BC HEALTH
Saved by @CodyyyGardner

1/16
Why do B12 and folate deficiencies lead to HUGE red blood cells?

And, if the issue is DNA synthesis, why are red blood cells (which don't have DNA) the key cell line affected?

For answers, we'll have to go back a few billion years.

 2/
RNA came first. Then, ~3-4 billion years ago, DNA emerged.

Among their differences:
🔹RNA contains uracil
🔹DNA contains thymine

But why does DNA contains thymine (T) instead of uracil (U)?

https://t.co/XlxT6cLLXg
3/
🔑Cytosine (C) can undergo spontaneous deamination to uracil (U).

In the RNA world, this meant that U could appear intensionally or unintentionally. This is clearly problematic. How can you repair RNA when you can't tell if something is an error?

https://t.co/bIZGviHBUc
4/
DNA's use of T instead of U means that spontaneous C → U deamination can be corrected without worry that an intentional U is being removed.

DNA requires greater stability than RNA so the transition to a thymine-based structure was beneficial.

https://t.co/bIZGviHBUc
5/
Let's return to megaloblastic anemia secondary to B12 or folate deficiency.

When either is severely deficient deoxythymidine monophosphate (dTMP*) production is hindered. With less dTMP, DNA synthesis is abnormal.

[*Note: thymine is the base in dTMP]

https://t.co/AnDUtKkbZh
6/
So one hypothesis is that megaloblastic anemia results from a deficiency in dTMP leading to an issue with DNA elongation (i.e., addition of nucleotides)

Some (#1) but not all (#2) data support this.

There is more to it.

1. https://t.co/vysYKm4Sst
2. https://t.co/PxjmJAsvwj
7/
To add to our explanation for how B12 and folate deficiencies hinder DNA synthesis, look back at the figure in tweet 5.

What would you anticipate increases in concentration in the setting of B12 or folate deficiency?
8/
B12 and/or folate deficiency result in issues with dTMP production. As dUMP is the precursor, the ratio of dUMP/dTMP rises.

Result: dUTP (uracil + deoxyribose triphosphate) is incorporated into DNA where dTTP should be!

https://t.co/54Bir7QA93
9/
But uracil doesn't belong in DNA!

In response to this misincorporation, attempts are made to repair these strands. U is removed but there isn't enough T to fill the gaps. Single and double-stranded breaks form resulting in non-functional DNA.

https://t.co/JXzqUpRyGc
10/
Without functional DNA, cell division is halted. RBC precursors undergo apoptosis.

Result: "ineffective erythropoiesis" and anemia!

To this point we've explained the anemia but haven't yet explained why the resulting RBCs are so large. That's next.

https://t.co/y5DVkAA8vj
11/
Remember that RNA doesn't uses thymine (it uses uracil). And only the thymine containing nucleotide (dTMP) requires B12/folate.

🔑Result: In B12/folate deficiencies, RNA synthesis is relatively unaffected!

https://t.co/lwmGWuOrFC
12/
In the nuclei of B12/folate deficient RBC precursors, DNA synthesis is poor leaving cells stalled and unable to divide.

But, in the cytoplasm, RNA and protein synthesis continues unabated.

Result: "nuclear-cytoplasmic asynchrony"
13/
Precursors with nuclear-cytoplasmic asynchrony are unable to divide into daughter cells. But the cytoplasm continues to expand.

When survivors eventually cast off their nucleus (and its DNA!) and appear in the peripheral blood, they will be huge.

They will be macrocytic!
14/
There are other explanations (see link).

And I admit this doesn't really explain why RBCs are more affected than other cell lines (though all ARE affected).

AND, why are neutrophils hypersegmented?

For these unanswered questions, I seek your help.

https://t.co/huX6xJOBhp
15/
Before closing, full disclosure: I had NO IDEA what "megaloblastic" referred to.

Was it the big RBCs? Was it the hypersegmented neutrophils?

Nope.

Megaloblasts are in the bone marrow. We still use this term despite the fact that nowadays most patients don't under biopsy.
16/16
➤In megaloblastic anemia, DNA synthesis is hindered by decreased dTTP and increased incorporation of dUTP
➤RNA synthesis remain relatively unaffected
➤This leads to:
💥Ineffective erythropoiesis ➛ anemia
💥Nuclear-cytoplasmic asynchrony ➛ macrocytosis

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Remember woman who tuk multiple @SriSriTattva products 4 range of problems frm diabetes 2 gas 2 liver disease & developed liver failure, listed for liver transplant?
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https://t.co/PXxI1Slyv2
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Before I go into results, I must say this was overwhelming. There was SO MUCH the lab identified, impossible to put everything here. So I made a summary. At the end of this thread, I have linked a full analysis described in Excel format. Some results were VERY concerning

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How did we analyse?
Here R links 2 methods
They R high end, done under strict protocols
Frm Ministry of Forest, Environment, Climate / NABL approvd Lab
ICP-OES https://t.co/O1CLhqVQAu
GC MSMS https://t.co/zRJoXyWQIr
FTIR https://t.co/goAembQ08p
Here is list V analysed 👇


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Sample names written on top (each column).
First 5 samples: C what we identified in #Ayurveda #medicines
Antibiotics
Steroids (anabolic/synthetic)
#NARCOTICS - LSD, Morphine
Blood thinners (possible reason Y bleeding tests were off the roof in the patient)
Heavy metals!


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Next 5 samples (total 10 now)
Mercury is clear winner. Almost all samples
See controlled substances - Butyrolactones https://t.co/CPz0FwPEOm, methylamine https://t.co/OZnXY7U9UQ
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#Ayush
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Websites and policy documents can be overwhelming. There’s a lot of loaded terms, there’s a whole bunch of things that your policy may or may not cover. It’s important to know and understand the details though, so you’re not surprised later.

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This one is for the real stats folks.

Let's deal with some objections to the deaths after flu vax/deaths after Covid vax comparison.

1) I agree Covid vaccine deaths are probably more likely to be reported than flu vaccine deaths. Are they 900 times more likely? Very doubtful...

2) Here's one good reason to think the gap may be small. The ratio of non-serious to serious Vaers reports is far HIGHER for the flu vax than for Covid. In other words, people have basically STOPPED filing non-serious event reports after Covid shots, because they are so common...

3) If people were clogging VAERS with Covid vaccine side effects reports because they are so sensitized to them, we'd see the opposite - tons of reports in every category. We aren't, though.

4) Children aside (and children do receive a lot of flu shots), the idea that the Covid vaccine is going to a meaningfully different population than the flu vaccine is nonsense. Flu campaigns are targeted at the elderly and healthcare workers, just like the Covid vaccine...

5) The correct area under the curve at risk post-Covid vaccinations is not 41 million doses x 8 weeks of followup. It's more like 41 million doses x 3 days. READ THE VAERS REPORTS YOURSELF. I have. The "he was hit by a bus a week after being vaccinated" isn't what's in there...
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Often the answer is 'all 4.' Yikes!

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Anxiety is contagious, we spread it and escalate it unless we know how to manage it.

This was perhaps my biggest lesson as a trauma chaplain - the very hard work of not catching someone's anxiety.

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When I caught it, I was no good to them. I no longer saw what was going on, I was now 'infected' by my own triggers, assumptions, the story I tell myself. I was all wrapped up in myself.

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Even in the very worst moment of their lives, even if they had me by the shoulders screaming, 'how could God allow this to happen?'

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Incidentally, early in chaplaincy, I thought this was an actual question. Because I was anxious, I was more infected by my need to answer than I was to simply be calm and present with them in their pain.

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Dhritarashtra's charioteer so that he could describe him the events of the upcoming war.

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This is how he described the face of the world:

सुदर्शनं प्रवक्ष्यामि द्वीपं तु कुरुनन्दन। परिमण्डलो महाराज द्वीपोऽसौ चक्रसंस्थितः॥
यथा हि पुरुषः पश्येदादर्शे मुखमात्मनः। एवं सुदर्शनद्वीपो दृश्यते चन्द्रमण्डले॥ द्विरंशे पिप्पलस्तत्र द्विरंशे च शशो महान्।

—वेद व्यास, भीष्म पर्व, महाभारत


Meaning:-

हे कुरुनन्दन ! सुदर्शन नामक यह द्वीप चक्र की भाँति गोलाकार स्थित है, जैसे पुरुष दर्पण में अपना मुख देखता है, उसी प्रकार यह द्वीप चन्द्रमण्डल में दिखायी देता है। इसके दो अंशो मे पीपल और दो अंशो मे विशाल शश (खरगोश) दिखायी देता है।


Meaning: "Just like a man sees his face in the mirror, so does the Earth appears in the Universe. In the first part you see leaves of the Peepal Tree, and in the next part you see a Rabbit."

Based on this shloka, Saint Ramanujacharya sketched out the map, but the world laughed
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