Tag Archives: epigenetics

Quinolones in our Environment

Why do some people have relapses of their fluoroquinolone toxicity symptoms? Why is fluoroquinolone toxicity an ongoing illness–a syndrome–and not a one-time event that ends once the drug is metabolized? Why do people seem sensitized after suffering from fluoroquinolone toxicity–with exposures to things that would be benign to healthy people throwing them into a relapse? Why does fluoroquinolone toxicity seem more like an autoimmune or neuroimmune disease than a drug allergy? What does fluoroquinolone toxicity have in common with autoimmune or neuro-immune diseases?

These are all perplexing questions about FQT/FQAD that currently we have no answers for. On the
website http://fluoroquinolonethyroid.com/ many ideas about possible mechanisms regarding some
of these questions are explored (here, here, and here). I found the most recent of these posts,
entitled Nature’s Quinolones: The 4Qs, to offer additional thought-provoking and insightful new
ideas to consider when thinking about questions like these.

This post is a summary of Nature’s Quinolones: The 4Qs, to share the information in it with the
Floxiehope.com audience. There is information in the original article that I won’t be covering in this
post, and I hope this summary inspires you to read more about the details in the original article. I
also hope that any researchers reading this will check out the original article, as it provides a more
comprehensive explanation, along with numerous references, that may be of use in your thought
processes about this topic.

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There is a bacteria that is ubiquitous in our environment called Pseudomonas aeruginosa, or P. aeruginosaP. aeruginosa is everywhere, including, “soil and water, lakes, streams, rivers, other fresh water, potable water, and sources such as sinks, showers, and hot tubs.” People with healthy immune systems deal with P. aeruginosa without incident. However, P. aeruginosa is a pathogen associated with hospital-acquired infections in immune-compromised individuals, and perhaps it may also be possible that some people have immune systems that over-react to to the bacteria, or its byproducts.

Like many other bacteria and some fungi, P. aeruginosa “communicate” with each other via something called Quorum sensing (QS). The P. aeruginosa QS molecules are able to turn bacterial genes on and off, such as instructing the bacteria to form biofilms under certain circumstances. Just as people with normal immune systems interact with P. aeruginosa without incident, people with normal immune systems also interact with the P. aeruginosa QS molecules without incident.

However, one of the possible ideas explored in Nature’s Quinolones: The 4Qs is that people who have been “floxed” may not react to the P. aeruginosa QS molecules without incident. Rather, perhaps they may be sensitized to the P. aeruginosa QS molecules, and their immune-system attacks these molecules, causing a potential autoimmune/neuroimmune reaction.

Why might “floxies” have an immune-system over-reaction to P. aeruginosa QS molecules?

Because one group of QS molecules that P. aeruginosa QS makes are actually quinolones–“nature’s quinolones” (heterocyclic 4-quinolone/quinolines – abbreviated the “4Qs”). These 4Qs produced by P. aeruginosa share the basic 4-quinolone backbone of the commercially synthesized quinolone antibiotics. (More information about this can be found in Nature’s Quinolones: The 4Qs, as well as the articles linked-to in the post, including 4-Quinolones: Smart Phones of the Microbial World.)

I don’t know about you, but this BLEW MY MIND.

The production of natural quinolones may answer the question – why do people have ongoing reactions to fluoroquinolone antibiotics that last long after the drugs “should” be out of their system? Could it be because they are constantly being re-exposed to quinolones in our environment–through a common bacteria producing them to communicate with other bacteria? Could it be that Fluoroquinolone Toxicity is an ongoing syndrome because it is an immune reaction (and/or sensitization) to chemicals that are ubiquitous in our environment?

Again, these are just possible ideas the author of  Nature’s Quinolones: The 4Qs is exploring, but it MAKES SO MUCH SENSE.

QS Qinolones act as “signaling molecules for other bacteria. FQs also act as “signaling molecules” within us. In particular, they seem to target cytokines, which are heavily involved in the signaling and amplification system in our immune systems.” Pharmaceutical fluoroquinolones are given in a large enough doses that perhaps they may signal the immune system to over-react–especially to the presence of other quinolones. Nature’s Quinolones: The 4Qs describes some possible mechanisms through which fluoroquinolones may affect the immune system, providing numerous references in additional links in the article supporting this. Fluoroquinolones (and/or the 4Qs if production in larger amounts due to severe infection such as sepsis, for example) may also trigger epigenetic “switches” to be “flipped” in the immune system, causing a change that leads to a constant over-reaction to quinolone molecules.

The author of Nature’s Quinolones: The 4Qs ponders:

“I wonder if some of my existing natural antibodies were “switched on” in a major way, leading to global or specific hypersensitivities. And based on what I now know about FQs acting as ‘signaling molecules,’ I’m guessing that one or more of my cytokines or receptors were hit especially hard by what my body perceived as a whopping dose of quinolones.”

An over-active immune system that is hyper-sensitive to minute amounts of molecules that are harmless, and even unperceived, to people with normally functioning immune systems, is not unheard-of. Many people with ME/CFS believe they have autoimmune/neuroimmune reactions to tiny molecules of mold, and even minuscule amounts of mold appear to make them severely ill. Common allergies are also a result of an over-sensitized immune system:

“If this seems like an extreme leap to make, consider, for example, two very common allergies: hay fever and peanut allergies. There are microscopic particles of pollen and dust floating around in the air that most of us never see, feel, are aware of, or react to – unless you’re a person with hay fever allergies. There are microscopic proteins and aflatoxins in peanuts that most of us never see, feel, are aware of or react to – unless you’re a person with a peanut allergy. The first allergy typically leaves people with itchy and runny eyes and nose. The second allergy can result in anaphylaxis and even death. The point being, it doesn’t take much of these substances to make a person miserable or even kill them – if they’re hypersensitive.”

Might some people suffering from fluoroquinolone toxicity be sensitive to minute amounts of quinolones in the environment? Might some people who live in more humid and moist environments, for example, have increased exposure to quinolones by P. aeruginosa QS molecules? Additionally, might the fluoroquinolones have made epigenetic changes to the immune systems of those suffering from fluoroquinolone toxicity that make them have autoimmune/neuroimmune-like reactions to quinolones, including the 4Qs? Again, it makes all the sense in the world to me, but it needs to be examined by someone with the capacity to test these ideas.

If fluoroquinolones change the genetic on/off switches in our immune systems, how do we flip those epigenetic “switches” again? That’s a very good question that I don’t know the answer to. Our environment is constantly affecting our genes though, and epigenetics is a burgeoning field of research. I’m hopeful that scientists will find targeted ways to flip gene switches. I’m also hopeful that, in the meantime, changes in your environment (eating healthy foods, reducing stress, supplements, etc.) may help you (the “floxie” reading this) to “switch” your immune system back to where you were pre-flox so that your body is not over-reacting to nature’s quinolones (if that’s occurring). I know that my body is not in a state of constant reactivity, and, as always, I hope that my recovery gives others hope for their recovery.

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Fluoroquinolone Toxicity and Other Illnesses are not Mutually Exclusive

Fluoroquinolone toxicity and other multi-symptom, chronic, illnesses are not mutually exclusive. It’s possible to be floxed and have Lyme Disease. It’s possible to be floxed and to have Epstein Barr Virus. It’s possible to be floxed and have an autoimmune disease. It’s possible to be floxed and have mercury or lead poisoning.

Often, people have to fight for fluoroquinolone toxicity to be acknowledged. Doctors, nurses, other medical professionals, as well as skeptical loved ones, will often dismiss fluoroquinolone toxicity as ” not real” or being “all in your (the patient/loved one) head.” When they suggest that fluoroquinolone toxicity isn’t real, they often suggest that maybe you, the patient/loved one, really have some other disease such as Lyme Disease, ME/CFS, fibromyalgia, lupus, M.S., Sjogren’s Syndrome, Epstein Barr, etc. This often puts floxies on the defensive, and they fight with their doctors to say, “No, I’m not sick because of ___ recognized illness, I’m sick because of fluoroquinolone toxicity. I was fine before I took Cipro, Levaquin, or Avelox. Now I’m sick. It’s the drugs.” You, the patient, the floxie, the person whose body hurts, is right. These drugs hurt you, and anyone who dismisses the possibility that fluoroquinolones can do serious, severe, and long-lasting harm to a person is wrong and misinformed. There is a massive amount of evidence of the damage that fluoroquinolones do to people. There are several mechanisms by which fluoroquinolones can cause multi-symptom, chronic illness. The warning labels on fluoroquinolones reflect that they are dangerous drugs with serious consequences. You ARE suffering from fluoroquinolone toxicity.

With that said, you may also have Lyme Disease, or Sjogren’s, or mercury poisoning, or something else. It’s possible, and I think that examining all possibilities for acknowledgement and treatment are helpful.

Having an autoimmune disease, or Lyme, or some other more acknowledged illness, does not mean that you aren’t floxed. As I just said, There is a massive amount of evidence of the damage that fluoroquinolones do to people. There are several mechanisms by which fluoroquinolones can cause multi-symptom, chronic illness. The warning labels on fluoroquinolones reflect that they are dangerous drugs with serious consequences. Fluoroquinolones are dangerous drugs. They are hurting, and disabling, too many people.

Illnesses do not always occur one at a time–they can occur simultaneously, and they can overlap. Definitions of diseases are fuzzy too, and if you want to read about how diseases are defined by the drugs that treat them (i.e., the pharmaceutical industry), read Dr. Terry Wahls’ book, The Wahls Protocol, in which she discusses how diseases are defined and developed.

Some people have suggested that fluoroquinolones trigger other diseases. Is this possible? Maybe. In I Believe I had a Predisposition on www.fluoroquinolonethyroid.com, JMR discusses the possibility that she had a predisposition toward autoimmune thyroid issues, and that fluoroquinolones triggered the expression of that illness. People have suggested that fluoroquinolones trigger the activation/release of dormant Lyme or Epstein Barr. In Do Fluoroquinolone Antibiotics Trigger Charcot-Marie-Tooth and Other Genetic Diseases? I discuss the possibility that fluoroquinolones trigger epigenetic changes in that lead to the expression of dormant genetic diseases. In Lead Toxicity: Secondary to Hyperthyroidism, Hyperparathyroidism . . . and Fluoroquinolone Toxicity?, JMR suggests that fluoroquinolones may have triggered the release/activation of lead in her body. Similarly, in Fluoroquinolones and Mercury Poisoning, I note that fluoroquinolones may trigger the release/activation of mercury in the body through the disruption of mineral homeostasis (or maybe through keeping the liver from detoxifying the body properly). Many people have noted that there is a huge amount of overlap in symptoms between fluoroquinolone toxicity and fibromyalgia, ME/CFS, and other “mysterious” illnesses of modernity. All these connections and possibilities should be explored.

The possible connections between fluoroquinolone toxicity and other illnesses doesn’t mean that fluoroquinolone toxicity isn’t real though. It is real–it’s very real. Whenever people assert that fluoroquinolone toxicity isn’t real, and that people are really suffering from some other illness, I always go back to the beagle puppies that were made lame by fluoroquinolones, and their precursor nalidixic acid. Those puppies may have had some sort of genetic predisposition toward being hurt by fluoroquinolones, but the damage done to them wasn’t really something else. Their lameness, their pain and suffering, was from the fluoroquinolones – period.

I also go back to the mechanism of action for fluoroquinolones. Fluoroquinolones are topoisomerase interrupters. The mechanism of action for Cipro/ciprofloxacin is:

The bactericidal action of ciprofloxacin results from inhibition of the enzymes topoisomerase II (DNA gyrase) and topoisomerase IV (both Type II topoisomerases), which are required for bacterial DNA replication, transcription, repair, and recombination.

This video illustrates the mechanism of action for fluoroquinolones:

Fluoroquinolones have been shown to deplete mitochondrial DNA, and otherwise damage mitochondria.

The ARE dangerous drugs that ARE hurting people.

AND, you may have Lyme Disease, or lupus, or another illness, as well. So, get tested, and determine a course of action that treats all your symptoms and illnesses. These illnesses are not mutually exclusive, and knowing what you’re dealing with is key to understanding how to approach it. Of course, be careful with the treatments, but knowledge, and an open mind, are almost certainly helpful.

Multi-symptom, chronic illnesses are difficult to understand, and they’re even more difficult to treat. Dealing with multiple multi-symptom, chronic, mysterious illnesses is even worse. Luckily, the things that help people with fluoroquinolone toxicity are often similar to the things that help people with chronic Lyme Disease, or ME/CFS. So, please don’t feel disheartened or overwhelmed if you are facing both fluoroquinolone toxicity and another disease. Hang in there, and know that hope is helpful no matter what the ailment.

 

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Fluoroquinolones and Epigenetic Triggers – Possible Connections with Charcot-Marie-Tooth Disease

The post, Do Fluoroquinolone Antibiotics Trigger Charcot-Marie-Tooth and Other Genetic Diseases?, was published on Hormones Matter today (3/7/16).

I hope that you find the connections to be interesting, and not too frightening.

A couple things to note: First, Charcot-Marie-Tooth disease has nothing to do with teeth – Dr. Tooth was one of the people who discovered and named it. Second, though there are potential connections between fluoroquinolone toxicity and several genetic diseases, this is just a hypothesis, so please take it as just that. The connections are interesting, and should be explored. However, I don’t want anyone reading this, or anything else I write, to think that you are doomed.

Many “floxies” have expressed that they feel as if they have aged 20 years in a matter of weeks or months. I wonder if, on a cellular level, they actually have. I wonder if fluoroquinolones age cells and, in doing so, trigger diseases that would have remained dormant until much later in life. I wonder how fluoroquinolones, and other pharmaceuticals, affect gene expression (epigenetics), and if those effects are passed down from one generation to the next. I honestly don’t know the answer to these questions.

IF the damage mechanism for fluoroquinolones is genetic damage, and underlying diseases are triggered, reactions would be different for each person. This could explain the huge variation in fluoroquinolone toxicity reactions. Unfortunately, if this is the case, I think that we’re a long way from proving connections between fluoroquinolones and the triggering of diseases that are thought to be genetic in nature. Epigenetics is a relatively new area of study, and the triggering of epigenetic changes via pharmaceuticals isn’t something that I’ve run across much in my research. I think that it’s a topic that deserves significantly more attention.

Please read and share “Do Fluoroquinolone Antibiotics Trigger Charcot-Marie-Tooth and Other Genetic Diseases?” Thank you!

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The following fascinating article was published under a Creative Commons License, meaning that it can be published freely. It was originally published on www.mosaicscience.com – a great site that I highly recommend you check out. The article is about uncovering some of the genes behind Charcot-Marie-Tooth Disease. It’s also about being your own biggest advocate, and pushing to solve health “mysteries.”

DIY diagnosis: how an extreme athlete uncovered her genetic flaw

When Kim Goodsell discovered that she had two extremely rare genetic diseases, she taught herself genetics to help find out why. Ed Yong tells her story.

Kim Goodsell was running along a mountain trail when her left ankle began turning inward, unbidden. A few weeks later she started having trouble lifting her feet properly near the end of her runs, and her toes would scuff the ground. Her back started to ache, and then her joints too.

This was in 2002, and Kim, then 44 years old, was already an accomplished endurance athlete. She cycled, ran, climbed and skied through the Rockies for hours every day, and was a veteran of Ironman triathlons. She’d always been the strong one in her family. When she was four, she would let her teenage uncles stand on her stomach as a party trick. In high school, she was an accomplished gymnast and an ardent cyclist. By college, she was running the equivalent of a half marathon on most days. It wasn’t that she was much of a competitor, exactly – passing someone in a race felt more deflating than energising. Mostly Kim just wanted to be moving.

So when her limbs started glitching, she did what high-level athletes do, what she had always done: she pushed through. But in the summer of 2010, years of gradually worsening symptoms gave way to weeks of spectacular collapse. Kim was about to head to Lake Superior with her husband, CB. They planned to camp, kayak, and disappear from the world for as long as they could catch enough fish to eat. But in the days before their scheduled departure, she could not grip a pen or a fork, much less a paddle. Kim, a woman for whom extreme sports were everyday pursuits, could no longer cope with everyday pursuits. Instead of a lakeside tent, she found herself at the Mayo Clinic in Rochester, Minnesota.

After four days of tests, Kim’s neurologist told her that she had Charcot–Marie–Tooth disease, a genetic disorder that affects the peripheral neurons carrying signals between the spinal cord and the extremities. It’s rare and carries a varying suite of symptoms, but Kim’s are typical, starting at the feet and heading upward. The neurologist explained that as her neurons died, the surviving cells picked up the slack by sprouting new branches – a workaround that masked the underlying degeneration until the rate of cell death outpaced the rate of compensation. Hence Kim’s crash.

The neurologist told her to come back in a year so he could check how quickly the disease was progressing, but that it would certainly progress. Charcot–Marie–Tooth has no cure.

The Goodsells drove home and Kim, exhausted, slept for two days. When she woke up, she got to work. “My reaction to things that I have no control over is to find out as much as I can about them,” she says. She started by reviewing her clinic notes, and quickly noticed something odd: there was hardly any mention of her heart.

Years before she learned that she had Charcot–Marie–Tooth, Kim discovered that she had another genetic disorder – one that affects the heart, arrhythmogenic right ventricular cardiomyopathy (ARVC). ARVC gradually replaces the heart’s synchronised beating muscle with fat and scar tissue. It nearly killed her once; she still has an internal defibrillator to keep her heart beating. But even though it was there in her medical records, her neurologist hadn’t seen fit to mention it in his report. “It meant nothing to him,” says Kim. “I thought: Wow, that’s really funny.”

It wasn’t the omission per se that bothered her. It was the implicit suggestion that her two life-long diseases – one of the heart, one of the nervous system – were unrelated. That, in the genetic lottery, she was a double-loser. That lightning must have struck her twice.

Surely not, she thought. Surely there must be a connection.

I meet Kim at La Ventana in Baja California, Mexico. She spends winters here, mostly kitesurfing. The sand and water are postcard-quality, but La Ventana has barely any resorts or big hotels. So in the still air of the morning when kites won’t fly, the beach is empty. Kim likes it that way. She has been up since dawn, cycling among the cacti and swimming in the ocean with pelicans and frigatebirds for company. She hauls herself out of the water, dries off, and sits on a small terrace overlooking the ocean. Her face is tanned and wrinkled, and she manifests no obvious signs of her two conditions. That’s partly because she has developed workarounds to mask and control her symptoms. She brushes her teeth on one foot to offset her balance problems. She uses massage balls and spends hours stretching to stop her muscles and joints from seizing up.

“See how I’m sitting?” she says. She has pulled her legs up on the chair to her left, and her back is curving that way too.

“My spine curves this way” – she nods to the right – “so I sit curving to the opposite side. I consciously do the opposite.”

She has a history of that. In 1979 Kim was a mathematically gifted pre-med student at UC San Diego, her hometown college. Her path was clear: graduate, and follow her older brother into medical school. But on a trip to South America – her first time out of San Diego – she ended up hiking for three months instead of working at a clinic as she’d planned. When she returned home, her academic future seemed pale and uninspiring. And then CB – her future husband, at this point a fellow student and regular running partner – started taking her out on wilderness hikes. “He introduced me to the mountains and I thought: this is life,” Kim says.

Within months of graduating Kim dropped out. Her brother, who had been a father figure to her growing up, was furious. “We hardly spoke. CB was his friend and he couldn’t even look at him,” she says. “He said I was being completely irresponsible.” Kim and CB married in 1983, and aside from a brief stint as restaurant owners, they have never had 9-to-5 jobs. They mostly earned a living by buying and remodelling run-down houses and selling them at a profit, and then heading into the wilderness until their supplies ran out. In 1995 they found themselves in La Jolla, California, working on an especially stressful renovation that left Kim drained.

That was when her heart problems began. Kim started having episodes of ventricular tachycardia – the lower chambers of her heart contracted so quickly that they pumped out their contents before they had a chance to fill up, compromising the flow of blood (and therefore oxygen) to the rest of her body. One minute she would be racing down Highway 1 on her bike; the next she would feel like she had been “unplugged”, as if “there was nothing driving anymore”. A cardiologist at Scripps Memorial Hospital told her she’d need an internal defibrillator, but Kim said no – she was worried it’d get in the way of wearing a backpack on a run, and she had faith that she’d be able to deal with the ventricular tachycardia by slowing down and relaxing. “I didn’t want something implanted in me that would limit my opportunities of experiencing life,” she says.

The next week, the Goodsells finished their renovation, packed up and headed into the Sierra Nevada with no return date in sight. It was an unorthodox solution to a life-threatening heart condition: to vanish into the boondocks, far away from any medical care, to do even more exercise.

The thing is, it was the right one. The outdoors rejuvenated her. She was gone for one-and-a-half years, and her heart behaved the whole way through. That unbroken streak only broke when the Goodsells rejoined their old lives in 1997. Back in California, they were once again cycling down Highway 1 when her heart started to beat erratically again. This time, it did not stop.

By the time the paramedics arrived, Kim was slumped against a wall and her chest was shaking. Her tachycardia had lasted for almost an hour and progressed to ventricular fibrillation – that is, her heartbeat was erratic as well as fast. She blacked out in the ambulance, on the cusp of cardiac arrest.

She woke up at Scripps Memorial Hospital. The same cardiologist was there to greet her. Through further tests he discovered that the muscle of her right ventricle was marbled with fat and scar tissue and not contracting properly. These are classic signs of ARVC. It had only been properly described in 1982, back when Kim was regularly signing up for triathlons. ARVC is a major cause of fatal heart attacks in young people, and athletes are especially vulnerable as exercise can accelerate the disease’s progress. And since Kim wouldn’t stop exercising, she finally conceded to the defibrillator. They implanted it the next day.

Kim referred to the implant as her “internal terrorist”. Every shock was debilitating and led to months of anxiety. She had to learn to cope with the device, and it took several years to regain the joy she drew from hardcore exercise. That was when the other symptoms started.

These diseases are rare. In a crowd of a million adults, around 400 will have Charcot–Marie–Tooth and between 200 and 400 will have ARVC. But genetic diseases in general are actually quite common – 8 per cent of people have at least one. This paradoxical combination has fuelled the rise of many online communities where people with rare disorders can find each other. Heidi Rehm, a geneticist at Harvard Medical School, studies a condition called Norrie disease that mostly affects the eyes and ears. She developed a registry for Norrie disease patients to share their experiences, and learned that almost all the men with the disease had erectile dysfunction. “A patient goes to their doctor with blindness and deafness, and erectile dysfunction isn’t the first thing you ask about!” says Rehm. “Patients drove that discovery.” Through communities, families often make connections about their medical problems that their doctors miss.

But Kim was never one for relying on others. She tried a support group when she got her implant, but it did nothing for her. She dipped her toes in patient forums, but was always frustrated by the rampant misinformation. “People just weren’t interpreting things correctly,” Kim says. “I wanted more rigour.”

She started by diving into PubMed – an online search engine for biomedical papers – hunting down everything she could on Charcot–Marie–Tooth. She hoped that her brief fling with a scientific education would carry her through. But with pre-med knowledge that had been gathering dust for 30 years and no formal training in genetics, Kim quickly ran headfirst into a wall of unfamiliar concepts and impenetrable jargon. “It was like reading Chinese,” she says.

But she persisted. She scratched around in Google until she found uploaded PDFs of the articles she wanted. She would read an abstract and Google every word she didn’t understand. When those searches snowballed into even more jargon, she’d Google that too. The expanding tree of gibberish seemed infinite – apoptosis, phenotypic, desmosome – until, one day, it wasn’t. “You get a feeling for what’s being said,” Kim says. “Pretty soon you start to learn the language.”

“Kim has an incredible ability to understand the genetic literature,” says Martha Grogan, a cardiologist from the Mayo Clinic and an old friend of CB’s who now coordinates Kim’s care. “We have a lot of patients who ask great questions but with Kim, it’s like having another research fellow.”

At the time the Goodsells were staying at a friend’s house at Lake Michigan. Kim would sit on the balcony for eight hours a day, listening to the water and teaching herself genetics. Too weak to explore winding hillside trails, she channelled her perseverance and love of isolation towards scientific frontiers and the spiralling helices of her own DNA. “I spent hundreds of hours,” she says. “CB lost me during this process.”

Kim looked at every gene linked to Charcot–Marie–Tooth – there are more than 40 overall, each one imparting a slightly different character to the disease. One leapt out: LMNA, which codes for a group of rope-like proteins that mesh into a tangled network at the centre of our cells. This ‘nuclear lamina’ provides cells with structural support, and interacts with a bunch of other proteins to influence everything from the packaging and activation of genes to the suicide of damaged cells. Given this central role, it makes sense that mutations in LMNA are responsible for at least 15 different diseases, more than any other human gene. These laminopathies comprise a bafflingly diverse group – nerve disorders (like Charcot–Marie–Tooth), wasting diseases of fat and muscle, and even premature ageing.

As Kim read about these conditions and their symptoms, she saw her entire medical history reflected back at her – the contracted muscles in her neck and back, her slightly misaligned hips and the abnormal curve in her spine. She saw her Charcot–Marie–Tooth disease.

She also saw a heart disorder linked to the LMNA gene that wasn’t ARVC but which doctors sometimes mistake for it. “Everything was encapsulated,” she says. “It was like an umbrella over all of my phenotypes. I thought: This has to be the unifying principle.”

Kim was convinced that she had found the cause of her two diseases, but the only way to know for sure was to get the DNA of her LMNA gene sequenced to see if she had a mutation. First, she had to convince scientists that she was right. She started with Grogan, presenting her with the findings of her research. Grogan was impressed, but pragmatic. Even if Kim was right, it would not change her fate. Her implant was keeping her heart problems under control, and her Charcot–Marie–Tooth disease was incurable. She didn’t see a point. But Kim did. “I wanted to know,” she says. “Even if you have a terrible prognosis, the act of knowing assuages anxiety. There’s a sense of empowerment.”

In November 2010 Kim presented her case to Ralitza Gavrilova, a medical geneticist at the Mayo Clinic. She got a frosty reception. Gavrilova told Kim that her odds of being right were slim. “I got this sense that she thought I’d made an unfounded shot in the dark,” says Kim. “That I didn’t understand the complexity of the genome. That I had been reading the internet, and they come up with all sorts of things there.”

Gavrilova pushed Kim towards a different test, which would look at seven genes linked to ARVC. Her insurance would cover that, but if she insisted on sequencing the DNA of her LMNA gene, she would have to foot a $3,000 bill herself. Why waste the money, when it was such an unlikely call? But Kim was insistent. She knew that the known ARVC genes explain only a minority of cases and that none of them was linked to neural problems. In all her searching she had found only one that covered both her heart and nervous problem. Eventually, Gavrilova relented.

Kim, meanwhile, disappeared down to Baja in Mexico. Gavrilova’s scepticism had worn her down and she fully expected that the results would come back negative.

When she returned home in May, there was a letter waiting for her. It was from Gavrilova. She had been trying to call for months. The test had come back positive: on one of her two copies of LMNA Goodsell had a mutation, in a part of the gene that almost never changes. LMNA consists of 57,517 DNA ‘letters’, and in the vast majority of people (and most chimps, monkeys, mice and fish) the 1,044th position is filled by a G (guanine). Kim had a T (thymine). “All evidence suggests that the mutation found in this patient might be disease-causing,” Gavrilova wrote in her report.

In other words, Kim was right.

“I’m beyond impressed,” says Michael Ackerman, a geneticist at the Mayo Clinic. He specialises in inherited heart disorders like ARVC that can cause sudden death at any time. Such diseases make for people who do their homework, but Ackerman describes most as “Google-and-go” patients who check their diagnosis online, or read up about treatment options. Kim had written up her research as a white paper – 36 pages of research and analysis. “Kim’s the only one who handed me her own thesis,” he says. “Of all the 1,000-plus patients I’ve taken care of, none have done extensive detective work and told physicians which genetic test to order.”

He thinks she nailed it too. It is unlikely to be the whole story – Kim almost certainly has other mutations that are affecting the course of her disease – but LMNA “is certainly the leading contender for a unifying explanation, without there being a close second,” he says. “The evidence is pretty good for this being a smoking gun.”

The test had vindicated her hypothesis, but it also raised some confusing questions. Heart problems are a common feature of laminopathies, but those mutations had never been linked to ARVC, Kim’s specific heart malfunction. Had she been misdiagnosed? A few months later, Kim stumbled across a new paper by a team of British researchers who had studied 108 people with ARVC and found that four had LMNA mutations (and none of the standard ones). “To the best of our knowledge, this is the first report of ARVC caused by mutations in LMNA,” they wrote. They didn’t know about Kim’s work – they couldn’t have, of course. But she knew. Kim had beaten them to it. “I was so excited, I was running up and down the beach,” she says.

When patients get solutions to their own genetic puzzle, it’s always professional geneticists who do the solving. Take James Lupski. He has been studying Charcot–Marie–Tooth for decades, and discovered the first gene linked to the condition. He also has it himself. In 2010 he sequenced his own genome and discovered a previously unidentified mutation responsible for the disease. In other cases anxious parents have been instrumental in uncovering the causes of their kids’ mysterious genetic disorders after long diagnostic odysseys, but only by bringing their cases in front of the right scientists.

Kim, however, was an amateur. And to her, sequencing was not a Hail Mary pass that would – maybe, somehow – offer her answers; it was a way of confirming a carefully researched hypothesis.

“People have been talking about empowering consumers since there was an internet,” says Eric Topol, a geneticist at the Scripps Clinic. “But finally, we’ve reached a point where someone can delve into their condition beyond what the top physicians at the Mayo Clinic could. They couldn’t connect the dots. She did.”

Topol, a self-described “digital medicine aficionado”, argues that Kim is a harbinger of things to come. In his book The Creative Destruction of Medicine, Topol foretells a future where doctors are no longer the gatekeepers of medical information. Advances like personal genetic testing or sensors that measure molecules in the blood will give patients the power to better understand themselves and to exercise more control over their healthcare. Medicine is becoming more democratic.

Kim is a vanguard of that change. She lacked academic knowledge, but she had several advantages over her physicians and other researchers in the field. She had detailed first-hand knowledge of her own symptoms, allowing her to spot connections in the scientific literature that others had missed. She could devote hours to learning everything about her niche disorders – time and focus that no clinician could reasonably spend on a single case. And she had unparalleled motivation: “There’s nothing that engages your curiosity more than being confronted by your death,” she says.

It is also becoming ever easier for that curiosity to lead to discovery. In the past geneticists would try to diagnose patients by looking at their medical history and deciding which genes might be worth sequencing, as Gavrilova tried to do for Kim. The approach makes sense, but it only ever confirms known links between genes and diseases.

One way of finding new links is to sequence a patient’s exome – the 1 per cent of their genome that contains protein-coding genes. It’s cheaper than sequencing a full genome, but allows researchers to hunt for disease-related genes by interrogating every possible suspect simultaneously, without having to whittle down the list first. “Suddenly, we’re finding patients presenting with Disease X who have mutations in genes never previously associated with that disease,” says Daniel MacArthur, a geneticist at Massachusetts General Hospital. “That’s happening in nearly every disease field right now.”

Exome sequencing is now barely more expensive than sequencing much narrower gene panels. MacArthur says that the cost has already fallen below $1,000 and may halve again this year. And once patients have that information, they could use it to find others with the same mutations and check if they have the same symptoms.

Currently, the results from DNA sequencing studies are largely squirrelled away in boutique databases that collate mutations for specific diseases or genes. The ironically named Universal Mutation Database covers mutations in only 34 genes, including LMNA. Broader ones exist, but for decades they have been incomplete, rife with mistakes, or inaccessible, even to other researchers – a sad state of affairs that MacArthur laments as the “single greatest failure in human genetics”. Now, though, the National Institutes of Health are developing an open database called ClinVar that covers all disease mutations. “A lot of us are putting our hopes on this,” says MacArthur. “We need to come up with resources that empower people to make surprising links, which is hard to do if the data are broken up by disease or gene.”

But for every Kim, there are others who research their own conditions and come up with wrong answers. In one study four non-specialist volunteers tried to diagnose 26 cases from the New England Journal of Medicine by Googling the symptoms. They got less than a quarter right. Genetic diseases arguably lend themselves to confusion and misinformation. They are often both debilitating and enigmatic, and getting sequenced can offer little comfort beyond a diagnosis. If mainstream science has no easy answers to offer, many patients will follow any lead, no matter how weak. “There’s a tendency for people to spin very convoluted stories on tenuous threads of evidence. Even scientists do that,” says MacArthur. “I have heard of a lot of rare-disease patients who come up with hypotheses about their disease, and very few turn out to be correct.”

Even Kim’s tale could have taken a different turn. Last year, a team from the Baylor College of Medicine sequenced the exomes of 250 people with suspected genetic disorders, and found that four of them had two diseases caused by mutations in different genes. In other words, Kim’s hunch about her two diseases sharing a common root could well have been wrong. Lightning does occasionally strike twice.

“We almost always have to spend time with patients decoding and recoding the impression that they’ve acquired about their disease from their own homework,” says Ackerman. Kim was an exception, he says, and her other physicians echo that view. She is unique. She is one-of-a-kind. She is extraordinary. High praise, but it conceals the implicit suggestion that she is an outlier and will continue to be.

“Bullshit,” says Kim. “I hear this all the time: that I’m an exception. That the patient of the future is not going to do what I did.” She bristles at the very suggestion. “I almost take offence when I hear that what I’ve done is exceptional.”

We are talking over coffee at La Ventana. This is her fifth winter here, and she and CB have just celebrated their 30th wedding anniversary. CB leans back against a wall, quiet and contemplative. Kim sits forward, animated and effusive. She’s drinking decaf because of her heart, but it’s not like she needs the caffeine. “Take Rodney Mullen. He’s a real genius,” she says. Mullen is not a figure from science or medicine. He is, in fact, a legendary skateboarder, famous for inventing mind-blowing tricks that previously seemed impossible. One of them is actually called the ‘impossible’. “He executes these movements that defy reason, films them and publishes them on YouTube,” Kim says. “And inevitably, within a few weeks, someone will send him a clip saying: This kid can do it better than you. He gave that trick everything he had, he’s pulling from all of his experience, and here’s this kid who picks it up in a matter of weeks. Because he learned that it’s possible to do that. Rodney just acts as a conduit. He breaks barriers of disbelief.”

Her protestations aside, Kim is unique. Throughout her life she had built up a constellation of values and impulses – endurance, single-mindedness, self-reliance and opposition to authority – that all clicked in when she was confronted with her twin diagnoses. She was predisposed to win. Not everyone is. But as genetic information becomes cheaper, more accessible and more organised, that barrier may lower. People may not have to be like Kim to do what she did.

Kim isn’t cured. Her LMNA discovery offered her peace of mind but it did not suggest any obvious treatments. Still, she has made a suite of dietary changes, again based on her own research, which she feels have helped to bring her nervous symptoms under control. Some are generic, without much hard science behind them: she eats mostly organic fruit, vegetables, nuts and seeds, and avoids processed food. Others are more tailored. She drinks ginger tea because it thins the blood – she says that many people with laminopathies have problems with clots. Whether her choices are directly slowing the progress of her diseases or triggering a placebo effect, she is fit and happy. Her defibrillator hasn’t shocked her in months. And, of course, she still exercises constantly.

Up the hill from the beach we can see the little yellow house where she wrote the 36-page booklet that put together all her research. It convinced her doctors, yes, but it did even more. She showed it to her brother, now an anaesthesiologist, and it allowed them to reconcile. “It’s like I’ve finally done something worthy with my life,” Kim says. “He told me I’d done some really good research and that I’d missed my calling as a medical researcher. I told him I think I’ve been doing exactly what I needed to do.”

This article first appeared on Mosaic and is republished here under a Creative Commons licence.

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Fluoroquinolones Deplete Iron and Lead to Epigenetic Changes

In my ciprofloxacin toxicity recovery story I note that:

I take a low dose iron supplement – only 5 mg. – daily. The brand of iron supplement that I use is Pur Absorb, but I’m guessing that other low-dose iron supplements will work equally well. Within just a couple days of starting taking the iron supplement, my energy levels increased dramatically. I could walk a mile without being exhausted afterward. In addition to improving my energy level, the iron supplement seems to make my muscles and tendons more supple and malleable. When my tendons are feeling tight, a dose of iron helps to loosen them up – within just a couple hours. Too much iron is really bad for you, so please be careful with supplementing it (ask your doctor, yada yada), but it helps me immensely.”

I’ve always wondered why iron helped me to recover from fluoroquinolone toxicity. In some ways, it didn’t make sense – iron is an oxidant (according to a doctor friend, it’s a bit more complicated than that, and in some situations iron can be an antioxidant and in others it can be an oxidant), and antioxidant supplements are what help most floxies. Also, iron is a component of the Fenton Reaction, and the Fenton Reaction is where, “Iron(II) is oxidized by hydrogen peroxide to iron(III), forming a hydroxyl radical and a hydroxide ion in the process. Iron(III) is then reduced back to iron(II) by another molecule of hydrogen peroxide, forming a hydroperoxyl radical and a proton. The net effect is a disproportionation of hydrogen peroxide to create two different oxygen-radical species, with water (H+ + OH–) as a byproduct.” Basically, iron can “donate or accept free electrons via intracellular reactions and help in creating free radicals.” Free radicals are ROS. Some of the nastiest ROS are created in the Fenton Reaction – hydroxyl radicals and hydroperoxyl radicals. According to “Oxidative Stress Induced by Fluoroquinolones on Treatment for Complicated Urinary Tract Infections in Indian Patients,” fluoroqinolones increase the production of ROS, and it has been postulated (by myself and others) that the mechanism for fluoroquinolone toxicity is an excess of ROS wreaking havoc on all systems of the body.

So, why did iron make me feel so much better?

It’s a question that has perplexed me for years.

Answers to that question can be found in the article, “Non-antibiotic effects of fluoroquinolones in mammalian cells” which was published in the July, 2015 issue of The Journal of Biological Chemistry. In this post I will highlight some of the more interesting findings from “Non-antibiotic effects of fluoroquinolones in mammalian cells.” All excerpts from the article are quoted and italicized.

Here we show that the FQ drugs Norfloxacin, Ciprofloxacin, and Enrofloxacin are powerful iron chelators comparable to Deferoxamine, a clinically-useful iron chelating agent.”

Fluoroquinolones suck iron out of (chelate) cells just as well as drugs that are meant to suck the iron out of cells (Deferoxamine). Iron is an essential mineral that is critical for transporting oxygen throughout the body. Chelation of iron from cells can be detrimental to health in multiple ways including, “delayed cognitive function, poor exercise performance and lowered immune function. In children, iron deficiency anemia can cause psychomotor and cognitive abnormalities resulting in future learning difficulties.

We show that iron chelation by FQ leads to epigenetic effects through inhibition of α-ketoglutarate-dependent dioxygenases that require iron as a co-factor.”

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Iron depletion leads to adverse epigenetic effects through inhibition of iron-dependent enzymes. This is a very big deal – Fluoroquinolones can change genetic expression (epigenetics) in human cells. Later in the article it is noted that, “This is the first study to show global epigenetic changes induced by FQ antibiotics.” It had been previously postulated in “Epigenetic side-effects of common pharmaceuticals: A potential new field in medicine and pharmacology” (2009) that all fluoroquinolone adverse effects were the result of epigenetic changes, but “Non-antibiotic effects of fluoroquinolones in mammalian cells” describes the first study of human cells that shows epigenetic changes caused by fluoroquinolones. Epigenetics wasn’t even a notion, much less a field of study, when the FDA approved fluoroquinolones, drugs whose mechanism of action is, “inhibition of the enzymes topoisomerase II (DNA gyrase) and topoisomerase IV (both Type II topoisomerases), which are required for bacterial DNA replication, transcription, repair, and recombination.” Think about that next time you pick up a drug from the pharmacy and assume that it’s safe because the FDA approved it.

Dioxygenases are enzymes that are necessary for aerobic life. Fluoroquinolones inhibit α-ketoglutarate-dependent dioxygenases, which require iron as a co-factor.  Depletion of α-ketoglutarate-dependent dioxygenases leads to changes in how genes are expressed.

Fluoroquinolones were also found to inhibit several demethylases, “enzymes that remove methyl (CH3-) groups from nucleic acids, proteins (in particular histones), and other molecules. Demethylase enzymes are important in epigenetic modification mechanisms. The demethylase proteins alter transcriptional regulation of the genome by controlling the methylation levels that occur on DNA and histones and, in turn, regulate the chromatin state at specific gene loci within organisms.” FQs were found to inhibit “Jumonji domain histone demethylases, TET DNA demethylases, and collagen prolyl 4-hydroxylases, leading to accumulation of methylated histones and DNA, and inhibition of proline hydroxylation in collagen, respectively. These effects may explain FQ-induced nephrotoxicity and tendinopathy.” (emphasis added).

Many possible mechanisms for the tendinopathy and compromised collagen integrity caused by fluoroquinolones have been proposed. It has been suggested that fluoroquinolone caused destruction of connective tissues are due to metalloprotease (MMP) malfunctions, magnesium depletion, and the NO/ONOO cycle. In “Non-antibiotic effects of fluoroquinolones in mammalian cells” it is asserted that iron chelation, and the inhibition of enzymes that utilize iron, are behind the fluoroquinolone-caused musculoskeletal adverse effects:

These results suggest, for the first time, that FQ treatment can cause unanticipated epigenetic effects. Moreover, we suggest that the well-established linkage between FQ treatment and tendinopathy reflects impairment of collagen maturation by FQ. We suggest that it is the inhibition of collagen 4 prolylhydroxylases by FQ mediated iron chelation, and repression of collagen P4H1 and LH1 transcription that underlies the peculiar tendinopathy side effects of FQ antibiotics.”

And:

FQ are potent iron chelators capable of inhibiting 2-KG dependent dioxygenases because of the crucial role of iron in the active site. We show that FQ treatment inhibits collagen maturation. Prolyl 4- hydroxylase and lysyl hydroxylase are iron dependent enzymes essential for the post-translational modification of collagen. Both play central roles in collagen maturation through hydroxylation of proline and lysine residues to mediate collagen cross-linking. Covalent crosslinks are required for the tensile strength of collagen fibers (64). We suggest that it is iron chelation by FQ that accounts for suppressed collagen hydroxylation, giving rise to tendinopathies.”

And:

Additionally, suppression of HIF-1α can have drastic effects on vascularization and energy metabolism in connective tissues, contributing to decreased blood flow in an already hypoxic and avascular tissue. We suggest that these three insults – inhibition of prolyl and lysyl dioxygenases, reduction of P4HA1 and LH1 mRNA levels, and reduced tendon vascularization upon HIF-1α depletion – together account for FQ induced tendinopathies.”

To sum up the excerpts, fluoroquinolones chelate iron from cells, this leads to inhibition of iron-dependent enzymes, which lead to epigenetic changes that result in collagen malformation and tendinopathies. It should also be noted that fluoroquinolones chelate other minerals, including magnesium, from cells, and magnesium-dependent enzymes are inhibited by fluoroquinolones as well.

All doctors and researchers, and the FDA, should note that in chelating necessary minerals from the body, fluoroquinolones are not only inhibiting necessary enzymatic reactions, they’re also changing genetic expression, and that the long list of severe adverse effects of fluoroquinolones may be due to adverse expression of genes. Neither long-term, nor intergenerational effects of fluoroquinolones are currently known.

So… what should floxies do with this information? Personally, I supplement iron and I find that it helps me immensely. Not everyone can, or should, supplement iron though. Too little iron is bad, but too much is also harmful. The prudent thing to do is to get your iron levels tested and to supplement if necessary under the care of your doctor.

When I corresponded with Dr. Maher, one of the authors of “Non-antibiotic effects of fluoroquinolones in mammalian cells,” he noted that, “I would simply emphasize that what we demonstrate in this work involves human cells grown in culture, and lab conditions, and we want to make it clear that these are findings of potential mechanisms of fluoroquinolone antibiotics that could be relevant for patients, but we provide no direct data related to human patients or treatments. Further studies will be required to understand if these or related effects actually occur in people.”

I am thankful to Doctors Badal, Her and Maher for their work on “Non-antibiotic effects of fluoroquinolones in mammalian cells!” Of course, caution should be used when drawing conclusions from their results. Though I shouldn’t draw conclusions about how FQs react in a complex human body from how human kidney cells react in a petri dish, I don’t think that it’s completely out of line to say that the potential implications of this research are huge. The chelation of minerals from cells by fluoroquinolones may be leading to epigenetic changes in the people who take fluoroquinolones. What this means for their health is not currently known.

The epigenetic adverse effects of fluoroquinolones were found to be reversible by exposing the floxed cells to iron, and studies have shown that magnesium, vitamin E, MitoQ and NAC can reverse some of the effects of fluoroquinolones, so please have hope, hang in there, and take your mineral supplements (under the supervision of your doctor, yada, yada).

 

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Fluoroquinolone Induced Gene Upregulation and ROS

The article, “The Fluoroquinolone Levofloxacin Triggers the Transcriptional Activation of Iron Transport Genes That Contribute to Cell Death in Streptococcus pneumonia” is difficult.  It’s not light reading.  I wish it was.  I wish the articles that have information about how fluoroquinolones affect cells were easy to understand and to read.  I wish that we had easy, simple answers about how fluoroquinolones lead to the myriad of adverse events that are listed on the FDA warning labels for them.  I wish that more was known about how fluoroquinolones work.  I wish that a list of definitions wasn’t necessary at the beginning of this blog post.  But this stuff is hard, and a list of definitions is necessary, so, hereyago (some definitions paraphrased from the Wikipedia article because it’s easiest and I’m not a biochemist – for more info, go to the wiki page, or elsewhere):

Reactive Oxygen Species (ROS):  “Reactive oxygen species (ROS) are chemically reactive molecules containing oxygen. Examples include oxygen ions and peroxides. ROS are formed as a natural byproduct of the normal metabolism of oxygen and have important roles in cell signaling and homeostasis.  However, during times of environmental stress (e.g., UV or heat exposure), ROS levels can increase dramatically. This may result in significant damage to cell structures. Cumulatively, this is known as oxidative stress. ROS are also generated by exogenous sources such as ionizing radiation.”  ROS can be incredibly nasty.  They can lead to cellular damage, including DNA damage, and are related to every chronic disease there is.  They’re also related to ageing.  As damage from ROS (also called oxidative stress and free radicals) accumulates, ageing and the diseases of old age occur.  Interestingly though, ROS are not all bad.  They serve as signaling mechanisms within cells and play a large role in turning genes on and off (epigenetics).  They need to be in balance.  If they’re not in balance, a whole lot of things can go wrong.  They’re kind of like tequila.  A shot of tequila mixed with lime juice and other goodies, is excellent in a margarita.  But if you drink the whole bottle, and then mix it with some whiskey, it’s really bad and destructive.  The ways that ROS work within cells is not linear and difficult to study.  Not a whole lot is known about ROS or how they affect human health.  The article, “Exercise-Induced Oxidative Stress: Cellular Mechanisms and Impact on Muscle Force Production” has a really nice over-view of various ROS and their effects.  It’s easier to think of them as different  alcoholic drinks though.  Some are beer – pretty benign unless you have a ridiculous amount of them.  Others are potent – more like Everclear – and they can do a lot of damage to you quickly.

Fenton Reaction:  “Iron(II) is oxidized by hydrogen peroxide to iron(III), forming a hydroxyl radical and a hydroxide ion in the process. Iron(III) is then reduced back to iron(II) by another molecule of hydrogen peroxide, forming a hydroperoxyl radical and a proton. The net effect is a disproportionation of hydrogen peroxide to create two different oxygen-radical species, with water (H+ + OH–) as a byproduct.”  Basically, iron can “donate or accept free electrons via intracellular reactions and help in creating free radicals.”  Free radicals are ROS.  Some of the nastiest ROS are created in the Fenton Reaction – hydroxyl radicals and hydroperoxyl radicals.  (“Exercise-Induced Oxidative Stress: Cellular Mechanisms and Impact on Muscle Force Production” has good info on both of those.)

Type II topoisomerases, gyrase and topoisomerase IV:  “Type II topoisomerases maintain DNA topology and solve the topological problems associated with DNA replication, transcription, and recombination (20). Gyrase introduces negative supercoils into DNA (21), whereas topo IV relaxes DNA and participates in chromosome partitioning (22). Chromosomal topology in Escherichia coli is maintained homeostatically by the opposing activities of topoisomerases that relax DNA (topo I and topo IV) and by gyrase.” (from “The Fluoroquinolone Levofloxacin Triggers the Transcriptional Activation of Iron Transport Genes That Contribute to Cell Death in Streptococcus pneumonia”)

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You got all that?  Even the definitions are difficult.  Now onto some highlights of the article, “The Fluoroquinolone Levofloxacin Triggers the Transcriptional Activation of Iron Transport Genes That Contribute to Cell Death in Streptococcus pneumonia.”

Basically, the researchers found that levofloxacin upregulated genes that are involved in iron uptake and triggered the Fenton reaction in certain bacteria.  The increase in reactive oxygen species that ensued contributed to the lethality of the levofloxacin.

There are a few interesting things that should be noted about this.  First, levofloxacin can upregulate genes.  How consequential is this?  Can eukaryotic genes be upregulated, or can only bacterial genes be upregulated?  What about mitochondrial genes?  What does upregulation of bacterial, mitochondrial and even eukaryotic nuclear genes do to the person who has taken levofloxacin?

Some interesting research is being conducted about the relationship between the microbiome and genetic, heritable traits.  This National Geographic article, “The Most Heritable Gut Bacterium is… Wait, What is That?” notes some of the relationships that are being explored.  Our genes can affect our microbiome, our microbiome can affect our genes, can the genes of our microbiome affect…. US?  Where does the microbiome stop and where do we begin?  Those are all questions that have not yet been answered.  Unfortunately, fluoroquinolones, like levofloxacin, are thoroughly messing up our microbiomes and even causing the upregulation/expression of certain genes.

The second thing of note from the article is that the upregulated genes caused the activation of the Fenton reaction in the bacterial cells.  Again, how does this affect our microbiome?  How does it affect US?  Hydroxyl radicals and superoxide anions are nasty ROS that damage everything in their wake.  What happens to the health of the microbiome, and the host (the person) when their gut is suddenly full of toxic ROS?  Leaky gut syndrome?  Autoimmune reactions?  The multi-symptom, chronic illness that is fluoroquinolone toxicity syndrome?

There is quite a bit of evidence that fluoroquinolones do to mitochondria what they do to bacteria – disrupt the process of DNA replication and reproduction and lead to destruction and cell death.  I think that mitochondrial destruction has a lot to do with fluoroquinolone toxicity.  However, I don’t think that the role of disruption of our microbiome and destruction of our gut bacteria should be overlooked.  The signaling that goes on within our microbiome, and between “us” and our microbiome, is critically important and poorly understood.  Triggering bacterial DNA destruction and death, upregulation of genes and the Fenton reaction – which leads to production of highly destructive ROS, is a very, very, very bad idea – even if it just stays within the microbiome.

The conclusion of “The Fluoroquinolone Levofloxacin Triggers the Transcriptional Activation of Iron Transport Genes That Contribute to Cell Death in Streptococcus pneumonia” is that:

“In conclusion, we have shown for the first time that fatDCEB transcription is regulated by the supercoiling level. The primary effect of the interaction of LVX-topo IV is the upregulation of the operon by local increase in DNA supercoiling. This upregulation would increase the intracellular level of iron, which activates the Fenton reaction, increasing the concentration of hydroxyl radicals. These effects were observed before the inhibition of protein synthesis mediated by LVX. All these effects, together with the DNA damage caused by the inhibition of topo IV, would account for LVX lethality. The possibility to increase FQs’ efficacy by elevating the levels of intracellular ferrous iron remains open.”

Because, apparently, seeing the big picture of the symbiotic relationship between the microbiome and the rest of the organism (the person), isn’t the goal.  The goal is to kill bacteria.  It’s ridiculously short sighted.  Sigh.

Because we’re in Floxieville, there has to be a paradox.  Supplementing iron helped me more than just about anything else.  Iron is one of the few supplements that made me feel markedly better immediately after taking it.  Other Floxies have reported that their ferritin levels are low post-flox.  The role of the Fenton reaction in fluoroquinolone toxicity would lead one to think that iron should be the last thing that a Floxie might need or want.  It helped me though.  I had more energy and even my tendons felt better when I started supplementing iron.  I don’t know if this has something to do with the kind of iron in my supplement/body – FE3 or FE2 – or if the iron had been converted to other chemical compounds and I needed to replace it, or what.  I do know that, as I said in the beginning of this post, this stuff is hard.

The Fluoroquinolone Levofloxacin Triggers the Transcriptional Activation of Iron Transport Genes That Contribute to Cell Death in Streptococcus pneumonia provides a good description of how fluoroquinolones work:

“The killing effect of FQs has been related to the resolution of reaction intermediates of DNA-FQ-topoisomerase complexes, which generates irreparable double-stranded DNA breaks (31). This could occur in E. coli by two pathways, one dependent on protein synthesis and the other independent of it. It has been shown that hydroxyl radical action contributes to FQ-mediated cell death occurring via a protein-dependent pathway (32). This result agrees with a recent proposal suggesting that, following gyrase poisoning, hydroxyl radical formation utilizing internal iron and the Fenton reaction (33) is generated and contributes to cell killing by FQs (34) as well as by other bactericidal antibiotics (35, 36). In this mechanism, proposed for Enterobacteriaceae (35, 37), the primary drug interactions stimulate oxidation of NADH via the electron transport chain that is dependent on the tricarboxylic acid cycle. Hyperactivation of the electron transport chain stimulates superoxide formation. Superoxide destabilizes the iron-sulfur clusters of enzymes, making Fe2+ available for oxidation by the Fenton reaction. The Fenton reaction leads to the formation of hydroxyl radicals that would damage DNA, proteins, and lipids (38), which results in cell death. Instead of a generalized oxidative damage, a recent study supports that the main action of hydroxyl radicals is the oxidation of guanine (to 8-oxo-guanine) of the nucleotide pool. The incomplete repair of closely spaced 8-oxo-deoxyguanosine lesions caused lethal double-strand DNA breaks, which would underlie much of the cell death caused by beta-lactams and FQs (39). However, recent investigations have questioned the role of hydroxyl radicals and intracellular iron levels in antibiotic-mediated lethality using antibiotic concentrations either similar to (40) or higher than (41) those used previously. The disparate results obtained using diverse antibiotic concentrations and times of treatment emphasize the complexity of the lethal stress response (42).”

Similar destruction happens in mitochondria.  As I mentioned though, even if it didn’t happen in mitochondria, and only happened in bacteria, that destruction and those reactions are horrible things to do to a person’s microbiome.  It is, after all, part of us.

All of the people at the FDA who think that it’s okay not to strictly regulate drugs that disrupt the process of DNA replication and reproduction, and lead to the upregulation of genes and induction of the Fenton reaction, which leads to high levels of highly reactive ROS, should be fired.  I’ve learned enough biochem in the last 3 years to know that induction of the Fenton reaction in any part of the body is a really bad idea.  The scientists at the FDA should be able to figure this out.

 

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Epigenetics and Fluoroquinolones: Now What?

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Per Dr. Chandler Marrs (who runs www.hormonesmatter.com), “Above and around genetic codes reside the on/off switches to many processes (the switching of genes on and off is epigenetics). If common medications, including fluoroquinolones, up or downregulate these processes and create new diseases, what is someone who takes them supposed to do? Can epigenetic changes be reversed? What is the patient to do with all the recent research on epigenetics? The research is all well and good, but what does it mean to the patient?”

Indeed.

Here is a post about how fluoroquinolones, and other common pharmaceuticals, affect epigenetics. There are currently more questions than answers and the right path is far from clear.

https://www.hormonesmatter.com/epigenetics-common-medications/

 

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Your Mighty Mitochondria

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Fun facts – Nalidixic acid, the chemical compound that is the base of all fluoroquinolones, was discovered in 1962. Mitochondrial DNA was discovered in 1967 (by Lynn Margulis who happened to be married to Carl Sagan). So, if you are under the impression that naladixic acid was tested for its affects on mitochondrial DNA, you would be wrong. Information regarding how mitochondria affect gene expression is being uncovered… um… now-ish. So, in the 30+ years that fluoroquinolones have been pushed, they have been used by the human population with zero knowledge of how they affect gene expression (both mitochondrial and nuclear). Gene expression, as you might imagine, is important.

More information can be found in this post, “Your Mighty Mitochondria” published on Hormones Matter:

http://www.hormonesmatter.com/mighty-mitochondria/

 

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