Diseases

How to stop viral vampires: virus life cycle and antiviral 101

Cyto Citadel 2

This is some of the research that contributed to the recently released Darwin’s Paradox: An international science mysteryhttp://amzn.to/2k8qJgi. Anti-virals are way more complicated that I first imagined.

The Battle for Cyto Citadel – A Primer in Antiviral Warfare

This is the story of viral vampires and their clone armies attacking the friendly territory defended by cyto citadels. Viruses, not quite alive, walking dead, attack cells, armored castles (Cyto Cidadel), defended by vaccines and drugs. Some are defeated.

Skirmish 1 – VACCINATION

All around the Cyto Citadel are roaming squads of deadly B-cell skirmishers and T-cell marauders searching for viral vampires. These forces are very effective and win most of their battles leaving vanquished vampires in their wake.

Unfortunately, they only attack vampires they have seen before. Any new viral vampires get by them unnoticed as if they were wearing invisibility cloaks.

Vaccines introduce B-cells and T-cells to recognized vampires of the viral armies, such as measles, mumps, rubella, polio, and hepatitis. Captain Cytoplasm uses as many vaccines as possible, but still many viral vampires get pass this defense, especially influenza viruses which constantly mutate into unrecognizable forms.

Skirmish 2 – ATTACHMENT

When the invisibility-cloaked vampires approach the Cyto Citadel, their first objective is to attach to the citadel walls to stage their break in. Medical sentries can stop some viral attacks before they attach to the wall.

Docosanol dragoons prevent herpes simplex viral vampires from attaching to the citadel walls. Unfortunately, if these loyal dragoons do not recognize the viral vampires, the invaders slip by undeterred.

Skirmish 3 – ENDOCYTOSIS

With the vampires at the wall, they need to worm their way through. The Cyto Citadel has strong walls to thwart this intrusion.

For example, even the dreaded HIV horde, causers of the AIDS scourge, can not penetrate the citadel without the help of CCR5 crackers or CXCR4 crashers. Blockers can be brought against CCR5 and CXCR4 to isolate the HIV horde outside the Citadel where they can do no damage.

Skirmish 4 – UNCOATING

Once inside, all is not lost. First of all the viral vampires come heavily armored for the battle to breach the citadel walls. Before they can do their real damage, they need to remove this armor. This is called uncoating.

Two antiviral armies, the amantadine arsenal, and the rimantadine rangers, prevent influenza vampires from releasing acid to dissolve their armor. Without this acid, they are stuck inside their own armor and helpless to do any damage.

Skirmish 5 – MUTAGENESIS

Once uncoated, the viral vampires break into the citadel storeroom to steal parts to build a vampire clone army. This is the last thing the citadel defenders want: a viral vampire clone army!

The citadel storerooms are infiltrated by ribavirin robots that fool the vampires to accepting mutating parts. When the vampires build clones from mutating parts, errors pile up and the clones die from error catastrophe. Too many errors equal dead clones.

Skirmish 6 – SYNTHESIS

Another attack on the synthesis of the viral clone army is to supply the vampires with the wrong parts. Reverse Transcriptase quartermasters delivering the wrong parts from inventory can foil the cloning efforts of some of the HIV horde, and the Hepatitis B horde also. The parts look right, but when used, the result is defective.

Skirmish 7 – REPLICATION

If a few clones get this far, all is not lost. Building a clone is a slow process. Unfortunately, once they are operational, they can replicate themselves. From a few clones, they can grow a full clone army.

Patrol of protease (pronounced PRO-TEA-AZE) inhibitors can stop the replication. Unfortunately, like all the fighters in the Cyto Citadel, patrols are very specific about who they will attack. Smart citadel defenders recruit as many different protease inhibitor patrols as possible.

If the HIV horde invades, the saquinavir, ritonavir, indinavirnelfinavir, and amprenavir patrols are recommended. For the hepatitis C horde, different patrols are needed: boceprevir and telaprevir.

The last defense: Skirmish 8 – EXOCYTOSIS

If the clone army is successfully put together, the Cyto Citadel is lost, but a lost battle is not a lost war. As a last ditch effort, oseltamivir (aka Tamaflu) can prevent the clone army from breaching the walls from the inside. With the clone army trapped in this citadel, other Citadels can be safe.

Good News and Bad News

The good news is that there are many ways the Cyto Citadel defenders can stop the viral vampires and their clone armies.

The bad news is that all the defenders are all very specific, and each different vampire attack must be met with the correct response. Unfortunately, some vampires mutate rapidly, so there is an arms race to keep finding new defenders. Even worse, for some viral attacks, there are no known defenders.

Map credit: Dyson Logos rpgcharacters.wordpress.com.

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Why didn’t I go to medical school?

Blood

This is some of the thinking that contributed to the recently released Darwin’s Paradox: An international science mysteryhttp://amzn.to/2k8qJgi. Novelists are always accused of adding biographical details, especially by their families. On their other hand they are advised to “write what you know.” The Ariq, a medical school dropout from Mongolia is a bit autobiographical. Yes, I have been to Mongolia.

I can’t stand the sight of needles or blood. When I go in for a blood test, I close my eyes and cringe. When it’s all over, I know it’s polite to assure the phlebotomist (that’s what they are called) that their technique was painless. I just can’t stand the idea of sticking a needle into me and drawing out my blood. When I get a vaccination, the nurses are concerned I might faint (more on that later). When I watch movies or television, I close my eyes and cover my face during any scenes with blood or needles.

I am not alone. About 3-4% of the population has something similar or even more severe. The condition is called: vasovagal syncope (sin-coe-pee), or neurally mediated syncope (NMS), or vasodepressor syncope, or even reflex syncope. Syncope is just the medical term for fainting. I don’t faint, because I follow the advice given to those who do: “don’t do that (whatever causes you to faint);” I don’t look at blood or needles. This condition is idiopathic, physician speak for: “I don’t know the cause.”

Medical Science might not know the cause of NMS, but that doesn’t mean nothing is known.

NMS has to do with the autonomic nervous system. That is the part of your nervous system responsible for automatic behaviors. You control what you put into your mouth, chew, and swallow, but once the food gets into your digestive tract, the autonomic nervous system takes over. Also, your autonomic nervous system keeps you breathing and your heart beating 24/7.

One part of the autonomic nervous system is the sympathetic nervous system which gets lots of press for its part in “fight or flight” responses. Vasovagal syncope is controlled/caused by the under-appreciated parasympatheic nervous system which controls “rest or digest” responses. That’s right! Fight-or-flight is not the only choice. One system prepares for action and the other for inaction. It is an over-reaction of the latter that causes fainting.

It is assumed that evolution has maintained this “rest or digest” response because it’s beneficial. Perhaps, if two people received severe traumas, the one who could lower their blood pressure had a better chance to survive by bleeding less and healing faster. Clearly, pumping the body full of adrenaline (fight-or-flight response) is not beneficial if you are bleeding profusely – in spite how often this is seen in action movies.

Here’s the movie scene I’d like to see. The hero and the antagonist wound each other. Now the antagonist gets mad, flexes her muscles, swinging her battle ax like crazy until she bleeds out over the passed-out body of our fainting hero. Evidently, that’s how my ancestors got this far and saying “not for the faint-hearted,” might not be true.

Also, the rest-or-digest response could work like a playing-dead response which is often beneficial when faced with an attacking animal.

So it seems that the meek have inherited 3-4% of the earth. Regardless, one way or another, my ancestors found a survival boost from their reaction to blood. I no longer need to be embarrassed. I have a name for my condition (actually four names) and assurance that I am not alone. I even can smugly know that many (genes) without reflex syncope did not make it this far. So there!

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Thinking of Zebras #Rabies #Bats #Chiroptera #Medical

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This is some of the research that contributed to the recently released Darwin’s Paradox: An international science mysteryhttp://amzn.to/2k8qJgi. When the pandemic strikes, the medical doctors are forced to look for more and more unlikely causes.

New medical students are regularly warned that when they hear hoof beats, they should think of horses, not zebras. Before they get their clinical experiences, new doctors treat all diseases as equally probable. After they become experienced, they naturally think of horses (the common causes) when they hear hoof beats (common symptoms).

This leads to an opposite problem. Experienced doctors have a blind spot when the hoof beats actually foretell zebras (a rare disease).

Consider this case from Canadian Journal of Infectious Disease, Volume 13, Number 2, March/April 2002.

A nine-year-old boy had upper arm pain and a slight fever. In a few days the pain extended down to his wrist and up to his shoulder and neck. The area was tender to touch and prevented him from sleeping. The next day he had tremors and was hospitalized.

This was followed by sore throat, difficulty swallowing, and intense itching. The doctors considered allergies and treated his with diphenhydramine (an antihistamine) which had little effect.

The tremors and spasms got worse, and the patient had difficulty speaking. Knee-jerk reflexes were normal, but the doctor considered epilepsy and ordered an electroencephalogram. This showed a slowing of brain activity, but not epilepsy.

The patient next developed aerophobia (fear of air blown on them) and hydrophobia (inability to drink water). This was accompanied by a rash, transient hallucinations, and intense itching.

The following day brought severe tremors of the face and all limbs, drooling, priapism, and the feeling of suffocation. At this point the doctors presumed that the patient had rabies.

Nine days later, “14 days after the onset of his initial symptoms, the patient presented a clinical picture compatible with brain death, was extubated and died.”

This is an example of how difficult it is to diagnose rabies, absent a reported bite.

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Here is another case from CDC Morbidity and Mortality Weekly Report, Volume 60, Number 14, April 15, 2011.

“The patient reportedly had awakened with a bat on his arm 9 months earlier, but had not sought medical evaluation. He went to a local emergency department (ED) on October 30 and soon after was hospitalized; he died 12 days later.”

Initially he was treated by a chiropractor for pain and numbness of his left hand and arm, lower neck and upper back. The chiropractic treatment relieved the back pain, but the arm numbness and tingling got worst.

At the hospital, the patient did not have a fever, blood pressure was normal, blood count and routine chemistries were normal. Strength and sensation were normal. The only symptoms were weakness of the left arm, elevated white blood cell counts, and elevated glucose. A CT scan also revealed some anomalies.

Most concerning, the patient had such difficulty breathing that he was put on ventilation.

AIDP and Guillain-Barre syndrome were the chief diagnoses considered at this point. MRI and entectromyography pointed to AIDP and treatment began.

A few days later, with the patient not improving, CSF (cerebrospinal fluid) analysis lead the staff to switch the diagnosis to meningoencephalitis. This treatment was also not effective.

At that point, “on November 4, the infectious disease physician asked the patient’s wife about any animal exposure history. … The wife had no knowledge of any recent animal bites. …
On November 8, another relative recounted an incident that had occurred approximately 9 months before onset of illness. The patient had told the relative about waking one night to a bat crawling on his arm. …
On November 11, the patient’s family elected to withdraw life support, and the patient died shortly afterward.”

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Here is a third case from CDC Morbidity and Mortality Weekly Report, Volume 59, Number 13, April 9, 2010.

When an apparently healthy man visited a clinic with fever and a cough, the clinician diagnosed bronchitis and prescribed antibiotics.

By the follow-up, the patient now had fever, chills, chest pains and left arm numbness. An electrocardiogram did not indicate a heart attack. The diagnosis was musculoskeletal pain and the patient was prescribed pain killers and muscle relaxants at this time.

Next visit the patient was agitated and restless, which was presumed to be a side-effect of the muscle relaxants. Hospital observation was recommended, but the patient went home.

The next day, the patient presented with twitches, high heart rate, low blood pressure, and fever. The doctor now considered sepsis and the patient was hospitalized.

The patient was intubated and tested extensively. The patient continued to deteriorate with low heart rate, low blood pressure, muscle wasting, and kidney failure requiring dialysis.

Two weeks after the initial clinic visit, rabies were considered. The patient died the next day.

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Sometimes those hoof beats are zebras.

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#Science #Research done right. Is #fructose dangerous? #Experiment design. #Nutrition #Diet

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Relax. Get comfortable. This is a story of real science. It is not click bait. It will require some thought. It will appeal to your left brain. It has nothing to do with cats.

This post is about a paper published in the peer-reviewed journal PLOS One titled Rescue of Fructose-Induced Metabolic Syndrome by Antibiotics or Faecal Transplantation in a Rat Model of Obesity. (Thanks to Dani for pointing this paper.)

Note this is not as authoritative as Science or Nature, but it is a couple of steps above Buzzfeed or Dr Oz.

Regardless, we are are going to review it and see how it is a example of good science.

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The paper opens with the assertion that fructose (aka Western Diet) is unhealthy: “A fructose-rich diet can induce metabolic syndrome, a combination of health disorders that increases the risk of diabetes and cardiovascular diseases.”

For the purposes of a scientific paper, this bold statement is understood to be merely an hypothesis.

Previous research has hinted at this conclusion with data like “It has been estimated that in the US the load of free fructose has increased from 158.5 kcal per person per day in 1978 to 228 kcal per person per day in 1998,” paired with “This substantial increase has paralleled the increased incidence of obesity.” However, this is merely correlation and scientifically useless for anything other than suggesting a hypothesis.

As good scientists, the authors acknowledge “the contribution of high-fructose diets to the development of obesity remains controversial, since some authors have not observed unequivocal evidence linking fructose consumption with metabolic disorder.” Note that the fructose conclusion is controversial because the evidence does not support it. Nothing is said about media personalities and opinion polls.

These scientists want to design an experiment to test the hypothesis to generate more evidence. This new evidence might support or reject the hypothesis. This is the Scientific Method and how science works, just like your were taught in school.

six1024px-Andean_cat_1_Jim_Sanderson

The first challenge these scientists must face is experimental design. As the hypothesis concerns people, it would be best to run the experiment on people. This won’t happen for two reasons. First, it is unethical to use people as test subjects. Among other criteria, the benefits must outweigh the cost, and the subjects must be protected from harm.

The experiment in question involves feeding subjects a diet expected to make them sick. This is not allowed.

[Aside: This restriction is why you see so many data analysis reports that try to figure out causes after the fact, by comparing people who happened to do one thing (eschew fructose) with people who happened to do another (consume lots of fructose). These reports come with many confounding factors, and are better for click-bait headlines than good science.]

The second reason people are not the test subjects is that they live too long. If we imagine that one needs to consume a high-fructose diet for 5% of their lifetime to see an effect, this is too long for people (around 4 years), but just right for rats (around 8 weeks). As lab rats are so important to medical research, the correspondence of rat age to human age is well studied and understood.

So the answer is to use short-lived rats. Much is known about rats, and particularly how to generalize from rats to people. Regardless, rats are also protected, and the experiment design is reviewed to protect the rats. (Rats are not protected as well as people, but they are protected.)

Treatment, housing, and euthanasia of animals met the guidelines set by the Italian Health Ministry. All experimental procedures involving animals were approved by “Comitato Etico-Scientifico per la Sperimentazione Animale” of the University “Federico II” of Naples.”

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The experiment divided the rats into two groups. The control group was fed a control diet and the experimental group was fed a fructose-rich diet. Aside from that single experimental variable, the scientists did their best to keep everything else the same. This is why these controlled experiments are so much better that those after-the-fact data studies mentioned above.

The energy content of the two diets was the same, because the composition was the same, except that half of the starch of the control diet had been substituted with fructose in the fructose-rich diet (Table 1). In addition, rats were pair-fed for the whole experimental period, by giving them the same amount of diet, both as weight and as caloric content. Each rat consumed the full portion of the diet fed them each day over the 8 week study period.”

Many tests were performed to evaluate the rats at the end of the experimental period. To spite the equivalence of caloric intake, the rats that consumed the fructose-rich diet had significantly more body fat.

At this point, their controlled experiment shows that the fructose-rich diet leads to increased body fat.

This is the common plaint of many dieters. Calorie and body fat do not correlate.

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At this point we have a nice experiment. We could possibly win a science fair with this, but these scientists took the next step.

They had shown that the fructose-rich diet causes a condition. They also believed that they knew the mechanism. Knowing the mechanism is even better than knowing a cause. Medical science moves forward when the mechanism is known.

This is why the discovery of vitamin C was more important than realizing that limes were a prophylactic for scurvy. Both discoveries were important, but the mechanism (vitamin C deficiency) led to new and improved treatments.

In the case of HIV/AIDS, no progress was made until the HIV virus was identified. Knowing the behaviors which transmitted HIV/AIDS was helpful, but the viral mechanism led to effective treatment.

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Now that the experiment had shown the existence of “fructose-induced metabolic syndrome,” the scientists hypothesized that the cause was a imbalance of micro-flora in the gut caused by the fructose-rich diet.

They further hypothesized that balance could be returned either with a targeted administration of antibiotics, or “faecal samples from control rats by oral gavage” to return balance. The fecal sample approach hypothesized that the control rats still had a healthy mix of gut micro-flora and introducing that healthy mix into the experimental rats would return them to a healthy balance and reverse the negative effects of their fructose-rich diet.

Happily (for the rats) both of these treatments improved the experimental rats’ condition.

Now that the scientists had experimentally shown they could cause fructose-induced metabolic syndrome and reverse it under controlled experimental conditions, we can all be confident that we are one step closer to understanding one cause and treatment for obesity and associated conditions.

There, that wasn’t so hard was it?

Post Script: I understand that no matter how difficult you might feel it is to reduce your consumption of high-fructose corn syrup (a major component of most non-diet soda pop), I imagine the yuch factor with fecal transplants is more off putting. However, as more is learned about gut flora, this may become a major new direction for medicine in the 21st century. Now might be a good time to start thinking positive thoughts about fecal transplantation.

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Live Long and Prosper #science #health

EscherichiaColi_NIAID

In the last two centuries, life expectancy has more than doubled from under 40 to over 70. This is the difference between parents burying their children and children not knowing both parents to today where grandchildren and grandparents are commonplace.

What has caused this dramatic extension in life expectancy? What has made living beyond 100 more common and childhood death more rare?

One suggestion might be antibiotics.

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20th century medicine was about antibiotics. Starting in 1911, over 100 different antibiotics were released. Some of the big ones were penicillin, tetracycline, doxycycline, amoxicillin, ciprofloxacin. Anitbiotics treat a wide range of diseases including: anthrax, whooping cough, pneumonia, botulism, and STDs. If you plan an international vacation, your doctor will give you ciprofloxacin for “traveler’s diarrhea.”

None of this would have been possible were it not for the 19th century discovery: GERMS! For 1000s of years prior to the 1800s, western medical theory was about humors. Health was controlled by the four humors: black bile, yellow bile, phlegm, and blood. When the humors were in balance you were healthy.

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When they were out of balance, you’d get sick, and you might be told to exercise more, eat healthier, be positive, pray, or if you could afford it, a doctor might try to balance the humors with medicines and procedures. These included bleeding, laxatives, and expectorants.

Before we laugh at two millenia of western medical science, reread that previous paragraph. Much of that advice, with the exception of bleeding, is still offered today. Thus, if we are honest, we can see the attraction of this commonsense medicine that let so many die.

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The 19th century changed all this (or did it?) with the discovery of specific germs for “anthrax, cholera, tuberculosis, leprosy, diphtheria, gangrene … plague, scarlet fever, tetanus, typhoid fever, pneumonia, gonorrhea and meningitis.”

This was all good, but germ theory and antibiotics only sometimes helped when people got sick. Penicillin was given credit for saving many lives in World War II, but the real gains came from preventions more than cures.

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The reasons that so many children and grandparents are alive is the long list of diseases that people growing up today have never seen — all thanks to vaccines.

Children are routinely protected from: chickenpox, diphtheria, influenza b, hepatitis A and B, measles, mumps, whooping cough, polio, pneumoccal, rotavirus, rubella, and tetanus. If you don’t recognize some of these diseases, it is not because they aren’t terrible or contagious, but because of vaccinations.

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Beyond these vaccines, if you are going to travel you might also get shots for meningitis, typhoid, and yellow fever.

The extension in life expectancy is not about cures, but about prevention.

The history of vaccination peaked during the period of 1880s (rabies) to 1950s (polio). However smallpox vaccination started much earlier in Asia with clear documentation in China during the 16th century, and vaccination development continues today, especially with the efforts to prevent Malaria.

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Quarantine … at home or away?

Scarlet Fever

Quarantine gets its name from a fourteenth century practice of requiring ships to dock in Venice harbor forty days before landing to prevent the spread of the Black Plague. (Quaranta is Italian for forty.)

While this sounds reasonable today, one has to wonder about the logic in a world where germs and contagious disease were unknown and inconceivable. Disease theory consisted of the imbalance of humors (blood, black bile, yellow bile, and phlegm) and various individual differences in environment, life style, and disposition. Two millenia of medical science barely recognized diseases as unique one from the other or contagious.

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Certainly some ships came from far away and had already seen plenty of time at sea, while others were local. Why quarantine all for forty days? Were there political, social, or racial reasons for these rules? Were exceptions made?

Quarantine started as an approach to isolate locations, originally ships, but later homes and villages were quarantined.

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An second approach was to isolate people. Quarantine locations began with leper colonies or lazarettos (after the parable of Lazarus). In this case, people were isolated at a location designated for that purpose. Again, recall that there was no concept of contagion. Most likely these people were isolated because others did not want to be near them or see them.

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Quarantine today is most often used in this second sense. At international borders pets may be sent to quarantine facilities.

In summary, some quarantine regimes are “no entry” regulations, much like the original Venician rules, but now extended beyond potentially sick people to include fruits and vegetables that can not be brought into places like California or Australia. Other quarantines are “no exit” isolations like the lazarettos. These are rarely seen today, though during the most recent Ebola panic in the United States, some people seemed ready to reinstate this practice.

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