Posts Tagged ‘covid 19’
Interferons – they’re there to help
some human interferon looks something like this, according to someone
When I first heard of interferon (singular), I thought it was a drug, some sort of miracle drug being touted as a cure-all. I had no idea. Recently I’ve heard that it, or they, are part of our innate immune system, which is different from our adaptive immune system, though what the differences are I have no idea. Again. So, it’s learning time.
Wikipedia vastly increases my knowledge with its first sentence on interferons (duh, I wonder why people don’t use it more):
Interferons … are a group of signaling proteins made and released by host cells in response to the presence of several viruses. In a typical scenario, a virus-infected cell will release interferons causing nearby cells to heighten their anti-viral defenses.
Host cells are the cells of larger organisms (such as ourselves) that ‘host’, willingly or not, viruses and other bugs, or organelles, whatever. Signalling proteins are explained, somewhat, in the second quoted sentence.
Anyway, interferons belong to the larger class of proteins known as cytokines, which I’ve heard of in relation to the ‘cytokine storm’, a reaction or over-reaction to viruses such as SARS-Cov2, but they do more than just signal, they interfere, as the name suggests. In fact they have multiple functions, such as ‘upregulating antigen presentation’. An antigen, as I almost recall, is a molecular structure, part of a pathogen that can be bound by an antigen-specific antibody. Antigen presentation is – well it’s too complex to explain here, though I feel I need to arm myself with as much immunological knowledge as possible against the misinformation out there.
So IFNs, as they’re known, come in 3 types, alpha, beta and gamma, based on the receptors through which they signal. They form part of the innate immune system, generally speaking, but there are in fact complex interactions between the innate and adaptive immune systems which immunologists are still trying to work out. I should point out here that my first understanding of interferon was no doubt based on a breakthrough in the eighties when interferons were created in the lab to treat certain types of cancer, and later in the treatment of hepatitis, multiple sclerosis and other conditions, though many of these interferon medications have been superseded by newer treatments with fewer side-effects.
My question arose through watching a Medcram video – update 128 – ‘innate immunity, interferon and Covid-19 in children’. I’ve used these updates in the past to reduce my general ignorance of immunology, virology and the like, but I’ve not watched any for a while. So, having just perused the Wikipedia article on IFNs and finding it way too complex for my small brain, I’ll base the rest of this piece on Dr Seheult’s Medcram presentation.
So, the innate and adaptive immune systems are presented pictorially. The innate system starts with a myeloid progenitor cell. These cells are described in ScienceDirect as ‘the precursors of red blood cells, platelets, granulocytes…’ and a bunch of other cells. In the Medcram pictorial, arrows from the myeloid progenitor cell lead to five other cell types – mast cells, basophils, neutrophils, monocytes and eosinophils. Arrows from the monocytes then lead to macrophages and dendritic cells. What do these have to with IFNs? I’m trying to find out.
Mast cells are types of granulocyte, and they contain granules ‘rich in histamine [which induces inflammation] and heparin [which prevents blood clotting]’. They play an important protective role in the immune and neuroimmune systems.
Basophils are also granulocytes, and a type of white blood cell (leukocyte). They’re the rarest and largest type of granulocyte, and are an inflammatory agent.
A neutrophil is ‘a type of immune cell that is one of the first cell types to travel to the site of an infection. Neutrophils help fight infection by ingesting microorganisms and releasing enzymes that kill the microorganisms. A neutrophil is a type of white blood cell, a type of granulocyte, and a type of phagocyte’ (National Cancer Institute – USA).
Eusinophils ‘are a variety of white blood cells (WBCs) and one of the immune system components responsible for combating multicellular parasites and certain infections in vertebrates’ (Wikipedia).
A monocyte is ‘a type of immune cell that is made in the bone marrow and travels through the blood to tissues in the body where it becomes a macrophage or a dendritic cell. Macrophages surround and kill microorganisms, ingest foreign material, remove dead cells, and boost immune responses. During inflammation, dendritic cells boost immune responses by showing antigens on their surface to other cells of the immune system. A monocyte is a type of white blood cell and a type of phagocyte’ (National Cancer Institute).
Now to return to the Medcram video, which tells me that the innate immune system includes macrophages and killer T cells (which are also part of the adaptive immune system). These combine to phagocytise, or ingest, viral or pathogenic material. This innate immune system is generally very strong in childhood and gets weaker with age. Interferon is a product of this innate system. Dr Seheult cites a recent article from Nature Biotechnology with the revealing title ‘Pre-activated antiviral innate immunity in the upper airways controls early SARS-Cov2 infection in children’. I’m fascinated with the idea of ‘pre-activated’ immunity here. As far as I know vaccines pre-activate immunity to viruses or pathogens by presenting the immune system with a part of that pathogen, or a protein unique to it. But with children, how is their immune system pre-activated? In any case, the article explains that ‘children displayed higher basal expression of relevant pattern recognition receptors [involving interferons] in upper airway epithelial cells, macrophages and dendritic cells, resulting in stronger innate antiviral responses upon SARS-Cov2 infection than in adults’. This finding highlights the importance of interferons and of perhaps trying to maintain their prevalence in older subjects. The article described children presenting in emergency with severe Covid19 as having an impaired IFN response, though the molecular mechanisms for this, and for the protective effects on those children with mild or no symptoms, were unknown.
So the article explains that higher levels of genes coding for RIG-1, MDA5 and LGP2 in the epithelial cells of the upper airways were found in children, but not in adults. RIG-1 is a pattern recognition receptor (PRR) of the innate immune system, responsible for type 1 interferon responses. MDA5 and LGP2 are members of the same family of PRRs. The key being more innate immune cells in that region in children, exhibiting strong antiviral action against SARS-Cov2. This is apparently what is meant by ‘pre-activated’, because these primed cells were already in the upper airways (i.e the nose) of children. However, there appears to be a narrow window of opportunity before viral reproduction, which is especially intense with SARS-Cov2, shuts down this innate immune response. The paradox, it seems here, is that SARS-Cov2’s proteins can effectively shut down interferon production, but at the same time the virus is highly sensitive to interferon. Anyway, it seems that if we can step up IFN production, assisting the body’s innate immune system, this may enable us to resist the virus (along with vaccination, effective mask wearing and physical distancing of course). One way to do this is by raising the core temperature of the body (inducing hyperthermia). At a core temp of 39 degrees celsius, the amount of IFN released from lymphocytes after mitogen stimulation (i.e inducing mitosis) increases ten-fold from just a degree or so below, at least in vitro. This may sound crazy, but the benefits of induced fever have been proven in various treatments for various infections, including viral infections, in the past, along with other ways of boosting the immune system (vitamin D, zinc and selenium) mentioned previously by Dr Seheult and other experts.
Science science science science science science. Don’t use social media to find out about SARS-Covid19 and its treatment. Never never never never. There are dozens of reputable scientific sites that will inform you, in the USA and in every other country – at least the WEIRD ones. Knowledge is power. Get informed.
References
https://en.wikipedia.org/wiki/Interferon
https://www.webmd.com/drug-medication/interferons-guide#1
Innate Immunity, Interferon, and COVID 19 in Children: Update 128 (video)
https://www.sciencedirect.com/topics/immunology-and-microbiology/myeloid-progenitor-cell
https://en.wikipedia.org/wiki/Mast_cell
https://www.healthline.com/health/basophils
https://www.cancer.gov/publications/dictionaries/cancer-terms/def/neutrophil
https://en.wikipedia.org/wiki/Eosinophil
https://www.cancer.gov/publications/dictionaries/cancer-terms/def/monocyte
https://en.wikipedia.org/wiki/RIG-I
https://en.wikipedia.org/wiki/MDA5
https://en.wikipedia.org/wiki/Mitogen
covid-19 – on civil liberties and death in the USA
Canto: So, in the USA, according to today’s Worldometer figures – and it’s not unreasonable to say that these figures are only as reliable as the reporting agencies, and are probably understated – there have been slightly more than 203,000 deaths from covid19 – that’s almost 250 times the number of deaths in Australia, which has one thirteenth of the US population. This is a stark illustration of the USA’s failure to protect itself against this virus, in comparison to some other countries. Maybe this is an unfair comparison, though I honestly don’t see why it would be, but we can make an even more stark comparison. The liberal democracy that is Taiwan, the world’s gold standard in terms of response to covid19, with its population only slightly smaller than Australia’s, has experienced seven deaths so far. So, to compare with the USA, that’s a fourteenth of the population, but the USA has suffered almost 30,000 times more deaths from the virus. Such are the almost unfathomably various degrees of success in dealing with this pandemic. I’ve chosen these more or less opposite ends of the spectrum – and, to be fair, the USA isn’t the shit standard (in comparison to gold), as Brazil’s performance is even worse – in order to reflect on how best to save lives, which is surely what we want to do above all else, as a matter of common humanity.
Jacinta: And our discussion will be based on a statement made by the US Attorney-General, William Barr, who described the current lockdown in the USA as the greatest erosion of civil liberties in the country since slavery. But maybe, as an outstanding humanist, and a follower of the meek and mild Jesus, a supporter of the downtrodden, who told his followers that it is easier for a camel to pass through the eye of a needle than for a rich man to enter the kingdom of God (Matthew 19: 23-26), Barr was speaking positively about the lockdown as a sacrifice that must be made to save lives – especially those of the poor, with whom he so strongly identifies as a follower of the aforementioned Jesus.
Canto: Well, that’s an interesting interpretation, but I think the more straightforward one is that he thinks people should be free to mix and mingle, in spite of the pandemic. In any case I’ve not heard of him wanting to impose any restrictions of any kind, in spite of the covid19 death rate in the country. It would be interesting to know what he makes of the fact that covid19 is disproportionately affecting the poor as well as African-American and Latino communities. He himself is a multi-millionaire, unlike Jesus, and Euro-American, also unlike Jesus. Yet he calls himself a Christian and believes that Judeo-Christian values, whatever they may be, are the basis of civilisation, at least in the USA. I’m not sure if he’s ever sampled any other society.
Jacinta: Which brings us to Taiwan. What is it that has made Taiwan the gold standard in dealing with this pandemic? Is it Christianity, of a different kind from that which the multi-millionaire Barr espouses, in spite of Jesus’ teachings? Or is it a very different, but equally, or more, effective tradition? Did Taiwan even experience a lockdown, of the type that Barr seems to have such strong feelings about?
Canto: So let’s explore Taiwan. in fact it has had a complex and very turbulent history, especially over the past century or so, one that, I’d say, would have made its citizens value their hard-won freedom rather more than those of most nations, including the US. I can’t imagine that these people, who’ve undertaken rebellion after rebellion, would allow their government to take away their ‘civil liberties’ without good reason. They just wouldn’t stand for it.
Jacinta: Could it be that they’re just more educated than ‘Americans’, as to their national interest? And even as to what’s required in dealing with a pandemic? It certainly seems that way.
Canto: In fact last month the US federal health secretary (I didn’t know they had one) was over in Taiwan praising the country’s covid19 response. That was a good thing to see.
Jacinta: Yes and many prominent nations are warming in their relations with Taiwan, not before time, and it’s annoying the Chinese government no end. But on covid19, I suspect many ‘Americans’ will dismiss Taiwan’s success as typical of Asian nations and their collective, ‘sheep-like’ mentality. Clearly, collective pro-community action trumps selfish individualism when it comes to pandemics, but I’m sure Taiwan’s success can’t be explained in such simplistic terms, as the Taiwanese have fought long and hard, against the communists, the Japanese and the Kuomintang, suffering massacre after massacre, to achieve multi-party democracy. So the idea that this is about tough-minded, risk-taking ‘sovereign citizens’ who won’t be pushed around by so-called health experts versus namby-pamby obedient puppets of the state who’re prepared to sacrifice their freedom just for the sake of their lives – well, this is surely a furphy.
Canto: So what do we make of this Barr character? He attacks ‘lock-downs’ – which are simply a needed response to the refusal by so many to wear masks and to practice physical distancing. Sometimes authorities need to clamp down, when so many lives are being lost. Every government, regardless of their place on the political spectrum, has done something to try to reduce the spread of this virus. As would be expected. And this has necessarily impinged on ‘civil liberties’, because there are obviously other priorities. So, again, what point is Barr trying to make?
Jacinta: I can’t honestly say, but it does appear that he’s opposed to lock-downs, so presumably he has other ideas for saving the lives of ‘Americans’, but I’ve no idea what they may be. He’s also said recently that ‘scientists aren’t seers’ and that ‘free people make their decisions through their elected representatives’, which is a little incoherent, because when it comes to epidemics, sensible people should obviously listen to the advice of epidemiologists, especially those who are expert in the disease, virus or pathogen in question, rather than to politicians. You don’t even have to be an adult to realise that.
Canto: Yes, people are free to decide on their own science by popular vote, but if they did, we’d still be living in caves and believing that the earth is flat. Such are the limits of democracy.
Jacinta: So in times like these, the politicians should work with the experts, which is exactly what’s happening in all those countries that have handled covid19 most successfully. It’s notable that when he talks about these freedoms and civil liberties he makes no mention of all the suffering and the deaths in the USA. It somehow doesn’t seem to be relevant to him. What a bizarre, creepy character.
Canto: Well, as a multi-millionaire – and I didn’t realise that politics was such a lucrative business – he very likely lives in one of those gated communities (with the emphasis on the gate rather than the community). Covid19 is disproportionately affecting African-Americans, Latinos, the poor, factory workers, prisons, aged-care facilities. Not really the sort of people you associate with gated communities. So I can only suppose he’s out of touch with much of the suffering. Lock-downs affect people universally – though obviously in different ways, depending on whether you’re in a mansion or a hovel – but the financial elites naturally don’t feel equal to the poor, and their ‘inequality’ is a matter of great pride to them. Barr is being a spokesperson for these types, I think. They’re having to suffer lock-downs because the less privileged are dying. It’s just not fair.
Jacinta: And I just want to add something here about scientists. I’ve met a few of them, and I wish I was one of their number. They don’t pretend to be seers – my experience is that they tend to be nerdy, self-effacing types, not power junkies as many politicians tend to be. They generally tend not to display all the knowledge they have – it often has to be dragged out of them, whereas the worst politicians often claim knowledge they don’t have and like to belittle the knowledge or understanding of their rivals. In this respect, Barr is very much the politician, and little else.
Canto: Yes, and meanwhile the deaths keep piling up in the USA, and at the federal level the scientists are being sidelined by the politicians, the CDC is being stifled, and the world watches on with alarm, disgust and sometimes a smug sense of superiority. It isn’t of course the end of US ascendancy – the states with the most massive weaponry will always be the most powerful – but as to moral authority, that’s fast disappearing. If you leave aside the many non-democracies, which nation is less worthy of respect and emulation than the USA? I can’t think of too many.
Canto: Well, on a more hopeful note, there’s an election coming, and the country may start to redeem itself. But it will take far more than an election to do that, IMHO.
reading matters 11 – encephalitis lethargica. Will it return?
Asleep, by Molly C Crosby, 2010
Canto: This was one of the saddest books I’ve read in a long time. It’s about a disease that arose, and was recognised, at around the time of the ‘Spanish flu’ of 1918, though it was more sporadic and long-lasting, and rather more mysterious. It’s also a kind of cautionary tale for those among us who downplay the impact of diseases and their effects, which are so often long-term and horrifically devastating. It’s humbling to realise that we just don’t know all the answers to the pathogens that strike us down.
Jacinta: And could revisit us, in mutated and perhaps even more deadly form, some time in the future. This book is about encephalitis lethargica, a disease that was personal to the author, as it infected her grandmother, whose entire life, though she lived to a goodly age, was clearly stunted by it. She was struck down at the age of 16, and slept for 180 days, and though she lived almost 70 years afterwards, she was robbed by this brain-blasting illness of the life of the mind, the rising above ourselves and grasping of the world that we’re attempting in this blog. Through sheer bad luck.
Canto: And as Crosby points out, her grandmother was far from being the worst-affected victim of this disease. People died of course, but others were disastrously transformed.
Jacinta: So let’s go to a modern website, a department of the USA’s NIH, the National Institute of Neurological Disorders and Stroke, for a definition:
Encephalitis lethargica is a disease characterized by high fever, headache, double vision, delayed physical and mental response, and lethargy. In acute cases, patients may enter coma. Patients may also experience abnormal eye movements, upper body weakness, muscular pains, tremors, neck rigidity, and behavioral changes including psychosis. The cause of encephalitis lethargica is unknown. Between 1917 to 1928, an epidemic of encephalitis lethargica spread throughout the world, but no recurrence of the epidemic has since been reported. Postencephalitic Parkinson’s disease may develop after a bout of encephalitis-sometimes as long as a year after the illness.
Canto: Yes, and having read Crosby’s book and knowing about the worst symptoms and a few heart-rending cases, the sentence that most strikes me here is, ‘The cause.. is unknown’. Apparently Oliver Sacks’ book Awakenings, which we haven’t read, is all about patients who have ‘awakened’, permanently damaged, from this bizarre disease, and that’s a book we now must read, though of course it will provide us with no solutions.
Jacinta: And no arms against its future devastation, should it return – and why wouldn’t it? Crosby and others have suggested that ‘fairy stories’ like Sleeping Beauty and Rip van Winkle may have been inspired by outbreaks of the disease. Of course this is conjecture, and only if the disease returns will we be able to attack it with the technology we’ve developed in the intervening century. As the neurologist Robert Sapolsky points out in his mammoth book Behave, (so mammoth that I can’t find the quote), the number of papers published on the brain, its activity and functions, in the 21st century, has grown exponentially. We might just be ready to counteract the long term horrors of encephalitis lethargica next time round, if it comes around.
Canto: Crosby’s book is organised into case histories, featuring people who fell into this bizarre torpid state for long periods, and when aroused, often behaved in anti-social and self-destructive ways that in no way resembled depression, between bouts of a ‘normality’ that was never quite normal. And one of the saddest features of these case histories, richly described in the notes of famous figures in early neuropsychology, such as Constantin von Economo, Smith Ely Jellife and Frederick Tilney, is that the victims disappeared into the void once it became clear that no known treatment could save them.
Jacinta: Yes, some may have died soon afterward, others may have lived on in a limbo, locked-in state for decades. In fact the symptoms of this disease were bewilderingly varied -various tics, hiccupping, catatonia, salivation, schizoid episodes… Encephalitis literally means swelling of the brain, and it doesn’t take a medical degree to realise this could cause a variety of effects depending on which area of the most complex organism known to humanity is most affected.
Canto: Encephalitis is usually caused by viruses, and of course viruses hadn’t been fully conceptualised when von Economo wrote his 1917 paper on what was to become known as encephalitis lethargica, as the role of DNA and RNA was unknown. However, von Economo was the first to recognise the vital role of a tiny, almond-shaped section near the base of the brain, the hypothalamus, in the distorted sleep patterns of these patients. He also wondered if there was a connection between the so-called Spanish flu and this sleeping sickness.
Jacinta: Yes, and this brings to mind the current nightmare pandemic. People, including of course epidemiologists, are wondering about the long-term effects of this virus, especially in those who seem to have recovered from a serious infection. Crosby writes of the situation a hundred years ago:
The war had provided the first opportunity encephalitis lethargica had to crawl across the world with little notice from the medical community. And by 1918, the pandemic flu had given it the second opportunity, stealing worldwide attention, infecting and killing millions. Epidemic encephalitis moved with the flu, almost like a parasite to a host, often attacking many of the same victims, receiving very little notice at all.
Of course there has been no sign of a return of encephalitis lethargica – as yet – from a medical community that is somewhat forewarned, but it’s clear that inflammation can have very diverse effects, especially when it involves the brain.
Canto: But it’s like an undefeated enemy that has gone into hiding. We’ve defeated smallpox; tuberculosis and polio are in heavy retreat; leprosy seems as remote to us as the Bible, but this sleeping sickness, some of the victims of which have died within our lifetimes, has tantalised us with its bizarre and devastating effects, but has never really given us a chance to fight it.
Jacinta: Yes fighting is what it’s all about. The anti-vaxxers and the natural health crowd seem to want to leave everything to our immune system, to let diseases take their course, killing and maiming a substantial percentage of the herd to let the remainder grow stronger. If they were to read some of these case studies, to witness the lives of young Rosie, Adam and Ruth, they would surely think differently, if they had a modicum of humanity.
covid19: autopsy analyses, biomarkers, von Willebrand factor
von Willibrand factor, a multimeric blood protein which plays a central role in blood clotting
Canto: So we’re working hard to get through what has been reported on medcram update 95, even though it’s taking us further behind the times in terms of what’s happening in the fight against this virus – there’s been some controversy on convalescent plasma recently for example – because it’s important to get the most out of every report before going onto the next one.
Jacinta: Yes, which means we need to work harder and faster. So in this study of a number of fatal cases of covid19 they found ‘no endothelial abnormalities on microscopic review, in alignment with previous studies’, which suggests that evidence of endothelial damage just doesn’t seem to be there, but they couldn’t rule out pro-coagulant endothelial dysfunction in the absence of ‘histopathological evidence of cell activation or erosion’, and they referred to another autopsy study with specialised equipment which ‘demonstrated ultrastructural endothelial damage’. So it seems they’re struggling with causes.
Canto: What they call the precise aetiology of the disease.
Jacinta: Yes that’s what we’re after. So they do mention elevated troponin in covid19, which appears to be found regularly. Troponins are ‘a group of proteins found in skeletal and cardiac muscle fibres that regulate muscular contraction’. As the update tells us, troponin tests measure cardiac-specific troponin in the blood as a sign of heart injury. This Australian site tells us more:
For patients who are hospitalised with COVID-19, mild elevation of troponin is common (19.7%) and frequently correlates with disease severity, acting as a marker for cardiac injury. The cause of troponin elevation in serious infection is multifactorial.
In the study under discussion, they consider that the elevated troponin has to do with ‘thrombosis of the microvasculature and cardiac veins’. This cardiac vein finding is apparently important – they found, they believe for the first time, that thrombosis of a cardiac vein can cause myocardial infarction. They also write about renal findings in their subjects, to ‘shed light on the pathogenesis of acute kidney injury in covid19’. They found virions in proximal tubular cells. A virion is essentially a full, active molecule of a virus (there’s still some disagreement about these definitions, it seems). The proximal tubules are components of nephrons, the most important functional units of kidneys. They found acute tubular necrosis and other damage, and noted that this was common to other covid19 autopsy findings, perhaps unsurprisingly as these tubular cells present ACE2, the receptor for the virus. Dr Seheult then goes on to another study from Switzerland. This study looked at 639 critically ill covid10 patients, to determine which factors were most associated with survival or otherwise. So in general they found that this group suffered a ‘moderate’ mortality rate of 24%. To understand the findings will require quite a bit of medico-immunological knowledge, but here goes: they found that ‘PCT and IL-6 levels remained similar in ICU survivors and non-survivors throughout the ICU stay’. PCT is procalcitonin. According to Medscape:
Procalcitonin (PCT) is a biomarker that exhibits greater specificity than other proinflammatory markers (eg, cytokines) in identifying sepsis and can be used in the diagnosis of bacterial infections. Procalcitonin is also produced by the neuroendocrine cells of the lung and intestine and is released as an acute-phase reactant in response to inflammatory stimuli, especially those of bacterial origin. This raised procalcitonin level during inflammation is associated with bacterial endotoxin and inflammatory cytokines.
IL-6 is interleukin-6. An opinion article in Frontiers in Microbiology entitled ‘The Role of Interleukin-6 During Viral Infections’ describes IL-6:
IL-6 is a pleiotropic cytokine produced in response to tissue damage and infections… Multiple cell types including fibroblasts, keratinocytes, mesangial cells, vascular endothelial cells, mast cells, macrophages, dendritic cells, and T and B cells are associated with the production of this cytokine….
Pleiotropic cytokines – a cytokine is a type of small protein – affect the activity of multiple cell types. The complex pleiotropic nature of IL-6 unsurprisingly implicates it in both pro-inflammatory and anti-inflammatory effects. So, PCT and Il-6 levels remained similar for these study subjects, but ‘CRP, creatinine, troponin, D-dimer, lactate, neutrophil count, P/F diverged within the first seven days.’ Okay, C-reactive protein (CRP) is produced in the liver, from which it enters the bloodstream, and its levels ‘start to increase very soon after any inflammation or infection affects the body’, according to Australia’s healthdirect website. Creatinine is a waste product found in everyone’s bloodstream, and it’s produced by muscle metabolism. It’s generally filtered out by the kidneys. Too much blood creatinine may be a sign of kidney dysfunction. D-Dimer, the fibrin degradation product, always contains ‘two D fragments of the fibrin product joined by a cross-link’. I won’t try to explain much further at present. Neutrophils, remember, are infection-fighting white blood cells, and P/F ratio, aka PaO2/FiO2 ratio, is, briefly, an assessment of lung function. So with that, and some more, the study looked at levels of different markers most associated with mortality. To quote from the study:
In contrast to risk factors in hospitalised patients reported in other studies, the main mortality predictors in these critically ill patients were markers of oxygenation deficit, renal and microvascular dysfunction, and coagulatory activation. Elevated risk of bloodstream infections underscores the need to exercise caution with off-label therapies.
Canto: That last point seems important- it’s all about the blood. Or mostly..?
Jacinta: They presented a number of graphs which Dr Seheult interprets for us, but basically they are all likely to mark higher levels of microthrombi in the patients who died, and this seemed more clearly so in the D-dimer levels. High lactate levels are a sign of anaerobic metabolism, a problem with oxygenation. Ischemic heart disease was also measured, and this has to do with narrowing of the arteries. So blood oxygenation, or lack thereof, and coagulation, which can happen just about anywhere, seems to be happening early, leading to a wide range of symptoms, especially in patients with comorbidities, some of them previously undetected.
Canto: So we’re moving on to update 96, which starts again with thrombosis due to endothelial damage causing increased production or release of von Willibrand factor (VWF).
Jacinta: Yes, and they’re apparently finding that different blood groups or types – and that’s a topic we could spend a lot of time on – affect the level and activity of VWF. As do other factors, according to Russian researcher Anna Aksenova:
The level and activity of VWF in the blood in people can be different. The lowest values are associated with von Willebrand disease. It is a hereditary blood disease that is characterized by spontaneous bleeding. Additionally, it differs markedly among healthy people. For example, it is higher among: African Americans than among Europeans; in men than in women; in adults than in children; and in the elderly than in middle-aged people. Also, academic papers have described the VWF and blood group relationship—its level is lower among people with blood group 0, and is higher among those with blood group A. The different amount and activity of VWF in people with different blood groups has a very interesting explanation: this protein is modified by oligosaccharide chains of antigenic determinants of the AB0 system (one of the blood group systems), and this affects its stability and activity.
She points out that ‘to date, the way in which the level of VWF is regulated in the blood has not yet been fully studied’, and then she describes some of what we do know, that it’s stored in special organelles (Weibel-Palade bodies) from where it’s secreted in multimeric form. She argues that, in order to determine the level of involvement of VWF in the progress of covid19, ‘large scale and comprehensive research’ needs to be carried out. Another article which is looking at emergency covid19 treatment has the title ‘targeting raised VWF levels and macrophage activation in severe covid19: consider low volume plasma exchange and low dose steroid’. It points out that VWF is such a large protein that it can only really be removed from the body through plasma exchange. This may be a way to reduce thrombosis in serious cases. Another interesting commentary piece is titled ‘microthrombotic complications of covid19 are likely due to embolism of circulating endothelial-derived ultralarge von Willebrand Factor (eULVWF) decorated-platelet strings’.
Canto: An embolism being a blockage, caused by an embolus. That embolus could be a blood clot (a thrombus) or a fat globule or an air or gas bubble.
Jacinta: Yes, and VWF can come in these long strings of platelets. In fact the platelets adhere to the strings. Anyway, that’ll do for now. We’ll go on about ivermectin and the Moderna vaccine trials next time.
References
Coronavirus Pandemic Update 95: Widespread Clotting on Autopsy; New COVID-19 Prognostic Data
Coronavirus Pandemic Update 96: RNA Vaccine; Ivermectin; von Willebrand Factor and COVID-19
https://www.medscape.com/answers/2096589-179642/what-is-procalcitonin-pct
https://www.frontiersin.org/articles/10.3389/fmicb.2019.01057/full
https://www.medicinenet.com/script/main/art.asp?articlekey=26197
https://www.healthdirect.gov.au/c-reactive-protein-CRP-test
https://medicalxpress.com/news/2020-07-complications-covid-von-willebrand-factor.html
covid19: monoclonal antibodies, symptomatic v asymptomatic, corticosteroids, comorbidities
keeping it simple, for now
Jacinta: Let’s look at monoclonal antibodies briefly before we continue with those medcram updates. Francis Collins, the somewhat controversial but scientifically reliable directer of the NIH in the USA, recently described ‘monoclonals derived from people who’ve survived covid19’ as the best hope for treatment in the absence of a vaccine. So what are these monoclonals? There are lots of useful videos on youtube that provide detail. I’m picking one from the JAMA network. The technology for producing these types of antibodies was developed in the mid-seventies. It was called ‘murine hybridoma’ technology, murine meaning ‘mice’. I remember first reading about monoclonal antibodies in a Scientific American article in the early eighties. It went straight over my head of course, but now it’s time to get a grip on them. So mice were injected with an antigen, which in general terms is a pathogen that induces an immune response. In more specific terms an antigen is a molecule or structure, part of a larger pathogenic molecule, that can be bound to by an ‘antigen-specific antibody’ or B cell receptor. B cells are lymphocytes that secrete antibodies. So the researchers induced this response, then isolated B cells from the spleen of the mice, which they fused with myelomas (cancerous plasma cells). Cancer cells are notoriously long-lived – see ‘the Immortal Life of Henrietta Lacks’ – so these fused cells, called ‘hybridomas’, act like B cells in producing antibodies, and like tumour cells in their ability to replicate. So these hybridomas can be grown in culture and each one can produce a single antibody type, which targets a single antigen type. Hence monoclonal. They can clone themselves for a specific antigen. So, once you know your antigen, you can create a ‘monoclonal’ specifically for it, or two or three to choose from. And now, with covid19 and with technological development, we can isolate monoclonal antibodies not from mice but from recovered covid19 patients. So that’s a somewhat over-simplified account – for more detailed info on monoclonal antibodies, this zero to finals video is excellent, and there are doubtless others. The target for this work is generally the S-protein of the SARS-CoV2 virus, with various particular sites being looked at, and a number of teams working on the research. Some are pretty well ready to go, with specific antibodies or sets of antibodies. The argument is that they could be used for high-risk groups such as ICU workers and nursing home clients, as a kind of temporary vaccine.
Canto: Okay, something else to keep track of. So update 93 discusses an article published in Nature Medicine – all the authors appear to be Chinese – which looks at 37 asymptomatic covid19-infected subjects and their antibodies, compared to those of 37 symptomatic subjects.
Jacinta: So they looked at their immunoglubulin G (IgG) levels. These are the most common types of antibody, created and released by plasma B cells. They graphed the IgG during the acute and convalescent phases, and they defined the acute phase as that in which the viral RNA was detectable in a respiratory specimen, and the convalescent phase as from eight weeks post-release from hospital. What the graph shows is that the IgG levels decreased from acute to convalescent in both symptomatic and asymptomatic cases, but more in the symptomatic cases. They also looked at ‘neutralisation rates’, which presumably refers to the effect of antibody activity. A positive effect means more neutralising antibodies are produced. These seemed about the same between the phases for both groups, but another graphic shows that in the convalescent phase, the symptomatic group have substantially more neutralising antibodies. It seems from this admittedly small study that asymptomatic subjects are at risk of reinfection, after a period of time.
Canto: And even symptomatic subjects after recovery, as we have obviously no longitudinal studies on anti-viral IgG levels, as the study points out.
Jacinta: Well that takes us to the next study, from Spain, which managed to round up almost 52000 participants. The study tells us between late April and mid-May the estimated seroprevalence (the percentage of inhabitants that had the virus) for the whole country was around 5%, depending on different test types and results, and with great variation between regions. Findings were that prevalence increased with increasing age. Looking at different jobs, those working in healthcare were clearly more at risk, and to a lesser but still significant degree, those working in nursing homes…
Canto: Which is still largely healthcare, but less trained, and often less prepared for this onslaught…
Jacinta: Point taken. And those living in the larger municipalities were more often infected than those in less densely populated regions. Interestingly, they found that the rapid (and cheap) fingerpoint test, which provides results within ten minutes, was pretty close to being as effective as an immunological assay, which is important as the delay in test results has been a major issue.
Canto: Amazing. Why aren’t they using this all the time? Everywhere?
Jacinta: That’s another issue – maybe later. Anyway, much of this study confirms the many smaller studies that have been conducted. They found that healthcare workers comprised 24% of all confirmed cases. This may be partly because they had more access to testing. There is so much to glean from this study, I can only skim. But here are some very interesting remarks in their conclusion:
One in three infections seems to be asymptomatic, while a substantial number of symptomatic cases remained untested. Despite the high impact of covid19 in Spain, prevalence estimates remain low, and are clearly insufficient to provide herd immunity. This cannot be achieved without accepting the collateral damage of many deaths in the susceptible population and overburdening of health systems. In this situation, social distance methods and efforts to identify and isolate new cases are imperative for future epidemic control.
Canto: So there are no easy solutions, and even a vaccine is not necessarily going to be the magic bullet everyone’s hoping for. The proof of the pudding will be in the eating, and we haven’t eaten any vaccines yet. They won’t be on the menu for a while, and it’ll be a lot longer before we can gauge their nutritional value.
Jacinta: Yes, what you’re saying is, we don’t know how long antibodies to this virus will last. We’re still in unexplored terrain with respect to this very unusual and deadly virus. An article published on the Jama Network quite a while ago is still relevant now in its conclusions, as nothing we’ve so far found disconfirms it:
… the immune response to covid19 is not yet fully understood and definitive data on post-infection immunity are lacking. Amidst the uncertainty of this public health crisis, thoughtful and rigorous science will be essential to inform public health policy, planning and practice.
Canto: Frustrating to many. So with update 94 we’re getting towards mid-July and they’re noting that things are hotting up, as the weather is cooling down, in Australia, though of course it bears no comparison to the US tragedy. They were talking about things getting worse in their autumn, but summer hasn’t given them any sort of break.
Jacinta: So update 94 first looks at inhaled corticosteroids, one of many medications being considered and perhaps used by health professionals, others being ivermectin (a broad-spectrum anti-parasitic drug) and nitric oxide, all without solid RCT-type evidence. Even so, case reports and other low-level studies show promise, and these are arguably desperate times. A study presented by Dr Seheult suggested that some corticosteroids showed positive immunological effects in case reports and in vitro. Interestingly, asthmatics have been prescribed corticosteroids quite regularly…
Canto: As have I, from time to time. At least I think it was corticosteroid…
Jacinta: Well, that’s interesting, I know you’re not asthmatic but with bronchiectasis you have asthma-like symptoms at times. And the good news for you, and generally interesting news for us all, is that ‘asthma patients with covid19 do not appear to have a higher rate of hospitalisation or mortality compared with other covid19 patients’. Indeed it may be the opposite, as data from Wuhan indicates that less than 1% of their hospitalised patients had asthma, compared to 5% in the general population. In New York, too, asthma wasn’t even in the top ten comorbidities, which is pretty striking for a virus that hits the lungs first. Similarly, COPD, which your ailment is surely associated with, comes in below diabetes, renal disease and a whole range of cardiovascular issues as a comorbidity factor. A possible reason for this is that the kind of chronic inflammation produced by asthma and COPD is associated with reduced ACE2 expression, meaning fewer receptors for the virus. So these conditions could actually be protective. And they might also be on corticosteroid inhalers, which may also be protective.
Canto: That sounds great. Let’s leave it there before I hear any bad news…
References
Coronavirus Pandemic Update 93: Antibodies, Immunity, & Prevalence of COVID-19 – New Data from Spain
Coronavirus Pandemic Update 94: Inhaled Steroids COVID-19 Treatment; New Pneumonia in Kazakhstan?
How do monoclonal antibodies work? Rituximab, infliximab, adalimumab and others
Coronavirus Treatment and Prevention with Monoclonal Antibodies
covid-19, more on fructose, vitamin D, treatments and the vagaries of testing
Canto: Ok, so note that in the graphic from the previous post, Australia is third highest in the group of 31 countries studied for caloric intake from sweeteners, but we don’t use HFCS much at all.
Jacinta: It might be a misleading graphic too. You might be forgiven for thinking that it somehow shows the USA as the most unhealthy, sweet-toothy country on the list, and Australia in third position, but since we’re more concerned here with links between fructose and covid-19 co-morbidities such as obesity, diabetes, cardiovascular problems and oxidative stress, the graphic doesn’t tell us much.
Canto: Yes so I found on this indexmundi site a list of 195 countries – and that’s all of them – showing prevalence of diabetes 1 and 2. That’s to say, the percentage of the adult population (from 20 to 79) that is diabetic. The USA ranks 43rd on that list, and Australia is down at 137th, level with Finland and Japan. But the site doesn’t name sources, and provides an end-note on the unreliability of much evidence: ‘National health authorities differ widely in capacity and willingness to collect or report information’. I should also add that though the USA is 43rd, the only other major nations above them are just about every Middle Eastern country, Pakistan, South Africa, Egypt, Sudan and Mexico. Make of that what you will.
Jacinta: Let’s avoid that rabbit hole, and return to medcram update 83, which briefly describes vitamin D3 (cholecalciferol) metabolism. This may involve a bit of repetition but that’s rarely a bad thing for us. So the D3 that we absorb or ingest goes to the liver and is hydroxylased at the 25th position (25-OH), but it doesn’t become activated until it’s again hydroxylased at the first position by the kidney (1,25-diOH, aka 1,25 dihydroxy vitamin D). And there’s another enzyme that can convert the vitamin to inactive forms.
Canto: With that, Dr Seheult looks at another article from 2013 which describes a rat study that indicates that if fed on a high fructose diet, lactating rats suffered reduced rates of active intestinal calcium transport and active vitamin D. Or, more, accurately I think, they didn’t get the increased rates and levels that would be expected during lactation. So, because calcium is essential for skeletal growth, the study says ‘our discovery may explain findings that excessive consumption of sweeteners compromises bone integrity in children’.
Jacinta: Interesting, and I presume that means consumption by the mother during pregnancy. Anyway, in more detail, what they found was that increased fructose intake inhibited the enzyme that converted vitamin D into the active form in the kidney, and promoted the enzyme responsible for the inactive forms. Disturbing, as Seheult says, for the excessive fructose in American diets, which may consequently affect calcium and vitamin D levels, though that would surely require more research.
Canto: Well, the same group released more research in 2014 which found that chronic high fructose intake in calcium-sufficient rodents (rats and mice) reduced their active vitamin D levels. And a 2015 study from Iran looked at something different but again having to do with effects on enzymes and metabolism. They looked at S-methyl cysteine (SMC), and this recalls the investigation of N-acetyl cysteine (NAC) a few updates ago. Found naturally in garlic and onions, SMC is described as a hydrophilic cysteine-containing compound, which they investigated for its putative effects against oxidative stress and inflammation. So they induced oxidative stress in rats via a high-fructose diet over 8 weeks and then dosed them with SMC. Results from the high fructose diet were – here goes – increased blood levels of glucose, insulin, malondialdehyde, and tumour necrosis factor-alpha.
Jacinta: Okay so the increased insulin is presumably a reaction to the increased glucose. Its role is to absorb excess blood glucose, and too much of it can result in hypoglycaemia, low serum glucose levels. Malondialdehyde (MDA) is described as a marker for oxidative stress, so it’s not good. Tumour necrosis factor (TNF or TNFα) is a ‘multifunctional cytokine’, and although cytokines (types of proteins) perform many vital functions, the cytokine storm that appears to be associated with oxidative stress and covid-19 is a bad thing.
Canto: But there were also decreased levels of glutathione (GSH), glutathione peroxidase (GPx) and catalase as a result of this fructose diet, and Seheult talked about these enzymes and such as important in reducing oxidative stress. However, the SMC dosing improved antioxidant enzyme activities and reduced levels of glucose, insulin and TNFα.
Jacinta: So this SNC seems another promising antioxidant treatment. Meanwhile, watch your sugar intake, especially with fructose. More studies required of course, but I suppose there are ethical issues involved in fattening up and inducing oxidative stress on human subjects with a high fructose diet. Okay updates 84 and 85 deal with questions that hospitalised covid-19 patients might want answered, so we’re going to skip those or we’ll never catch up on these updates. With update 86 they’re into the second half of June and noticing a resurgence of the virus. So at the Johns Hopkins site they’ve ‘working to fill the void of publicly accessible covid-19 testing data’, because without testing you obviously can’t work out the numbers.
Canto: But more than testing itself, the turnaround of results is a problem. A young woman was just on the tube saying it took three weeks to get her test results, which renders the test useless. And another person on the tube reported that she’d tested positive, felt generally okay or asymptomatic, then tested negative, after which she came down with a heavy case replete with many of the covid-19 symptoms, and then tested positive again. How can this happen?
Jacinta: It’s still a mysterious virus, but to return to the update and Johns Hopkins, they’re generally looking at US data, but I’m interested in understanding the testing process and how well it maps the prevalence of this virus. The website has a graphic which shows the fairly rapid rise in daily testing from March through to June (with a drop-off from mid-June, when perhaps they thought it was more under control), and the number of positive daily tests, which hasn’t of course risen so much, so that the percentage of positive test results has gradually fallen. The WHO recommends that the percentage of positive tests, the positive percentage rate (PPR), in nations or states where there’s widespread testing, should be under 5% for at least fourteen days before those states can start ‘relaxing’, but I’ve read different, more flexible recommendations elsewhere from health authorities, so it seems still a matter of educated guesswork with an unpredictable pandemic.
Canto: For the different US states, looking at the figures now in mid-August, the figures are weird. Washington has a PPR of 100% (?!) and are testing 1 in every 10,000, so it seems they’re only testing those they know are positive? That’s top of the list and bottom is North Carolina with a PPR of -13.1, and yes that’s a minus, and they’re testing -.09 in every thousand, and I’ve no idea what that means.
Jacinta: But most states’ figures are clear enough. New York is at 0.8% PPR with over 4 tests per 1000, which is good, but Nevada, Idaho and Florida are at over 16% PPR, each with around 1.5 tests per 1000, and that’s obviously a problem. An indication of the lack of centralised control of the situation – it’s hard to compare data from state to state. Anyway, the key, some say, is to scale the testing to the size of the epidemic in that nation/state, not to the state’s population – but how can you do that when you’re using the testing to determine the size of the epidemic?
Canto: Well presumably if nobody is reporting unusual, covid-like symptoms, as is the case here in South Australia, you don’t need to spend so much time, money and energy on testing. Not the case in the USA. Anyway, in this update, Dr Seheult noted, as we have been, that the case numbers for covid-19 are increasing, but the death rate is decreasing slightly, or at least levelling off. Possibly a result of more testing combined with better treatment. They may also be catching weaker levels of the virus due to measures put in place. But there’s no evidence as yet that the virus itself has become less potent, and this seems unlikely.
Jacinta: And speaking of treatments, the steroid dexamethasone is apparently reducing mortality by as much as 35% for covid-19 patients on ventilation, according to a WHO preliminary report of work done at Oxford. It’s only good for those with severe hypoxia and associated problems though, but its a cheap, off-patent medication which can be added to the box of tricks for ICUs, once the data is confirmed.
Canto: Okay, next time….
References
Coronavirus Pandemic Update 83: High Fructose, Vitamin D, & Oxidative Stress in COVID-19
Coronavirus Pandemic Update 86: COVID-19 Testing & Cases Increasing but Daily Deaths Decreasing
https://www.indexmundi.com/facts/indicators/SH.STA.DIAB.ZS/rankings
https://coronavirus.jhu.edu/testing
covid-19: vitamin D, fructose and oxidative stress
So looking at the Medcram coronavirus update 82, approaching mid-June, we find that many of the monitoring websites give the impression that case rates are falling in the USA and elsewhere….
The update also looks at diabetes as a risk factor for covid-19. It discusses data from China linking mortality to blood sugar levels. Glycated haemoglobin (HbA1c) was brought up in a previous post, though there are different ways of measuring it – I’ll keep to the percentages. The normal HbA1c should be below 6%, though presumably not too far below, as can happen for diabetics that over-medicate. Your HbA1c measure tells you what your blood sugar level has been over the last two-month period, approximately. So, to quote from the study:
the researchers found an increased mortality risk associated with any form of previously undiagnosed elevated blood glucose at the time of admission among 453 patients hospitalised with laboratory-confirmed SARS-CoV2 infection
One would imagine that, with the oxidative stress that SARS-CoV2 brings on, diabetics or pre-diabetics not on medication might be more at risk than those on regular medication with a consequently relatively low HbA1c. This is the kind of association found here.
The update goes on to discuss an article on race and covid-19 mortality in England, which has a supposedly open-access National Health Service (NHS), which in fact has been subject to savage cuts from successive conservative governments. The article concludes, unsurprisingly, that BAME (i.e Black, Asian and Minority Ethnic) persons are ‘at increased risk of death from covid-19 even after adjusting for geographic region’. Suggestions for reducing these apparent inequities include ensuring adequate income protection, reducing occupational risks, reducing barriers in accessing healthcare and providing culturally and linguistically appropriate services. Of course, these problems exist within all countries with substantial immigrant populations, many of whom are more exposed to the virus than others.
Vitamin D is next revisited, with an article entitled ‘Vitamin D deficiency in Europe: pandemic?’, which was actually published back in 2016. Now I note from some of the comments on this update that there’s a lot of hype and apparent misinformation on vitamin D out there, so I want to dwell on this, for my own education.
The article refers to a Vitamin D Standardisation Program (VDSP) which has developed protocols to look at serum vitamin D data from differently-aged European populations, ‘to better quantify the prevalence of vitamin D deficiency in Europe’. So they applied these protocols to 14 different population studies, looking at serum 25-hydroxyvitamin D [25(OH)D]. Vitamin D has five different types, but the pertinent one for human health is D3, aka cholecalciferol, which is made by the skin when exposed to sunlight, and is also found in foods and supplements. D3 is hydroxylated by the liver at the ’25 position’, according to Seheult. Presumably this is a position on the D3 molecule where a hydroxyl group is added. 25(OH)D refers to the molecule after this hydroxylation, but before it becomes activated by further hydroxylation at position 1 by the kidney. So they looked at this molecule in a number of studies using ‘certified liquid chromatography – tandem mass spectrometry on biobanked sera’. Combined with other standardised serum data, data was collected from almost 56,000 patients, and the findings were that 13% of them, regardless of category, had serum levels seriously below normal, especially during the winter months. 40% were below the generally accepted norm. The problem was considerably exacerbated in dark-skinned ethnic sub-groups.
Back to 2020, and an article looking at the role of vitamin D in the prevention of covid-19 infection and mortality. It noted that ‘Vitamin D levels are severely low in the aging population especially in Spain, Italy and Switzerland’, so this is obviously a covid-19 co-morbidity factor. The article goes on to describe the mechanism of vitamin D’s action in the body, the details of which I’ll pass over, but it does involve ACE-2 and angiotensin 1,7, and also many other factors including macrophage development. With all this they raise the question of widespread vitamin D supplementation, which is apparently a hot topic beyond strictly scientific media, as mega-doses of vitamin D are being argued for on certain social media platforms, and even in the comments to this update. There are messy arguments going around about safe upper limits. Dr Seheult simply reports the article’s concern about ‘popular information channels’ spruiking the use of vitamin D3 above the generally accepted safe upper limit of 4000 international units per day. There is of course a battle here, not only in relation to vitamin D3, between those who demand proper trialling and vetting of medications and supplements and those looking for quick fixes. In any case, modest, regular dosing of the vitamin seems to be most effective.
Update 83 goes intensively into a very important and interesting health topic, which has been quite controversial and also revelatory of late; the role of fructose in our diet, and how it works in our bodies. So to refresh – which is always good for me, at least – about the issue of oxidative stress and how it is exacerbated by SARS-CoV2. So we have oxidative stress in the form of an excess of superoxide and reactive oxygen species (ROS). The SARS-CoV2 virus enters the cell via the ACE2 receptor, blocking angiotensin-converting enzyme 2 (ACE2) from converting angiotensin-2 (AT-2) to angiotensin 1,7 (AT-1,7). AT-2 promotes superoxide production, while AT-1,7 inhibits it. This problem is in addition to the effect of SARS-CoV2 itself in bringing about an increase in polymorphonuclear leukocytes (PMNs), which are white blood cells such as neutrophils, basophils and eosinophils. These also lead to increased superoxide production, and more oxidative stress. An essential feature of oxidative stress is that it can result in endothelial cell dysfunction. These cells line the vascular system that feeds the body’s major organs. This dysfunction brings about an increase in von Willibrand factor which leads to clotting and thrombosis. Recent analysis of autopsies found that covid-19 patients had nine times more lung clotting than control groups including influenza patients.
So the point of all this is that not having oxidative stress in the first place will be an important prophylactic against the virus. As Dr Seheult relates from the coalface, it’s those with a high BMI, with kidney and cardiovascular issues, and with diabetes, that seem to be at most risk of succumbing to the virus. Also, those with apparently normal HbA1c but with increased glucose were about 10 times more likely to have serious complications associated with the virus. This raises the question of diet, specifically bad diet.
We then go back to 2017 and an article, or compendium of articles, published in Nutrients. Its title is ‘fructose consumption in the development of obesity and the effects of different protocols of physical exercise on the hepatic metabolism’. So fructose is a simple sugar or monosaccharide which combines with glucose to form the disaccharide sucrose. There are two forms of fructose (and of glucose), which are enantiomers, which is to say they have opposite chirality, which gives them different reactive properties. They’e called D-fructose and L-fructose. They’re six-carbon sugars, and D-fructose is the prominent form in the body. Sucrose links together a molecule of glucose with one of fructose, so that sucrose (table sugar) is essentially 50% fructose. Fructose is added to many foods as a sweetener, particularly in the form of high fructose corn syrup (HFCS) and this has become controversial, in case you didn’t know. It’s not such as issue in Australia, where we mostly use cane sugar as a sweetener, but it features in imported processed foods, and in many sweetened drinks. So how does fructose impact on obesity and oxidative stress? To quote from the abstract of the above-named article, ‘studies indicate that fructose may be a carbohydrate with greater obesogenic potential than other sugars’. The article provides a compendium of such studies and how fructose affects glucose metabolism in the liver, adversely affects hepatocyte function and engenders inflammatory responses. It also advocates physical exercise for reduction of symptoms and as harm-minimisation practice. An experiment on rodents in which half were fed on fructose, the other half on sucrose (50% fructose, 50% glucose), the fructose-fed rodents gained more weight, and over time that extra weight involved an increase in abdominal adipose tissue and increased serum triglyceride levels:
Moreover, several studies corroborated the evidence that high fructose consumption might lead to accumulation of adipose tissue, systematic inflammation, obesity, oxidative stress and consequently insulin resistance in different tissues.
And there’s much more on the same lines, with relevant references. Dr Seheult describes other articles and studies over the last ten years identifying fructose and HFCS and their relationship to type 2 diabetes prevalence. One interesting article, which looked at HFCS alone, and surveyed diabetes on a global level, found that ‘diabetes prevalence was 20% higher in countries with higher availability of HFCS compared to countries with low availability’ and these results were adjusted for BMI, population, GDP and other factors. Greatest use of HFCS was in the USA, which of course has the highest rate of diabetes, and is leading the world in covid-19 cases.
References
Coronavirus Pandemic Update 82: Racial Disparities with COVID-19 & Vitamin D
Coronavirus Pandemic Update 83: High Fructose, Vitamin D, & Oxidative Stress in COVID-19
https://www.sciencedirect.com/science/article/pii/S0899900714001920
Covid-19: act quickly, test widely, maintain distance
So Covid-19 is the inescapable pandemic, the great test of administrations worldwide. We’re beyond blaming China for inflicting this upon the world, though this shouldn’t be forgotten, as mistakes need to be remedied. But now we’re looking elsewhere for praise and blame. Few people are keen to praise the Chinese government for its methods, however effective they might be. They’re looking to more humane governments, those that have achieved similar results without the brutality.
A much-discussed essay from Imperial College London compares suppression with mitigation, and favours suppression, and this is proving controversial, as others say it’s overly pessimistic, citing apparent success in flattening the curve in South Korea, for example. Of course there’s the difficulty of knowing whether reported data is reliable, whether testing is thorough enough and so forth. This article from The Conversation looks at South Korea’s success and suggests it may be as much due to its surveillance technology regime as to its effective virus testing program. Other countries, such as Taiwan and Singapore, have also been very successful, apparently, though with a much smaller case load. Another enigma appears to be India. It has been praised for shutting its borders early, but surely there would be a difficulty in obtaining reliable figures in such a diverse patchwork of a nation. Still, if we take its reported figures on face value, it has been an outstanding success story, so far.
South Korea’s success has much to do with its sophisticated biotech industry (something we in Australia can also boast of), which can produce tests quickly. It also has a well-developed healthcare system, apparently. It has done more testing than any country, other than China, so its figures are likely to be more reliable. But it can also track contacts of Covid-19 sufferers through debit and credit cards and mobile phones (the country is at the top of per capita users of these items). The country also employs CCTV surveillance more than just about any other country in the world, and this is mostly acceptable to its citizenry. My own conversations tell me that such surveillance would cause much greater concern here.
So the pandemic will continue to be combated with a variety of methods by different countries, all looking to others to see what works and to modify working methods to suit their own people. Keep alert for success stories and analyse them, see if they can be replicated. Italy appears to be a disaster, but not everywhere. In the northern town of Vo, where the first Italian Covid-19 death was reported, health authorities managed to lock down and test all 3000 of its residents at the outset, and found a 3% infection rate. The infected, most of whom displayed no symptoms, were quarantined, and a later large-scale test found the rate had been reduced to less than 0.5%. Of course, this is a small town, but the lessons are obvious. Test widely and act swiftly, and make sure you’re prepared for this sort of situation, unlike the USA, where federal neglect under the wanker in the white palace has virtually eviscerated its CDC. The CDC’s failure to provide test kits to state public health labs at the start of the outbreak has massively hampered the ability to isolate and trace contacts of the infected, so important during the early stages. Labs around the country are still struggling to fill the void, while the wanker engages in the standard down-playing, over-promising and blame-shifting that’s inherent to him.
Here in Australia we’re ranked 21st in the number of cases, not great for a sparsely populated island nation, far from the epicentre, though our connections with China, and our slowness in shutting down travel from that country, is the likely explanation. The good news is that we’ve recorded only seven deaths from a little over a thousand cases so far. The bad news is that the curve isn’t flattening, with more than a hundred new cases recorded in the last 24 hours. Stop press: make that more than 200, and Australia has jumped to 19th in the number of cases, though still only 7 deaths thankfully. I’ve just listened to a press conference by our Prime Minister and Chief Medical Officer announcing closures to pubs, restaurants, cinemas and cafes for the foreseeable. Schools, however, are to remain open, with everyone expected to follow distance rules of four square metres. This is all extremely unnerving. I’ve been asked to teach tomorrow, with different classes starting at different times to prevent crowding on arrival and departure. I’ve agreed to do it, though I’m over sixty with a pre-existing bronchial condition (but it’s more the over seventies that are at risk). Much of the questioning at the press conference was about the school situation, with states such as Victoria not apparently being aligned with the federal government on whether they should remain open. It may be difficult to maintain the four square rule in a relatively dynamic, interactive classroom, and then there’s the question of virus spread by people who haven’t been tested and show no symptoms. Our students have already been here for a while, and I’m presuming, without much knowledge, that infectiousness is greatest in the early stages of contracting the virus. There are also rumours, mentioned in the press conference, that the young may be ‘super-spreaders’. The Chief Medical Officer claimed that there was no evidence to this effect, and I note that the term is rather frowned upon as ‘unscientific’, but without more widespread testing we really don’t know what, or who, we’re dealing with when we enter a classroom.
Meanwhile, just in the past 24 hours there’s been a spike of cases here in South Australia, all from people recently returned from overseas and interstate. Of course, these are the people who would be tested… And, Australia has now jumped to 16th in the world for number of cases, but the death toll remans the same – in fact we have the lowest mortality rate of all the top twenty countries, according to worldometer, but I’m personally a bit skeptical of these figures.
May we live in interesting times…?
Covid 19, bird flu, etc – why China?
The recent coronavirus now has an official name, Covid 19, and the death toll at present is a little under 2000, considerably more than that for the SARS coronavirus of 2003. It has spread to at least two dozen countries according to ABC reporting. I note that the WHO are emphasising how co-operative the Chinese authorities have been, I suspect as an attempt to keep those channels of communication and co-operation open, or to open them wider. The infamously over-controlling Beijing government is faced with a dilemma as its economy is taking a major hit – it desperately wants to get over this epidemic, which means downplaying it as much as possible, but its dependence on international trade means having to co-operate with those over whom it has no control. The Middle Kingdom has always been sensitive about this issue of control and dominance, which clashes with the co-operative spirit of modern global trade relations.
Having said that, Chinese authorities have certainly learned from the reaction to their fairly disastrous early handling of the SARS coronavirus outbreak in 2002. In terms of the really essential stuff, co-operation and information-sharing have rapidly improved – motivated by the apolitical spirit of research, detection and problem-solving that constitutes science’s unique value.
Of course, one of the questions being asked, with Covid 19, the SARS virus, and other viruses such as H7N9 avian influenza virus (which had a very high mortality rate), is ‘Why China?’ An article from late 2017 in the Smithsonian magazine provides a plausible if shocking answer.
It seems imprinted in Chinese culture that freshly killed-birds and other animals are tastier and somehow healthier than anything frozen or otherwise processed. The Chinese government has, in the past, been reluctant to interfere with the demand for freshly slaughtered produce, and it’s likely that, even if it enforced a clamp-down, the market would go underground. Melinda Liu, author of the Smithsonian article, described the scene at one of these markets, in the Sichuan city of Chingzhou:
Half a dozen forlorn ducks, legs tied, lay on a tiled and blood-spattered floor, alongside dozens of caged chickens. Stalls overflowed with graphic evidence of the morning’s brisk trade: boiled bird carcasses, bloodied cleavers, clumps of feathers, poultry organs. Open vats bubbled with a dark oleaginous resin used to remove feathers. Poultry cages were draped with the pelts of freshly skinned rabbits. (“Rabbit meat wholesale,” a sign said). These areas – often poorly ventilated, with multiple species jammed together – create ideal conditions for spreading disease through shared water utensils or airborne droplets of blood and other secretions.
Flu viruses can crop up and mutate anywhere – for example, the H5N2 flu strain which broke out in the USA in 2015 led to the slaughter of 48 million poultry – but China’s mixed farming habits, in which poultry and other livestock live in close proximity with their keepers, together with the taste for freshly slaughtered and disturbingly exotic meat, and the conditions in many markets and slaughter-yards, presents a massive cultural problem for China’s huge and increasingly mobile population. The country will have to come to terms with these issues, sooner rather than later, if it wants to recapture and grow beyond the leading economic role it led before the advent of Covid 19.
References
https://www.smithsonianmag.com/science-nature/china-ground-zero-future-pandemic-180965213/
https://www.who.int/emergencies/diseases/novel-coronavirus-2019
https://www.who.int/influenza/human_animal_interface/influenza_h7n9/en/