The Sky Is Falling

You ever get the idea that scientists are out to get us? Or is Hollywood just really on top of things? Check out this story of impending disaster involving the UN, Space flights, nuclear weapons, and impending doom. Apparently we are all gonna die in 2036. Luckily, by that time I will have finally graduated medical school, made a dollar or two, and hopefully will have had a little fun along the way. Of course I don't know if we'll make it to 2036 at our current rate of worldwide political shambles. To think Before 9/11, I thought we lived in such a happy tolerating world.

Brekky, V-Day Style

Yeah, here is a picture of our buttermilk chocolate chip pancakes I made for breakfast (who says I'm not romantic?). I've also included a picture of Gob, after I let him lick some of the strawberry junk I made to put on top of the pancakes.

So, funny stories...A couple days ago, I mentioned to Andrew and Garrett that I wished they would post everybody's grade next to their name so we all knew how everybody else was doing. At the time I knew it was wishful thinking. Then yesterday, the DAY after I made the wish, one of our professors accidentally forwarded an email to our entire class that contained an excel spreadsheet with everybody's name and grade from this past test. Wow, I'm good. Oh, and there was an accompanying email, about an your later, asking everybody not to read the previous one. Of course by this time ;-), I had already opened and performed an extensive analysis on my classmates grades. It was good to see that I am in about the top 25% of my class, though I have to admit that I want to get that up a little. Nothing like a reality check on where you stand to give you a little oomph to step it up a notch. Of course, everybody in the class got the same "oomph," so we'll see how the next test goes. With the quick turnaround on this wish, I think I'm gonna ask for some rich uncle to leave me a couple mil so I can drop out of med school and travel the world. I'll keep you posted on this one.

On a side note, my truck was having starter problems the other day. I would turn the key and nothing would happen. I knew the battery wasn't dead, because it would start eventually without any problems. So, I figured it was the starter. I went and bought a new one and a book to figure out how to replace it. I figure if I am gonna fix things like brains and bones some day, I might as well be able to fix my car as well. Luckily, I am smart enough to call my dad on all things car related. He is kind of like me in refusing to allow anyone else to work on his car. I guess that's where I get it from. He put the thought into my mind that it probably isn't the starter. By this point, after talking to the guys at the auto store and researching on the internet, i was pretty sure that it was the starter. Not wanting to make an expensive mistake, however, I decided to crawl under the truck and wiggle the cables. Well, that actually worked. I haven't had any problems since.

Glycolysis Lecture

I thought I would post my notes from one of my lectures today. I guess I am posting in order to vent about the amount of information we are dished out in a span of two hours (oh, and I had two other hours worth of information on Kidney acid/base balance as well today). Oh, and I will be tested on this on Monday (along with about two hundred pages of other information, ranging from genetics to signaling cascades, to membrane transport. It is like every other week I am studying for finals. I don't know what I am gonna do when I am trying to bring all this together next year for the boards.


Glycolysis - Biochemistry

1. all cells can undergo glycolysis
2. occurs in the cytoplasm
3. RBC's can only undergo glycolysis for energy
   
4. glucose - phosphate - lactate

Glucose - 2 pyruvate

• can go to CO2 + H2O in presence of mitochondria and oxygen
• if no mitochondria or O2, converted into lactate instead (add two H, through reduction)
• anaerobic glycolysis - no oxygen
  
• if converted into CO2 + H2O - Aerobic Glycolysis

RBC's

• no mitochondria present
• high O2 levels, but in absence of mitochondria, cannot undergo aerobic glycolysis
• glucose converted into lactate only
• cancer cells also convert gluc to lactic acid
• still have mitochondria, but grow under hypoxic conditions
• cells proliferate in the cancer tissue faster than vasculogenesis
• can't make vasculature fast enough
• however, even in presence of oxygen in the laboratory, still undergo anaerobic glycolysis
• during change from normal to cancer, metabolic phenotype changes
• theory behind is that when tumor cells use mitochondria for energy, can make a lot of ATP, but it comes with a price:
• also produces reactive O2 species - converted into toxic metabolites
• tumors don't want the toxic metabolites

glucose - lactic acid - only produces two net molecules of ATP

• if converted to CO2 and H2O, will make 32 ATP

glucose to pyruvate -

• 1 NAD into NADH2 + H (NAD used up)
• if you cannot regenerate the NAD, glycolysis will stop
  
• when pyruvate into lactic acid, regenerate the NAD
• this only happens in aerobic respiration (using mitochondria)
• keeps the glycolysis going
• purvate can now enter mitochondria to go to H2O and CO2
• tumor cells are able to convert to lactic acid, thereby regenerating NAD without mitochondria
• LA causes the surrounding area to become acidic (pH around 6)

• tumor can't do anything with the LA, so dumps it into the surrounding
• will not acidify under aerobic conditions because mitochondria takes care of pyruvic acid
• normal conc of 1.4mM LA in body (RBC also dumps LA)

Glycolysis - don't need to know the sturcture of the intermediates

1. glucose converted to G6P (uses ATP, enzyme by GK) - irreversible
2. G6P reversibly converts to F6P (uses PGI - phospho-gluco isomerase)
1. rearranges 2nd carbon to a keto group
3. F1,6BP (fructose 1,6 bisphosphate) - uses ATP as source for phosphate group (mediated by PFK-1 - phosphofructokinase 1) - phosphorylates at C1
1. irreversible
4. F1,6BP broken directly down the middle using ALDOLASE
1. breaks at the 3C
2. makes DHAP (dihydroxyacetonephosphate) and GAP (glycerol...phosphate)
   
3. reversible reaction by PTI (phosphotrioseisomerase)
4. DHAP can convert to GAP
5. so, use Glucose and 2 ATP to covert to two molecules of GAP
6. GAP converted into 1,3BPG by GAPDH (GAP dehydrogenase)
1. 1,3BPG has two phosphates
2. use Pi as the phosphate donor (this is why not a kinase, does not use ATP)
3. catalyzes an oxygenation-reduction reaction - removes 2 H
1. converts NAD to NADH + H
2. readily reversible reaction
4. 1,3BPG is a high energy compound
   
1. means it gives off more E than ATP
   
5. C1 has the acid anhydride - high E bond
6. when hydrolyzed, can use the E from bond to convert ADP to ATP (is converted to 3PG)
   
1. uses PGK - phosphoglycerate kinase (ADP to ATP conversion, so a kinase)
2. this is a freely reversible reaction under normal conditions in the cell
1. irreversible in the laboratory
7. 3PG converted to 2PG by PGM (phosphoglycerate mutase)
1. changes the location of the phosphate group from the 3 to the 2
2. freely reversible reaction
8. 2PG converted to PEP by enolase (removal of a water molecule)
1. dehydration of 2PG - double bond to CH2
2. still linked by an ester linkage, but is an enol because of double bond
3. very high energy bond, even though is an ester linkage (usually low E)
4. when hydrolyzed convert 14.8KCal E
5. can now provide the energy to make ATP
9. PEP - Pyruvate (uses PK - pyruvate kinase)
1. irreversible reaction
1. know which ones are irreversible steps (GK/HK, PFK1, PK)
   
10. converted to lactate under certain conditions
1. converts nadh + h to nad using LDH (lactate dehydrogenase)

stuff to know: GAPDH

1. GAP to 1,3BPG using up a Pi
2. arsenate substitutes for Pi in this reaction
1. structurally very similar
2. arsenic toxicity recpaces the substrate
3. instead of phosphate, arsenate as the substrate
3. instead of 1,3BPG, you get 1-arseno3-P-glycerate
1. gives rise to 3PG + arsenate
2. highly toxic to the cell
3. GAPDH still active, just now catalyzes a different reaction
4. normally GAP to 3PG, energy source for ATP
1. in presence of arsenate, converted to the 1-arseno-3-p-glycerate
2. converted to 3PG, however, here you do not make that 1 molecule of ATP
5. so, look at ATP synthesis in cell with and without arsenic poisoning
1. normally -2ATP and +4ATP
1. net production of +2ATP
2. Arsenic poisoning: -2ATP, +ATP
1. net production of 0 ATP
6. Arsenic poisoning: RBC's lyse
1. this is not what kills you
2. arsenic can react with any protein in the body with a thiol group
3. ATP production is shut down all over the body because will substitute for the Pi normally used in ATP production
   
1. shuts down ATP production all over the body

substrate level phosphorylation - ATP made in absence of mitochondria and O2

1. 2 steps in normal glycolysis
2. in presence of arsenic, one of the steps is bypassed by arsenate
1. shuts off ATP production
2. toxic to all cells
3. hemolytic anemia

Need to remember the enolate step:

1. inhibited by fluoride
2. used in laboratory to block glycolysis to do an accurate sugar count
3. gycolysis shut off by RBC

Need to remember 1,3BPG into 3PG producing 1 ATP using PGK

1. also can be converted to 2,3BPG and then to 3PG thereby sidestepping the direct route
1. No ATP production in this case
2. can happen in all cells, but especially in RBC's
3. 2,3BPG important for O2 binding in RBC's
4. sigmoid O2 binding curve for RBC's - positive cooperativity
1. add 2,3BPG, decreases the O2 affinity, shifts the O2 binding curve to the right
2. does not change PO2 in lung because is maxed out
3. makes big difference in the tissues because of low PO2
4. Hb now releases O2 for the tissues to use
2. so, if you have a patient with a dissociation curve shifted to the right
1. patient has a higher than normal concentration of 2,3BPG in the cell as compared to normal

Reactions involved in Fructose and Galactose

Fructose: monosaccharide present in sucrose, fruit juices, honey

1. normal constituent in our diet
2. first converted into F1P (FK fructo-kinase)
   
1. broken down by F1P-aldolase into DHAP and glyceraldehyde
1. when defective, causes genetic disorder
   
2. DHAP can enter the glycolytic pathway
3. glyceraldehyde can be converted to GAP

Galactose: breast milk (lactose)

1. Galactose to Galactose1P by GK (galactose kinase)
2. converted to G1P by UDP glucose to UDP galactose
1. uses Galactose1P-uridil transferase
3. converted to G6P
4. UDP galactose to UDPgluc by another enzyme

Regulation of Glycolysis:

• regulated at the irreversible reactions
• HK/GK
• PFK-1
• PK

HK - all cells - high affinity to glucose

• Km=0.1mM
• G6P inhibits this enzyme

GK catalyzes the same reaction

• only expressed in the liver and pancreas (organs responsible for blood gluc regulation)
  
• glycogen storage in these places
• low affinity enzyme, Km around 10mM
• under low Gluc levels, does not operate (low Km)
• regulated by inhibitors in liver and panc
• inhibitory protein that can bind to GK - activity goes down
• glucokinase-inhibitor complex
• regulated by F6P (inhibits GK)
  
• one of the intermediates in glycolysis
• reverse reaction facilitated by F1P (activator of GK)

• GK enzyme induced by insulin
• insulin is a hypoglycemic hormone - will reduce blood gluc levels
• insulin thereby gets the liver to undergo increased glycolysis
• more insulin, lower the blood glucose levels
• hormones that increase the gluc levels (ie, glucagon), linear relationship (when high, high gluc)

PFK-1 - most important regulatory enzyme of glycolysis

• F6P to F1,6BP
• inhibited and stimulated by certain compounds
• inhibited by ATP and citrate
• when they have a lot of ATP, will shut off pathways that stim ATP in cells
• citrate is the starting point for the TCA cycle
• stimulated by AMP, Pi, F2,6BP
  
• when cells are E deficient, want to rev up glycolysis
• Pi stimulates by providing substrate
  
• F2,6BP activator of F1,6BP
  
• not an intermediate in glycolysis

Liver:

• glucagon is a hyperglycemic hormone
• inhibits glycolysis by raising glucose levels in body
• increases cAMP, increases PKA
• PKA phosphorylates target proteins
• regulates the levels of F2,6BP
• F6P to F2,6BP by PFK-2 (differs from PFK-1)
• reverse reaction mediated by F2,6BPase
• regulates liver, on the same protein - PFK-2/F2,6BP-ase protein - target of PKA
• so, gluc activates cAMP which activates PKA which activates PFK-2/F2,6BPase protein
• PFK-2/F2,6BPase protein activation depends on whether or not is phosphorylated
• so, glu - cAMP - PKA activated - PFK-2 inactive, F2,6BP-ase activated (breaks down F2,6BP)
  
• F2,6BP level goes down
  
• so, all this is controlled by phosphorylation of PFK-2/F2,6BP-ase
• bottom like, glucose levels go up, cAMP up, decrease in F2,6BP
• cAMP levels and F2,6BP have an inverse relationship
• So, F2,6BP goes down which normally activates PFK-1
• PFK-1 inactivated (which is the most important regulatory mechanism of glycolysis)
• glycolysis goes down or shuts off
• cAMP shuts off glycolysis in the liver (only in the liver)
• cAMP normally turns on glycolysis:

Heart muscle - cAMP leads to an increase in glycolysis

• this is what happens in a panic attach
• adrenal medulla produces Epi
• Epi to the heart tissue, increases cAMP in the cell
• leads to an increase in F2,6BPlevels
• direct relationship
• PFK-2/F2,6BPase protein - uses a different gene for the same enzyme
• has the opposite effect

• Epi - increases cAMP - increased PKA - increase in PFK-2 activity - increase in F2,6BP, increases PFK-1, increases glycolysis
• know difference between liver and heart in terms of cAMP

clinical conditions:

• diabetes type I - no insulin
• type II - insulin, but not active (resistance)
• insulin activity goes down in both types
• causes the glucagon activity to go up (glucagon and insulin are reciprocal)
• glucagon/insulin ratio is higher than normal
• causes cAMP to go up in liver - leads to F2,6BP decrease, PFK-2 down, Glycolysis decrease
• leads to hyperglycemia
• pyruvate kinase deficiency (PK)
• gluc normally to PEP to Pyr through PK
• if complete absence of PK, no survival
• genetic muation leads to about 20% decrease of activity
• hemolytic anemia due to RBC insufficiency (ATP depleted, lysis of RBC's)
• leads to jaundice (Hb metabolism - bilirubin)
• backup of all intermediates (buildup)
• includes 2,3BPG (1,3BPG converts to 2,3BPG)
  
• shifts O2 dissociation curve to the right
• PK patients have increased 2,3BPG
• Hereditary Fructo intolerance - (HFI)
• F1-P-aldolase deficient
• normally takes F1P to DHAP + glyceraldehyde
• F1P builds up, leads to increased GK
• beta cells of pancreas ramp up GK activity
• follow effects of gluc, GK on the pancreas beta cells - leading to insulin secretion into the blood
• GK stimulates insulin secretion
• gluc - GK (ramped up)- ATP - Shuts K channels - depolar., increases Ca levels - insulin release
• hyperinsulinemia
• hypoglycemia
• assoc with hyperuricemia (gout)
• must avoid fructose in the diet
• breast feeding okay
• symptoms are vomiting, liver disease (F1P accumulation), jaundice - more bilirubin (dysfunctional liver)
• be able to tell disease from the symptoms
• Galactosemia - two types
• galacto kinase defect (GK defect)
• mild form - presence of cataracts are the only presenting symptom - easily treatable
  
• G1P-uridil-transferase defect - more sever form of disease, assoc with cataract, and other problems
• mental retardation
• liver disease, jaundice
• tx by avoiding galactose in the diet - no breastfeeding
  

incentives

Today I realized how much I am like Haley's kids. I need incentives, I need a lot of them and I need them often. It gets hard when you study all the time to get excited about studying. It gets old and after putting in 6 hours in a given day it is easy to give up and say that is enough (and really, it probably should be). However, if I'm gonna get an A in biochemistry and physiology, I need to study a little more. You would think that getting an A is incentive enough, but that A doesn't come until the end of the semester, and my current standing isn't posted anywhere online where I can easily access it. So, the A incentive does not meet my criteria for incentives. Luckily, there are other little incentives that float in front of me every now and then that keep me focused. For example, I study with Andrew. He is really smart and I really want to be smarter than him (which will not happen any time soon, by the way). But, I study hard so that I can know the material better than him. Another incentive I have is the competitive residency interest group meetings that I go to. Today I attended the cardiology IG and the radiology IG. Both are very competitive fields that require good grades. At these meetings, they remind you how good your lifestyle can be and how good the money will be if you study hard now. Again, good incentive for me to put in those extra few hours at the end of the day.

Okay, my other incentive for going to study after I am done with this entry: I just discovered this new drink called "Vault" which drinks like a soft drink but kicks like an energy drink (or something like that). Anyway, it has like 4x the caffeine as my normal coke and I just finished polishing off a 20oz like a half hour ago and I am wired. Bring on the intracellular signal transduction cascades! I'm ready to make you mine.

a couple thoughts on doctoring

Learning about genetics is a real eye opener. We barely finished sequencing the human genome within the past couple years and already there are new treatments flying out all over the place as a direct result of that project. We are just beginning to knock on the door of human disease as it relates to our human blueprint. As we decipher the raw data we are made of, we are learning at an accelerated rate what makes us tick, and what messes up our clockwork. We are finding mutations every day that cause normal Mendelian diseases (remember the green and yellow peas?) like sickle cell anemia and cystic fibrosis, not to mention the multifactorial diseases that involve a vast array of genes interacting with each other. As we find the root defect in these diseases, we are also finding ways to correct the problems.

Since being in medicine, I am convinced that gene therapy is the way of the future. I don't know what this will mean for mankind, but at the strides we are making in everyday diseases, I fully believe that in my lifetime I will see gene therapy moving to the front of the disease treatment line. It is a good time to be in the medical field, to be a part of the vast improvements in medical care that we will see. Of course when America adopts socialized medicine and we get rid of "evil profits," I imagine that the current rate of discovery and innovation will slow down, but that is another topic altogether.

Other thoughts on doctoring: Today, after visiting with a patient in the hospital (I'll call him Harry) I realized that I have no desire for general practice medicine. I don't think I am cut out for living my life in a constant struggle to fix people's lives. One of the problems with western medicine is a tendency to treat symptoms instead of disease, but when the vast majority of disease are not curable, what else can you do? I want to go into a specialty where I can fix things. Many people have things that are broken and I want to help them live better lives by taking care of that which I have control over. This is why I think I would like opthalmology, orthopedics, or some other type of surgery.

I don't see myself working with people on a day to day basis trying to bring about behavior change. I can't see myself working with diabetics, for example, trying constantly to bring their blood sugar under control in order to tame their heart disease, blood clots, and kidney failure. I'd rather fix broken bones, reconstruct noses, or fix eyes that aren't working.