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Biological differences between men and women impact perception of pain and choice of medication
Biological differences between men and women impact perception of pain and choice of medication
From Wired Magazine – Women’s Pain Is Different From Men’s—the Drugs Could Be Too
Men and Women can’t feel each other’s pain. Literally. We have different biological pathways for chronic pain, which means pain-relieving drugs that work for one sex might fail in the other half of the population.
So why don’t we have pain medicines designed just for men or women? The reason is simple: Because no one has looked for them. Drug development begins with studies on rats and mice, and until three years ago, almost all that research used only male animals. As a result, women in particular may be left with unnecessary pain—but men might be too.
Now a study in the journal Brain reveals differences in the sensory nerves that enter the spinal cords of men and women with neuropathic pain, which is persistent shooting or burning pain. The first such study in humans, it provides the most compelling evidence yet that we need different drugs for men and women.
“There’s a huge amount of suffering that’s happening that we could solve,” says Ted Price, professor of neuroscience at the University of Texas, Dallas, and an author of the Brain article. “As a field, it would be awesome to start having some success stories.”
Modern-day pain control is notoriously dismal. Our go-to medicines—opioids and anti-inflammatories—are just new versions of opium and willow bark, substances we’ve used for thousands of years. Although they are remarkably effective in relieving the sudden pain of a broken bone or pulled tooth, they don’t work as well for people with persistent pain that lasts three months or longer.
Some 50 million people struggle with pain most days or every day, and chronic pain is the leading cause of long-term disability in the United States. Women are more likely than men to have a chronic pain condition, such as arthritis, fibromyalgia, or migraines.
Meanwhile, pain medications are killing us. About 17,000 people die each year from prescribed opioids as clinicians write almost 200 million opioid prescriptions, or more than one for every two American adults.
The failure to include sex differences in the search for better pain relief stems in part from flawed but deep-seated beliefs. “[Medical researchers] made the assumption that men and women were absolutely identical in every respect, except their reproductive biology,” says Marianne Legato, a cardiologist who began sounding an alarm in the 1980s about differences in heart attack symptoms among women. She went on to pioneer a new field of gender-specific medicine.
The physiology of pain is just one of many ways that men and women differ, she says. But she isn’t surprised that no sex-specific medicines have emerged. The medical community—including pharmaceutical companies—didn’t appreciate the variation between men and women, including in their metabolisms, immune systems, and gene expression.
“If there were differences in how their drugs worked between men and women, they didn’t want to hear about it,” she says.
… Tailoring new medicines to men or women would be revolutionary, particularly considering that it took many years for women (and female animals) to get included in pain research at all.
Fearful of potential birth defects, in 1977 the FDA cautioned against including women of childbearing age in clinical trials, which meant women used drugs solely designed for men. By 1993, the thinking had changed, and Congress passed a law requiring the inclusion of women in clinical trials funded by the National Institutes of Health. Although clinical trials now include both men and women, they often don’t report results by sex.
https://www.wired.com/story/womens-pain-is-different-from-mens-the-drugs-could-be-too/
Why the sexes don’t feel pain in the same way
Why the sexes don’t feel pain the same way – After decades of assuming that pain processing is equivalent in all sexes, scientists are finding that different biological pathways can produce an ‘ouch!’. Amber Dance, Nature, 3/27/2019
Robert Sorge was studying pain in mice in 2009, but he was the one who ended up with a headache.
At McGill University in Montreal, Canada, Sorge was investigating how animals develop an extreme sensitivity to touch. To test for this response, Sorge poked the paws of mice using fine hairs, ones that wouldn’t ordinarily bother them. The males behaved as the scientific literature said they would: they yanked their paws back from even the finest of threads.
But females remained stoic to Sorge’s gentle pokes and prods1. “It just didn’t work in the females,” recalls Sorge, now a behaviourist at the University of Alabama at Birmingham. “We couldn’t figure out why.” Sorge and his adviser at McGill University, pain researcher Jeffrey Mogil, would go on to determine that this kind of pain hypersensitivity results from remarkably different pathways in male and female mice, with distinct immune-cell types contributing to discomfort2.
Sorge and Mogil would never have made their discovery if they had followed the conventions of most pain researchers. By including male and female mice, they were going against the crowd. At the time, many pain scientists worried that females’ hormone cycles would complicate results. Others stuck with males because, well, that’s how things were done.
Today, inspired in part by Sorge and Mogil’s work and spurred on by funders, pain researchers are opening their eyes to the spectrum of responses across sexes. Results are starting to trickle out, and it’s clear that certain pain pathways vary considerably, with immune cells and hormones having key roles in differing responses.
This push is part of a broader movement to consider sex as an important variable in biomedical research, to ensure that studies cover the range of possibilities rather than gleaning results from a single population.
Sex differences in pain responses
Current Opinion in Physiology, Volume 6, December 2018, Pages 75-81, by Robert E Sorge, Larissa J Strath
Sex differences have been reported in the experience of pain and in the prevalence of chronic pain conditions. However, recently work has uncovered biological differences in the utilization of immune cells and basic function of afferents that shed light on the underpinnings of these sex-dependent findings. In addition, work in healthy controls and chronic pain patients have highlighted biases in attribution of pain and assessment of pain intensity that further reinforce sex differences.
Together, the combination of biological differences, distinct psychological coping strategies and outside bias result in the maintenance of disparities in the experience of pain based on sex. Recognition of sex differences and the underlying mechanisms can only improve treatment and patient outcomes.
Does Gender Influence Pain Sensitivity?
Biology may play a role in nociception and analgesia, and researchers are examining the potential effects of social and psychologic factors. Neurology Reviews. 2017 May;25(5):16-19
Biologic differences may explain gender differences in pain sensitivity. Research during the past 20 years has suggested that microglia play an important role in nociception. Newer data, however, indicate that microglial involvement in pain may be specific to males. Because the majority of animal research had been performed in male rodents, this observation had not been made previously, said Dr. Mogil.
He and his colleagues injured male and female mice to induce mechanical allodynia. The mice exhibited the same amount of mechanical allodynia, regardless of gender. The investigators next administered minocycline, a glial inhibitor, to the mice. The intervention reversed the allodynia in male mice, but not in female mice. Using fluorocitrate or propentofylline in place of minocycline produces the same result, said Dr. Mogil. Research into the biologic basis for pain modulation in females is ongoing.
All Pain Is Not the Same
Psychologist Discusses Gender Differences in Chronic Pain, Translating Research in Women’s Health and Mental Health to Practice.
Women experience chronic pain longer, more intensely and more often than men, according to a psychologist who works with both men and women dealing with diseases and conditions that leave them suffering.
“Chronic pain affects a higher proportion of women than men around the world,” said Jennifer Kelly, PhD, of the Atlanta Center for Behavioral Medicine. “We need to encourage women to take a more active role in their treatment and reduce the stigma and embarrassment of this problem.”
Speaking Thursday at the 118th Annual Convention of the American Psychological Association, Kelly said the latest research offers interesting insights into how physicians and mental health providers can better treat women with chronic pain.
… The American Psychological Association, in Washington, D.C., is the largest scientific and professional organization representing psychology in the United States and is the world’s largest association of psychologists.
Women suffer needless pain because almost everything is designed for men
Why women are 50 percent more likely to be misdiagnosed after a heart attack and 17 percent more likely to die in a car crash. By Sigal Samuel, Apr 17, 2019, Vox
In medical lore, the term “Yentl syndrome” has come to describe what happens when women present to their doctors with symptoms that differ from men’s — they often get misdiagnosed, mistreated, or told the pain is all in their heads. This phenomenon can have lethal consequences.
Many, many women have had this experience when they go to the doctor. I had it myself, years ago. As a spate of articles about the phenomenon has come out in the past couple of years, more people have begun talking about a “gender pain gap.”
In a new book, Invisible Women: Data Bias in a World Designed for Men, the British journalist and feminist activist Caroline Criado Perez argues that this is part of a larger problem: the “gender data gap.”
Basically, the data our society collects is typically about men’s experience, not women’s. That data gets used to allocate research funding and make decisions about design. Because most things and spaces — from pain medications to cars, and from air-conditioned offices to city streets — have been designed by men with men as the default user, they often don’t work well for women.
Even when researchers do gather data from women as well as men in their studies, they often fail to sex-disaggregate it — to separate out the male and female data they’ve collected and analyze it for differences. That’s crucial, because a new pain medication that’s ineffective for men may work great for women, but you’d never know it if you mixed all their data together.
All this gives rise to a powerful possibility: What if we can reduce suffering for half the population, simply by ceasing to design everything as if it’ll only be used by men?
Criado Perez’s book discusses how biased design shows up pretty much everywhere, but the issues she identifies in the realm of health are the most striking because they’re the most dangerous.
I spoke to Criado Perez about why the medical system treats women’s pain differently, whether we need to design drugs specifically for women, and how she dealt with the gaslighting she experienced while working on the book. A transcript of our conversation, lightly edited for length and clarity, follows.
Not just in humans – gender differences are in other mammals
Sorge RE, Mapplebeck JC, Rosen S, et al. Different immune cells mediate mechanical pain hypersensitivity in male and female mice. Nat Neurosci. 2015;18(8):1081-1083.
A large and rapidly increasing body of evidence indicates that microglia-to-neuron signaling is essential for chronic pain hypersensitivity. Using multiple approaches, we found that microglia are not required for mechanical pain hypersensitivity in female mice; female mice achieved similar levels of pain hypersensitivity using adaptive immune cells, likely T lymphocytes. This sexual dimorphism suggests that male mice cannot be used as proxies for females in pain research.
Backup The Particle Physics of You
This is a class backup of the article, The particle physics of you, 11/03/15 By Ali Sundermier. Symmetry Magazine.
Not only are we made of fundamental particles, we also produce them and are constantly bombarded by them throughout the day.
https://www.symmetrymagazine.org/article/the-particle-physics-of-you
Fourteen billion years ago, when the hot, dense speck that was our universe quickly expanded, all of the matter and antimatter that existed should have annihilated and left us nothing but energy. And yet, a small amount of matter survived.
We ended up with a world filled with particles. And not just any particles—particles whose masses and charges were just precise enough to allow human life. Here are a few facts about the particle physics of you that will get your electrons jumping.
The particles we’re made of
About 99 percent of your body is made up of atoms of hydrogen, carbon, nitrogen and oxygen. You also contain much smaller amounts of the other elements that are essential for life.
While most of the cells in your body regenerate every seven to 15 years, many of the particles that make up those cells have actually existed for millions of millennia. The hydrogen atoms in you were produced in the big bang, and the carbon, nitrogen and oxygen atoms were made in burning stars. The very heavy elements in you were made in exploding stars.
The size of an atom is governed by the average location of its electrons. Nuclei are around 100,000 times smaller than the atoms they’re housed in. If the nucleus were the size of a peanut, the atom would be about the size of a baseball stadium. If we lost all the dead space inside our atoms, we would each be able to fit into a particle of lead dust, and the entire human race would fit into the volume of a sugar cube.
As you might guess, these spaced-out particles make up only a tiny portion of your mass. The protons and neutrons inside of an atom’s nucleus are each made up of three quarks. The mass of the quarks, which comes from their interaction with the Higgs field, accounts for just a few percent of the mass of a proton or neutron. Gluons, carriers of the strong nuclear force that holds these quarks together, are completely massless.
If your mass doesn’t come from the masses of these particles, where does it come from? Energy. Scientists believe that almost all of your body’s mass comes from the kinetic energy of the quarks and the binding energy of the gluons.
The particles we make
Your body is a small-scale mine of radioactive particles. You receive an annual 40-millirem dose from the natural radioactivity originating inside of you. That’s the same amount of radiation you’d be exposed to from having four chest X-rays.
Your radiation dose level can go up by one or two millirem for every eight hours you spend sleeping next to your similarly radioactive loved one.
You emit radiation because many of the foods you eat, the beverages you drink and even the air you breathe contain radionuclides such as Potassium-40 and Carbon-14. They are incorporated into your molecules and eventually decay and produce radiation in your body.
When Potassium-40 decays, it releases a positron, the electron’s antimatter twin, so you also contain a small amount of antimatter.
The average human produces more than 4000 positrons per day, about 180 per hour. But it’s not long before these positrons bump into your electrons and annihilate into radiation in the form of gamma rays.
The particles we meet
The radioactivity born inside your body is only a fraction of the radiation you naturally (and harmlessly) come in contact with on an everyday basis. The average American receives a radiation dose of about 620 millirem every year. The food you eat, the house you live in and the rocks and soil you walk on all expose you to low levels of radioactivity. Just eating a Brazil nut or going to the dentist can up your radiation dose level by a few millirem. Smoking cigarettes can increase it up to 16,000 millirem.
Cosmic rays, high-energy radiation from outer space, constantly smack into our atmosphere. There, they collide with other nuclei and produce mesons, many of which decay into particles such as muons and neutrinos. All of these shower down on the surface of the Earth and pass through you at a rate of about 10 per second. They add about 27 millirem to your yearly dose of radiation. These cosmic particles can sometimes disrupt our genetics, causing subtle mutations, and may be a contributing factor in evolution.
In addition to bombarding us with photons that dictate the way we see the world around us, our sun also releases an onslaught of particles called neutrinos. Neutrinos are constant visitors in your body, zipping through at a rate of nearly 100 trillion every second. Aside from the sun, neutrinos stream out from other sources, including nuclear reactions in other stars and on our own planet.
Many neutrinos have been around since the first few seconds of the early universe, outdating even your own atoms. But these particles are so weakly interacting that they pass right through you, leaving no sign of their visit.
You are also likely facing a constant shower of particles of dark matter. Dark matter doesn’t emit, reflect or absorb light, making it quite hard to detect, yet scientists think it makes up about 80 percent of the matter in the universe.
Looking at the density of dark matter throughout the universe, scientists calculate that hundreds of thousands of these particles might be passing through you every second, colliding with your atoms about once a minute. But dark matter doesn’t interact very strongly with the matter you’re made of, so they are unlikely to have any noticeable effects on your body.
The next time you’re wondering how particle physics applies to your life, just take a look inside yourself.
Artwork by Sandbox Studio, Chicago with Ana Kova.
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RNA World
Background vocabulary: monomer and polymer
Life today
Living things have genetic information stored in a polymer of DNA.
That info gets copied into polymers of RNA.
That is translated, with the help of mRNA, into polymers of proteins.
And each of these steps needs special enzymes.
Interesting thought
Life in today’s cells, and even viruses, is wicked complicated.
Hard to imagine all it all evolved, all at once. But who says it had to do it all at once?
Maybe one simple kind of reaction developed, then later, other kinds of reactions, and then over a loooong period of time, even other types.
Life in the very beginning
Perhaps once upon a time, RNA was all that life had.
Pieces of RNA were both the genes and the catalyst.
e.g. RNA could do base pairing with itself, bend, and graph other molecules.
RNA sequences could be copied by other RNAs.
Only later did DNA and proteins evolve.
This is the idea of the RNA world
A hypothetical stage in the history of life on Earth
Idea – RNA developed before DNA and proteins developed.
Alexander Rich first proposed the concept in 1962
Growing amounts of evidence for this is strong enough that the hypothesis has gained wide acceptance.
How is RNA like DNA?
Both can store and replicate genetic information;
How is RNA like an enzyme?
Both can catalyze (start) chemical reactions.
Are any enzymes today made of RNA?
the ribosome is composed primarily of RNA.
Ribosomes are part of many important enzymes, such as Acetyl-CoA, NADH, etc.
So why does life depend on DNA replication nowadays?
DNA is more stable than RNA
What does RNA, and DNA, look like?
How would RNA monomers assemble into polymers?
How could copies be made?
So let us look at the possible in steps, in order.
At the far left is long ago… then an RNA based world of life developed… and later a DNA and protein based world of life developed.
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Oils
“Oil” is a general name for any kind of molecule which is
nonpolar
that just means that its electrons are evenly distributed
PHET Polar molecules app
liquid at room temperature
of course, it could become solid if cooled, or evaporate if heated
Molecule has one end which is hydrophobic and another end which is lipophilic
The hydrophobic end likes to stick to water molecules. But hates sticking to oils.
The lipophilic end likes to stick to oil molecules, but hates sticking to water,
Made with many C and H atoms
Oils are usually flammable. Here we see oils in an orange skin interacting with a candle.
So Petroleum is?
Petroleum is a mix of naturally forming oils, which we drill from the Earth, and use in a variety of ways. See our article on petroleum and producing power.
Rotary catalytic mechanism of mitochondrial ATP synthase
Introduction
(Text in this section adapted from “ATP synthase.” Wikipedia, The Free Encyclopedia. 27 Mar. 2019.)
ATP synthase is an enzyme that creates the energy storage molecule adenosine triphosphate (ATP).
ATP is the most commonly used “energy currency” of cells for all organisms. It is formed from adenosine diphosphate (ADP) and inorganic phosphate (Pi).
The overall reaction catalyzed by ATP synthase is:
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ADP + Pi + H+out ⇌ ATP + H2O + H+in
The formation of ATP from ADP and Pi is energetically unfavorable and would normally proceed in the reverse direction.
In order to drive this reaction forward, ATP synthase couples ATP synthesis during cellular respiration to an electrochemical gradient created by the difference in proton (H+) concentration across the mitochondrial membrane in eukaryotes or the plasma membrane in bacteria.
Molecular animation of ATP synthase
Here is a three dimensional animation of all the proteins working together in this complex. We see it situated in a lipid bilayer (organelle membrane.)
Here is another animation of a similar complex.
Video
Rotary catalytic mechanism of mitochondrial ATP synthase
Learning Standards
(TBA)
Biology, Chemistry, Simple machines
Epistasis
The following intro comes from – Biology 110H Basic Concepts, Stephen, haeffer; Variation in Dominance, Multiple Alleles, Epistasis, Pleiotropy, and Polygenic Inheritance, Penn State.
Sometimes a gene at one location on a chromosome can affect the expression of a gene at a second location (epistasis). A good example of epistasis is the genetic interactions that produce coat color in horses and other mammals.
In horses, brown coat color (B) is dominant over tan (b).
Gene expression is dependent on a second gene that controls the deposition of pigment in hair.
The dominant gene (C) codes for the presence of pigment in hair, whereas the recessive gene (c) codes for the absence of pigment.
If a horse is homozygous recessive for the second gene (cc), it will have a white coat regardless of the genetically programmed coat color (B gene) because pigment is not deposited in the hair.
The figure above demonstrates this scenario. Several of the white horses have genotypes for brown or tan coat color in the first gene, but are completely white because they are homozygous recessive for the gene controlling pigment deposition.
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Great resource here – “The term epistasis describes a certain relationship between genes, where an allele of one gene (e.g., ‘spread’) hides or masks the visible output, or phenotype, of another gene (e.g., pattern). Epistasis is entirely different from dominant and recessive, which are terms that apply to different alleles of the same gene (e.g., ‘bar’ is dominant to ‘barless’ and recessive to ‘check’).”
Click Epistasis, Genetic Science Learning Center, Univ of Utah
Epistasis: Gene Interaction and Phenotype Effects
By: Ilona Miko, Nature Education 1(1):197
Epistasis: Gene Interaction and Phenotype Effects. Nature education.
Elements necessary for life
Major elements – CHONSP
Carbon – Used as the major building unit of all organic molecules.
Hydrogen – major component of water. Major component of all organic molecules.
Oxygen – major component of water. Must be transported by our red blood cells.
Nitrogen – needed in all amino acids and proteins. Needed in chlorophyll, which is necessary for photosynthesis.
Sulphur – Used in in fats, body fluids, skeletal minerals, and most proteins.
Phosphorus – Necessary to make DNA and RNA. Also a component of bones and teeth.
Microbial Genomics and the Periodic Table, Lawrence P. Wackett, Anthony G. Dodge and Lynda B. M. Ellis
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Microbial Genomics and the Periodic Table, Lawrence P. Wackett, Anthony G. Dodge and Lynda B. M. Ellis
There are many essential trace elements in humans
Arsenic – “Despite its poisonous reputation, may be a necessary ultratrace element for humans. It is a necessary ultratrace element for red algae, chickens, rats, goats, and pigs. A deficiency results in inhibited growth (*)
Boron – essential for cell membrane characteristics and transmembrane signaling
Calcium ions are essential for muscle contractions and the clotting of blood. Necessary for cell walls, and bones.
Chlorine – Digestive juices in the stomach contain hydrochloric acid.
Chromium – essential trace element that potentiates insulin action and thus influences carbohydrate, lipid and protein metabolism.
“Chromium is an essential trace element and has a role in glucose metabolism. It seems to have an effect in the action of insulin. In anything other than trace amounts, chromium compounds should be regarded as highly toxic.” (*)
“Cobalt salts in small amounts are essential to many life forms, including humans. It is at the core of a vitamin called vitamin-B12. “ (*)
“Copper is essential for all life, but only in small quantities. It is the key component of redox enzymes and of haemocyanin.” (*)
Fluorine forms a salt with calcium. This salt makes the teeth and bones stronger.
“Iodine is an essential component of the human diet and in fact appears to be the heaviest required element in the diet. Iodine compounds are useful in medicine.” (*)
Iron – used in the hemoglobin molecules, allows your blood to hold oxygen. Iron is only about 0.004 percent of your body mass,
Magneisum “Chlorophylls (responsible for the green colour of plants) are based upon magnesium. Magnesium is required for the proper working of some enzymes.” (*)
Manganese – essential for the action of some enzymes
“Molybdenum is a necessary element, apparently for all species. … plays a role in nitrogen fixation, enzymes, and nitrate reduction enzymes.” (*)
Nickel is an essential trace element for many species. Unknown if so in humans.
“Potassium salts are essential for both animals and plants. The potassium cation (K+) is the major cation in intracellular (inside cells) fluids (sodium is the main extracellular cation). It is essential for nerve and heart function.” (*)
Selenium – essential component of one of the antioxidant defense systems of the body
“essential to mammals and higher plants, but only in small amounts…. may help protest against free radical oxidants and against some heavy metals.” (*)
Silicium – probably essential for healthy connective tissue and bone
Sodium (Na+) and potassium (K+) ions – transmission of nerve impulses between your brain and all parts of the body.
Tin – expected to have a function in the tertiary structure of proteins
Tungsten is needed in very tiny amounts in some enzymes (oxidoreductases)
Vanadium – possible role as an enzyme cofactor and in hormone, glucose, lipid, bone and tooth metabolism.
“Zinc is the key component of many enzymes. The protein hormone insulin contains zinc.” (*)
(*) WebElements: THE periodic table on the WWW
https://www.webelements.com/arsenic/biology.html
Australopithecus skeleton
Australopithecus skeleton
A team of Northeast Ohio researchers announced a rare and important find – the partial skeleton of a 3.6 million-year-old early human ancestor belonging to the same species as, but much older than, the iconic 3.2 million-year-old Lucy fossil discovered in 1974.
Less than 10 such largely intact skeletons 1.5 million years or older have been found. Greater Cleveland researchers have played leading roles in three of those discoveries, reinforcing the region’s prominence in the search for humanity’s origins.
The new specimen is called Kadanuumuu (pronounced Kah-dah-NEW-moo). The nickname means “big man” in the language of the Afar tribesmen who helped unearth his weathered bones from a hardscrabble Ethiopian plain beginning in 2005.
“Big” is an apt description of both Kadanuumuu’s stature and his significance. The scientists who analyzed the long-legged fossil say it erases any doubts about stubby Lucy and her kind’s ability to walk well on two legs, and reveals new information about when and how bipedality developed.
“It’s all about human-like bipedality evolving earlier than some people think,” said Cleveland Museum of Natural History anthropologist Yohannes Haile-Selassie,
– http://www.cleveland.com/science/index.ssf/2010/06/partial_skeleton_from_lucys_sp.html
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“Many dozens of A. afarensis fossils have been uncovered since Lucy was discovered in 1974, but none as complete as this one. Kadanuumuu’s forearm was first extracted from a hunk of mudstone in February 2005, and subsequent expeditions uncovered an entire knee, part of a pelvis, and well preserved sections of the thorax.
“We have the clavicle, a first rib, a scapula, and the humerus,” says physical anthropologist Bruce Latimer of Case Western Reserve University in Cleveland, Ohio, one of the co-leaders on the dig. “That enables us to say something about how [Kadanuumuu] was using its arm, and it was clearly not using it the way an ape uses it. It finally takes knuckle-walking off the table.” At five and a half feet tall, Kadanuumuu would also have towered two feet over Lucy, lending support to the view that there was a high degree of sexual dimorphism in the species.”
– Archaeology, “Kadanuumuu” – Woranso-Mille, Ethiopia Volume 64 Number 1, January/February 2011 by Brendan Borrell
Alzheimer’s disease
Alzheimer’s disease
Possible causes of Alzheimer’s diseases
We currently don’t know the cause of all forms of Alzheimer’s disease. There may be more than one cause. But today we have increasingly strong evidence that many cases are caused by a combination of a genetic mutation and Herpes virus.
Prions
Two proteins central to the pathology of Alzheimer’s disease act as prions—misshapen proteins that spread through tissue like an infection by forcing normal proteins to adopt the same misfolded shape—according to new UC San Francisco research.
Using novel laboratory tests, the researchers were able to detect and measure specific, self-propagating prion forms of the proteins amyloid beta (A-β) and tau in postmortem brain tissue of 75 Alzheimer’s patients. In a striking finding, higher levels of these prions in human brain samples were strongly associated with early-onset forms of the disease and younger age at death.
by University of California, San Francisco
Alzheimer’s disease is a ‘double-prion disorder,’ study shows
Herpes virus
Alzheimer’s: The heretical and hopeful role of infection
David Robson writes
…. The “amyloid beta hypothesis” has inspired countless trials of drugs that aimed to break up these toxic plaques. Yet this research has ended in many disappointments, without producing the desired improvements in patients’ prognosis. This has led some to wonder whether the amyloid beta hypothesis may be missing an important part of the story. “The plaques that Alzheimer observed are the manifestation of the disease, not the cause,” says geriatrics scientist Tamas Fulop at the University of Sherbrooke in Canada.
Scientists studying Alzheimer’s have also struggled to explain why some people develop the disease while others don’t. Genetic studies show that the presence of a gene variant – APOE4 – can vastly increase someone’s chances of building the amyloid plaques and developing the disease.
But the gene variant does not seal someone’s fate as many people carry APOE4 but don’t suffer from serious neurodegeneration. Some environmental factors must be necessary to set off the genetic time bomb, prompting the build-up of the toxic plaques and protein tangles.
Early evidence
Could certain microbes act as a trigger? That’s the central premise of the infection hypothesis.
Itzhaki has led the way with her examinations into the role of the herpes simplex virus (HSV1), which is most famous for causing cold sores on the skin around the mouth. Importantly, the virus is known to lie dormant for years, until times of stress or ill health, when it can become reactivated – leading to a new outbreak of the characteristic blisters.
While it had long been known that the virus could infect the brain – leading to a dangerous swelling called encephalitis that required immediate treatment – this was thought to be a very rare event. In the early 1990s, however, Itzhaki’s examinations of post-mortem tissue revealed that a surprising number of people showed signs of HSV1 in their neural tissue, without having suffered from encephalitis.
Importantly, the virus didn’t seem to be a risk for the people without the APOE4 gene variant, most of whom did not develop dementia. Nor did the presence of APOE4 make much difference to the risk of people without the infection.
Instead, it was the combination of the two that proved to be important. Overall, Itzhaki estimates that the two risk factors make it 12 times more likely that someone will develop Alzheimer’s, compared to people without the gene variant or the latent infection in their brain.
Itzhaki hypothesised that this was due to repeated reactivation of the latent virus – which, during each bout, invades the brain and somehow triggers the production of amyloid beta, until eventually, people start to show the cognitive decline that marks the onset of dementia.
Itzhaki says that her findings were met with a high degree of scepticism by other scientists. “We had the most awful trouble getting it published.” Many assumed that the experiments were somehow contaminated, she says, leading to an illusory result. Yet she had been careful to avoid this possibility, and the apparent link between HSV1 infection and Alzheimer’s disease has now been replicated in many different populations.
One paper, published earlier this year, examined cohorts from Bordeaux, Dijon, Montpellier and rural France. By tracking certain antibodies, they were able to detect who had been infected with the herpes simplex virus. The researchers found that the infection roughly tripled the risk of developing Alzheimer’s in APOE4 carriers over a seven-year follow-up period – but had no effect in people who were not carrying the gene.
“The herpes virus was only able to have a deleterious effect if there was APOE4,” says Catherine Helmer at the University of Bordeaux in France, who conducted the research.
To date, the most compelling evidence for the infection hypothesis comes from a large study in Taiwan, published in 2018, which looked at the progress of 8,362 people carrying a herpes simplex virus. Crucially, some of the participants were given antiviral drugs to treat the infection. As the infection hypothesis predicted, this reduced the risk of dementia.
Overall, those taking a long course of medication were around 90% less likely to develop dementia over the 10-year study period than the participants who had not received any treatment for their infection.
“It’s a result that is so striking, it’s hard to believe,” says Anthony Komaroff, a professor at Harvard Medical School and a senior physician at Brigham and Women’s Hospital in Boston, who recently reviewed the current state of the research into the infection hypothesis for the Journal of the American Medical Association. Although he remains cautious about lending too much confidence to any single study, he is now convinced that the idea demands more attention. “It’s such a dramatic result that it must be taken seriously,” he says.
Komaroff knows of no theoretical objections to the theory. “I haven’t heard anyone, even world-class Alzheimer’s experts who are dubious about the infection hypothesis, give a good reason why it has to be bunkum,” he adds. We simply need more studies providing direct evidence for the link, he says, to be able to convince the sceptics.
– from Alzheimer’s: The heretical and hopeful role of infection, BBC Future, David Robson, 6th October 2021
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Alzheimer’s disease: mounting evidence that herpes virus is a cause, The Conversation US, Oct 19, 2018
Ruth Itzhaki, Professor Emeritus of Molecular Neurobiology, University of Manchester
More than 30m people worldwide suffer from Alzheimer’s disease – the most common form of dementia. Unfortunately, there is no cure, only drugs to ease the symptoms. However, my latest review, suggests a way to treat the disease. I found the strongest evidence yet that the herpes virus is a cause of Alzheimer’s, suggesting that effective and safe antiviral drugs might be able to treat the disease. We might even be able to vaccinate our children against it.
The virus implicated in Alzheimer’s disease, herpes simplex virus type 1 (HSV1), is better known for causing cold sores. It infects most people in infancy and then remains dormant in the peripheral nervous system (the part of the nervous system that isn’t the brain and the spinal cord). Occasionally, if a person is stressed, the virus becomes activated and, in some people, it causes cold sores.
We discovered in 1991 that in many elderly people HSV1 is also present in the brain. And in 1997 we showed that it confers a strong risk of Alzheimer’s disease when present in the brain of people who have a specific gene known as APOE4.
The virus can become active in the brain, perhaps repeatedly, and this probably causes cumulative damage. The likelihood of developing Alzheimer’s disease is 12 times greater for APOE4 carriers who have HSV1 in the brain than for those with neither factor.
Later, we and others found that HSV1 infection of cell cultures causes beta-amyloid and abnormal tau proteins to accumulate. An accumulation of these proteins in the brain is characteristic of Alzheimer’s disease.
We believe that HSV1 is a major contributory factor for Alzheimer’s disease and that it enters the brains of elderly people as their immune system declines with age. It then establishes a latent (dormant) infection, from which it is reactivated by events such as stress, a reduced immune system and brain inflammation induced by infection by other microbes.
Reactivation leads to direct viral damage in infected cells and to viral-induced inflammation. We suggest that repeated activation causes cumulative damage, leading eventually to Alzheimer’s disease in people with the APOE4 gene.
Presumably, in APOE4 carriers, Alzheimer’s disease develops in the brain because of greater HSV1-induced formation of toxic products, or less repair of damage.
New treatments? The data suggest that antiviral agents might be used for treating Alzheimer’s disease. The main antiviral agents, which are safe, prevent new viruses from forming, thereby limiting viral damage.
In an earlier study, we found that the anti-herpes antiviral drug, acyclovir, blocks HSV1 DNA replication, and reduces levels of beta-amyloid and tau caused by HSV1 infection of cell cultures.
It’s important to note that all studies, including our own, only show an association between the herpes virus and Alzheimer’s – they don’t prove that the virus is an actual cause. Probably the only way to prove that a microbe is a cause of a disease is to show that an occurrence of the disease is greatly reduced either by targeting the microbe with a specific anti-microbial agent or by specific vaccination against the microbe.
Excitingly, successful prevention of Alzheimer’s disease by use of specific anti-herpes agents has now been demonstrated in a large-scale population study in Taiwan. Hopefully, information in other countries, if available, will yield similar results.
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Corroboration of a Major Role for Herpes Simplex Virus Type 1 in Alzheimer’s Disease
Ruth F. Itzhaki, Nuffield Department of Clinical Neurosciences, University of Oxford, Oxford, United Kingdom
Front. Aging Neurosci., 19 October 2018, https://doi.org/10.3389/fnagi.2018.00324
Strong evidence has emerged recently for the concept that herpes simplex virus type 1 (HSV1) is a major risk for Alzheimer’s disease (AD). This concept proposes that latent HSV1 in brain of carriers of the type 4 allele of the apolipoprotein E gene (APOE-ε4) is reactivated intermittently by events such as immunosuppression, peripheral infection, and inflammation, the consequent damage accumulating, and culminating eventually in the development of AD….
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How an outsider in Alzheimer’s research bucked the prevailing theory — and clawed for validation
Sharon Begley, Stat News, 10/29/2018
Robert Moir was damned if he did and damned if he didn’t. The Massachusetts General Hospital neurobiologist had applied for government funding for his Alzheimer’s disease research and received wildly disparate comments from the scientists tapped to assess his proposal’s merits.
It was an “unorthodox hypothesis” that might “fill flagrant knowledge gaps,” wrote one reviewer, but another said the planned work might add little “to what is currently known.” A third complained that although Moir wanted to study whether microbes might be involved in causing Alzheimer’s, no one had proved that was the case.
As if scientists are supposed to study only what’s already known, an exasperated Moir thought when he read the reviews two years ago.
He’d just had a paper published in a leading journal, providing strong data for his idea that beta-amyloid, a hallmark of Alzheimer’s disease, might be a response to microbes in the brain. If true, the finding would open up vastly different possibilities for therapy than the types of compounds virtually everyone else was pursuing.
But the inconsistent evaluations doomed Moir’s chances of winning the $250,000 a year for five years that he was requesting from the National Institutes of Health. While two reviewers rated his application highly, the third gave him scores in the cellar. Funding rejected.
Complaints about being denied NIH funding are as common among biomedical researchers as spilled test tubes after a Saturday night lab kegger. The budgets of NIH institutes that fund Alzheimer’s research at universities and medical centers cover only the top 18 percent or so of applications. There are more worthy studies than money.
Moir’s experience is notable, however, because it shows that, even as one potential Alzheimer’s drug after another has failed for the last 15 years (the last such drug, Namenda, was approved in 2003), researchers with fresh approaches — and sound data to back them up — have struggled to get funded and to get studies published in top journals. Many scientists in the NIH “study sections” that evaluate grant applications, and those who vet submitted papers for journals, have so bought into the prevailing view of what causes Alzheimer’s that they resist alternative explanations, critics say.
“They were the most prominent people in the field, and really good at selling their ideas,” said George Perry of the University of Texas at San Antonio and editor-in-chief of the Journal of Alzheimer’s Disease. “Salesmanship carried the day.”
Dating to the 1980s, the amyloid hypothesis holds that the disease is caused by sticky agglomerations, or plaques, of the peptide beta-amyloid, which destroy synapses and trigger the formation of neuron-killing “tau tangles.” Eliminating plaques was supposed to reverse the disease, or at least keep it from getting inexorably worse. It hasn’t. The reason, more and more scientists suspect, is that “a lot of the old paradigms, from the most cited papers in the field going back decades, are wrong,” said MGH’s Rudolph Tanzi, a leading expert on the genetics of Alzheimer’s.
Even with the failure of amyloid orthodoxy to produce effective drugs, scientists who had other ideas saw their funding requests repeatedly denied and their papers frequently rejected. Moir is one of them.
For years in the 1990s, Moir, too, researched beta-amyloid, especially its penchant for gunking up into plaques and “a whole bunch of things all viewed as abnormal and causing disease,” he said. “The traditional view is that amyloid-beta is a freak, that it has a propensity to form fibrils that are toxic to the brain — that it’s irredeemably bad. In the 1980s, that was a reasonable assumption.”
But something had long bothered him about the “evil amyloid” dogma. The peptide is made by all vertebrates, including frogs and lizards and snakes and fish. In most species, it’s identical to humans’, suggesting that beta-amyloid evolved at least 400 million years ago. “Anything so extensively conserved over that immense span of time must play an important physiological role,” Moir said.
What, he wondered, could that be?
In 1994, Moir changed hemispheres to work as a postdoctoral fellow with Tanzi. They’d hit it off over beers at a science meeting in Amsterdam. Moir liked that Tanzi’s lab was filled with energetic young scientists — and that in cosmopolitan Boston, he could play the hyper-kinetic (and bone-crunching) sport of Australian rules football. Tanzi liked that Moir was the only person in the world who could purify large quantities of the molecule from which the brain makes amyloid.
Moir initially focused on genes that affect the risk of Alzheimer’s — Tanzi’s specialty. But Moir’s intellectual proclivities were clear even then. His mind is constantly noodling scientific puzzles, colleagues say, even during down time. Moir took a vacation in the White Mountains a decade ago with his then-6-year-old son and a family friend, an antimicrobial expert; in between hikes, Moir explained a scientific roadblock he’d hit, and the friend explained a workaround.
Moir’s inclination toward unconventional thinking took flight in 2007. He was (and still is) in the habit of spending a couple of hours Friday afternoons on what he calls “PubMed walkabouts,” casually perusing that database of biomedical papers. One summer day, a Corona in hand, he came across a paper on something called LL37. It was described as an “antimicrobial peptide” that kills viruses, fungi, and bacteria, including — maybe especially — in the brain.
What caught his eye was that LL37’s size and structure and other characteristics were so similar to beta-amyloid, the two might be twins.
Moir hightailed it to Tanzi’s office next door. Serendipitously, Tanzi (also Corona-fueled) had just received new data from his study of genes that increase the risk of Alzheimer’s disease. Many of the genes, he saw, are involved in innate immunity, the body’s first line of defense against germs. If immune genetics affect Alzheimer’s, and if the chief suspect in Alzheimer’s (beta-amyloid) is a virtual twin of an antimicrobial peptide, maybe beta-amyloid is also an antimicrobial, Moir told Tanzi.
If so, then the plaques it forms might be the brain’s last-ditch effort to protect itself from microbes, a sort of Spider-Man silk that binds up pathogens to keep them from damaging the brain. Maybe they save the brain from pathogens in the short term only to themselves prove toxic over the long term.
Tanzi encouraged Moir to pursue that idea. “Rob was trained [by Marshall] to think out of the box,” Tanzi said. “He thinks so far out of the box he hasn’t found the box yet.”
Moir spent the next three years testing whether beta-amyloid can kill pathogens. He started simple, in test tubes and glass dishes. Those are relatively cheap, and Tanzi had enough funding to cover what Moir was doing: growing little microbial gardens in lab dishes and then trying to kill them.
Day after day, Moir and his junior colleagues played horticulturalists. They added staph and strep, the yeast candida, and the bacteria pseudomonas, enterococcus, and listeria to lab dishes filled with the nutrient medium agar. Once the microbes formed a thin layer on top, they squirted beta-amyloid onto it and hoped for an Alexander Fleming discovery-of-penicillin moment.
How an outsider in Alzheimer’s research bucked the prevailing theory — and clawed for validation. Stat News
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Autoimmune disease
Autoimmune diseases occur when the body’s immune system targets and damages the body’s own cells.
Our bodies have an immune system: a network of special cells and organs that defends the body from germs and other foreign invaders.
At the core of the immune system is the ability to tell the difference between self and nonself: between what’s you and what’s foreign.
If the system becomes unable to tell the difference between self and nonself then the body makes autoantibodies (AW-toh-AN-teye-bah-deez) that attack normal cells by mistake.
At the same time, we always have regulatory T cells. They keep the rest of our immune system in line. If they fail to work correctly then other white blood cells can mistakenly attack parts of our body. This causes the damage we know as autoimmune disease.
The body parts that are affected depend on the type of autoimmune disease. There are more than 100 known types.
Overall, autoimmune diseases are common, affecting more than 23.5 million Americans. They are a leading cause of death and disability. Some autoimmune diseases are rare, while others, such as Hashimoto’s disease, affect many people.
(Intro adapted from U.S. Department of Health & Human Services, Office on Women’s Health)
Causes
There are many different auto-immune diseases. Each one has a separate cause. In fact, each particular autoimmune disorder itself may have several different causes.
Medical researchers are still learning how auto-immune diseases develop. They seem to be a combination of genetic mutations and some trigger in the environment.
TBA: The hygiene hypothesis
Examples
Crohn’s disease
Diabetes (Type 1 diabetes mellitus)
Guillain-Barre syndrome
Inflammatory bowel disease (IBD)
Lupus (Systemic lupus erythematosus)
Multiple sclerosis (MS)
Rheumatoid arthritis
Treatment
Many autoimmune disorders can now be partially treated with biologics (artificial biological molecules.) These biologics modulate the immune system. These can treat – but not cure – some auto-immune diseases.
Infliximab, etanercept, adalimumab, etc.
Learning Standards
Massachusetts Comprehensive Health Curriculum Framework
Students will gain the knowledge and skills to select a diet that supports health and reduces the risk of illness and future chronic diseases. PreK–12 Standard 4
Through the study of Prevention students will
8.1 Describe how the body fights germs and disease naturally and with medicines and immunization.
Through the study of Signs, Causes, and Treatment students will
8.2 Identify the common symptoms of illness and recognize that being responsible for individual health means alerting caretakers to any symptoms of illness
8.5 Identify ways individuals can reduce risk factors related to communicable and chronic diseases
8.13 Explain how the immune system functions to prevent and combat disease
Benchmarks for Science Literacy, AAAS
The immune system functions to protect against microscopic organisms and foreign substances that enter from outside the body and against some cancer cells that arise within. 6C/H1*
Some allergic reactions are caused by the body’s immune responses to usually harmless environmental substances. Sometimes the immune system may attack some of the body’s own cells. 6E/H1
KaiserScience 