The Tuberculous Granuloma is High Yield for the USMLE

Ahh the Granuloma - a great example of topic that overlaps multiple subjects and any topic that brushes borders with the likes of pathology, immunology and microbiology make for great questions. Here are 5 steps to the granuloma in perfect 3^rd grader doodle form:

Step 1: Inhale the red, ACID FAST rod

M. tuberculosis is only acid fast why?

B/c of the MYCOLIC ACID in the cell wall resists decolorization with acid-alcohol and so it remains red which is the color of the initial stain, carbol fuchsin.

What else stains acid fast? Nocardia which is “partially acid fast”

Step 2: Phagocytosis by alveolar macrophages

Circulating monocytes roll on the vascular endothelium (d/t selectins) and adhere to it (d/t ICAMs) and then transmigrate into the affected area where they are called tissue macrophages.

Macrophages are the main players in the formation of a granuloma

Step 3: Antigen Presentation

Step 4: T Cell Activation

CD4 T Cells are involved

The TH1 subtype

No CD4 T Cells? No Granuloma. AIDS patients who loose their CD4 t-cells well before loosing their CD8 T Cells will make very weak if any granulomas.

Step 5: Macrophage Activation

Did I mention what the main player of a granuloma is? Oh yea, its the macrophage.

The Caseous Granuloma

Note that the caseous necrosis is cottage cheese like and is due to the destruction of the M. TB organism's cell wall's mycolic acids (mycolic acids are lipids).

Viruses are High Yield for the USMLE Step 1

I suggest when trying to memorize viral structures make a priority list. Common viruses and ones that also overlap with pathology are the ones to focus on here since they can be asked about in many different ways.

Knowing DNA vs RNA is the most important distinguishing feature. Furthermore, f you know if its DS or SS you'll probably get the points.

Enveloped vs Naked: If you can memorize enveloped vs. naked for each virus then god bless, but I like this:
Envelopes are made of a lipid bilayer which are prone to destruction by the environment whereas naked viruses are more resistant to environmental stresses.

A 46 year old female who has genital warts (d/t HPV) takes a shower in her home during which time the virus sheds on the floor. Later her child presents with a wart on his toe.

This all happened since this virus had its tough nucleocapsid for protection and not a wimpy envelope. Take home message is if the virus is capable of fomite transmission it is probably naked.

Play odds, especially for rare viruses with less of a chance of being asked. I walked into the exam knowing that if I saw an RNA virus that looked deadly or pretty rare I would guess that it is SS (-) linear w/envelope.

Here is my list of High Yield Viruses and why I think they have a great chance of being asked

• Herpesviruses - DS linear DNA
  
• this family includes so many viruses that overlap with pathology I list it first since I think this is most important.
  
• All the viruses that cause hepatits - see First Aid for them since these are important!
  
• Note that Hep B carries the reverse transcriptase enzyme with it just like the retroviruses do.
  
• HIV - SS (+) linear RNA
  
• If you don't get at least 1 question on AIDs I will give you my blog. Seeing if you know virus structure is a possible secondary question.
• Papovavirus - DS (-) linear
• besides HPV causing cervical cancer don't forget about molluscum contagiosum which causes the umbilicated wart (center of wart is depressed like an "innie" belly button).
• Paramyxoviruses - SS (-) linear RNA with helical capsid symmetry
  
• this family is responsible for causing croup (parainflunza virus), bronchiolitis (d/t RSV), measles and mumps.
• Parvovirus - SS linear DNA
  
• It, along with Hepadnavirus, is exception to the rule that all DNA viruses are linear.
  
• It overlaps with pathology since it causes aplastic anemia in patients with sickle cell disease
  
• Pt might give you a history of having recent contact with a kid who had a slapped cheek appearance.
• Blood labs will give you a low RBC count with low reticulocytes (less than or equal to 3% of hematocrit - I wouldn't freak out about not knowing how to correct a reticulocyte count).
• Influenza virus (an orthomyxovirus) - SS (-) linear segmented RNA
• the NBME and practice questions I've seen love the fact that this genome is segmented since:
• Genetic shift - if our influenza virus recombines with a pig's or chickens genome we get pandemics - we're all screwed (small minor mutations lead to drifts causing an epidemic in a much smaller area w/ much less people). involved)
• If you digest the genome and view it with northern blotting you will see each of these (7 or 8) segments as separate bands.
  

Vitamin K is High Yield for the USMLE Step 1

• Vit. K is needed for the γ-carboxylation of clotting factors 2, 7, 9 and 10
• This gives them a Ca binding site
• This explains why the vit. K dependent factors are the same factors that are dependent on calcium
• Deficiency:

o Primary problem is an inability to γ-carboxylate factors 2, 7, 9 and 10

• therefore, factors ARE made but can NOT be activated by Ca
• Involves several factors, including factor 7 which:
• has the shortest t½ of all the clotting factors
• therefore, factor 7 is the first factor unable to be activated
• Since factor 7 is specific to the extrinsic pathway the extrinsic pathway is affected first
• Since the prothrombin time (PT) is a measure of the extrinsic pathway, it is the value expected to be elevated first
• Leads to ↑↑PT (AND eventually ↑PTT) – therefore, PT is most sensitive since its ↑’d 1^st
• Bleeding time, a measure of platelet function, is normal since platelets are not affected
• Deficiency can be seen in the following patients:
• Newborns born at home
• Breast milk has low levels of vit K
• All babies in the US are given vit. K shots @ birth in the hospital to prevent hemorrhagic disease of the newborn
• Pts on broad spectrum antibiotics
• Bacteria in colon synthesize much of our vit. K
• Pts w/ steatorrhea
• Loss of fat in the stools also leads to a loss of the fat soluble vitamins, including vit. K
• Vitamin E toxicity
• Inhibits vitamin K dependent carboxylation of clotting factors
• Treatment
• Vitamin K Injection
• If bleeding is serious then give fresh frozen plasma

Testable Anemias That Do Not Always Make It To The Books

Here are some anemias that aren't always thought of in the same breath as many other anemias.

• Vitamin C deficiency - since vitamin C enhances non-heme iron absorption in the gut, a vitamin C deficiency can cause a iron deficiency (microcytic and hypochromic) anemia.
• Vitamin E (alpha-tocopherol) deficiency - Vit. E prevents the peroxidation of lipid cell membranes by free oxygen radicals since vit. E is an anti-oxidant. When deficient in vit. E, one sign is acanthocytes in the peripheral blood smear. When these spiny RBCs burst it causes a hemolytic anemia
  
• Similarly, in abetalipoprotinemia, an autosomal recessive disorder of lipid absorption may manifest with acanthocytosis in part because vitamin E (a fat soluble vitamin) is also not being absorbed.
• Orotic Aciduria - megaloblastic anemia unresponsive to folate or B12. A number of wordy enzymes may be deficient but the essential problem here is pyrimidine synthesis and so DNA synthesis is subsequently impaired.
  
• This is very similar to B12 and folate deficiencies since in both of these cases, DNA synthesis is also impaired.
  

Burkitt's Lymphoma is High Yield for the USMLE Step 1

Burkitt Lymphoma
a form of non-Hodgkin's lymphoma

Associated with Epstein Barr Virus and is commonly located in the jaw of Africans (the classic patient)

(source)

Classic Translocation = t(8;14) which moves the c-myc gene on chromosome 8 right next to the Immunoglobulin (Ig) Heavy Chain.

Here is a joke for you. I hope you find it hilarious. Okay, a giggle will do. Tell it to someone else, embrace the awkwardness that ensues and that should tattoo it to your brain for a while.

How come Mick ate one for?

-----Here is what the joke really means----
come Mick = c-myc
ate = 8 - since c-myc is on chromosome 8
one = 1
for = 4

To get heavy!
heavy = Ig Heavy chain which is on chromosome 14


And here's a little doodle to drive it on home:


That big guy there is Mick (myc) who has just ate (8) one (1). For (4) what? To get heavy.
c-myc is on chromosome 8
Ig Heavy chain is on chromosome 14

Believe me, this joke is much funnier if you're telling it to yourself when you are looking at a question on it.

Here is what some practice questions I've seen ask and is mentioned in various review therefore I made sure I knew this for my exam although I had to look it up again for this post.

The function of c-myc: c-myc is a proto-oncogene which codes a protein that regulates nuclear transcription. When it is moved next to the gene for the Ig heavy chain it becomes constantly active since the body is constantly making Ig heavy chains. At this point it is now called an oncogene. c-myc now causes the B-cells to constantly reproduce themselves over and over again. This results in a high grade lymphoma

This is in contrast to B-cell follicular lymphomas in which BCL-2 (a gene which promotes apoptosis). When BCL-2, a tumor suppressor gene, is translocated it becomes functionally inactive and so B-cells can't undergo apoptosis the same anymore. This is an example of low grade tumor.

So I think this is how you should think about it: Burkitt's lymphoma is when B-cells actively divide whereas in B-cell follicular lymphomas, B-cells don't die.

Also, here's the classic"Starry Sky Appearance"

(source: pathguy.com)

I just want to point out here what that refers to. The dark purple areas are really just a bunch of neoplastic B-cells that are dividing much more rapidly now that c-myc is always active. ("Dark is Dividing") The stars are the lighter areas which are much fewer in number - these are the macrophages. I'm not sure what they are doing there, but I do know that they are NOT the problem. Perhaps they are trying to help out in getting rid of the tumor.

That's what I think is really important for this tumor that seems to be a pretty hot topic for the exam.

Thiamine is HY for the USMLE Step 1

THIAMINE aka Vitamin B1

Active form: Thiamine Pyrophosphate (TPP)

Main reactions in which thiamine is a cofactor:
These dehydrogenase reactions generate NADH in the mitochondria which enter the electron transport chain to generate ATP, therefore the patient has a problem making ATP.

Cofactors required by the above 2 enzymes are
Thiamine
Lipoic acid
CO2
Folate
NAD+
Which can be remembered by the phrase, "Tender Love and Care for Nancy"

(Thiamine is also a cofactor for transketolase which catalyzes 2 Carbon transfers in the HMP shunt (pentose phosphate pathway) - required to make Ribose 5 phosphate for nucleotide synthesis)

Classic patient is a Malnourished Alcoholic

Signs and symptoms of deficiency:

Wernicke's Encephalopathy

• Peripheral neuropathy
  
• due to Wallerian degeneration; not drawn (source: Boards and Wards, 3rd Edition)
• occurs since ATP is needed for myelin production and ATP isn't being made to the same quantity
  
• Neuropathy may manifest as foot drop or wrist drop much like lead poisoning does in adults
  
• Wernicke's encephalopathy is reversible (We-versible Wernicke's)

________

Say the above patient was given glucose without correcting his thiamine deficiency, it would precipitate...

Korsakoff's Amneisa

These are the Mammillary Bodies:

These are the mammillary bodies on drugs:

Any questions?
(source: The Medical Journal of Australia )

• anterograde and retrograde amnesia
  
• Bilateral hemorrhagic necrosis of mammillary bodies
  
• mammillary bodies are in the hypothalamus and are part of the limbic system
  
• irreversible
  

Treatment: IV Thiamine and THEN glucose

Myocardial Infarctions Are HY for the USMLE

The formula for a Myocardial Infarction essentially is

Oxygen demand > (greater than) Oxygen supply

Myocardial tissue must therefore switch from aerobic to anerobic metabolism which generates only 2 ATP.

***AT REST THE HEART IS EXTRACTING ALMOST ALL OF THE O2 FROM ITS BLOOD SUPPLY***

therefore, for oxygen supply to increase, more blood must be pumped to the heart tissue (MOA of nitrates for ischemic chest pain). If supply cannot meet demand, the heart tissue may infarct.

Hacking Myocardial Infarctions on the EKG
The leads these changes are seen are listed in my drawing (see below)

• Peaked or Inverted T Waves - often earliest sign of ischemia
  
• ST segment
• Elevation
• Differential diagnosis: Prinzmetal's Angina
  
• a vasospasm of the smooth muscle of the artery
• Si/Sx: chest pain at rest
• cardiac enzymes = negative (differing it from an MI)
• Depressed in stable angina and subendocardial MI
  
• Deep Q waves
  
• These do not go away after the MI. Ever.
  
• therefore, deep Q waves indicats the patient may have suffered an MI

Squamous Cell Lung Carcinoma's Paraneoplastic Syndrome is HY

A 56 year old male has a 65 pack year smoking hx. He is seeing you today about recently having coughed up blood. He knows that this might be lung cancer and asks you for your expert opinion. Labs show hypercalcemia. Bronchoscopy reveals cells with atypical mitosis with some nuclei containing 3 to 4 metaphases.
The question is, it squamous or small cell cancer?


You really have to remember that squamous cell carcinoma releases PTHrP causing hypercalcemia.

Squamous Cell = Hypercalcemia

And since small and squamous both start with the letter S, I often mistake the 2 so here is what I made up to remember calcium when I hear squamous cell.

Calcium’s abbreviation is Ca²⁺ which looks like Calcium squared (Calcium²).

Squamous ≈ squared. And there you have it.

Tabes Dorsalis

• This is a manifestation of tertiary (late) syphilis called neurosyphilis
• caused by infection with treponema pallidum, a spirochete
• tertiary syphilis also turns the vasa vasora (blood vessels that supply other blood vessels, eg aortic root) into a bunch of granulomas →:
• Aortic regurgitation – know how to recognize!
• Diastolic decrescendo murmur heard best along the left sternal border
• Aneurysm of the ascending aorta
• Note that tabes dorsalis only affects the dorsal horns.
• This patient had a positive (+ve) Rhomberg's sign
• Rhobmerg's sign
• Patient's balance is fine with his eyes open
• Visual input supplies spatial awareness/proprioception
• Upon closing his eyes the pt sways
• loss of proprioception from dorsal column

(If patient is swaying with eyes open and closed, this is likely a lesion in the cerebellum or vestibular system (eg. CN VIII) and would NOT qualify as a +ve Rhomberg's sign)

• Can you guess the level from which this spinal cord section was taken

A) C1
B) C4
C) T4
D) L4
E) S1

Answer posted on 4/2/07

Note the lateral horns (sometimes called intermediolateral cell column):
(I have circled the right one and have drawn an arrow to the left one)
This area of white matter contains preganglionic sympathetics which arise from the hypothalamus and will synapse onto a postganglionic sympathetic fiber in the paravertebral (aka chain) ganglion. Question for you... would the neurotransmitter used here be
a) norepinephrine (Norepi)
b) epinephrine (Epi)
c) acetylcholine (ACh)
d) glycine (Gly)
e) glutamate (Glu)
f) seratonin (5-HT)

Answer is c) Ach
Remember, all preganglionic autonomic fibers use ACh
Epinephrine is released from the adrenal medulla when preganglionic sympathetic fibers release ACh onto it.

Now, back to the level of the spinal cord:
Since we are talking about sympathetic (aka thoraco-lumbar) outflow, you should know right away that this slide must therefore have been sliced from somewhere between T1-L2.
Knowing this would have gotten you the right answer to my question.

If the question writer is out for your blood he may ask you to distinguish between 2 choices within the range of the lateral horn. Notice the shape of the above section. Now compare it to an upper lumbar section. See the difference? The lumbar section has only one dorsal column and it is just a lot more round. That "just a lot more round" part (I bet) is enough to differentiate for purposes of the exam. But feel free to knock yourself out, I know I did.

Molecular Mechanisms of Apoptosis

Apoptosis is HY for the USMLE Step 1. Here is my attempt to illustrate the molecular basis of apoptosis summarized from Robins.

Epstein Barr Virus

• Attaches and activates B-lymphocytes CD21 (CR2) receptor
• These activated B cells promotes T cell proliferation
• The effected B-lymphocytes are NOT what are detected by the monospot test.
• Atypical lymphocytes (“Downy Cells”)
• Detected by the monospot test
• AKA (heterophile antibody test)
• Are CD8⁺ T lymphocytes
• Associated with:
• Heterophile positive infectious mononucleolus
• Burkitt's Lymphoma
• Nasopharyngeal Carcinoma
• Structure
• a "HAPPy" double-stranded linear DNA virus (see First Aid virus section)
  

Hypomagnesemia and PTH

One point which gets you an easy point but otherwise easy to miss is that hypomagnesemia can cause hypocalcemia since magnesium is necessary for the production of PTH.

	PTH	Calcium	Phosphate	Si/sx
Primary Hyperparathyroidism	↑	↑	↓	stones, bones, abdominal groans and psychic moans"
Chronic Renal Failure (→Vit D def.)	↑	↓	↑ - can’t be excreted
Hypercalcemia (malignancy)	↓	↑	↑
Hypomagnesemia	↓	↓	↓	Hypocalcemia that responds to Mg 2+ infusion