an autodidact meets a dilettante…

‘Rise above yourself and grasp the world’ Archimedes – attribution

Posts Tagged ‘medicine

some thoughts on regression to the mean and what causes what

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Regression effects are ubiquitous, and so are misguided causal stories to explain them. Daniel Kahneman

Canto: So here’s an interesting thought, which in some ways is linked to the placebo effect and our attributing recovery from an illness to something we ate, drank or did, rather than to the silent and diligent work of our immune system. You know about the regression to the mean concept?

Jacinta: Of course. It’s a statistical phenomenon that we tend not to account for, because we’re always looking for or imagining causal effects when they don’t exist.

Canto: Well, they do exist but we attribute the wrong causal effects – we don’t account for ‘bad luck’, for example, which of course is caused, usually by factors we can’t easily uncover, so for convenience we give it that name. For example, a golfer might be said to have had an unlucky day with the putter because we observe that she she went incredibly close to dropping a number of difficult long putts, but none of them went in, so she made five over par instead of even. Of course every one of those failed putts was caused – one because her aim wasn’t quite true, another due to a tuft of grass, another because of a last moment gust of wind and so on… 

Jacinta: And some of those causes might be deemed unlucky, because on a less windy day, or with a better maintained green, those putts might’ve gone in.

Canto: Okay okay, there is such a thing as luck. But luck, I mean real luck, like the effect of a sudden gust of wind that nobody could’ve factored in, tends to even itself out, which is part of regression to the mean. But let me get back to illness. Take an everyday illness, like a cold, a mouth ulcer (which I suffered from recently)…

Jacinta: Or a bout of food poisoning, which I suffered from recently…

Canto: Yes, something from which we tend to recover after a few days. So the pattern of the illness goes something like this – Day 1, we’re fine. Day 2, we feel a bit off-colour. Day 3 we definitely feel much worse. Day 4, much the same. Day 5, starting to feel better. Day 6, definitely a lot better. Day 7, we’re fine. So it follows a nice little bit of a sine wave – two peaks and a trough – as shown above. 

Jacinta: So you’re saying that getting back up to the peak again is regression to the mean?

Canto: Well, sort of, but you’re getting ahead of me. Maybe it isn’t precisely, because a mean is the midpoint in a fluctuation between two extremes. Sort of. Anyway, let me explain. When you’re ill, you can choose to ride it out, or you can go to a doctor, or take some sort of medication, or some concoction recommended by a friend, or a reflexologist, whatever. But here’s the thing. You’re not likely to go to the doctor/acupuncturist/magus on day 2, when you’re just starting to feel queasy, you’re much more likely to go when you’re at the bottom of the trough, and then you’ll attribute your recovery to whatever treatment you’ve received, when it’s really more about regression to the mean. Sort of.

Jacinta: Hmmm. I agree that we’re unlikely to rush to the doctor or even the medicine cabinet when we’re just feeling a bit queasy, but that’s probably because experience tells us we’ll feel better soon – that maybe we’re already at the bottom of a little trough. But when we start going into a deeper trough, naturally we start getting worried – maybe it’s pneumonia, or tuberculosis…

Canto: Or diphtheria, malaria, typhoid, cholera, bubonic plague, acute myeloid leukaemia….

Jacinta: Don’t mock, I’ve had all of those. But it’s interesting to think of illness and wellness in this wave form. I’m not sure if it works as regression to the mean. Because wellness is just, well, feeling well. Feeling ‘normal’ or okay. We don’t tend to feel super-well – do we?

Canto: You mean you don’t believe in biorhythms? So you think the line pattern would be like, a straight horizontal one with a few little and big troughs here and there, and then finally off the cliff and straight down to death?

Jacinta: Well, no, isn’t it a slow decline into second childhood and mere oblivion – sans teeth, sans eyes, sans taste, sans everything?

Canto: Haha well not so much with modern medicine – though my hearing’s starting to go. But one of them-there invisible implants should fix that, at a price. But you’re probably right – what we call wellness at sixty is a lot different from the wellness we felt at twenty, but we’re probably lucky we can’t feel our way back to that twenty-something feeling. But getting back to the case of the person who applies a treatment and then gets better, there are, I suppose, three scenarios. The treatment caused the improvement, the treatment had no effect (the person improved for other reasons – such as our super-amazing immune system), or the treatment actually had a detrimental effect, but the person got better anyway, probably due to our wondrous immune system.

Jacinta: So that’s where the placebo idea comes in. And our tendency to over-determine for causality. You mention something like a cold, which is generally a viral infection, and mostly rhinoviral. The symptoms, like a runny nose and a sore throat, are actually caused by a mixture of the virus itself and the immune system fighting it, but mostly the latter….

Canto: Yeah, is that about antigens, or antibodies, I always get confused…

Jacinta: Well, it’s very very complicated, with T cells, immunoglobulin and whatnot, but essentially antigens are the baddies which trigger an antibody response, so antibodies are the goodies. So, if someone has a cold then unless they know their immune system is compromised in some way, the best thing is to let their immune system do its job, which might cause a few days’ discomfort, like extra phlegm production as the system, the antibodies or whatever, attempts to expel the invaders.

Canto: Yes, but the immune system is invisible to us, and is vastly under-estimated by many people, who tend to like to see something, like a big bright red pill, or a reflexology foot massage, or a bunch of needles needling their chi energy points, or unblocking their chakras…

Jacinta: Can they see their chakras?

Canto: No, but the magus can, with his various chakra-probing methods, and aural and oratorical senses developed over a lifetime – that’s why he’s a magus, dummy.

Jacinta: Yeah, and I’m sure we can all feel when our chakras are unblocked. It’s sort of like body plumbing.

Canto: So, getting back to reality, there is definitely something like this regression to the mean, to our own individual ‘normal’, but maybe ever-declining physical and mental state, that our wonderful immune system helps us to maintain, a system we rely on more than we realise….

Jacinta: Yes, but you know, it’s good that we don’t realise it so much, because think of all the acupuncturists, Alexander technicians, anthroposophicalists, antipharmaceuticalists, aromatherapists, auriculotherapists and ayurvedicists whose jobs might be on the line – and that’s just the A’s! Then we have the baineotherapist, the bead therapists and the bowen therapists, not to mention the chakra scalpel weaponmasters… can you imagine all those folk not being able to make a living?

Canto: Okay, that’s enough. It truly is a sad thing to think upon, but never fear, your horror scenario will never eventuate, my faith in human nature tells me….

The statin controversy

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Never edit your own writing! Brian J Ford.

one thing thing you can be sure of – this claim (posted by a British chiropractor) is meaningless bullshit

I read Ben Goldacre’s quite demanding book Bad pharma some years ago, and that’s where I learned about statins, but I don’t recall much. I do recall that, not long after I read the book, I was at a skeptics meet-up when Dr Goldacre’s name came up. The man next to me started literally spitting chips at the mention – he was eating a massive bowl of chips and was grossly overweight (not that I’m assuming anything from this – just saying, haha). He roolly didn’t like Dr Goldacre. What went through my head was – some people may be really invested in having a magic pill that allows them to live forever and a day no matter what their diet or lifestyle.

I’ve just discovered that Goldacre has a new book out, entirely on this topic, which I intend to read, but my current decision to explore the issue is based on listening to Dr Maryanne Demasi’s talk, ‘statin wars – have we been misled by the evidence?’, available on YouTube. I very much recall the massive Catalyst controversy a few years ago, when a two-part special they did on statins led finally to the demise of the program. Without knowing any details, I thought this was a bit OTT, but when I heard Dr Norman Swann, a valued health professional and presenter of the ABC’s Health report, railing about the irresponsibility of the statin special, I frankly didn’t know what to think.

So statins are lipid-lowering medications that come in various flavours, including atorvastatin, fluvastatin, lovastatin and rosuvastatin. Lipitor, a brand name for atorvastatin manufactured by Pfizer, is the most profitable drug in the history of medicine. I’ve never taken statins myself, and I’m starting this piece as a more or less total beginner on the topic. I’ve read the Wikipedia entry on statins, which is quite comprehensive, with a very long reference list. Of course it’s not entirely comprehensible to a lay person, but that’s not a criticism – immunobiology and related research fields are complex. It’s also clearly pro-statin. It includes this interesting sentence:

 A systematic review co-authored by Ben Goldacre concluded that only a small fraction of side effects reported by people on statins are actually attributable to the statin.[63]

It’s interesting that Goldacre, and nobody else, is mentioned here as a co-author. It makes me wonder…

My only quibble, as a lay person, is that the positive effects of these statins, and their relatively few side-effects, seems almost too good to be true. I speak, admittedly, as a person who’s always been ultra-skeptical of ‘magic bullets’.

Which brings me to issues raised in Dr Demasi’s talk, and not addressed in the Wikipedia article. They include the idea, promoted by an ‘influential group’, that statin use should be prescribed for everyone over 50, regardless of cholesterol levels. Children with high cholesterol levels are being screened for statin use and Pfizer has apparently designed fruit-flavoured statis for use by children and adolescents. Others have suggested using statins as condiments in fast-food burgers, and even adding statins to the public water supply. It’s easy to see how such ‘innovations’ involve making scads of money, but this isn’t to deny that statins are effective in many if not most instances, and we should undoubtedly celebrate the work of the Japanese biochemist Akiro Endo, who pioneered the work on enzyme inhibitors that led to the discovery of mevastatin, produced by the fungus Penicillium citrinum.

But Demasi made some other interesting points, firstly about how drug companies like Pfizer might seek to maximise their profits. One obvious way is to widen the market – for example by lobbying for a lowering of the standard level of cholesterol in the blood considered dangerous. From the early 2000s in the US, ‘high cholesterol’ was officially shifted down from as high as 6.5 down to below 5, moving vast numbers of people onto having a ‘need’ for these cholesterol-lowering drugs. Demasi points out that this lowering wasn’t based on any new science, and that the body responsible for these decisions, the National Cholesterol Education Program (NCEP), was loaded with people with financial ties to the statin industry. To be fair, though, one might expect that doctors and specialists concerned with cholesterol to be invested, financially or otherwise, in ways of lowering it. They might also have felt, for purely scientific reasons, that the level of cholesterol considered dangerous was long overdue for adjustment.

Another change occurred in 2013 when two major heart health associations in the US decided to abandon a single number in terms of risk factors for heart disease/failure. Instead they looked at cholesterol, blood pressure, weight, diabetes and other factors to calculate ‘percentage risk’ of cardiovascular problems. They evaluated this risk so that if it was over 7.5% in the next 10 years, you should be prescribed a statin. A similar percentage risk system was used in the UK, but the statin prescription started at 20%. Why the huge discrepancy? Six months later, the Brits brought their threshold down to 10%. The US change brought almost 13 million people, mostly elderly, onto the radar for immediate statin prescription. The method of calculation in the US was independently analysed, and it was found that they over-estimated the risk, sometimes by over 100%. Erring on the side of caution? Or was there a lot of self-interest involved? It could fairly be a combination. The term for all this is ‘statinisation’, apparently. It’s attributed to John Ioannidis, a Stanford professor of medicine and a noted ‘scourge of sloppy science’. If you look up statinisation, you’ll find a storm of online articles of varying quality and temper on the issue – though most, I notice, are five years old or more. I’m not sure what that signifies, but I will say that, while we’ll always get the anti-science crowd baying against big pharma, vaccinations and GM poison, there’s a clear issue here about vested interests, and the need to, as Demasi says, ‘follow the money’.

This brings up the issue of how trials of these drugs are conducted, who pays for them, and who reviews them. According to Demasi, the vast majority of statin trials are funded by manufacturers. Clearly this is a vested interest, so trial results would need to be independently verified. But, again according to Demasi (and others such as Ioannidis and Peter Gotzsche, founder of the nordic Cochrane Collaboration) this is not happening, and ‘the raw data on statin side-effects has never been released to the public’ (Demasi, 2018). This data is held by the Cholesterol Treatment Triallists’ (CTT) collaboration, under the Clinical Trial Service Unit (CTSU) at Oxford Uni. According to Demasi, who takes a dim view of the CTT collaboration, they regularly release meta-analyses of data on statins which advocate for a widening of their use, and they’ve signed agreements with drug companies to prevent independent examination of research findings. All of this is described as egregious, which might seem fair enough, but Elizabeth Finkel, in a long-form article for Cosmos magazine in December 2014, takes a different view:

.. [the CTT] are a collaboration of academics and they do have access to the raw data. It is true that they do not share that data outside their collaboration and are criticised by other researchers who would like to be able to check their calculations. But the trialists fear mischief, especially from drug companies seeking to discredit the data of their rivals or from other people with vested interests. Explains [Professor Anthony] Keech, “the problem with ad hoc analyses are that they can use methods to produce a particular result. The most reliable analyses are the ones done using the methods we published in 1995. The rules were set out before we started.” And he points out these analyses are cross-checked by the academic collaborators: “Everything is replicated.”

As a regular reader of Cosmos I’m familiar with Finkel’s writings and find her eminently reliable, which of course leaves me more nonplussed than ever. I’m particularly disturbed that anyone would seriously claim that everyone over fifty (and will it be over forty in the future?) should be on these medications. I’m 63 and I take no medications at all, which I find a great relief, especially when I look at others my age who have mini-pharmacies in their homes. But then I’m one of those males who doesn’t visit doctors much and I have little idea about my cholesterol levels (well yes, they’ve been checked and doctors haven’t raised them to me as an issue). When you get examined, they usually find something wrong….

In her talk, Demasi made a comparison with the research on Tamiflu a few years ago, when Cochrane Collaboration researchers lobbied hard to be allowed to review trial data, and it was finally revealed, apparently, that it was certainly not as effective and side-effect free as its makers, Roche, claimed it to be. The jury is still out on Tamiflu, apparently. Whether it’s fair to compare the Tamiflu issue with the statin issue is a matter I can’t really adjudicate on, but if Finkel is to be believed, the CTT data is more solid.

There’s also an issue about more side effects being complained of by general users of statins – complaints made to their doctors – than side effects found in trials. This has already been referred to above, and is also described in Finkel’s article. Many of these complaints of side-effects haven’t been able to be sheeted home to statins, which suggests there’s possibly/probably a nocebo effect at play here. But Demasi suggests something more disturbing – that many subjects are eliminated from trials during a run-in period precisely because the drug disagrees with them, and so the trial proper begins only when many people suffering from side-effects are excluded. She also notes, I think effectively, that there is a lot of play with statistics in the advertising of statins (and other drugs of course) – for example a study which found that the risk of having a heart attack on statins was about 2% compared to 3% on placebos was being advertised as proving that your heart-attack risk on statins is reduced by a third. This appears to be dodgy – the absolute percentage difference is very small, and how is risk actually assessed? By the number of actual heart attacks over period x? I don’t know. And how many subjects were in the study? Were there other side-effects? But of course we shouldn’t judge the value of statins by advertising guff.

Another interesting attack on those expressing doubts about the mass prescription of statins has been to call them grossly irresponsible and even murderers. This seems strange to me. Of course doctors should be all about saving lives, but they should first of all be looking at prevention before cure as the best way of saving lives. Exercise (mental and physical) really is a great form of medicine, though of course not a cure-all, and diet comes second after exercise. Why the rush to medicalise? And none of the writers and clinicians supporting statins are willing to mention the financial bonanza accruing to their manufacturers and those who invest in them. Skepticism is the lifeblood of science, and the cheerleaders for statins should be willing to accept that.

Having said that, consider all the life-saving medications and procedures that have preceded statins, from antibiotics to vaccines to all the procedures that have made childbirth vastly safer for women – who cares now about the pharmaceutical and other companies and patentees who’ve made their fortunes from them? They’re surely more deserving of their wealth than the Donnie Trumps of the world.

So, that’s my initial foray into statins, and I’m sure the story has a way to go. In my next post I want to look at how statins work. I’ve read a couple of pieces on the subject, and they’ve made my head hurt, so in order to prevent Alzheimer’s I’m going to try an explanation in my own words – to teach myself. George Bernard Shaw wrote ‘those who can, do, those who can’t teach (it’s in Man and Superman). It’s one of those irritating memes, but I prefer the idea that people teach to learn, and learn to teach. That’s why I love teaching, and learning…

By the way, the quote at the top of this post seems irrelevant, but I keep meaning to begin my posts with quotes (it looks cool), so I’m starting now. To explain the quote – it was from a semi-rant by Ford in his introduction to the controversial dinosaur book Too big to walk (I’ve just started reading it), about writers not getting their work edited, peer reviewed and the like, and being proud or happy about this situation. This, he argues, helps account for all the rubbish on the net. It tickled me. I, of course, have no editor. It’s hard enough getting readers, let alone anyone willing to trawl through my dribblings for faults of fact or expression. Of course, I’m acutely aware of this, being at least as aware of my ignorance as Socrates, so I’ve tried to highlight my dilettantism and my indebtedness to others. I’m only here to learn. So Mr Ford, guilty as charged.

References

Dr Maryanne Demasi – Statin wars: Have we been misled by the evidence?

https://en.wikipedia.org/wiki/Statin

https://cosmosmagazine.com/society/will-statin-day-really-keep-doctor-away

https://en.wikipedia.org/wiki/John_Ioannidis

https://www.smithsonianmag.com/science-nature/what-is-the-nocebo-effect-5451823/

http://www.center4research.org/tamiflu-not-tamiflu/

Written by stewart henderson

September 9, 2019 at 9:44 pm

Always chemical: how to reflect upon naturopathic remedies

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most efficacious in every case

So here’s an interesting story. When I was laid up with a bronchial virus (RSV) a few weeks ago, coughing my lungs up and having difficulty breathing, with a distinct, audible wheeze, I was offered advice, as you do, by a very well-meaning person about a really effective treatment – oregano oil. This person explained that, on two occasions, he’d come down with a bad cough and oregano oil had done the trick perfectly where nothing else worked.

I didn’t try the oregano oil. I followed my doctor’s recommendation and used the symptom-relieving medications described in a previous post, and I’m much better now. What I did do was look up what the science-based medicine site had to say about the treatment (I’d never heard of oregano oil, though I’ve had many other plant-based cures suggested to me, such as echinacea, marshmallow root and slippery elm – well ok I lied, I found the last two on a herbal medicine website).

I highly recommend the science-based medicine website, which has been run by the impressively-credentialed Drs David Gorski and Steve Novella and their collaborators for years now, and which thusly has a vast database of debunked or questionable treatments to explore. It’s the best port of call when you’re offered anecdotal advice about any treatment whatsoever by well-wishers. Not that they’re the only people performing this service to the public. Quackwatch, SkepDoc, and Neurologica are just some of the websites doing great work, but they’re outnumbered vastly by sites spreading misinformation and bogus cures, unfortunately. It’s almost a catch-22 of the internet that you have to be informed enough to use it to get the best information out of it.

As to oregano oil specifically, Scott Gavura at science-based medicine proves a detailed account. I will summarise here, while also providing my own take. Firstly people need to know that when a substance, any substance –  a herb or a plant, an oil extracted therefrom, or a tablet, capsule or mixture,something injectable or applied to the skin, whatever – is suggested as a treatment for a condition, they should consider this simple mantra – always chemical. That’s to say, a treatment will only work because it has the right chemistry to act against the treated condition. In other words you need to know something (or rather a lot) about the chemistry of the treating substance and the chemistry of the condition being treated. It’s no good saying ‘x is great for getting rid of coughs – it got rid of mine,’ because your cough may not have the same chemical cause as mine, and your cough in February 2007 may not have the same chemical cause as your cough in August 2017. My recent cough was caused by a virus (and perhaps I should change the mantra – always biochemical – but still it’s the chemistry of the bug that’s causing the problem), but no questions were asked about the cause before the advice was given. And you’ll notice when you look at naturopathic websites that chemistry is very rarely mentioned. And I’m not talking about toxins.

Gavura gives this five-point test for an effective treatment:

When we contemplate administering a chemical to deliver a medicinal effect, we need to ask the following:

  1. Is it absorbed into the body at all?
  2. Does enough reach the right part of the body to have an effect?
  3. Does it actually work for the condition?
  4. Does it have any hazardous, unwanted effects?
  5. Can it be safely eliminated from the body?

The answer to Q1 is that oregano oil contains a wide variety of chemical compounds, particularly phenolic compounds (71%). It’s these phenolic compounds that are touted as having the principal beneficial effects. However, though we know that there’s some absorption, we don’t have a chemical breakdown. We just don’t know which phenolic compounds are being absorbed or how much.

Q2 – No research on this, or on absorption generally. Topical effects (ie effects on the skin) are more likely to be beneficial than ingested effects, as the oil can maintain high concentration. This would have no effect on a cough.

Q3 – According to one manufacturer the oil has ‘scientifically proven results against almost every virus, bacteria, parasite, and fungi…’ (etc, etc, but shouldn’t that be bacterium and fungus?). In fact, no serious scientific research has ever been conducted on oregano oil and its effectiveness for any condition whatsoever. So the answer to this question is  – no evidence, beyond anecdote.

Q4 – There have been reports of allergic reactions and gastro-intestinal upsets, but the naturopathy industry is more or less completely unregulated so you can never be sure what you’re getting with any bottle of pills or ‘essential oils’. As Gavura points out, the lack of research on possible adverse effects, for this and other ‘natural’ treatments, is of concern for vulnerable consumers, such as pregnant women, young or unborn children, and those with pre-existing conditions.

Q5 – At low doses, there’s surely no concern, but nobody has done any research about dosing up on carvacrol, the most prominent component of oregano oil, which gives the plant its characteristic odour. Other organic components are thymol and cymene.

 

So there’s no solid evidence about oregano oil, or about the mechanism for its supposed efficacy. But what if my well-wisher was correct, and something in the oregano oil cleared up his cough – twice? And did so really really well? Better than several other treatments he tried?

Well, then we might be onto something. Surely a potential billion-dollar gold-mine, considering how debilitating your common-or-garden cough can be. And how, if not cleared up, it can leading to something way more serious.

So how would a person who is sure that oregano oil has fantastic curative properties (because it sure worked for him) go about capitalising on this potential gold-mine? Well, first he would need evidence. His own circle of friends would not be enough – perhaps he could harness social media to see if there were sufficient people willing to testify to oregano oil curing their cough, where other treatments failed. Then , if he had sufficient numbers, he might try to find out the causes of these coughs. Bacterial, viral, something else, cause unknown? It’s likely he wouldn’t make much headway there (most people with common-or-garden coughs don’t go to the doctor or submit to biochemical testing, they just try to ride it out), but no matter, that might just be evidence that the manufacturer was right – it’s effective against a multitude of conditions. And yet, it seems that oregano oil is a well-kept secret, only known to naturopathic companies and health food store owners. Doctors don’t seem to be prescribing it. Why not?

Clearly it’s because Big Pharma doesn’t support the stuff. Doctors are in cahoots with Big Pharma to sell attractive pills with long pharmacological names and precise dosages and complex directions for use. Together they like to own the narrative, and a multi-billion dollar industry is unlikely to be had from an oil you can extract from a backyard plant.

Unless

Our hero’s investment of time and energy has convinced him there’s heaps of money to be made from oregano oil’s miraculous properties, but that same investment has also convinced him that it’s the chemical properties that are key, and that if the correct chemical formula can be isolated, refined and commercialised, not only will he be able to spend the rest of his life in luxury hotels around the globe, but he will have actually saved lives and contributed handsomely to the betterment of society. So he will join Big Pharma rather than trying to beat it. Yes, there would have to be a massive upfront outlay to perform tests, presumably on rats or mice at first, to find out which chemical components or combinations thereof do the best job of curing the animals, who would have to be artificially infected with various bugs affecting the respiratory system, or any other bodily system, since there are claims that the oil, like Lily the Pink’s Medicinal Compound™, is ‘most efficacious in every case’.

But of course it would be difficult for any average bloke like our hero to scratch up the funds to build or hire labs testing and purifying a cure-all chemical extract of oregano oil. Crowdsourcing maybe, considering all the testimonials? Or just find an ambitious and forward-thinking wealthy entrepreneur?

Is that the only problem with the lack of acceptance, by the medical community, of all the much-touted naturopathic cures out there? Lack of funds to go through the painstaking process of getting a purefied product to pass through a system which ends with double-blind, randomised, placebo-controlled human studies with large sample sizes?

Permit me to be sceptical. It’s not as if the chemical components of most herbal remedies are unknown. It’s highly unlikely that pharmacologists, who are in the business of examining the chemistry of substances and their effects for good or ill on the human body, haven’t considered the claimed cornucopia of naturopathic treatments and the possibility of bringing them into the mainstream of science-based medicine to the benefit of all. Yes, it’s possible that they’ve missed something, but it’s also possible, indeed more likely, that people underestimate the capacity of our fabulous immune system, the product of millions of years of evolution, to bring us back to health when we’re struck down by the odd harmful bug. When we’re struck down like this, we either recover or we die, and if we don’t die, we tend to attribute our recovery to any treatment applied. Sometimes we might be right, but it pays to be skeptical and to do research into a treatment, and into what ails us, before making such attributions. And to do so with the help of a good science-based medical practitioner. And remember again that motto: always chemical. 

 

Written by stewart henderson

August 24, 2018 at 10:18 am

a bit more on cell cultures, cell mortality and patients’ rights

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Human connective tissue in culture, 500x. Image courtesy of Dr. Cecil Fox (photographer)/National Cancer Institute.

Canto: Well, we’ve followed up Meredith Wadman’s The vaccine race with Rebecca Skloot’s The immortal life of Henrietta Lacks, which intersects with Wadman’s book in describing cell cultures and their value in modern medicine and genetics. So are ready to talk about all this again?

Jacinta: Yes, this book tells a compelling history of the Lacks family as well as a story of the ethics around human cell cultures, based on the HeLa cell line taken from the cervix of Henrietta Lacks in 1951, shortly before she died of cervical cancer.

Canto: A very aggressive adenocarcinoma of the cervix, to be precise, though the tumour was misdiagnosed at the time.

Jacinta: Yes, her bodily state and her sufferings make for grim reading. And the cells were taken sans permission, in a pioneering era of almost no regulation and a great deal of dubious practice.

Canto: The wild west of cell and tissue culturology.

Jacinta: George Gey, the guy who ordered these cells to be taken, was a great pioneer in cancer and cell culture research, but he and others found it very difficult to keep human cells alive in vitro, so he was much surprised and delighted at his success with Henrietta’s tumour cells.

Canto: They were the first ever cells to live beyond the Hayflick limit, though that limit wasn’t spelt out by Hayflick until 1961.

Jacinta: And wasn’t accepted for decades after that. And the reason for their apparent immortality, a rare thing in untreated cells, was their cancerous nature. Human cancer cells contain an enzyme known as telomerase, which rebuilds the telomeres at the ends of chromosomes. Normally these telomeres, often described as like the protective caps at the ends of shoelaces, shorten and so become less protective with each cell division.

Canto: So if we could stop cancer cells from producing telomerase, you’d stop all that metastasising…

Jacinta: Sounds easy-peasy. And if we could introduce telomerase into non-cancerous cells we could all live forever.

Canto: Bet they haven’t thought of that one. So if this cell line was cancerous, how could they be of so much value? How could they be of any use at all, since the aim, I thought, was to produce ‘clean’ cells, like the WI-38 cells Hayflick produced ten years later? Remember how they had so many problems with monkey cells, which were full of viruses?

Jacinta: Well, forget viruses for the moment, the exciting thing about the HeLa cells was that they stayed alive and multiplied, which was rare, and so they could be experimented on in a variety of ways.

Canto: But did they use the cells for vaccines? The 1954 Salk polio vaccine was tested using these cells. How can you do this with cancerous cells?

Jacinta: Well it was the suitability of these cells for mass-production that made them ideal for test-driving the Salk vaccine, and of course their prolific nature was tied to their cancerous nature – Henrietta’s cancer seemed to be horribly fast-spreading, it was just about everywhere inside her at her death. Her cancer was caused by the human papilloma virus (HPV) and I’ve read that this may have had something to do with their prolific nature. She also had syphillis, likely contracted from her philandering husband, and this suppresses the immune system, allowing the cancer cells to multiply more rapidly. But even though they were cancer cells they shared many of the properties of normal cells, including the production of proteins and susceptibility to bacterial and especially viral infections. Of course you would never inject HeLa cells into humans, but their malignancy is an advantage in that you get the results of say, viral infection of cells as they reproduce, much more quickly than with normal cells, because of their reproductive rate. It seems old George Gey hit the jackpot with them, though he never made any more money out of them than the Lackses did.

Canto: They initially used rhesus monkey cells to test their antibody levels in response to Salk’s killed polio virus, but they were too hard to get and too expensive, and the HeLa cells were an excellent alternative because they were easily infected by the virus… and they reproduced with unprecedented alacrity.

The malignancy of immortality (or vice versa). A HeLa cell splitting into two new cells. The green spots are chromosomes. Courtesy Paul D. Andrews)

Jacinta: Yes, that’s to say, they readily produced antibodies, and so could be experimented on to produce the level of antibodies to create immunity. But growing cell cultures in vitro and maintaining them in a viable state, that’s been a decades-long learning process. Tissue culture these days is big business, which has led to the murky ethical questions about tissue ownership that Skloot refers to at the end of her book.

Canto: Yes but I for one am quite clear about that issue. I’m more than happy for researchers to use any tissue that comes from, say, a biopsy done on me. Is that tissue mine, when it’s removed from my body?

Jacinta: Well, is it? Think of locks of hair kept from a loved one – something that happens a few times in Skloot’s book. Wouldn’t you be moved by a lock of hair that you knew came from someone you loved but who was no longer around? Wouldn’t you feel you had hold of a part of her? Not just a memory of her?

Canto: Interesting. I think I’d be in two minds about it. I’d think, yes, this is her hair, a small part of her, and that would bring all the emotion of identity with it. But then, what I know about science and cells tells me this is just hair, it’s not what makes her her. It’s nowhere near it. Our hair is discarded all the time.

Jacinta: If you had some of her brain cells? Or heart tissue haha?

Canto: Nothing but ultra-ultra minuscule parts of the whole. And essentially meaningless when disconnected from that whole. But this misses the point that the value of this tissue for research outweighs by far, to me at any rate, the sentimental value that you’re talking about.

Jacinta: But for some people, and some cultures, the intactness of the human entity, after death say, is of deep-rooted significance. Are you not prepared to respect that?

Canto: But we slough off our trillions of cells all the time. Even as a kid I was told we replace our cells every seven years. Of course it’s much more varied and complicated than that, but the general point of constant renewal is true.

Jacinta: Yes but they’re your cells, with your DNA in them, nobody else’s.

Canto: Well people are prepared to be operated on, which inevitably kills or removes cells, and in doing so they give themselves up to experts in healing their bodies and often saving their lives, so it would seem to me pretty mean-spirited not to allow those experts to make use of what’s removed, which is of no obvious use to them.

Jacinta: I think you have a good argument there, but what if these mad scientists use your cells for some nefarious purpose?

Canto: Well, call me a trusting soul, but why would they do that? And what nefarious purpose could they use them for?

Jacinta: Well it mightn’t even be nefarious. With the modern commercialisation of cell and gene technology, they might find your tissue perfect for developing something patentable, out of which they make shitloads of money while preventing independent research on the tissue, so using your cells in a way that you might strongly disapprove of. But you wouldn’t have the slightest say, as things stand today. Rebecca Skloot describes examples of this kind in the Afterword to her book. There’s been a raging debate about commercialisation and gene patents and patients’ rights for some time now in the USA, and no doubt elsewhere, with scientists and other stakeholders ranged along the spectrum. In fact, these are the last words of Skloot’s book, published in 2010:

2009: More than 150,000 scientists join the American Civil Liberties Union and breast cancer patients in suing Myriad Genetics over its breast-cancer gene patents. The suit claims that the practice of gene patenting violates patent law and has inhibited scientific research.

Canto: Right. As her investigations reveal, it’s not just about patients wanting a share of the loot from research on their cells, and so using the courts to bog everything down and hinder that research, it’s often about researchers themselves wanting to cash in, and patients joining with other researchers to try to free up the system for the common good. So how’s the Myriad Genetics case going, and how’s the situation regarding patient rights in this field, several years on?References

Jacinta: Well in the case of Myriad, it was all highly complex and litigious, with suits and countersuits, which the company mostly lost, in particular in a landmark (and unanimous) Supreme Court decision of 2013, in which they found that ‘merely isolating genes that are found in nature [in this case the BRCA-1 and BRCA-2 genes] does not make them patentable’. But of course this wasn’t so much about patients’ rights in the material that was once part of their bodies. It’s not all about money – though much of it is, and if you don’t want the money landing in lawyers’ pockets, the best thing is to have clear guidelines, disclosure, and fully developed and complex consent procedures. My impression from doing a fairly shallow dive on the issues is that we’re a long way from sorting this out, in an increasingly complex and lucrative field. Our own federal government’s NHMRC has a booklet out, available on PDF, called ‘Ethics and the exchange and commercialisation of products derived from human tissue: background and issues’, which is already six years old, but I don’t see anything in the legislative pipeline.

Canto: Looks like an issue to be followed up, if we have the stomach for it.

Jacinta: It pays to be informed, that’s one obvious take-away from all this.

References
Rebecca Skloot, The immortal life of Henrietta Lacks, 2010
Meredith Wadman, The vaccine race, 2017

Written by stewart henderson

July 3, 2017 at 12:22 pm

some more stuff we’ve learned about vaccines

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Vaccinology, I would say that it’s not rocket science. It’s a lot harder than rocket science.

Alan Schmaljohn, virologist, 2014

 

Canto: So, reading The Vaccine Race, by Meredith Wadman – maybe we should just do book reviews? – I find myself getting excited, or confused, by a passage, and wanting to do more research, and then forgetting about it…

Jacinta: It’s probably pretty normal to forget 95% of what you read within a week or so of having read it. You just hope the things you retain are the principal things.

Canto: Yeah well, I was probably hoping the book would help me get my head around how vaccines work, as well as providing juicy and inspiring tales of heroism and malpractice in the history of vaccine development, and it has helped, but I think I’d need to read half a dozen such books and watch a dozen videos before it penetrated my thick skull…

Jacinta: Yes, for example, when I found myself reading, well into the book, about Leonard Hayflick’s human diploid cells, taken from the lungs of an aborted foetus, which were used to provide a sort of base for creating vaccines against all sorts of diseases, most notably rubella, I thought ‘obviously the author has explained human diploid cells, probably in great detail, before, but I can’t recall a whit’…

Canto: That’s what comes of reading too many books at once, and spreading your focus. You know it’s a myth that women can multi-task better than men, but the major finding of research is that multi-tasking is bad for everyone. Let’s resolve to read books one at a time, from start to finish.

Jacinta: Resolved. Anyway, diploid cells are just standard human cells, with 23 pairs of chromosomes. The only other human cells are haploid sperm and eggs, with 23 unpaired chromosomes. Hayflick’s cell line, gathered in the fifties, was ‘cleaner’ than the cells previously used from other animals, such as monkey kidney cells, which contained many viruses. I used the index.

Canto: So these cells were taken from the lungs of a foetus, and Hayflick was able to produce a cell line from them, that’s to say a line of almost endlessly reproducing cells, I’m not sure how that worked, but these cells, which had to be free of every virus or pathogen, would then be somehow injected with, say, the rubella virus, in some sort of reduced form, so as to produce antibodies in those who are vaccinated. The trick with vaccinology, it seems, is to produce a safe vaccine with no side effects, or minimal side effects, but with enough potency to produce a reaction, thus producing antibodies to the antigens in the vaccine. The vaccine must contain antigens, must have some potency, otherwise it’s useless. And every immune system is subtly different, so producing a one-size-fits-all vaccine is in many respects a monumental undertaking. I may have this completely wrong by the way.

Jacinta: Probably only partially wrong, let’s not be absolutists. What about this difference between killed vaccines and live vaccines. Can we talk about that?

Canto: Well first I want to understand how a ‘cell line’ is produced. How were Hayflick’s famous WI-38 (human diploid) cells produced in a constant stream from the lungs of a single legally aborted foetus in 1962?

Jacinta: Let me try to summarise Wadman’s description of the process from this online article. The tiny lungs were minced up and then placed in a container with a mix of enzymes that separated them into individual cells. These cells were separated again into small glass bottles, and a ‘nutrient broth’ was added, causing the cells to divide. thus began the most thoroughly described, studied and utilised human cell line to date, from which was created vaccines for rubella, rabies, adenovirus, measles, polio, chicken pox and shingles.

Canto: A nutrient both? You mean ‘at this point a miracle happens’?

Jacinta: Well, this was a well-established miracle, only previously it was done with non-human cells, and still is. Monkey and canine kidney cells, chicken embryo fibroblasts, hamster ovary cells… Of course using human cells was bound to be controversial.

Canto: So – obviously the cells in these tiny lungs would’ve gone on dividing had the foetus survived, so microbiologists had worked out a way, of making this happen – mitosis, isn’t it? – outside the host. How long have they been able to do this?

Jacinta: Well the first vaccine was created by Edward Jenner in the late eighteenth century, but they weren’t actually culturing cells then. Cell culture is a broad term meaning a process of growing cells – obviously by cell division – outside of their natural environment, usually in a lab. A cell line (e.g. Hayflick’s WI-38 cells) is ‘a population of cells descended from a single cell and containing the same genetic makeup’, to quote Wikipedia. Cell culture started with the maintenance of cell tissue independent of the host animal in the late nineteenth century, but techniques advanced rapidly in the 1940s and 50s to support virology and the manufacture of vaccines. A key event was the growing of poliovirus in monkey kidney cells in 1949, for which John Enders, Tom Weller and Fred Robbins won the Nobel Prize. Their methods were used by Jonas Salk and others to produce the first polio vaccine.

Canto: But the problem with using monkey kidney cells was that they potentially carried their own viruses, right? Which may or may not be harmful to humans, and how would they know? Without using human guinea pigs?

Jacinta: Human subjects, yes. And there’s also the question of the potency of the virus being used, presumably to stimulate the production of antibodies. Is it just a question of stimulating enough antibodies? And isn’t there an obvious danger of infecting subjects with the virus itself? Presumably a killed virus solves that problem, but is it really effective?

Canto: Yes, Wadman’s book has been fascinating on the politics of the vaccine race, but I’m still left much confused – probably due to stupidity or inattentiveness – as to how some vaccines work better than others, and how a cell line – I know it’s essentially about exponential growth – can produce enough material for millions of vaccine doses.

Jacinta: Yes it’s about exponential growth, and it was once thought that, given the right conditions, these cells could go on multiplying ad infinitum, to immortality so to speak, but it was Hayflick who showed this not to be true in a much-cited paper. Even so, the number of replications of individual cells assured a sufficient supply of cells for generations. And since then, much more has been discovered about cell ageing and its causes, what with telomeres and telomerase, but that’s another story. As to why vaccines developed from the WI-38 cells have been so much less problematic than others, it clearly has much to do with their being ‘clean’ human foetal cells, with no other lurgies lurking.

Canto: So let me get this clear. The WI-38 cells are provided to different labs that are wanting to create a vaccine for, say, measles. Or that have already created a vaccine, or at least have isolated the virus – but then of course viruses can’t be isolated, they need cells to survive in. So they get the WI-38 cells, and then they inject them with the virus – killed or attenuated – and then they start trialling it on rats or mice or something, trying out different strengths of the virus, without really having much idea whether the dose will translate to humans, so they must find some willing volunteers (or, in the early days, orphaned or intellectually disabled kids) to experiment on, making sure they err on the conservative side initially, then upping the dosage? I’m no doubt simplifying and speculating wildly here.

Jacinta: yes and I’m no wiser  than you, but it’s a good thing we have people taking these risks, and working so hard in this field –  with clearer ethical guidelines than before – because millions of lives have been saved by vaccines, and so much has been learned about our immune system in the process of developing them.

 

Wadman, Meredith. The Vaccine Race. Doubleday 2017.

https://www.historyofvaccines.org/content/articles/human-cell-strains-vaccine-development

http://www.nature.com/news/medical-research-cell-division-1.13273

https://www.ncbi.nlm.nih.gov/pubmed/25903999

https://en.wikipedia.org/wiki/Cell_culture

Written by stewart henderson

June 11, 2017 at 7:39 pm

Traditional Chinese medicine? You must be joking

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bear bile, a TCM that tortures and kills bears and prevents humans from receiving effective treatments - just one of the horrors of TCM

bear bile, a TCM that tortures and kills bears and prevents humans from receiving effective treatments – just one of the horrors of TCM

If we don’t know what’s in them, it’s very difficult to predict the interactions, … that’s obviously of great concern if they are been given to children, or pregnant women, the potential outcomes there are very serious.

Murdoch University biochemist Dr Garth Maker

There’s nothing particularly positive to say about naturopathic treatments generally – some of which (homeopathy, reflexology, iridology, acupuncture and cupping, to name a few) are not so much ‘natural’, whatever that means, as examples of comprehensively failed hypotheses (hardly worthy of the name). But so-called traditional Chinese medicine is on the lowest rung, considering how much damage it has done, not only to humans but to other species that have been horribly exploited in its name. The latest damning finding about what is actually contained in many of these unregulated pills will probably barely create a ripple amongst the anti-science crowd, but nevertheless it needs to get as much publicity as possible. You never know, maybe someone, somewhere will take notice (and we’re fighting a real battle here, because if you go online to find out about TCM, you’ll find the whole internet disturbingly skewed towards the positive). Please, if only for the sake of the children exposed to this crap by ignorant parents, let’s do something about this. It’s an effing outrage.

Written by stewart henderson

December 13, 2015 at 11:36 pm

introducing canto and jacinta: solutions for the post-antibiotic era?

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Florence Nightingale

Florence Nightingale

Jacinta: Well hello Canto, let’s welcome each other to the Urbane Society of Skeptical Romantics, where we like to talk… and not much else.

Canto: Very productive and constructive talk Jacinta, but the proof will be in the pudding.

Jacinta: Well I hope it’s not a recipe for disaster. What shall we talk about today?

Canto: Well I’m thinking medicine today – the discipline, not the stuff you consume.

Jacinta: Well I don’t consume much medicine at the worst of times, being fit, positive, eternally youthful and beautiful.

Canto: That’s okay, I’ll take your share – so you know there’s a bit of a crisis with antibiotic resistance.

Jacinta: Yes, natural selection in action, or is that human-induced, unintended-consequence-style artificial selection?

Canto: Well I’m not intending to delve into the natural v artificial quagmire here, or even into the science of antibiotics. I’ve just been reading about a couple of alternative ways – one old and one new – of killing off nasty infecting bacteria in hospitals. Ever caught one of those secondary infections in hospital Jass? No of course you haven’t.

Jacinta: Last time I was in hospital I was the infection – had to be forcibly removed from the victim by a crack team of medicos and placed in isolation until deemed safe to take my chances at thriving and multiplying along with my fellow bugs.

Canto: Well I’m sure they made the right decision.

Jacinta: The jury’s still out. Tell me of the ways.

Canto: Remember Florence Nightingale?

Jacinta: One of my heroes, apart from her valetudinarianism. Though I suspect that might just have been her way of keeping everyone at a distance so she could get on with things in her way. She was a voluminous correspondent just like Darwin, another sufferer from mysterious ailments. So what about her?

Canto: She revolutionised nursing and hospital treatment, sanitation and such, right? One of her many insights was that patients convalescing from the Crimean battlefields benefitted enormously from throwing open the windows of the rather unhygienic field hospitals set up for them. Nightingale wards were built to her design, with high sash windows kept open to renew the air around the sick. This worked a treat, though it took more than a century to verify the effect experimentally, using E coli in an open rooftop environment. The bugs died within 2 hours in the open air, but in an enclosed environment they lived on.

Jacinta: Right, so this has obvious relevance to those horrible superbugs they talk about…

Canto: Like MRSA?

Jacinta: Yeah. What’s that?

Canto: Multi-resistant, or more accurately methicillin-resistant staphylococcus aureus.

Jacinta: Yeah, golden staph, just as I thought. So that’s interesting. I don’t see modern hospitals blowing in the wind really. Sounds far too hippy for the 21st century. Isn’t it all tightly controlled and air-conditioned these days? Recycled air and legionnaire’s disease? Okay, only kidding, I’ve not heard of any hospital outbreaks of that, but these hospital superbugs must surely be caused by a contaminated environment, yes? Should we bring back Nightingale wards? And why did they go out of fashion?

Canto: Well, not only did she get fresh air right, she had the windows faced to let in as much sunlight as possible, and it was only learned later that sunshine was a great germ-killer, especially in the case of tuberculosis, which ravaged all the crowded cities…

Jacinta: Yeah and picked off all those writers, like Chekhov, and the Brontës, and D H Lawrence, and Keats. Didn’t he write an ode to Florence Nightingale?

Canto: No no that was another nightingale, but at its height TB was killing one in five in the cities; but it’s probable that the sunlight was boosting levels of vitamin D, which in turn boosts the immune system. So by the turn of the century, fresh air and sunlight was all the go. TB patients were wheeled onto balconies, to be exposed to the bracing elements.

Jacinta: Ah, but of course all that changed with the discovery of antibiotics.

Canto: Right, and thanks to these miracles of modern medicine, rotten air and dark dankness came back into fashion, sort of. I mean, all sorts of infections were being vanquished by these pills and it seemed as if diseases would fall like ninepins.

Jacinta: I suspect you’re oversimplifying..

Canto: Well it must’ve seemed that way to the general public. And of course fresh air could turn into howling winds, and sunlight into clouds and rain. Controlled temperatures and conditions might’ve seemed safer, and the cleansing power of aircons was over-estimated.

Jacinta: Oh yes… Climat air-conditioning, Breezair, Bonaire – more than an air-conditioner, a tonic to the system.

Canto: But now of course the diseases are returning in resistant forms, and we’ve hit a wall in terms of antibiotic manufacture. There’s very little new stuff coming on-stream. And now, hospitals are being seen as a problem again, just as in Ms Nightingale’s day.

Jacinta: Yes, but there are new post-antibiotic treatments in the pipeline, such as phage therapies, in which bacteria are destroyed by genetically engineered viruses, and drugs that…

Canto: Okay Jass, that’s for another conversation, and these new treatments are a bit futuristic as yet. Meanwhile, we need to heed Ms Nightingale’s hygienic advice. Apparently, the recent emphasis on simple hand washing has been paying huge dividends, in reducing the incidence of MRSA and Clostridium difficile.

Jacinta: So we were getting complacent, forgetting the basics?

Canto: Well, we’d been lulled by the success of modern medicine into thinking the old precautions needn’t apply. And further studies have confirmed the cleansing power of even the mildest breezes, and hospitals have begun to open up in response.

Jacinta: But not only that, we now know more about good old-fashioned sunlight and its curative powers, don’t we?

Canto: Okay, the stage is yours.

Jacinta: Well, there was some breakthrough research done using standard UV lamps in a TB ward. Guinea pigs were used (I mean real guinea pigs), and their signs of infection were drastically reduced. Now, there are some regions of the world with high rates of TB, and of HIV, which of course weakens their immune system and makes them susceptible…

Canto: I thought TB was just about eradicated.

Jacinta: Well it’s now resurgent in some parts, so we’re back to looking at other modes of prevention. So UV lighting is proving very effective, but not applied directly, because direct exposure is quite dangerous – think of tanning beds and the like. But what is interesting is that they’ve experimented with different UV wavelengths – ultraviolet light covers the spectrum from 10 to 400 nanometres – and found a sweet spot at 207 nm. At that wavelength the UV light is absorbed by proteins and penetrates a little way into human cells but doesn’t reach any DNA to effect mutations. But it does affect bacteria, drastically. They absorb the light and die.

Canto: Very clever.

 

Jacinta: Quite. This sweet spot technology was first used in operating theatres, to kill airborne bacteria that could immediately settle in open incisions and the like. There’s a suggestion now that UV lamps at that wavelength should be deployed in all hospitals.

Canto: So that’s one solution, but getting back to fresh air, has anyone found a solution that eliminates the drawbacks? I mean, knocking equipment around, bringing in pollution and pathogens from outside, not to mention patients falling out of windows?

Jacinta: Well, some of those risks could easily be minimised, but there are more technological fixes. The production of hydroxyl radicals has been shown to kill bacteria…

Canto: Hydroxyl radicals? WTF?

Jacinta: Molecules with a short lifespan, produced in the atmosphere when ozone, the unstable allotrope of oxygen, reacts with water. This reaction is catalysed by organic molecules in the air, and a while back a company managed to build machines that produce these hydroxyls, for use in hospitals. They were quite effective, but the company went bust. So we’re back to good ventilation and getting patients out on balconies. And perhaps locating hospitals out of the way of cities.

Canto: Okay, so back to the future.

Jacinta: Or forward to the past.

Canto: Well thanks for this charming discussion and we look forward to many more.

Here’s an interesting commercial video about how a hydroxyl generator works
https://www.youtube.com/watch?v=a_V9HbBVM6Q
hat-tip to: Frank Swain, ‘A breath of fresh air’ in New Scientist Collection: Medical Frontiers.

Written by stewart henderson

August 9, 2015 at 9:02 am