[History/World War I] November 11th Armistice: what can we learn from its 100th celebration?

Yesterday was the 100th anniversary of the end of the World War 1, also referred as the “Armistice”. On the 11th day of the 11th month of the calendar, the ceasefire will take place at 11:11 of the morning. You cannot imagine the meaning of this ceasefire without imagining the quietness of the wasteland. No more the sound of the artillery and the constant shelling. No more the sound of the machine guns reaping hundreds of soldiers as they come. No more the noise of bullets flying around the “No Man’s Land”. That was it.
The Armistice floated in the idea since October 1918 as Germany loss where becoming unbearable despite having earlier signed the treaty of Brest-Litovsk that ended their fight on their Eastern flank. Bulgaria, the Austro-Hungarian and the Ottoman Empire have also dropped the war and signed armistice with the Allied Forces, cornering Germany. It was also a tumultuous time for the German Empire, shaken by an uprising that will bring down the Prussian Empire and lead to the creation of the Republic of Weimar further sealed Germany’s fate.
The armistice process was a rushed compromised and negotiation, only meant to stop the war and allowed time to sign a peace Treaty. It was the brainchild of the US, under the Guidance of Woodrow Wilson with his “Fourteen Points”. On November 6th, Berlin received the latest note from Wilson and on November 9th, the German delegation led by
Matthias Erzberger met the French delegation represented by Marechal Ferdinand Foch in Compiegne (located about 30 miles North of Paris. 30 miles West of Reims and 100 miles West of Verdun).
But it was certainly not yet the end of the war, only shifted from the trenches to the office room. It will be extended several times until the Peace Treat of Versailles signed on June 28th 1919 (a symbolic date coming after the 5th anniversary of the death of Franz Ferdinand, the same even that led to the explosion of the powder keg). It is also a lesson of history that you cannot achieve long-lasting peace by subjection of your adversary into a harsh humiliation and financial burden of repairs for the harm done. Germans call it “Der Diktat”. Indeed this Peace Treaty only set up a fertile ground for a coming war despite everyone thought that such war would be the “end of all war” due to its worldwide involvement and by the savagery expressed in it.
The world came out completely broken by this war (with the exception of the United States, becoming de facto the new superpower). Gone were these colonial super-powers that have been soliciting his colonials to fight a war distant from their land (Canada, Australia, New-Zealand, Indus for the British Empire; Africa and South-East Asia for France), as it marked the beginning of the end for these colonies. Gone was the Russian Empire with the Bolshevik Revolution of 1917, only to see the mother eating her own child like any revolutions and the rise of one of the most cruel dictator (Joseph Staline). The nationalism that fueled Europe during the 25 years preceding the beginning of the war was slowly transitioning into the rise of fascisms across Europe during the following 25 years: Austria-Germany (Hitler), France (Petain and the Vichy Regime), Italy (Mussolini),  Spain (Franco)….
Those who pander on nationalism as “the same than patriotism” or glorify it as “My country first” should seriously take a textbook, visit Verdun and learn a lesson of history. Nationalism cost the lives of millions of humans (military and civilians), the lives of millions of animals (horses, donkeys, cows, goats….) and hundred of thousands of acres of arable lands, polluted by toxic chemicals and by unexploded devices.
The huge human cost that decimated and maimed a whole generation will lead to new artistic currents like surrealism (in particular, the “eau-forte” paintings by Otto Dix are giving a a view on the “gueule-casses”), new areas of medicine such as orthopedics and plastic surgery will boom on the survivors of the Great War.
My home region (Alsace), suffered twice from this war as it saw its children being divided and fighting each other into a fratricide: two members of the same family line could be facing each other in the trench, one serving with the French while the other one serving with the German.
This fratricide divide was only amplified after the victory in which clearing the past was a due process: imagine asking a people that have been speaking German for 50 years (on top of their cultural dialectal German), to speak exclusively in French. And being punished if you ever being caught speaking German.
Yet, there is some hope, that after all these lives gone we realize how much a waste and useless a war fueled by nationalism is. The two most ferocious enemies of yesterday are now the brotherly partners of todays Europe. Yesterday it was Macron-Merkel sincere hugging, continuing over 30 years of Fresh-German partnership symbolized by Francois Mitterrand (former French President) and Helmut Kohl (former German Chancellor). These two men that grew during World War 2, holding their hands together as they saluted the fallen on both sides at the Duaumont Fort in Verdun, show how can we harbor brotherly love once we set our differences (fueled by nationalism) aside and see that upon death we are all human.
I come from a town juxtaposed to the Rhine river, facing a German town on the other shore. These two cities are now very strong partners, with a solid bridge extended between them, making a bond between these two cities and symbolized by a Tramway crossing such bridge. The best remedy to war is the appeasement of our nationalistic fervors, cooperation versus competition (the formation of the European Union as we know it today was only founded at its beginning by a simple agreement between six countries on steel and coal tariffs), finding our commonalities instead of spearing our differences as a defiance and arrogance.
To all the fallen of this war, I would like to thank them for their service, for their courage and their ultimate sacrifice.

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[Sciences/Junk Sciences] Zeolites, blood-brain barrier and “Autism Detox” scam.

Recently, it came to my attention of another scam popped up on social media. This scam came in form of the “Autism Detox” page on Facebook coming with the following description:
IMG_2005

“Zeolite”, “blood-brain barrier”, ‘detoxify toxins and heavy metals” and “cellular level”.
Incredible how much amount of BS claims can be packed in such a small vaporizer. Not only this was enough BS, the owner of this page went the extra mile and claims it is an “autism detox” as well.
I call this an utter amount of BS and since I am a scientist, I will explain why it is an utter amount of BS.

1. What are zeolites?
Zeolites are crystalline structure made of aluminum, silicium and oxygen. These crystals are formed by the aggregation of 4 oxygen atoms around aluminum Al3+ and Silicium Si4+ (notice how Avers that yells “shark” on aluminum in vaccines are fine absorbing aluminum from zeolites).
These frameworks of AlO4 and SiO4 can form 3-D geometrical structures harboring charges and possibly acting as a caging structure as shown below (Moshoeshoe et al., Am J Mat Sci 2017):

As you can see different structures exist. Now, which zeolites are used in the product described in this “detox”? According to the vendor website (https://www.coseva.com/toxin-removal/advanced-trs/), clinoptilolite (CLI) (amongst water and a proprietary formula). According to Mosheoshoe and colleagues, CLI harbors the following chemical composition ((Na,K)6(Si30Al6O72) •20H2O)) and harbor the following crystalline structure:
Clinoptilolite

Notably, CLI also display one of the lowest cation exchange capacity (CEC) of 2-2.6 mEq/gram. In summary, CLI is a small zeolite crystalline structure with limited cation exchange (against Ca2+, K+ and Na+). First, it shows that these compounds have a molecular weight exceeding the size recommended for small molecules (~832 Da>500 Da), a ring size bigger than the tight junction pore (5.6 Angstroms>4 Angstroms) and an non-negligeable amount of molecular charges. All these features make CLI very unlikely to cross the blood-brain barrier and no studies have provided a direct experimental evidence that CLI crosses the BBB.

2. Does zeolites even cross the GI tract?

Good question! The only paper that I found discussing about zeolites is a paper from Cefali and colleagues (Cefali et al., Pharm Res 1995). Unfortunately I cannot access the paper but the abstract provides two important parameters: Cmax and AUC. In particularly, it also provides the value of aluminum hydroxide (yep, that stuff found in vaccines).
Cmax is indicative of the maximal concentration reached upon administration via extravascular route (IM, PO or SC). The AUC is representative of the total amount that reached the circulation from the time of administration until the time the drug becomes undetectable in blood. From the abstract we have the following information The mean plasma silicon AUC values (+/- S.D.) were 9.5 +/- 4.5 [Note: Zeolite A], 7.7 +/- 1.6, 8.8 +/- 3.0, 6.1 +/- 1.9 mg.hr/L [Note: Aluminum Hydroxide] and the mean plasma silicon Cmax values (+/- S.D.) were 1.07 +/- 1.06 [Note: Zeolite A], 0.67 +/- 0.27, 0.75 +/- 0.31, 0.44 +/- 0.17 mg/L [Note: Aluminum Hydroxide] for Zeolite A, sodium aluminosilicate, magnesium trisilicate, and aluminum hydroxide respectively. Although mean silicon AUC and Cmax values were elevated when compared to baseline after administration of the silicon containing compounds, only the AUC from Zeolite A reached statistical significance (p = 0.041). The mean plasma silicon Tmax values (+/- S.D.) were 7.9 +/- 6.4, 5.8 +/- 4.6, 6.9 +/- 6.3 and 8.5 +/- 3.4 hrs for Zeolite A, sodium aluminosilicate, magnesium trisilicate and aluminum Hydroxide respectively.”. Since we have a Cmax and AUC value for Zeolite A and aluminum hydroxide very similar, we can assume that both compounds may likely show similar bioavailability. Considering the bioavailability of Al is very low (0.3%), it is very likely that zeolite and CLI may not show a higher value that this one. Thus, out of 100g ingested of zeolite, maybe less than 0.3g will likely reach the bloodstream. In conclusion the amount of zeolite capable to cross the GI is very small and considering the volume of a TRS “Detox” (28mL), the amount of zeolite capable to cross the GI tract after swallowing a whole bottle of it is likely to be ZERO.

3. What about the rest of the claims?
As far we have seen:
1) CLI absorption at the GI tract is likely close to ZERO, even if you sip a whole bottle at once (see 2).
2) CLI cannot cross the BBB because of the physicochemical constrains (see 1). The only paper listed in Pubmed is a letter written to a journal with no scientific evidence or experimental data backing up the claim (https://www.ncbi.nlm.nih.gov/pubmed/23224491).
3) The claim of detox is utterly BS: there are two organs that do it for you. The liver and the kidneys. Thats it.
4) Heavy metal detox mostly occurs via renal (kidney) filtration. Even if zeolites can trap ions like Na+ or K+, I still have to find a paper that shows me it can trap heavy metals (Cd2+, Pb2+, Hg2+…..). CLI has been shown to only trap three ions (Ca2+, Na+ and K+) with the poorest ability.
5) Claiming that autism be cured is not fallacious but criminal. Until now, there is no cure for autism. There is no evidence that chelating ions cure autism (chelation therapies have even been proven to be dangerous and responsible for the death of at least one boy). There is also no published mechanism of action demonstrating how a treatment can reverse a condition mostly identified as genetic.

 

[Metal/Opera Metal] Lux in Tenebris – To a New Eternity (EP)

After deciding to put an end on Darkonelly project band few years ago, Marion-Lamita have been working hard behind the scene to produce something different. The announcement back then left me skeptical and somehow disappointed. We can say that  her new project Lux in Tenebris has been producing something interesting. After releasing some solo titles on Youtube (that left me in a limbo, neither being enthusiastic nor being pessimistic about), Lux in Tenebris has released its first EP titled “To A New Eternity” last Friday. Because it is an EP, I don’t give a score but I will anyway give my thoughts on it. The first thing that strikes is the contribution of Liv Kristine (ex-Theatre of Tragedy, ex-Leaves Eyes). Liv has been always been supportive of small bands, in particular during their freshman album. Delain, Hydra…..
This is an EP of 7 titles lasting about 35 minutes with two interludes. We start the EP with  “Divine Mankind” bringing us Marion’s soprano voice, that same haunting voice from Darkonelly. What I like about, in this time in which female-fronted metal symphonic metal is facing a huge glut of bands relying heavily on post-production, is the very particular moderate use of the keyboards. The music in this one is okay, sometimes a bit cheesy. Tony is in the growls on this one, a first time for him. Fairly good for a first-timer. The second one, “Chaos in Beauty” is sounding in my opinion more interesting, sometimes reminding me of Therion. Thats a good track you should listen.
The third track “Mystic Euphonia”, is my opinion the worst track of the album. I don’t know, it must be the beginning of the song that induce some aversive reaction. I don’t like it. At all. The first interlude “Temple of The Soul” has this kind of tribal vibe that is not bad. “Triangle of Light” is my opinion, the best of the EP. It has this pharaonic vibes by the beginning of the song, a very good mixture of the guitars and the synthesizers. It gives me “la palate” so it must be good. Quickly follows the second interlude “The Imperator’s Arrival”.  The last song “The Grand Design”, again featuring Liv Kristine.  It is quite good, decent work here and I would definitely recommend listening to the song.

After almost four years since the disbanding of Darkonelly project, this is the first significative piece of work (in the form of a EP) to emerge from Marion’s effort during her transition into Lux In Tenebris. Although the EP is overall quite pleasant to listen, at this stage I consider it as a fairly rough and raw diamond. Considering it is a project mostly driven by Marion at this point, it is a decent EP to give a try on. It shows some potential, but at this time it needs refining to achieve an optimal shape. It also tells you that having Liv on board is likely that their artistic potential is here. Lets let the sunrise shed some lights and allow the project to emerge from the darkness into light, when opera and metal shed through the darkness.

 

[Videogames/Xbox360] Fallout 3 – 10th Anniversary

Yesterday marked the 10th anniversary of the release of Fallout 3 by Bethesda, about 10 years after Fallout 2 was released. It was special, as its celebration came as I was beta-testing (through the BETA program) of Fallout 76, enjoying the 2 hours that Bethesda allowed players on the server.
. Initially, the Fallout 3 that we have been playing with is not the intended Fallout 3 that was expected from the original authors. Indeed, the creators of the original franchise were working on Fallout 3 under the project name “Van Buren” that was an evolution of the original series to an enhanced 3D isometric view. Following the bankruptcy filling of Interplay, Bethesda Software acquired the IP of the franchise, put the “Van Buren” project in a drawer and kept the franchise dormant for years. Only to reveal some aspect of it at the E3 previously to its release. At that time, Facebook and Twitter were not as developed as they are now, so I learnt a lot from glancing information on the Net.
Fallout 3 has a special meaning for me. It came few days after I was discharged from the hospital following surgery. I just had my first scientific paper accepted for publication in a peer-reviewed journal and I was engaging into a journey called “thesis dissertation writing” (you only grasp it when you experience what it is like to spend two months writing and stumbling into writing blocks). I did not have yet a current generation console as I was more of a casual gamer (did not have much time for that, between two toddlers and long days on the lab bench). Yet, I was really interested to get my hands on this game. PC was out of question since I was a Mac person (even with Parallels, the MacBook Intel GMA950 was not meeting the requirements for playing Fallout 3). I was therefore left between an Xbox360 and a PS3. I went with the Xbox360 for many reasons but primarily because I saw in the Xbox lineage a direct descendant of the SEGA Dreamcast. I am a SEGA fan, and I always kept Sony guilty on accelerating SEGA demise. Like it or not, I was not impressed by most of Sony PS1/PS2 library, as I always felt that the visual over the gameplay was the prime motivator.
I got my first Xbox, an Xbox Arcade (512MB memory) because I was on a budget, from a Swiss Gamestop (I think it was a time Gamestop started to invade Europe), with a Swiss-German copy of Fallout 3 (because it was the only version I could put my hand on with the console, later traded it to a UK version). Plugged in and the first thing you get on is the loading screen and the music of Inon Zur, that will set the tone for the Fallout series by Bethesda (with the exception of Fallout: New Vegas and Fallout 76 that are not using the same tones).
You start with the character creation as you are born in a Vault 101 clinic. This was the first time you could shape your character as much in terms of body and face feature (the original Fallout only allowed you to choose name, age and gender). The experience at the vault is marked by sequence of life (toddler to give you the basic controls, setting the S.P.E.C.I.A.L.; child 10th birthday giving you the choice of dialog and basic shooting skills); 16th and the G.O.A.T.). Upon which, the game really starts as you are awaken by the Overseers’ daughter telling you to run for your life as your Dad left and you are now considered as persona non-grata. Here we are, starting with just a security baton, a security guard outfit and fighting off radroaches while wandering into a 3D vault. Until you reach the Vault 101 door. You see the massive vault door opening, sliding and leading you to the exit of the cavern. As you walk out, you are blinded by the sun. A bright light, only to be welcome by the grayness of the Wasteland. You wander around discovering a lost civilization, yet you also see that life has survived out there, even lead to the rebuilding of some sort of civilization as you encounter Megaton.
You encounter for the first time dialogs with non-playable characters, learn the basic trade and barter (basically as a homeless, as I made my first caps selling the junk I cleaned around (such as cups, plates, silverware, junk cans, empty bottles….). You quickly learn the mechanic and learn about the armor/weapons conditions and repair. It was a blast to finally be able to wander into the Wasteland in a 3D environment. Also the ability to revisit the V.A.T.S. system that brought back some of the experience I had with the original Fallout (except that now it was a real-time) and the quickly-annoying “bullet-time” effect.
Yes Fallout has it dose of gore, but it was too clean. Gone was the dark humor, the sarcasm of the original. It felt too polite for me. Even the chems had little incentive for me (except the Buffout). Also gone the use of transportation vehicle, that as this day remains out of reach. I remember my first attempt to fix the motorcycle standing near a wall in Springvale HS, only to scrap parts from it.
Fallout 3 also introduced the infamous concept of “DLC” making you pay for the add-ons and really make you consider if waiting for the “Game Of The Year Edition” was the better choice. With the initial game price tag being about $60, and 5 DLCs being $10 each, you quickly end up spending double the sum on the game (not even mentioning the Collectors Edition, that could bring it to you up to $200). Also, the more-than-generous skills that basically made you expert in everything by level 20 and also the most ridiculous ending (right before the final quest, you find a sentient and friendly Super-Mutant named Fawkes that is immune to radiation. Yet, they ask you to sacrify your life to enter the water purifier belching lethal doses of radiation, in which you ultimately die from).
Yet, despite these defaults, I liked it and spent a good 200 hours playing this game over and over. It was a pleasure to visit the locations, with an impressive job done by the developers to map most of DC monuments and the region to match the real geography with a certain accuracy.
Since I still have an Xbox360, I may be tempted to fire again this game, while waiting for Fallout 76 to come.
“War. War never changes….”

[Sciences/Junk Sciences] Reconsideration of the immunotherapeutic pediatric safe dose levels of aluminum (Lyons-Weiler and Ricketson, J Trace Elem Med Biol 2018)

This is a post I wanted to write about a long time ago but for some reasons, I have been putting on the back burner for many different reasons.
You know what can be the most irritating to read? Papers from anti-science in general. You see, if the data was sound, the experimental setup was robust then I would consider their arguments are valid and sound. The problem with the anti-science papers I have been reading so far (anti-vaccines, anti-GMOs) are most of the time written by scientists that are lacking the expertise and credentials (in terms of publication record) to discuss on a topic, are based on speculation (the experimental data to support their hypothesis is at best paper-thin), the experimental data are most of the time missing the rigor and paradigm needed to make an objective outcome and often cherry-pick the literature.
Under normal conditions, such papers would not even pass a normal peer-review filter and would have been rejected outright. Yet, such papers found their way in very low impact factor journals or in predatory journals (that will publish any garbage study, as long as there is a valid payment method).

1. Who are the authors?
This is the case of this manuscript written by James Lyons-Weiler and Robert Ricketson. In this study, they claim that the current immunization schedule is dangerous, blaming on the extraordinary amount of aluminum and using questionable and speculative pharmacokinetics to support their claims (of course, there is no experimental data to support their claims, only speculation). A tenet in scientific publication is to assess how credible the authors are in the field, this can be judged by the authors affiliation and publication records. James Lyons-Weiler has  (according to his LinkedIn profile) a PhD in Ecology, Evolution and Conservation Biology and currently affiliated to the “Instittute for Pure and Applied Knowledge”. This is not a scientific institute as the Salk Institute, but rather an frontstore for some quackery posing as a “scientific institute”. The second author, Robert Ricketson, is no better. Indeed, he is even worse. Apparently Dr. Ricketson has a history of medical malpractice as a spine surgeon, and has been implicated in a medical malpractice lawsuit in 2001 for inserting a screwdriver in a patient spine. At the publication date, Ricketson affiliation is another “scientific institute” named “Hale O’mana’o Research” in Edmond, OK. A quick verification on his LinkedIn profile suggest that these two Ricketson are the same Ricketson. To summarize, we have two authors with ZERO expertise in pharmacokinetics (including one doctor that got fined over $5 millions for medical malpractice), working in institutes with questionable scientific credientials but established anti-vaccine stance, under the disguise of “vaccine safety” (here and here), published in a journal in which a notorious anti-vaccine scientist is sitting in the editorial board. Is it surprising? For me, it is not. Just a classical MO for anti-vaccine scientist.

2. What the paper is about?
You can find the paper here, since it is behind paywall I cannot legally share the information, so I would request the reader to corroborate my claims by getting the full-text. In this study, the authors consider the safety studies done in animals are not correct and underestimate the toxicity of aluminum because they are based on animal body weight. And thats where the trouble start. The authors solely consider the amount of aluminum injected into animals and patients SOLELY based on the body weight.
They ignore the administration route, they ignore the existing literature and even questions the outcomes and recommendation of the World Health Organization as mentioned as “We found two important errors in the provenance and derivation of provisional aluminum intake levels from World Health Organization (WHO; Supplementary Material) which, unfortunately, led to overestimation of safe exposure levels.” That’s a bold statement by the beginning, coming from two non-experts in pharmacokinetics and toxicokinetics.
So how do they ended up using such claim? By using a derived version of the Clarke’s equation:

Child dose (mg) = Adult Dose (mg) * (child bodyweight (lbs)/adult bodyweight (lbs))

The Clarke’s equation is a common equation used for therapeutic dosing, as we commonly refer to administer doses as x mg/kg. Knowing the patient weight, you can easily calculate the dose administered.  This formula is great…….if you already know the target concentration (or the average plasma concentration) you aim to target. This is usually supported by empirical data and further confirmed by lab tests (you can dose the drug in the patient plasma and assess if such amount falls within the therapeutical window). But this equation tells you nothing about the pharmacokinetics of the drug, or about the bioavailability of the drug, or differences in the administration routes.
It only tells you one thing “How many miligrams of X should I administer to obtain a plasma concentration of X falling into therapeutical range?” That’s it. You assume a dosing regimen (mg/kg), you know your patient weight (in kgs) and thus you can obtain the dose needed (loading dose or maintenance dose).  However, the authors manipulated the equation to be able to transpose the minimal risk level from adults to children as the following:

CED (mg/kg)= HED(adult) mg/kg x [BW(child) (kg)/BW(adult) (kg)]

The rest of the paper is SOLELY based on speculation, no experimental data to support the claim (we rather have a post hoc ergo fallacy unfolding). If the authors wanted to make their claims valid, they would provide experimental data (in forms of blood sampling) for 2 months babies before immunization (baseline control) and 6-24 hours after immunization to show that Al levels in plasma are significantly altered by the immunization. But they never show that data.
Indeed, what they show is a blatant misuse of the data and recommendation of the FDA and a serious miscalculation that a 12th grader would not even do.
They compared the dietary MRL as “JECFA provisional tolerable daily intake from dietary and additive exposures of 140 μg/kg/day and current provisional tolerable daily intake of 290 μg/kg/day per day both before and after the safety factor of 10 is applied (Fig. 3).
We end up in the classical cases of “apples versus oranges” and trying to make the claim they are the same. Which they are not. Yes, both are extravascular routes and follow similar fate. But in the same time, we have to compare the physics-chemical aspects and the bioavailability of Al in both routes. One is administered by oral route, the other by intramuscular route. In both cases, the bioavailability falls within the same range, with the oral showing about 0.3% and the IM from 0.6% (based on Flarend et al., Vaccine 1997) and 0.9% (Yokel and McNamara estimate, Pharm Tax 2001).

What the authors show us is basically a graph that assume the WHOLE Al injected in 100% bioavaialable at once, exceeding the MRL adjusted to pediatrics) as seen in Figure 4:
Lyons_Weiler_2018_Fig4

There is one thing to consider: The ATSDR. The ATSDR considers the MRL of 1mg/kd/day of ingested aluminum (that is about 100x lower than the NOAEL and adjusted to the bioavailability, as described here: https://www.atsdr.cdc.gov/toxprofiles/tp22-c8.pdf). If we assume a bioavailability of 0.3%, then we expect that out of 1mg/kg/day ingested, we can estimate that about 3microg (or 0.003mg)/kg/day would contribute in the total burden in the Al plasma level. This graph would be correct if 100% of the aluminum injected ended up in the systemic circulation at ONCE and spiked Al levels significantly high. But thats not the case, and the authors blatantly ignored this critical information, coming from previous studies. In order to compare these two items, you have to compare and estimate how much of each of these routes will contribute in the total Al plasma/blood levels.
You cannot just plot the total amount injected (adjusted per kg) and assume it is representing the same variable than estimated plasma levels from the MRL. Now, let consider that the Al injected is available at the rate of 1% a day, the graph will look more like that.

Lyons_Weiler_2018_Fig4_Adjusted

You see, we have a complete different scenario. If we consider that the aluminum is slowly released into the body at a rate of 1% per day we are now being way under the MRL and within safe levels. Again, we consider the MRL of 1mg (1000microg)/kg/day. If we consider a 0.3% bioavailability and difference in 5th and 95th percentiles weight (grey bars), we conclude that the daily burden of Al via dietary route should not exceed a value ranging from 13.20-18.72microg/day. Our values matches the MRL from Lyons-Weiler. In other words, our assumption is correct. If we consider an average weight of 5.35kg (50th percentile) at 2 months and 1mg as a cumulative dose of the immunization occurring the same day (conservative estimate), the amount delivered that day would be 0.187mg or (187microgram). Considering a bioavailability of 1% per day via IM, we have about 1.87microgram of burden from the vaccine added each day to a maximum MRL of 16.05microgram/day for the 50th percentile (weight 50th percentile=5.35kgs). Thats about 11.7% aluminum to be removed from the daily MRL, but within negligible range to have a statistical significance (you need at least 30% to consider it as statically meaningful).  This of course has to be confirmed by studies assessing plasma levels of Al after injections but there are already a literature out there with such data avaialable and reported here and here. Both studies concluded no changes in total Al plasma levels in regard of the vaccination status, including 6-24 hours after immunization.

3. Concluding remarks

Anti-science know how to bangs for their bucks, by sensationalizing claims knowing that the lay person will not or be capable to verify their claim. Most of the times, such claims come from persons that are legitimate scientists in their field, but completely speak out of their expertise domain. This is a common trope we see when people cite Linus Pauling, Otto Warburg or Luc Montagnier. Each of them have done remarkable discoveries in their field, got their Nobel Prizes but once they speak outside their expertise have proven to be wrong or have seen their claims manipulated by quack-peddlers. Lets take Linus Pauling that has been incremental in modern chemistry by describing the chemical bonds, but later claimed cancer(s) can be cured with Vitamin C. Coincidentaly, he died of prostate cancer in 1994.
Same applies in this paper. We have two authors with ZERO knowledge of pharmacokinetics, yet they have given themselves the role to demonize aluminum at all cost, bending and occulting facts to fit their narrative and their conclusion. This paper is the evidence that they are not serious about “vaccine safety”. They are staunch anti-vaccines, and they will use their status of scientists to vilify it at all costs, even if it means reaching outside their expertise, make extraordinary claims without extraordinary evidences (they did not have evidence for this study) and get published in a journal that will favor their claims and obviously lacked the rigor in the review.
Negating the neurotoxic effects of aluminum is not a correct statement either. Aluminum is neurotoxic, but as anything in toxicology it is all about the dose. And one parameter that is critical to assess the safety of aluminum is its plasma level. This safety level is driven by how much aluminum access the systemic circulation (from IV parenteral nutrition bags or from extravascular routes such as vaccines or dietary exposure). What matter at the end is the Al plasma levels and the FDA set a limit on that daily exposure (5 micrograms/kg/day via IV route). This is a problem encountered by patients suffering from non-functional kidneys (95% of aluminum is cleared via renal route) and from patient continuously fed via IV route (total parenteral nutrition).
Both Lyons-Weiler and Ricektson failed to applied basic concepts of pharmacokinetics, ignored the differences between vascular and extravascular routes and willfully used a calculation method that is not appropriated for this purpose. I would even what is worse is that none of their claims is supported by hard data, making their claims even more questionable.
Unfortunately, such “junk paper” felt through the cracks of peer-review and has been used repeatedly used by anti-vaxxers as supporting evidence. As Andrew Wakefield has his second paper removed after 16 years, how long it will take to remove that paper?
I dont know but the damage is done, and until “vaccine safety” scientists come with robust and foul-proof studies published in highly respected journals, they will be considered by me and others as junk scientists, keeping on feeding the literature with their garbage studies that should have been wiped out by a rigorous peer-review process.

 

[Neurosciences/BBB] Brain Endothelial Erythrophagocytosis and Hemoglobin Transmigration Across Brain Endothelium: Implications for Pathogenesis of Cerebral Microbleeds (Chang et al., Frontiers Cell Neurosci 2018)

I usually don’t post BBB papers on my blog because most of the time they address concepts or answers questions that are not relevant for the public in general, but I thought this one was an interesting paper to share. This is an original article published by Rudy Chang and colleagues in Frontiers in Cellular Neuroscience las month. It is open-access, that allows everyone to access to it. Another interesting feature is the disclosure of the reviewers that help improve the peer-review process and transparency.
Why I found this paper interesting? Its because it propose a novel mechanism of cerebral microbleeds, without affecting the tight junction complexes. In the field, when we consider brain bleeds, we consider a loss of the barrier function and a massive brain leakage. Such phenomenon occurs when you have an hemorrhagic stroke due to an aneurysm, or due to a arterioveinous malformation resulting in an unstable blood vessel. The presence of blood in the brain parenchyma is harmful for two reasons:
1) You are injecting a volume inside a closed space (cranium) that will lead to an increased mechanical pressure (intracerebral pressure) and ultimately brain damage by tissue crunching.
2) Red blood cells (RBCs) may be damaged (hemolysis) and release their content into the extracellular space. Heme is toxic at high concentration (through mechanisms that yet to be identified) and can further damage neurons via generations of free radicals and other damage-inducing signaling pathways.
In this article, they demonstrate that you may achieve a similar outcome than brain bleeds without having a leaky BBB. In particular, this study demonstrate the ability of damaged RBCs to cross the BBB via transcytosis (via an engulfment inside the BBB and the exit to the other side). For this study, they used bEND.3 cells (an immortalized mouse brain endothelial cells) and compared mouse RBC that were considered healthy or induced damage via tert-butylhydroperoxide (t-BHP). t-BHP induces oxidative stress (via the release of radical oxygen species such as hydroxyl radicals), in this case leading to the exposure of a particular phospholipid named “phosphatidylserine” (PS) from the inside to the outside of the cell surface membrane.
In this study, they demonstrated that oxidative stress mattered in RBC cell adhesion to b.End3 cells. Treatment of b.End3 cells with t-BHP or LPS (a bacterial membrane lipid, commonly used to induce an inflammation state at the BBB) failed to yield similar results. in addition to demonstrating the ability of RBC to adhere on b.End3 cell surface (the first step needed for cellular transcytosis), they also demonstrated the ability to have these cells to engulf and get trapped into these cells. This process appeared slow and it took about 18-24h to see a significant number of RBCs inside the cells. Finally, they show that such RBCs were capable to migrate through the b.End3 monolayers and popped out in the other side. Similar outcome was observed in vivo, but to a certain extent.
It is a very interesting study, because it can maybe explain some aspect of diseases associated with RBCs such as cerebral malaria (we can imagine that Plasmodium may use RBCs as a Trojan horse to cross the BBB). However, I also have some criticism of the study. First, it uses the b.End3 that has fairly poor barrier function (TEER<100Ohms.cm2), much less than the tightness expected in vivo (>2000Ohms.cm2). The second issue is inherent to working with non-human cells. Do we have the same outcome when it comes to the human BBB and human RBCs? Maybe this phenomenon is exclusive to rodents and may have limited impact in humans. Finally, and as seen with the in vivo data, RBCs maybe able to cross the BBB but they maybe likely get retained by 1) the basement membrane supporting brain endothelial cells and 2) rest in a limbo state in the perivascular space (a virtual space between the basement membrane and an external protein mesh called “glia limitans” wrapped around cerebral blood vessels). We have some hints as RBCs appear juxtaposed near the vasculature, as stuck by a mesh surrounding the vessels. I don’t think that RBCs can cleave such mesh because I assume they don’t have the molecular machetes (matrix metalloproteinases) to cut their way through. Yet, I think it is a very interesting paper, that work to be investigated with a human BBB model, using a more robust model.

[Videogames] Fallout 2 – PC (20th Anniversary)

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Bigger, louder, stronger, better! This how I would qualify Fallout 2. Today is the 20th anniversary of the release of Fallout 2 on PC. It was certainly the best second of a game franchise series, taking where its predecessor left and making it even more awesome.
Yes, it has its lot of glitches and bugs (including some due to last-minute changes for censorship issues) but it was all in glory of the 3-D isometric RPG.

It all starts with Louis Armstrong “Give Me A Kiss to Build a Dream On” with a Vault-Tec video explaining to the dwellers about how to get ready to exit the Vault 13 and use the GECK (Garden of Eden Construction Kit) to provide a sort of terraforming condition. As the huge blast door opens and people get out from the vault, we see strange mechanized alien-like creatures starting to blow their Gatling chain gun against the civilians. Here starts Fallout, generations after the original Vault Dweller left the Vault 13 being expelled by the Overseer because considered too subjective and possibly a threat to his own power. Who knew? A simple Vault Dweller, that saved not only the Vault from a programmed death due to a doomed water chip but also by disrupting the plot of the “Master” and his army of Super-Mutants.
We only knew that he/she left and mingled with the locals, and settled somewhere in Oregon, not to far to a city named Klamath (bringing it likely near Klamath Falls, OR). Generations passed and the legend of the “Chosen One” remains. But things are changing, and not for the good. The elder remembers about the words of the Chosen One, talking about this magical artifact called the GECK that can save the village.
You start as a local tribe in the village of Arroyo, set for the initiation with only a spear and your courage. As you may through the initiation, you gain strength and ultimately face the strongest man in the village as a duel. As you survived the fight and win it, you are awarded the “Holy Relicate” in the form of the original Vault 13 jumpsuit. You quickly discover a wrecked Vertibird looking similar to the introduction, and three “aliens” corpses nearby. Almost telling you that your goal is to seek assistance from the Vault 13.
As you go through the game, you learn about the surroundings, meet with the locals and face the racism towards the tribal. Even one of your companion, Sulik, is reminding you of your origins. You meet new folks, but also some wild characters. You encounter gecko hunters making a good fortune from gecko hides (one of the character you meet is Tycho that teach you the art of hiding gecko skins), you encounter slaves and slaveholders (one of them is called “Metzger” that is the German meaning of butcher), you encounter a successful Vault called Vault 8 in which they were able to build a city around their vault (called Vault City). Sure they have the technology, but they also have kept the worst of humanity (racism, refusal to help foreigners resulting in a slum on the outskirt of the city). You encounter friendly ghouls living near a Poseidon nuclear plant in a city called Gecko (and meet Harold). You meet Marcus, a super-mutant that once fought a BOS Knight named Jacob and after days of fighting established a friendship and helped settled the town of Broken Hills. You also find an old car that upon repair become a valuable asset (and the most annoying bug). Oh, did I mentioned about New Reno? Yep, basically Reno, NV with blackjacks and hookers…..
Not only the adventure is awesome, but the dark humor in it, all peppered with important reference to pop-culture make it an awesome experience. You can only understand why fans are so much in love of Fallout:New Vegas is by playing this game.
Of course, now the game is old and it will very unlikely run on Windows 10. You can download it on GOG.com and should be able to run it on PC (I am not sure they provide you with OSX version).
Move on and let the “kamasutra master” perk run amok in the wastelands.