Step 1 Complicated Concepts Thread

[TheSeanieB]

ASK AND ANSWER TOUGH QUESTIONS RELATED TO STEP 1.

Starting with me:
physiologic chloride shift - When CO2 diffuses into a RBC, it quickly converts with H2O to H+ and HCO3- so that CO2 will continue to passively diffuse into the RBC. The HCO3- is then excreted into the plasma by a Cl-/HCO3- exchanger. When the RBC enters the pulmonary capillaries, the process reverses. HCO3- is taken up by exchange for a Cl-. It combines with H+ to creates CO2 +H2O. The CO2 then diffuses out of the RBC and ultimately into the alveoli. This process allows for maximal CO2 excretion by a RBC.

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[JP2740]

eh, I don't think that's testable. Maybe just guess something to do with E6 or E7?

E6 inhibits P53, E7 inhibits Rb, both of which are cell cycle regulators (this part is in first aid). Much like the mechanism of tumor production, it causes uncontrolled proliferation (not in first aid). HPV Strains 16, 18 have e6, e7 and thus are the carcinogenic strands (first aid)

 

[Pinkleton]

I posted this in another thread but got little love, here it is:

What blood vessel takes unconjugated bilirubin to the liver for conjugation? FA says macrophages release the unconjugated bilirubin, but where exactly? I assume that since most of this occurs in the spleen, it would be into the splenic artery and hence the portal vein? Maybe during hemolytic anemia it would be via the hepatic artery? Just trying to build an anatomical relationship on the topic

 

[TheSeanieB]

E6 inhibits P53, E7 inhibits Rb, both of which are cell cycle regulators (this part is in first aid). Much like the mechanism of tumor production, it causes uncontrolled proliferation (not in first aid). HPV Strains 16, 18 have e6, e7 and thus are the carcinogenic strands (first aid)

Thanks!! That make sense. More understanding = less memorization

 

[SLC]

I posted this in another thread but got little love, here it is:

What blood vessel takes unconjugated bilirubin to the liver for conjugation? FA says macrophages release the unconjugated bilirubin, but where exactly? I assume that since most of this occurs in the spleen, it would be into the splenic artery and hence the portal vein? Maybe during hemolytic anemia it would be via the hepatic artery? Just trying to build an anatomical relationship on the topic

Splenic vein, not splenic artery.

 

[addo]

Thanks guys. I guess a possible exception would be an alcoholic who drinks beers, since most beers are rich in folate

From what I understand is that folate deficiency can be due to malnutrition, but more importantly especially in chronic alcoholics is that alcohol actually affects folate metabolism, causing intestinal malabsorption, decreasing hepatic uptake and increasing urinary excretion of folate. So even though they might get an acceptable daily intake, folate deficiency may still occur in the long run.

 

[Jamiu22]

Does anyone really know why desmopressin is used to treat Von Willinbrand Disease? FA says that it helps to release stored vWF from the endothelial cells, so I'm assuming this is the reason why we have low vWF in this scenario anyways... but what does that have to do with desmopressin?

 

[MLT2MT2DO]

Does anyone really know why desmopressin is used to treat Von Willinbrand Disease? FA says that it helps to release stored vWF from the endothelial cells, so I'm assuming this is the reason why we have low vWF in this scenario anyways... but what does that have to do with desmopressin?

I always assumed the way it works on V2 receptors in the arterioles

 

[SLC]

I always assumed the way it works on V2 receptors in the arterioles

This is correct. Vasopressin stimulates vWF release from endothelial cells when it binds the V2 receptor.

Bonus points to who can come up with a mechanism for why it's also useful in Hemophilia A...

 

[MLT2MT2DO]

This is correct. Vasopressin stimulates vWF release from endothelial cells when it binds the V2 receptor.

Bonus points to who can come up with a mechanism for why it's also useful in Hemophilia A...

Gary Von Willebrand the 3rd?

 

[SLC]

Gary Von Willebrand the 3rd?

You lost me.

 

[MLT2MT2DO]

You lost me.

No clue, just being a smart arse.

 

[Pinkleton]

Also, remember that desmopressin does NOT bind to V1 receptors like vasopressin so no pressor effect

I have a simple Q about fetal circulation. FA says deoxgenated blood enters the right ventricle while oxygenated blood does not (it is shunted though the foramen ovale into the RA). How the heck does the heart separate the blood like that?

 

[SLC]

No clue, just being a smart arse.

Desmopressin/Vasopressin also releases Factor VIII when it binds the V2 receptor. And there's an added bonus that vWF stabilizes Factor VII in the circulation (it normally has a very short half life).

So two mechanisms, increasing release of Factor VIII; and increased stability of Factor VIII through increased vWF.

 

[Jamiu22]

This is correct. Vasopressin stimulates vWF release from endothelial cells when it binds the V2 receptor.

Bonus points to who can come up with a mechanism for why it's also useful in Hemophilia A...

University of Wikipedia

"Factor VIII is bound to vWF while inactive in circulation; factor VIII degrades rapidly when not bound to vWF. Factor VIII is released from vWF by the action of thrombin."

Since we all agree that desmopressin stimulates release of vWF... and we can all agree that vWF protects factor VIII.. I'm guessing, if an individual isn't completely deficient of the factor.. it would protect the little that they have.

Another theory I could come up with is that since vWF assist with platelet aggregation, if you are deficient in factor VIII, you at least can stop bleeding faster, lol... although it's only a temporary hemostatic plug... it's still better than just bleeding to death, haha

 

[Jamiu22]

Also, remember that desmopressin does NOT bind to V1 receptors like vasopressin so no pressor effect

I have a simple Q about fetal circulation. FA says deoxgenated blood enters the right ventricle while oxygenated blood does not (it is shunted though the foramen ovale into the RA). How the heck does the heart separate the blood like that?

Gravity... deoxygenated blood is coming from the head, and flowing down... so when it enter's the SVC, it's more likely to flow to the right ventricle... on the other hand, when oxygenated blood comes in, it's coming from a lower elevation, and the heart tilted in an angle such that when blood gets into the IVC, it's directed to the foramen ovale.

Now to the $1000,000 question... how does the heart seperate the two... I'm guessing this would depending on the pressures in the venous and arterial system in coordination with the beating heart. Since babies are born alive, it just has to be....

 

[blaqmamba]

Just to be sure, during pregnancy (or any time for that matter), an increase in SHBG causes a decrease in free Testosterone, but the increased TBG doesn't cause any change in T4/T3?
and vice versa with lower TBG

 

[JP2740]

Just to be sure, during pregnancy (or any time for that matter), an increase in SHBG causes a decrease in free Testosterone, but the increased TBG doesn't cause any change in T4/T3?
and vice versa with lower TBG

No, I think it goes like this... Pregnancy-> increased TBG -> increased TOTAL thyroid -> stable free t4 and thus, no hyperthyroidism despite altered lab value.

Edit: nevermind, I misunderstood what you were asking, but I'll still leave my thing up because it took me 10 seconds lol

 

[JP2740]

How do you guys find it easiest to get down medication side effects?

 

[blaqmamba]

No, I think it goes like this... Pregnancy-> increased TBG -> increased TOTAL thyroid -> stable free t4 and thus, no hyperthyroidism despite altered lab value.

Edit: nevermind, I misunderstood what you were asking, but I'll still leave my thing up because it took me 10 seconds lol

Haha yeah that's what I said. I was just trying to make sure I was right that free testosterone can actually decrease when SHBG is increased (ie, during pregnancy), but that the same relationship doesn't apply to TBG

 

[JP2740]

Haha yeah that's what I said. I was just trying to make sure I was right that free testosterone can actually decrease when SHBG is increased (ie, during pregnancy), but that the same relationship doesn't apply to TBG

Hmm I didn't know that about SHBG, thanks lol. I just knew the TBG relationship. TBG is increased (pregnancy) and decreased (androgen steroid use) which increases/decreases total thyroid but with steady T4/3.

But pregnancy->increased SHBG->stable total testosterone, but decreased testosterone? Is that right?

 

[dbeast]

Anybody have a comprehensive list of the motile bacteria? Just when I think I know them all, a new one pops up out of nowhere. So far:

Salmonella
Pseudomonas
E. coli
Listeria
Vibrio

Any others jump out?

 

[dbeast]

Gravity... deoxygenated blood is coming from the head, and flowing down... so when it enter's the SVC, it's more likely to flow to the right ventricle... on the other hand, when oxygenated blood comes in, it's coming from a lower elevation, and the heart tilted in an angle such that when blood gets into the SVC, it's directed to the foramen ovale.

Now to the $1000,000 question... how does the heart seperate the two... I'm guessing this would depending on the pressures in the venous and arterial system in coordination with the beating heart. Since babies are born alive, it just has to be....

Aren't fetuses upside down?

 

[blaqmamba]

Anybody have a comprehensive list of the motile bacteria? Just when I think I know them all, a new one pops up out of nowhere. So far:

Salmonella
Pseudomonas
E. coli
Listeria
Vibrio

Any others jump out?

proteus

 

[SLC]

Anybody have a comprehensive list of the motile bacteria? Just when I think I know them all, a new one pops up out of nowhere. So far:

Salmonella
Pseudomonas
E. coli
Listeria
Vibrio

Any others jump out?

proteus

Spirochetes (Borrelia spp., Leptospires, Treponemes, B. pilosicoli)
B. cereus
C. tetani, C. botulinum

 

[Jamiu22]

Aren't fetuses upside down?

lol... u r right!

 

[JP2740]

lol just memorize it and alcohol brain dump it after the exam

 

[dbeast]

lol... u r right!

I love the explanation though

 

[Jamiu22]

I love the explanation though

LOL; gravity was definitely the wrong choice of word... BIG TIME.... but rather, I should have said.. that blood flows through the heart moving in the same direction with which it came in - so that's why

- blood coming from below (IVC) go into the foramen ovale and
- blood coming from SVC go through to the RV.

I think.

 

[Pinkleton]

Lol thanks. Gravity or not, as long as it helps me remember this pointless crap, then I'm happy

 

[MLT2MT2DO]

Can anyone explain the physiology behind Type 2 (proximal) Acute tubular necrosis?

 

[Jamiu22]

Can anyone explain the physiology behind Type 2 (proximal) Acute tubular necrosis?

Source: Recall from a USMLE_RX I missed

• Type1: Can't get rid of H+ ion; you get hypokalaemia trying to compensate for the acidic condition - distal.
• Type2: Can't reabsorb HCO3- ion; you also get hypokalaemia trying to compensate for the acidic condition - proximal
• Type4: Kidney doesn't respond to aldosterone, so increase in andosterone production - since you are not responding to aldosterone, you get hyperkalamia - resulting in acidosis

 

[MLT2MT2DO]

Source: Recall from a USMLE_RX I missed

• Type1: Can't get rid of H+ ion; you get hypokalaemia trying to compensate for the acidic condition - distal.
• Type2: Can't reabsorb HCO3- ion; you also get hypokalaemia trying to compensate for the acidic condition - proximal
• Type4: Kidney doesn't respond to aldosterone, so increase in andosterone production - since you are not responding to aldosterone, you get hyperkalamia - resulting in acidosis

This is straight from FA but what is going on in Type 2.

Why is the pH <5.5 in the lumen when you can't reabsorb HCO3? If it comes down to the intercalated cells in the medulla then why do I have hypokalemia?

 

[JP2740]

Can anyone explain the physiology behind Type 2 (proximal) Acute tubular necrosis?

Think about proximal RTA as affecting the proximal tubule (i know, duh). Think about it in two ways. Either there is a defect in secreting H+ or there is a defect in absorbing HCO3-. Remember that RTAcidosis refers to acidosis in the BODY due to a failure of acidifying the urine. If you can't secrete H+, you can't absorb HCO3- in the proximal tubule. Usually, H+ is secreted, combined with HCO3- in the urine to form CO2 + H2O (carbonic anhydrase needed). CO2 diffuses into the PT cell, combines back with H2O and forms HCO3-, and thus HCO3- is reabsorbed. So if you can't secrete H+, you lose HCO3-.

Fanconi syndrome is a cause, a bunch of different ion/molecular reabsorption problems here, including HCO3-. An intuitive cause is a carbonic anhydrase inhibitor. There's some other ones, it's not always obvious that it results in RTAII, but you just have to know in some way the PT cell is dysfunctional so it won't secrete H+ or it won't reabsorb HCO3- for some reason (like WIlson's disease, buildup of Copper somehow causes it, maybe by keeping HCO3- in the urine? Idk).

Importantly though, the distal intercalated alpha cells can still secrete H+/NH4+ (refer to first aid diagrams), so the urine comes out as acidic in the end even though there is extra bicarb. That is a big difference between TII and TI (cannot acidify urine due to dysfunctional H+ secretion in distal intercalated alpha cell), in which the urine comes out basic. Once again, TI has a bunch of causes... I think a favorite is obstruction though.

For memorizing purposes you can think TI (distal) = can't secrete H+; TII (proximal) = can't reabsorb bicarb (but can secrete H+ distally)

 

[tiedyeddog]

Can anyone explain the physiology behind Type 2 (proximal) Acute tubular necrosis?

http://www.anaesthesiamcq.com/AcidBaseBook/ab8_5.php

Type 2 RTA is also called proximal RTA because the main problem is greatly impaired reabsorption of bicarbonate in the proximal tubule.
At normal plasma [HCO3], more than 15% of the filtered HCO3 load is excreted in the urine. When acidosis is severe and HCO3 levels are low (eg <17 mmols/l), the urine may become bicarbonate free. Symptoms are precipitated by an increase in plasma [HCO3]. The defective proximal tubule cannot reabsorb the increased filtered load and the distal delivery of bicarbonate is greatly increased. The H+ secretion in the distal tubule is now overwhelmed by attempting to reabsorb bicarbonate and the net acid excretion decreases. This results in urinary loss of HCO3 resulting in systemic acidosis with inappropriately high urine pH. The bicarbonate is replaced in the circulation by Cl-.
The increased distal Na+ delivery results in hyperaldosteronism with consequent renal K+ wasting. The hypokalaemia may be severe in some cases but as hypokalaemia inhibits adrenal aldosterone secretion, this often limits the severity of the hypokalaemia.
Hypercalciuria does not occur and this type of RTA is not associated with renal stones. During the NH4Cl loading test, urine pH will drop below 5.5.
Note that the acidosis in proximal RTA is usually not as severe as in distal RTA and the plasma [HCO3] is typically greater than 15 mmol/l.

 

[MLT2MT2DO]

Think about proximal RTA as affecting the proximal tubule (i know, duh). Think about it in two ways. Either there is a defect in secreting H+ or there is a defect in absorbing HCO3-. Remember that RTAcidosis refers to acidosis in the BODY due to a failure of acidifying the urine. If you can't secrete H+, you can't absorb HCO3- in the proximal tubule. Usually, H+ is secreted, combined with HCO3- in the urine to form CO2 + H2O (carbonic anhydrase needed). CO2 diffuses into the PT cell, combines back with H2O and forms HCO3-, and thus HCO3- is reabsorbed. So if you can't secrete H+, you lose HCO3-.

Fanconi syndrome is a cause, a bunch of different ion/molecular reabsorption problems here, including HCO3-. An intuitive cause is a carbonic anhydrase inhibitor. There's some other ones, it's not always obvious that it results in RTAII, but you just have to know in some way the PT cell is dysfunctional so it won't secrete H+ or it won't reabsorb HCO3- for some reason (like WIlson's disease, buildup of Copper somehow causes it, maybe by keeping HCO3- in the urine? Idk).

Importantly though, the distal intercalated alpha cells can still secrete H+/NH4+ (refer to first aid diagrams), so the urine comes out as acidic in the end even though there is extra bicarb. That is a big difference between TII and TI (cannot acidify urine due to dysfunctional H+ secretion in distal intercalated alpha cell), in which the urine comes out basic. Once again, TI has a bunch of causes... I think a favorite is obstruction though.

So the intercalated cells are responsible for acidifying the urine to <5.5? If that's the case and intercalated cells are still exchanging K+ for H+ and to an excessive amount why is hypokalemia instead of hyperkalmeia a feature?

 

[JP2740]

This is straight from FA but what is going on in Type 2.

Why is the pH <5.5 in the lumen when you can't reabsorb HCO3? If it comes down to the intercalated cells in the medulla then why do I have hypokalemia?

Hypokalemia is caused by aldosterone secretion because the patient ends up losing Na+ and fluids in their urine. In the PT, there is an apical Na+/H+ exchanger, and a basal Na+/HCO3- symporter (for reabsorbing). If you aren't reabsorbing HCO3- or secreting H+ or both, then that probably contributes to a Na+ loss. You can try to remember that as CA inhibitors cause sodium loss (doesn't it? not sure lol) as well as RTA type II

 

[MLT2MT2DO]

http://www.anaesthesiamcq.com/AcidBaseBook/ab8_5.php

Type 2 RTA is also called proximal RTA because the main problem is greatly impaired reabsorption of bicarbonate in the proximal tubule.
At normal plasma [HCO3], more than 15% of the filtered HCO3 load is excreted in the urine. When acidosis is severe and HCO3 levels are low (eg <17 mmols/l), the urine may become bicarbonate free. Symptoms are precipitated by an increase in plasma [HCO3]. The defective proximal tubule cannot reabsorb the increased filtered load and the distal delivery of bicarbonate is greatly increased. The H+ secretion in the distal tubule is now overwhelmed by attempting to reabsorb bicarbonate and the net acid excretion decreases. This results in urinary loss of HCO3 resulting in systemic acidosis with inappropriately high urine pH. The bicarbonate is replaced in the circulation by Cl-.
The increased distal Na+ delivery results in hyperaldosteronism with consequent renal K+ wasting. The hypokalaemia may be severe in some cases but as hypokalaemia inhibits adrenal aldosterone secretion, this often limits the severity of the hypokalaemia.
Hypercalciuria does not occur and this type of RTA is not associated with renal stones. During the NH4Cl loading test, urine pH will drop below 5.5.
Note that the acidosis in proximal RTA is usually not as severe as in distal RTA and the plasma [HCO3] is typically greater than 15 mmol/l.

I'm confused by the bolded portions. Sorry renal/cardio are my weakest subjects by far

 

[MLT2MT2DO]

Hypokalemia is caused by aldosterone secretion because the patient ends up losing Na+ and fluids in their urine. In the PT, there is an apical Na+/H+ exchanger, and a basal Na+/HCO3- symporter (for reabsorbing). If you aren't reabsorbing HCO3- or secreting H+ or both, then that probably contributes to a Na+ loss. You can try to remember that as CA inhibitors cause sodium loss (doesn't it? not sure lol) as well as RTA type II

Ok, I think this was my missing piece that I wasn't tying together. Thank you very much for the help everyone.

 

[tiedyeddog]

I'm confused by the bolded portions. Sorry renal/cardio are my weakest subjects by far

Ok, I think what it is saying is you have this occur (turn to page 483 in FA2013 to follow along with me.)

1. HCO3 is not reabsorbed in the proximal tubulue. This backs up the intake of CO2 into the proximal tubule and also prevents the pumping OUT of H+.
2. If hydrogen is not being pumped out, the NA/H antiporter is not working. Salt is now high in the proximal tubule LUMEN.
3. Salt and bicarb makes it's way down to the collecting tubule. Macula densa cells sense the high salt flow and signal the renin-angiotensionigen system ->aldosterone is increased.
4. Aldosterone causes NA to be absorbed and K and H to be pumped out. This makes the pH below 5.5. NA is conserved but K is lost.

 

[tiedyeddog]

What I don't get is how this causes hypophosphatemic rickets yet type I does not? Where does PO4 get lost at?

 

[JP2740]

What I don't get is how this causes hypophosphatemic rickets yet type I does not? Where does PO4 get lost at?

Decreased vitamin D -> Decreased phosphate absorption?

Maybe... acidosis->bone loss->Ca release-> decreased PTH release-> decreased VitD -> Decreased phosphate?

I am finding on google there are Na+/Phosphate symporters in the PT. That's probably it and not my crazy stupid idea lol

 

[tiedyeddog]

I am finding on google there are Na+/Phosphate symporters in the PT. That's probably it and not my crazy stupid idea lol

I bet that's it, man kidneys suck. They are like a black box of voodoo magic.

 

[MLT2MT2DO]

Ok, I think what it is saying is you have this occur (turn to page 483 in FA2013 to follow along with me.)

1. HCO3 is not reabsorbed in the proximal tubulue. This backs up the intake of CO2 into the proximal tubule and also prevents the pumping OUT of H+.
2. If hydrogen is not being pumped out, the NA/H antiporter is not working. Salt is now high in the proximal tubule LUMEN.
3. Salt and bicarb makes it's way down to the collecting tubule. Macula densa cells sense the high salt flow and signal the renin-angiotensionigen system ->aldosterone is increased.
4. Aldosterone causes NA to be absorbed and K and H to be pumped out. This makes the pH below 5.5. NA is conserved but K is lost.

Pretty sure #3 is the opposite of how the Macula densa works.

But ty

 

[loveoforganic2]

For pharm, is permissive effect a type of potentiation? Or does the fact that say, a corticosteroid, could be completely out of the system yet still increase the effect of sympathomimetics on blood pressure put permissive effect into an entirely different category?

Sorry... 1st I've ever heard the term permissive effect was it coming up in a UW question

 

[tiedyeddog]

Pretty sure #3 is the opposite of how the Macula densa works.

But ty

You're definitely right

 

[tiedyeddog]

Anyone have any tips for what antibiotics are used for what infections? This still seems like a mystery to me....

 

[bangarang]

Anyone have any tips for what antibiotics are used for what infections? This still seems like a mystery to me....

Same here. It's all jumbled up in my head somewhere.

 

[bangarang]

Can anyone simplify the whole LDL/HDL/VLDL pathway with the apoproteins and chylomicrons? So far I've been coasting on superficial knowledge. I really have no clue how it all works.

 

[tiedyeddog]

Can anyone simplify the whole LDL/HDL/VLDL pathway with the apoproteins and chylomicrons? So far I've been coasting on superficial knowledge. I really have no clue how it all works.

I was going to look for better diagrams tomorrow if you can wait until then. FA really doesn't explain it at all.

 

[bangarang]

For pharm, is permissive effect a type of potentiation? Or does the fact that say, a corticosteroid, could be completely out of the system yet still increase the effect of sympathomimetics on blood pressure put permissive effect into an entirely different category?

Sorry... 1st I've ever heard the term permissive effect was it coming up in a UW question

The way I understood it was that a hormone with permissive effects only sensitizes the body to a response from a certain drug (via increased transcription of genes, upregulation of receptors, etc.), meaning it increases the body's response to a drug without having any effects itself, like thyroid hormone increasing the body's response to epinephrine by increasing the number of receptors. Thyroid hormone in and of itself doesn't act or bind the adrenergic receptors.

I think according to the definition of potentiation, two different drugs act on different aspects but produce the same response, so those two drugs would have an effect greater than the summation of each of those drugs alone. This is different than the permissive effect because the two different drugs can individually produce a response. I hope this makes sense. Someone correct me if I'm wrong.

I was going to look for better diagrams tomorrow if you can wait until then. FA really doesn't explain it at all.

Thanks, man. I haven't been able to find a good diagram for the pathway, and that's probably why I haven't learned it. I might try to look in Costanzo in a bit.