Archive for the ‘pandemic’ Category
covid19 – the European CDC shows the way
poverty and crowding in Peru – BBC picture
Canto: The US response to the pandemic continues to be massively hampered by political muzzling of and interference with the science, especially at the federal level, but the Medcram updates continue to inform us, and to be, or pretend to be, indifferent to this political interference.
Jacinta: Yes, and update 109 has introduced us to the European CDC’s website, which provides us with a wealth of information, on the progress of the pandemic itself in European countries, but also in the political response to it, and how those two things interact.
Canto: The country overview page, and it’s currently updated to week 39 of the pandemic, is as data-rich as anyone can imagine, a statistician’s wet dream, but interpretation of the data needs to be handled carefully.
Jacinta: Dr Seheult does some interpretation of some of the data in his medcram update 109, but there’s so much more in there, and so much more to say. So let’s take a European country at random – Denmark – and look closely at the stats.
Canto: But before that, let’s look at some general European trends they report. It’s fascinating:
By the end of week 39 (27 September 2020), the 14-day case notification rate for the EU/EEA and the UK, based on data collected by ECDC from official national sources, was 113.6 (country range: 9.9–319.9) per 100 000 population. The rate has been increasing for 70 days.
So the EU is the European Union and the EEA is the European Economic Area. I’m not sure what is meant by ’14-day’ but I presume the case notification rate is simply the case rate, as far as they can ascertain from the data supplied to them – the cases they’ve been notified about. It’s good that they make that distinction, shifting the onus on the notifiers. So it’s 113.6 cases per 100,000 population over the whole region, and has been rising for over two months – a second wave.
Jacinta: I think ’14 day’ just means the rate over the previous 14 days. They report every seven days for the previous 14 days, so there’s a 7-day overlap. That data is not only dependent on the reliability of particular reporting countries, it’s also dependent on testing levels, obviously. So in the general trends they tell us which countries are doing the most testing. Highest is Denmark, followed by Luxembourg, Iceland, Malta and Cyprus. Small countries, unsurprisingly.
Canto: With all this, it’s interesting from Dr Seheult’s analysis of the data that the death rate isn’t mapping with the case rate, thankfully, and that the age of people contracting the virus in the second wave is much lower, which seems weird.
Jacinta: Probably explained by an increase in testing since the early days. Now they’re catching milder and asymptomatic cases. It suggests, of course, that the case rate was much higher during the first wave, when the testing regime was still being put together. So let’s look at Denmark, and now we have data for week 40. There are four graphs, and in the first we see the case notification rate experiencing a big bump peaking in April with the death notification rate mapping pretty closely with that bump. Then there’s a gradual falling away in both figures, until August when the case rate starts to rise again, but not the death rate. Then in September that case rate rises very sharply, rising well above the April bump, though in the last week it seems to have leveled off at this high level. But the death rate has stayed pretty well level and quite low. Now that raises questions that the other graphs might help to answer. The second graph looks at the testing rate – tests per 100,000. The testing rate was pretty flat and low from February into April, but after the April rise in cases the testing began to rise from late April into May. It flattened and even dipped a bit into June. It stayed fairly steady through the northern winter, but of course at a high level compared to the earliest period, then it started to rise in August, presumably in anticipation of a rise in cases as the colder weather arrived. That rise in testing peaked at a very high level in late September, but has dropped quite sharply in the the last week or so.
Canto: Interesting, so that does strongly suggest a sharp rise in mild cases being ‘caught’, and presumably dealt with, as the death rate hasn’t spiked at all.
Jacinta: Yes, though we don’t know how well those cases have been dealt with – people are talking about ‘long covid’, people possibly having long-term issues. The two graphs don’t really give us granular detail – hospitalisation rates for example. So the third graph breaks the notified case numbers into age groups, and the results are fascinating. The first wave bump shows that most of the cases recorded were in the older age groups, particular those at 80 or over. There were cases in all age groups, but very few under 15. However, in the second wave, the cases found were predominantly in the young. In fact the 15-24 age group was way out in front, followed by the 25-49 group. Even the under 15s were well above the oldest age groups. So what does this mean? It seems to suggest that the older, and perhaps wiser, are recognising the dangers, especially to their age group, and taking fewer risks, and that the younger are still not very sick but can be carriers of the virus and more than ever a danger to the older generation.
Canto: I wonder is Denmark ‘typical’ in this regard?
Jacinta: There are variations of course, but the general trend is much the same. The fourth graph shows test positivity – the percentage of people who tested positive. There was a massive spike in positive test results in March, up to around 16 -17%, but this dropped as sharply at it rose, due presumably to the rapid rise in testing from that period. By May it was around 1% and it has remained much the same since, as the number of tests administered has never been higher, in spite of the recent drop I mentioned. It’s still much higher than it was pre-September.
Canto: But there are more than four graphs as we’ve found. We’ve looked at the data for notification rates and testing, there are other graphs which look at ICU and hospitalisation rates, public health response measures, and which break the nation down into specific regions.
Jacinta: Yes, it’s particularly important to look at public health measures – restrictions on mass gatherings, closures or partial closures of public spaces, workplaces and schools, the mandating or recommendations around face masks, and map them against notification rates, hospitalisations and so forth. The picture that emerges is generally pretty clear, though sadly some countries, such as the USA and Brazil, aren’t paying heed to the fact that public health measures save lives as well as a lot of suffering.
Canto: Well we should be talking about the governments rather than the countries, when we’re talking about public health measures. So I’ve assumed that the CDC in the USA has been hobbled by the Trump debacle, so I’ve gone to the Johns Hopkins site to see what detailed info they provide. Indeed they do have a lot of useful data both for the USA and other countries, though little on the effect of public health measures. An interesting graph they present on mortality shows that, in terms of deaths per 100,000 persons – and they show only the top 20 nations – Peru is on top, followed by Brazil, Ecuador, Spain, Mexico, the USA and the UK, in that order.
Jacinta: Well we know about the macho governments of Brazil, the UK and the USA – not that government is always entirely to blame, but it’s a key indicator – so what about the national governments of those other countries?
Canto: Well other key indicators would be the country’s wealth, or lack thereof, and its healthcare infrastructure, but as to government, Peru had a federal election in January this year – it’s a multi-multi-multi-party system with the most popular party getting only 10% of the vote. The result was that Martin Vizcarra retained the presidency. He appears to be a genuine reformist who has tried to implement stay-at-home orders, but widespread poverty and overcrowding are major problems there. Brazil we already know about. Ecuador’s current President is Lenin Moreno, a right-wing figure who has slashed government funding and seems obsessed with destroying political opponents. He has a popularity rating of 8%, according to an article in Open Democracy, and his mishandling of the pandemic has been extreme. Spain is a ‘parliamentary monarchy’, and its current Prime Minister is Pedro Sanchez, leader of a leftist coalition. Currently there’s a battle with right-wing local authorities, especially in Madrid, to enforce lockdowns as a second wave hits the country. So it’s the usual problem there of non-compliance, it seems. And Mexico is, as is I think well known, a country with a lot of poverty and a lot of problems. Its governmental system has long been a minefield – in fact I’d love to learn more about its chequered history. Currently the President is Andrés Manuel López Obrador, a veteran politician who has been a member of various parties and is essentially a political centrist. So again it’s about lack of political control, poverty, lack of services, overcrowding and so forth. As to the UK, years of conservative government have gutted the NIH, there has been a ton of mixed messaging from the top… I’m getting sick of all this. I want to go to Taiwan.
Jacinta: Hmm. How’s your Chinese? Things are pretty covid-safe here in South Australia. Here’s hoping a safe and effective vaccine is ready by next year, and some big improvements are made in certain countries, with a return to justice and human decency…
References
Coronavirus Pandemic Update 109: New Data From Europe As COVID 19 Infections Rise
https://www.ecdc.europa.eu/en/covid-19/country-overviews
https://coronavirus.jhu.edu/us-map
https://www.bbc.com/news/world-latin-america-53150808
https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(20)31955-3/fulltext
stuff on covid19 and immunology
Canto: Well it’s a great time to be living in quiet South Australia, with a global pandemic raging in many places elsewhere..
Jacinta: Particularly the US, which we’ve long been focussing on, maybe in a schadenfreude kind of way.
Canto: Yes or maybe in a lazy way, because we’re so inundated by American media, social media, cable news, the NYT, the WaPo, the Atlantic, Politico, the Medcram lecture series, it just seems easier to plug into US info these days. Which makes me wonder…
Jacinta: And all hell’s breaking loose with Trump having come down with covid19 and the misinformation machine starting to overheat. Currently – October 5 – according to the Worldometer figures, which we’ve been using since the start of the pandemic – the USA has suffered 214,611 deaths, more than a fifth of the world’s deaths by that database’s figures.
Canto: Yes, we’ve noticed that the US media always has figures a little below ours – I presume because they’re using the Johns Hopkins figures, which seem to have a time lag. We can’t say which is more reliable of course. Complete reliability for all sources is unlikely.
Jacinta: In any case the USA has spectacularly failed to get on top of this virus, and is still experiencing high case-rates and death-rates, though the variations between states are constantly changing, and tell their own complex story. Overall, though, unless something drastic happens, the US is on track to have suffered 250,000 to 300,000 deaths by the end of the year – and I haven’t accounted for the winter season.
Canto: Yes and that’s no outlier prediction, that’s just a very simple forward projection.
Jacinta: I’m half-wondering when the Trump administration will try to throw cold water – or bleach perhaps – at the covid figures, as they’ve tried to misinform with everything else to do with the virus, including Trump’s condition and the timeline of his infection. But I want to look at what we’re hearing from the Walter Reed medicos about his treatment, and more generally about immunology and the virus’ progress. From the figures, it doesn’t seem as if anything is working very effectively, but Trump will be getting treatment that isn’t widely available to anyone else in that country, and we’re getting no clear answers as to how he’s faring.
Canto: The treatment everyone’s reporting on currently is the ‘antibody cocktail’ produced by the drug company Regeneron. This was made available through an emergency use authorisation, and unsurprisingly there’s now demand pressure on the product. He’s also on the antiviral remdesivir, and the steroid dexamethasone, and it seems he’s been given oxygen, though medical and other experts have had to read between the lines of public announcements to work out what exactly is going on.
Jacinta: Yes, many experts suspect he’s been sicker than he’s been prepared to admit, and of course the Democrats and health officials are all wishing him well and ‘praying for him’ in their American way. Frankly, I hope he dies, for the simple reason that his death will likely save thousands of lives, as it will stem the flow of misinformation, and scare even his dumbest followers into wearing masks, physically distancing and generally starting to act sensibly and humanely. It will have been the best thing he’s ever done with his life. But enough controversy, let’s look at immunology and treatment. According to the NYT, Trump has also been taking Vitamin D, zinc, the hormone melatonin, and famotidine, an anti-heartburn medication.
Canto: So he’s fit as a fiddle, then?
Jacinta: Hmm. As we know, Dr Seheult on Medcram has spoken of the benefits of zinc and vitamin D, as well as remdesivir and dexamethasone, but none of these treatments have been subjected to rigorous clinical trials in relation to SARS-CoV2 as yet. It’s my guess that Trump himself is pushing the envelope to be treated with these drugs, though it could also be that he’s actually quite sick, as I’ve said. And unless he actually dies, it could be that we’ll never know.
Canto: He won’t die. Anyway, what about Regeneron, and these monoclonal antibodies?
Jacinta: Well we’ve talked about them before, but they’ve been mostly used in the past against cancer cells. In fact they’re finding uses in many medical fields but they’re tricky to manufacture, and would be expensive to roll out…
Canto: Actually I’ve heard some reports that it’s polyclonal antibodies they’re giving him. Is there a difference? I thought maybe because they were giving him a ‘cocktail’ of monoclonal antibodies, this amounted to polyclonal…?
Jacinta: Well, who knows what they’re actually giving him, but according to my reading, researchers have engineered (cloned) immune cells that produce specific antibodies – antibodies to a specific antigen, or more accurately, to the epitope, or binding site, of that antigen. That’s monoclonal antibodies. Polyclonal antibodies can bind to multiple epitopes, which sounds better but maybe they’re harder to manufacture in an effective form.
Canto: So these monoclonal or polyclonal antibodies are proteins, synthesised versions of proteins produced by the immune system. Is it that, due to the virus, the body is prevented from producing these antibody proteins naturally, or can’t produce enough of them, or what?
Jacinta: What I gather is that the response to the virus varies – some are producing antibodies, some aren’t. A report came out last week about Regeneron’s treatment, this ‘cocktail of two monoclonal antibodies’:
The company showed slides with detailed data from 275 infected people in a placebo-controlled trial that ultimately plans to enrol 2100 individuals who are asymptomatic or, at worst, moderately ill. The analysis divides patients into two groups: those who had detectable antibodies against SARS-CoV-2 at the trial’s start and those who did not, a so-called seronegative group. The monoclonal cocktail showed little effect on people who already had antibodies against the virus. But it appeared to help the seronegative patients, powerfully reducing the amount of virus found in nasopharyngeal swabs and alleviating symptoms more quickly.
So it appears to boost the immune system of those who haven’t, or haven’t yet produced antibodies to the virus. So, useful for those in the earliest phase of having contracted covid19. But all of this has to be more thoroughly tested – for example, would the treatment work as a general preventive?
Canto: There’s another company, Eli Lilly, which has been trialling a single monoclonal antibody treatment, with slightly different results – both companies have given low-dose and high-dose treatments, and Regeneron found no statistically significant difference, whereas Lilly found the high dose ineffective – which is good news as the lower dose will presumably be cheaper to manufacture, with fewer adverse effects, if any. The two companies have a slightly different approach to using their medications – though this might change in such a fluid situation. Regeneron is thinking of developing diagnostic tools to identify those most in need of the treatment, e.g those with the highest viral load, and those with low antibody levels (serology). Lily, on the other hand, are thinking that any covid19-positive people at higher risk – diabetics, overweight, or simply elderly – should be given the treatment, if possible.
Jacinta: In the meantime, the dangers of this virus are constantly being underplayed by this administration under pressure, clearly, from the Boy-King, while a large cluster of people who’ve had contact with him, either at the White House or on any of his jaunts around the country. Exactly who set off the cluster will probably never be known, because it sounds like they’re refusing, again under the orders of a clearly incompetent wee boy, to engage in contact tracing!
Canto: It’s a SNAFU to be sure. Apparently one of this number – 34 at last count – is gravely ill in hospital. It’s like we’re watching an episode of ‘Horrible Histories’ in real time. It’s good to see that the polls are predicting a landslide. That means if the actual numbers come in and it’s close, it may be to do with the dirty business Trump and the Republican ‘leadership’ appear to be trying on vis-à-vis voter suppression. And then all hell will break loose.
Jacinta: Hell will break loose no matter what happens. This next month or two will be a cracker for us non-Americans. We’re certainly living in interesting times. But seriously, my condolences to the American people.
References
https://www.sciencemag.org/news/2020/09/provocative-results-boost-hopes-antibody-treatment-covid-19
https://www.worldometers.info/coronavirus/country/us/
Coronavirus Pandemic Update 97: Vitamin D & COVID-19 Immunity, The Endothelium, & Deficiencies
Coronavirus Pandemic Update 77: Remdesivir Update; COVID-19 in Mexico
Coronavirus Pandemic Update 88: Dexamethasone History & Mortality Benefit Data Released from UK
covid19: monoclonal antibodies, symptomatic v asymptomatic, corticosteroids, comorbidities
covid-19 stuff: NAC, glutathione, RT-PCR testing, re-positives
So, more struggles with biochemistry. Update 70 talks again about N-acetylcysteine (NAC), but goes on to talk about glutathione, and whether glutathione itself might be a type of medication. So let’s get clear, or try to.
Glutathione is a naturally occurring and abundant thiol polypeptide in animal cells. A thiol has an SH (sulfanyl) group attached to a hydrocarbon chain, essentially. As we know, it’s an antioxidant which can be reduced by NAC, and they have structural relations. As Dr Seheult describes glutathione, it’s a combination of three amino acids, with cysteine at the centre. The other two are glycine and glutamate, and the cysteine and the glycine together effectively make up N-acetylcysteine – so NAC is described as a by-product or precursor of glutathione. A case report (regarded as the weakest level of scientific evidence) describes efficacious treatment of two patients with Covid-19-type symptoms using IV and oral glutathione. This and other studies and analyses seem to be begging for full-scale clinical trials to be carried out, but nothing as of mid-May. The treatments could be effective for hypoxemia in particular, due to the action on the disulphide bonds in VWF which are leading to platelet-rich thrombosis.
In his update 71 Seheult broaches the controversial topic of hydroxychloroquine, along with azithromycin and zinc. He suggests there’s evidence that hydroxychloroquine can act as a ‘zinc ionophore’, inducing zinc uptake into cells. Zinc inhibits the RNA-dependent RNA polymerase which SARS-CoV-2 utilises to reproduce. There has been a retrospective study suggesting that treatment with this combination may ‘result in a statistically significant reduction of mortality’, though maybe this hasn’t borne more careful analysis considering the cold water being poured on chloroquine as a treatment in recent months. It may be because it just doesn’t raise zinc levels sufficiently. The findings of the study do suggest the treatment has a statistically significant effect on reducing symptoms in hospitalised patients who are not in ICU – that is, they have relatively mild symptoms. No significant effect for ICU patients.
I should add here that now in August health authorities are warning against any unprescribed use of hydroxychloroquine as a prophylactic due to ineffectiveness and side-effects.
Update 72 began by looking at the sensitivity and specificity of antibody tests available, presumably in the USA. A study examined ‘four new commercially available serological assays [i.e blood serum tests]’, from three German and one US company, and it was found that they all ‘have a sufficient sensitivity and specificity for identifying individuals with past SARS-CoV2 infection’. Of course, the principal issue with the testing is the time it takes to receive results, but maybe that’ll be addressed anon.
Apparently (news to me in very safe – so far – South Australia where hardly anyone I know has had to be tested) there’s a difference between sensitivity and specificity, illustrated by the ‘spin’ and ‘snout’ mnemonic. For a highly specific test if you test positive you’re very sure to be in trouble, and for a highly sensitive test if you test negative you’re sure to be out of danger.
Dr Seheult next describes a retrospective study which looks at glycosylated haemoglobin (HbA1c) as a Covid-19 risk factor. A person’s HbA1c levels (how much glucose is attached to their haemoglobin) are a measure of diabetes. A1c (blood sugar level) is measured in percentages, with 5-6% being normal. The study found that ‘high HbA1c levels is associated with inflammation, hypercoagulability and low SaO2 [oxygen saturation] in Covid-19 patients, and the mortality rate (27.7%) is higher in patients with diabetes’. So HbA1c levels need to be looked at as a priority.
The update next looks at dentistry during the pandemic, for which there’s been little guidance, at least from the CDC. Apparently, during the AIDS crisis, dentists were viewed as modes of transmission, partly due to a NYT article on the subject. In any case, fewer people are now seeing their dentists for obvious reasons, which could lead to an oral health crisis. A number of diseases, including coronary disease, are linked to periodontal problems, so this can exacerbate the pandemic – and dental health, in Australia as in the USA, is not treated with the same gravitas as other forms of health.
Update 73 starts with a look at testing, particularly the reverse transcriptase polymerase chain reaction (RT-PCR) test. So the coronavirus has these spike proteins protruding from a bilipid membrane, with the RNA wrapped inside bound together by disulphide bonds and the like, I think. The protein shell around the virus is called the nucleocapsid. Of course the RNA’s code is specific to SARS-CoV2, so a test needs to look at a segment of the viral RNA and identify it with sufficient – essentially total – specificity. RNA is made up of the four base pairs adenine (A), uracil (U), guanine (G) and cytosine (C), with A pairing always with U and G with C. With that I’m going to switch to Scientific American for more detail.
A test starts with a sterile swab from the back of the nasal passage, aka a sample. Sample collection needs to be done properly, or it could lead to a false-negative result. If there’s viral RNA present, it’s extracted and used to produce a complementary strand of DNA – that’s where the reverse transcriptase enzyme comes in, reversing the usual transcription process from DNA to RNA. This material is then amplified – thousands of copies are made – to ensure a measurable result. The different available test kits generally vary in the segment of genetic material chosen.
I’m hearing that there are serious delays, in the USA at least, in delivering test results. This is extraordinary as, according to the Scientific American article, which is dated late March,
the FDA recently began granting emergency use authorization (EUA) to rapid diagnostic PCR tests that manufacturers say can deliver results in less than an hour. The authorization allows medical devices that have not yet been approved by the agency to be used during public health emergencies.
What’s happening? According to very recent article from Quartz magazine, the problem is that there are too many kinds of tests. The EUA system was utilised, partly because of the urgency, partly because of the disastrous problem caused by the use of faulty reagents by the CDC back in February. Now there are about 150 tests that have been given EUA approval. Testing delays at first resulted mainly from lack of general lab equipment and PPR for the testers, but increasingly there are problems due to different types of tests, the variability of the tests, knowing which test to use, having the right equipment for each test, the prioritising of certain groups, such as front-line health workers, over others, confirmation of test results by other labs, and of course the overload in demand. We’re talking about the USA here, of course, and it just seems another case of lack of centralised control and uniformity in a state with a failed federal government.
Returning to update 73, Seheult describes a situation in which a SARS-Cov2-infected individual’s immune system has broken down the virus into ineffectual strands of RNA, proteins and other particles. It’s possible that a RT-PCR test could pick up on an RNA fragment, and produce a positive test result in these apparently recovered patients, and in fact this has often occurred. This is called a re-positive. The update describes a study by the South Korean CDC which provides valuable evidence on these re-positive cases. Some 280 re-positive subjects were studied, and about half of them displayed Covid-19 symptoms (on average 14 days after ‘recovery’). Presumably this re-positive finding was after they’d tested negative, i.e they’d first tested positive, then negative, then later positive again, though this isn’t clear. In any case, they checked a percentage of the subjects for antibodies and the result was almost entirely positive. They checked a larger sample for viral particles and found ‘not a single whole viral particle’, according to Dr Seheult, by which I presume he means anything that was replicable or active. They also looked at close contacts of the subjects, in large numbers, and all of them tested negative. So the finding was that these re-positives were, it seemed, the results of ultra-sensitive testing that was picking up viral RNA fragments that were in effect innocuous. This would seem to be a lesson for developing the right types of test. Hopefully a lesson learned.
References
Coronavirus Pandemic Update 70: Glutathione Deficiency, Oxidative Stress, and COVID 19
Coronavirus Pandemic Update 71: New Data on Adding Zinc to Hydroxychloroquine + Azithromycin
Coronavirus Pandemic Update 72: Dentists; Diabetes; Sensitivity of COVID-19 Antibody Tests
Coronavirus Pandemic Update 73: Relapse, Reinfections, & Re-Positives – The Likely Explanation
https://www.scientificamerican.com/article/heres-how-coronavirus-tests-work-and-who-offers-them/
https://qz.com/1886940/why-covid-19-test-results-take-so-long/
SARS-Cov2 and oxidative stress
So I feel it’s time for me to get back to the epidemiology and immunology stuff that I know so little about, especially as it pertains to SARS-Cov2. Watching Dr Seheult’s Medcram updates again after a long hiatus, and catching up with them from the end of April, I note that he’s arguing – and I presume this is a mainstream view, as he clearly keeps an eye on the latest research – that the virus mostly does its damage in attacking the body’s endothelium, and that this in turn causes oxidative stress. The endothelium is a thin layer of cells, or a layer of thin cells, that form the inner lining of the blood and lymph vessels (one day I’ll find out what lymph actually is and does).
Oxidative stress is associated with an imbalance in the level of oxidants such as super-oxide anion and hydrogen peroxide, reduced forms of oxygen (with extra electrons). I don’t really understand this, so I’ll start from scratch. But just preliminary to that, the effects of oxidative stress are manifold. Here’s a summary from news-medical.net:
Oxidative stress leads to many pathophysiological conditions in the body. Some of these include neurodegenerative diseases such as Parkinson’s disease and Alzheimer’s disease, gene mutations and cancers, chronic fatigue syndrome, fragile X syndrome, heart and blood vessel disorders, atherosclerosis, heart failure, heart attack and inflammatory diseases.
It’s known that SARS-Cov2 enters via the lungs, and does damage there, but it’s now thought that most of the damage is done in the endothelium. To understand this, Dr Seheult is going to teach me some ‘basic’ stuff about metabolism, oxidation, energy production and such. So, we start with mitochondria, the energy-producing organelles inside our cells, which have their own DNA passed down the female line. Looking into a mitochondrion, we have the matrix inside, and around it, between the inner and outer membranes, is the inter-membrane space (IMS). Our food, broken down into its essential components, carbs, fats and proteins, is absorbed into the matrix, and somehow turned into ‘two-carbon units’ called acetyl coenzyme A. This is metabolism, apparently. These molecules go through a famous process called the Krebs cycle, of which I know nothing except that it’s about more metabolism… Although now I know that it produces electrons, tied up in two important molecules, NADH and FADH2. These electrons ‘love to be given up’, a way of saying they ‘want’ to be reduced. The molecule that gives up electrons is said to be oxidised, the receiving molecule is reduced. So think of a molecule being reduced as the opposite of losing, rather counter-intuitively. The oxidised molecule is the one that loses electrons. All this is about energy production within the matrix, and the aim is to end up with a molecule I’ve heard and forgotten much about, adenosine triphosphate (ATP). This molecule is the energy molecule, apparently, and the energy is produced by ‘knocking off’ one of the phosphates, according to Dr Seheult, leaving, apparently, adenosine diphosphate (ADP) plus ‘energy’ (clearly, this part needs a little more detail). So going from the diphosphate form to the triphosphate requires energy, going the other way releases energy – none of which really explains why ATP is the body’s energy source. Anyway…
Returning to the carbs, fats and proteins, they go through these mitochondrial processes to produce electrons which want to reduce stuff. So NADH goes to the membrane which separates the IMS from the matrix of the mitochondrion, where proteins can be found that are willing to accept electrons, i.e. to be reduced. The electrons are brought in ‘at the very top of the scale’ (?) and lose some of their reducing ability, so they go down to a lower state of reduction, and protons are pumped into the IMS. (I’m sure this is all true but making sense of it is another matter. It certainly makes me think of proton pump inhibitors, drugs that reduce gastric reflux, but that would be the subject of another set of posts). Then ‘it goes to another species’ by which I think Seheult means another protein, judging from the video, but what he means by ‘it’ I’ve no idea. The NADH? The wave/body of electrons? Anyway, things keep going down to a lower level, becoming more oxidised, and more and more protons are pumped out. So there comes to be a very high concentration of protons (H+) in the IMS, creating a very low PH (high acidity). Meanwhile, the electron transport chain has gone down so many levels that it can only reduce oxygen itself, which by accepting electrons turns finally into water. It’s apparently essential to have sufficient oxygen to keep this cycle going, and to keep the protons pumping, because the protons in the IMS want to move to a place of lower concentration, in the matrix. In doing this, they pass through a channel, which involves, somehow, a coupling of ADP to ATP. Without enough oxygen, this process is stymied, ATP can’t be supplied, leading to insufficient energy and cell death.
So, I think I understand this, as far as it goes. Now, if you over-eat, with lots of high-calorie fats and carbs entering the cells, you’ll likely end up with a surplus of electrons, tied up in NADH and FADH2, which can cause problems. This is where super-oxides come in.
Oxygen is the final electron acceptor in the electron transport chain, and when you add an electron to this final acceptor you get a super-oxide, an oxygen molecule with an additional electron, aka a radical. These are very reactive and dangerous. They can cause DNA damage and serious inflammation, and the body uses them to kill bacteria. If you add another electron, you get H2O2, hydrogen peroxide, and another one again produces a hydroxy radical, OH. Another electron gives water, so it’s these intermediate molecules that are called ‘dangerous species’. Cells such as neutrophils (a type of white blood cell) make these, via an enzyme called NADPH oxidase, as part of their defence against antigens, but an accumulation of these radicals is problematic and needs to be dealt with.
One enzyme the body uses to bring down these accumulating radicals is super-oxide dismutase (SOD), which takes two super-oxides and converts them into O2 and H2O2. SOD comes in three types, related to where they reside – in the mitochondria, the cytosol and the extracellular matrix. These enzymes are powered by zinc, copper and, in the mitochondria, manganese. So what happens to the extra hydrogen peroxide created? An enzyme called glutathione peroxidase (GPx) reduces H2O2 to water by giving it two electrons. Where do these electrons come from? According to Seheult, and this is presumably ‘basic’ microbiology, the antioxidant glutathione has two forms, oxidised and reduced. The reduced form is 2GS-H, with a hydrogen bonded to the sulphur group. The oxidised form is G-S-S-G, a disulphide bond replacing the hydrogen. With the reduced form, GPx donates its extra two electrons to H2O2, reducing it to water. The glutathione system is recharged by reducing it back with NADPH, which has two electrons which are converted to NADP+ (?) Glutathione reductase is the key enzyme in that process. It might take me a few lifetimes to get my head around just this much.
Meanwhile there’s another system… Catalase, an iron-boosted enzyme, can convert two molecules of H2O2 into O2 and H2O. This occurs in organelles called peroxisomes. The major point to remember in all this is that super-oxides are harmful species that can cause oxidative stress, and the major solutions come in the form of SOD and GPx. In fact the general name for these harmful molecules – super-oxides, hydrogen peroxide, and hydroxy radicals – is reactive oxygen species (ROS).
So we have to relate all this to the effects of SARS-Cov2, which enters the body through the ACE-2 (angiotensin-converting enzyme-2) receptor. According to a 2008 research paper, ACE-2, the receptor for which is blocked by SARS-Cov2, ‘confers endothelial protection and attenuates atherosclerosis’. Quoting from the paper, we find a section called ‘ACE-2 modulates ANG II(angiotensin 2)-induced ROS production in endothelial cells’. The researchers’ essential finding was that ‘ACE-2 functions to improve endothelial homeostasis’, and it seems this function is being disrupted by SARS-Cov2. As Dr Seheult puts it, SARS-Cov2 inhibits the inhibitor, that is it inhibits ACE-2, which normally acts to regulate angiotensin 1,7 (not explained in this particular video), thus allowing NADPH oxidase to keep producing super-oxides, with the resultant oxidative stress. As Seheult concludes here, subjects with compromised systems caused by diabetes, cardiovascular disease or obesity, affecting the production or effectiveness of SOD and GPx, might be relying on ACE-2 and angiotensin 1,7 to maintain some semblance of health. Are these the subjects that are succumbing most to the virus? That’s to be explored in future videos, and future posts here.
Reference
Coronavirus Pandemic Update 63: Is COVID-19 a Disease of the Endothelium (Blood Vessels and Clots)? (video by Dr Roger Seheult – clearly a hero in this time)
Covid-19: the USA and a bit of ranting
Jacinta: So I note that, unsurprisingly, there are some Americans protesting about physical distancing and lockdowns, while their nation has proved to us all that their overall handling of this pandemic has been the worst on Earth by a long way. I mean, apologies to all those who are working their arses off on the frontline, and to the innocent victims, and to the governors and other leaders trying their level best, but the sheer size of the US failure compared to just about any other country is a fantastic advert for American exceptionalism.
Canto: Well yes, the USA has failed massively in its handling of Covid-19, though of course the virus has been very patchy in its incidence around the nation, for reasons nobody can quite understand. But here’s an interesting metric in comparing the USA to Australia, and anyone can check this on the Worldometer figures. The USA’s population is approximately 13 times that of Australia, but as of today, April 21, the death toll from Covid-19 in the USA is approximately 600 times that in Australia. Compare also Taiwan, one of the world’s best performed country so far, which has a similar population to Australia. This very close neighbour of China has a death toll so far of 6, compared to the USA’s 42,518.
Jacinta: Yes, yes, so what does this say about the USA when you get so many otherwise intelligent people there still clinging to the bullshit claim that their country is the greatest on the planet? Adam Schiff said it in his otherwise excellent speech at the end of the impeachment process – and today, listening to a Sam Harris interview with Caitlin Flanagan (someone I’ve never heard of but who seemed otherwise perfectly rational), I heard her say exactly the same thing – or not exactly. She said that she really believed (almost as if she wished it were so) that America is the world’s greatest country. As if intensity of belief counted for anything. But I doubt that the USA is ahead of the rest of the world in any field worthy of measuring, apart from military might, and that’s surely a questionable value.
Canto: Hmmm, so why don’t you tell me what you really think? But isn’t this just a bit of harmless patriotism after all? We’re expected to love our country, as a value.
Jacinta: Well, I just don’t. I’ve just never had that feeling. Call me aberrant. Or contrary. I’ve often been described as a contrarian, but on this I agree with Venki Ramakrishnan, the Nobel Prize-winner, whose excellent book Gene Machine we’ve just read. He was inundated with congratulatory calls and honorary awards from India after winning the prize, even though he’d had nowt to do with the country since he was a teenager. It started to annoy him, because as he wrote, we don’t get to choose where we’re born. An obvious truth that seems to escape most people. But I’m also a contrarian in that I often find myself undermining my own responses. For example, I want to respond to patriots by calling myself a humanist, but then I think ‘I didn’t get to choose to be a human, why should I be jingoistic about humanity? Birds are pretty cool too.’ Isn’t that contrarian?
Canto: Hmmm. Ramakrishnan was tragically led astray by the transnational values of science haha. And birds can’t do science. I wonder about the blow to US credibility of this event though. They’ve completely failed in the readiness and collaboration Bill Gates wrote about in that New England Journal of Medicine article back in late February. I mean, they’re advancing with possible treatments no doubt, but testing is a shambles from what I’ve heard, and the federal government is non-existent under the boy-king. What little there is of it just gets in the way.
Jacinta: The irony of it is that the more their government fails, the more the libertarians and the knee-jerk anti-government loons will feel vindicated. And now I hear that our own Dear Leader thinks that we should have a more co-ordinated international response but maybe without the WHO. I mean, wtf? Seems to be trying to crawl up the boy-king’s capacious arse. Wrong side of history, mate.
Canto: So I’ve been avidly watching this series of Medcram videos on the pandemic. They’re informative on the science, on immunology and new types of vaccines and treatments, but they’re also a fascinating look back on the innocent-seeming days of six or seven weeks ago, when there were hardly any deaths outside of China. Watching them only adds to my sense of the unreality of it all, somehow. Anyway, microbiology’s a fun topic to learn about don’t you think?
Jacinta: Along with all the others. It’s certainly a lot more calming and inspiring than politics.
References
https://www.nejm.org/doi/full/10.1056/NEJMp2003762
Gene machine, by Venki Ramakrishnan