it is important for this function that they act fast and are then removed from the system. In this case we are talking about nerves running to two major targets of interest, the diaphragm to allow breathing and the heart. The chemical in question is acetylcholine. When you breath, acetylcholine is released from the nerves and acts on (for example) the muscles of the diaphragm brings air in and out. The acetylcholine is then REMOVED from the tissue by the enzyme “acetylcholinesterase”. If it is not removed the muscle stays locked up and can’t relax…. you therefore can’t take another breath. Meanwhile, back at the heart, the heart rate would tend to increase to get some more of that oxygen-depleted blood around the system…. but it can’t, because acetylcholine, now at excessive levels acts at the heart to actively slow it. Usually, any ACh wafting about in the body is broken down in milliseconds in the actual place it is released (brain, heart, lung/diaphragm)… or just seconds if it over-spills into the blood. Now it is washing about slowing the heart and halting the breathing. Other effects? Of course, I anticipate some confusion, salivation and even stomach cramps…

How is it treated? It is widely reported that Vx and sarin are treated with atropine. This is a cheap and cheerful drug we use ourselves a lot experimentally (It speeds the heart in an interesting and predictable way). It is pretty safe, I have even seen a whole class (not mine!) given atropine as part of a class demonstration. It was originally a natural chemical extracted from belladonna. The story goes that Roman… ummmm… lady people in the “entertainment” industry of the time put it in their eyes; the pupillary dilation apparently conveys the impression that the wearer is full of lust? You know that look? …no me neither. Now a biological unknown. HOW atropine treats novichok/VX/sarin poisoning is NOT entirely clear. Let’s back up: Acetylcholine acts on two different classes of the target protein (“receptors”); so called muscarinic and nicotinic (yes nicotinic is the target also activated by cigarettes). The first of these targets (muscarinic) is found on the heart; the second (nicotinic) is found in the diaphragm. Yes, you will hear heaps of experts trotting out to tell you that it blocks the action of acetylcholine right? Wrong. Yes of course it does; but it only blocks muscarinics and typically you die to of nicotinic actions in the diaphragm. So this is my point (eventually); one expert after another trots out to explain that the muscarinic blocker atropine works by blocking the actions of acetylcholine even though they must know the fatal actions of novichok/sarin/VX mostly do no involve muscarinic protein targets!! So how does it really work? No one knows. OK, there is literature to suggest that, in contravention to 100 years of pharmacology, atropine has a small degree of “off-target effects” on the “wrong” type of acetylcholine target and this is JUST enough to save someone’s life. Other benefits will be that it speeds up the heart, under these circumstances that's a good thing. …the other unpleasant effects, salivation and cramps will be dealt with by atropine’s accepted actions. Of course (no time to check literature, but off the top of my head) oximes are also used. These seem to bind the organophosphate (VX/novichok/sarin) and take it out of action. Next, you’d have to keep people on a respirator until the agent eventually gets metabolised and clears. Eventually it should!!! Hang on in there guys.

Other recent Russian assassinations:–2018–3

Tuesday, 30 January 2018

Do Lecturers Shit?

"Do lecturers get nervous?" 

I have been asked on more than one occasion the question "do lecturers get nervous before lectures?" So I thought I'd pull together to a few answers to potential questions like this.
1) Do lecturers get nervous before lectures?

Answer: Yes indeed some do. This is because they are animals closely related to humans and they have feelings, similar in a number of ways, to humans. To get stressed and nervous, to one degree or another is a common feature of animals including humans and lectures.

2) Do lectures get sad when told their lectures are rubbish?

Answer: Strangely some do. It is not fully understood why, but it could be the many hours they put into it combined with some genetic materials in common with humans.

3) Do lectures go to shops?

Answer: yes I often see the Tweet or hear the words "I just saw Dr X in xxxx (name of shop)" and also I have heard the comment "I just saw lecturer x walking along the street". Both of these phenomena are entirely possible. Like humans, lecturers sometimes have to move from one physical space to another. Often this involves walking or other form of transport. In fact some lecturers have dens, called "homes" where they go at night for shelter. These are often "off campus" and so they have evolved methods to get from Uni to their den and this sometimes involves some element of walking.

4) Do lecturers shit? 

Answer: (A) Indeed they do (not clinical lecturers obviously). Shitting is a naturally evolved process common to many types of human and animal. (B) Usually this is Done in private, and so reports of such activity are generally rare.

5) Do lecturers have to spend much time preparing lectures? 
Answer: Same answer as (4B).

6) Do lecturers mate? 
Answer: No. No they definitely don't do that. They just appear on campus one day.