Let's establish a few facts about cefepime:
🔺4th generation cephalosporin antibiotic
🔺Excretion = exclusively in the urine (mostly as unchanged drug)
🔺Readily crosses the blood-brain barrier (so it easily accesses the brain)
https://t.co/rjYG1BfGPR
1/15
Why can cefepime cause neurological toxicity?
And why is renal failure the main risk factor for this complication?
The answer requires us to learn about cefepime's structure and why it unexpectedly binds to a certain CNS receptor.
#MedTwitter #Tweetorial
Let's establish a few facts about cefepime:
🔺4th generation cephalosporin antibiotic
🔺Excretion = exclusively in the urine (mostly as unchanged drug)
🔺Readily crosses the blood-brain barrier (so it easily accesses the brain)
https://t.co/rjYG1BfGPR
The first report of cefepime neurotoxicity was in 1999.
A patient w/ renal failure received high doses of cefepime and then developed encephalopathy, tremors, myoclonic jerks, and tonic-clonic seizures.
✅All symptoms resolved after hemodialysis.
https://t.co/u7JLVitQpp
Cefepime neurotoxicity is surprisingly common, occurring in up to 15% of treated critically ill patients (w/ symptoms varying from encephalopathy to seizures).
💡The main risk factors = renal failure and lack of dose adjustment for renal function.
https://t.co/nxbnzSq8AR
What about cefepime induces neurotoxicity?
One clue is that it's not the only antibiotic that causes neurotoxicity, particularly seizures.
This actually is a class effect w/ other beta-lactam antibiotics (including penicillins and carbapenems).
https://t.co/Lf4BhON9IY
Recall that beta-lactam antibiotics all share a common structural feature: a beta-lactam ring.
https://t.co/iWXweuG4Ct
A 1971 study in cats implicated beta-lactam rings as the source of neurotoxicity.
High doses of penicillin were used to induce seizures.
🔑But pre-incubation w/ the enzyme beta-lactamase (disrupts the beta-lactam ring) blocked all seizure activity.
https://t.co/M3lDiXm88N
So why can beta-lactam antibiotics like cefepime cause neurotoxicity?
It turns that they block the binding of the inhibitory neurotransmitter gamma aminobutyric acid (GABA) to its receptor.
🔑Cephalosporins block GABA particularly effectively.
https://t.co/Eo0OlTduOE
The GABA receptor has two subtypes (A and B), and the A subtype functions as a ligand-gated Cl⁻ ion channel.
Cefepime binds to the GABA-A receptor and blocks Cl⁻ influx, which correlates with its ability to induce seizure activity.
https://t.co/l2f9QHHEEW
We've established that cefepime blocks GABA.
This induces neuro-excitation leading to seizures and other neurotoxic manifestations such as tremors and encephalopathy.
💡But why is there such a strong link with renal failure?
An obvious explanation would be that, since cefepime is renally cleared, elevated serum and CNS drug levels build up.
This is supported by the observation that cefepime and other cephalosporins block GABA in a concentration-dependent manner.
https://t.co/l2f9QHHEEW
But increased drug levels might not be the only reason that patients w/ renal failure are predisposed to neurotoxicity.
The milieu around neurons seems to matter as well.
This experiment in rat brain slices simulated a "renal" milieu by using a hyperkalemic medium around neurons.
⚡️Exposure to higher potassium levels significantly increased the ability of cefepime to induce epileptiform discharges.
https://t.co/vb3p4xXdTm
Let's ask one final question.
Why can cefepime (and other beta-lactam antibiotics) block the GABA receptor?
Exactly why hasn't been well-studied but it likely reflects sufficient structural similarity w/ GABA.
https://t.co/KN7I6ACXvb
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Why is this the most powerful question you can ask when attempting to reach an agreement with another human being or organization?
A thread, co-written by @deanmbrody:
2/ First, “X” could be lots of things. Examples: What would need to be true for you to
- “Feel it's in our best interest for me to be CMO"
- “Feel that we’re in a good place as a company”
- “Feel that we’re on the same page”
- “Feel that we both got what we wanted from this deal
3/ Normally, we aren’t that direct. Example from startup/VC land:
Founders leave VC meetings thinking that every VC will invest, but they rarely do.
Worse over, the founders don’t know what they need to do in order to be fundable.
4/ So why should you ask the magic Q?
To get clarity.
You want to know where you stand, and what it takes to get what you want in a way that also gets them what they want.
It also holds them (mentally) accountable once the thing they need becomes true.
5/ Staying in the context of soliciting investors, the question is “what would need to be true for you to want to invest (or partner with us on this journey, etc)?”
Multiple responses to this question are likely to deliver a positive result.
Why is this the most powerful question you can ask when attempting to reach an agreement with another human being or organization?
A thread, co-written by @deanmbrody:
Next level tactic when closing a sale, candidate, or investment:
— Erik Torenberg (@eriktorenberg) February 27, 2018
Ask: \u201cWhat needs to be true for you to be all in?\u201d
You'll usually get an explicit answer that you might not get otherwise. It also holds them accountable once the thing they need becomes true.
2/ First, “X” could be lots of things. Examples: What would need to be true for you to
- “Feel it's in our best interest for me to be CMO"
- “Feel that we’re in a good place as a company”
- “Feel that we’re on the same page”
- “Feel that we both got what we wanted from this deal
3/ Normally, we aren’t that direct. Example from startup/VC land:
Founders leave VC meetings thinking that every VC will invest, but they rarely do.
Worse over, the founders don’t know what they need to do in order to be fundable.
4/ So why should you ask the magic Q?
To get clarity.
You want to know where you stand, and what it takes to get what you want in a way that also gets them what they want.
It also holds them (mentally) accountable once the thing they need becomes true.
5/ Staying in the context of soliciting investors, the question is “what would need to be true for you to want to invest (or partner with us on this journey, etc)?”
Multiple responses to this question are likely to deliver a positive result.
THE MEANING, SIGNIFICANCE AND HISTORY OF SWASTIK
The Swastik is a geometrical figure and an ancient religious icon. Swastik has been Sanatan Dharma’s symbol of auspiciousness – mangalya since time immemorial.
The name swastika comes from Sanskrit (Devanagari: स्वस्तिक, pronounced: swastik) &denotes “conducive to wellbeing or auspicious”.
The word Swastik has a definite etymological origin in Sanskrit. It is derived from the roots su – meaning “well or auspicious” & as meaning “being”.
"सु अस्ति येन तत स्वस्तिकं"
Swastik is de symbol through which everything auspicios occurs
Scholars believe word’s origin in Vedas,known as Swasti mantra;
"🕉स्वस्ति ना इन्द्रो वृधश्रवाहा
स्वस्ति ना पूषा विश्ववेदाहा
स्वस्तिनास्तरक्ष्यो अरिश्तनेमिही
स्वस्तिनो बृहस्पतिर्दधातु"
It translates to," O famed Indra, redeem us. O Pusha, the beholder of all knowledge, redeem us. Redeem us O Garudji, of limitless speed and O Bruhaspati, redeem us".
SWASTIK’s COSMIC ORIGIN
The Swastika represents the living creation in the whole Cosmos.
Hindu astronomers divide the ecliptic circle of cosmos in 27 divisions called https://t.co/sLeuV1R2eQ this manner a cross forms in 4 directions in the celestial sky. At centre of this cross is Dhruva(Polestar). In a line from Dhruva, the stars known as Saptarishi can be observed.
The Swastik is a geometrical figure and an ancient religious icon. Swastik has been Sanatan Dharma’s symbol of auspiciousness – mangalya since time immemorial.
The name swastika comes from Sanskrit (Devanagari: स्वस्तिक, pronounced: swastik) &denotes “conducive to wellbeing or auspicious”.
The word Swastik has a definite etymological origin in Sanskrit. It is derived from the roots su – meaning “well or auspicious” & as meaning “being”.
"सु अस्ति येन तत स्वस्तिकं"
Swastik is de symbol through which everything auspicios occurs
Scholars believe word’s origin in Vedas,known as Swasti mantra;
"🕉स्वस्ति ना इन्द्रो वृधश्रवाहा
स्वस्ति ना पूषा विश्ववेदाहा
स्वस्तिनास्तरक्ष्यो अरिश्तनेमिही
स्वस्तिनो बृहस्पतिर्दधातु"
It translates to," O famed Indra, redeem us. O Pusha, the beholder of all knowledge, redeem us. Redeem us O Garudji, of limitless speed and O Bruhaspati, redeem us".
SWASTIK’s COSMIC ORIGIN
The Swastika represents the living creation in the whole Cosmos.
Hindu astronomers divide the ecliptic circle of cosmos in 27 divisions called https://t.co/sLeuV1R2eQ this manner a cross forms in 4 directions in the celestial sky. At centre of this cross is Dhruva(Polestar). In a line from Dhruva, the stars known as Saptarishi can be observed.
