http://www.usmle.org

The materials can be downloaded in pdf format in:

http://www.usmle.org/Examinations/step1/2011Step1.pdf

The content outlines for this exam has been updated by a subcommittee of the step I committee.

The updated content can be found in this link:

http://www.usmle.org/Examinations/step1/step1_content.html

USMLE committee recommends to students considering to exam Step I after May 2011 to be familiarized with the previous (2010) and the updated content outlines.

In future posts we will discuss the topics associated to the sample questions related to Biochemistry that are included in these materials.

Extraordinary Measures is a 2010 film about parents trying to save their children affected by Pompe Disease, A Glycogen Storage Disease produced by mutations on a gen that makes the enzyme acid alpha Glycosidase (GAA), a lysosomal hydrolase.

 Pompe disease is a rare (estimated at 1 in every 40,000 births), inherited and often fatal disorder that disables the heart and muscles.

The movie is based on the true story of John and Aileen Crowley, whose two youngest children were affected with Pompe Disease.

The real John Crowley

As you know Glycogen storage diseases are genetic enzyme deficiencies that result in excessive glycogen accumulation within cells. Additional symptoms depend on the particular enzyme that is deficient.

There are different forms of Glycogen Storage Diseases (aka Glycogenoses), including the Type Ia GSD or Von Gierke’s disease, caused by hepatic deficiency of Glucose 6 Phosphatase, the Type IV or Andersen’s Disease, caused by deficit of branching enzyme in various organs, including the liver, and the GSD Type V or McArdle’s Disease (caused by muscle deficiency of Glycogen Phosphorylase), among others.

GSD Type II or Pompe’s Disease was described by Pompe in 1932, when he studied a girl who suffered from a cardiopathy caused by glycogen accumulation.

The National Institute of Neurological Disorders and Stroke (NINDS), an Institute of the National Institutes of Health System, describe the disease in these terms:

“Early onset (or infantile Pompe disease is the result of complete or near complete deficiency of GAA.  Symptoms begin in the first months of life, with feeding problems, poor weight gain, muscle weakness, floppiness, and head lag. Respiratory difficulties are often complicated by lung infections.  The heart is grossly enlarged. More than half of all infants with Pompe disease also have enlarged tongues.  Most babies with Pompe disease die from cardiac or respiratory complications before their first birthday. 

Late onset (or juvenile/adult) Pompe disease is the result of a partial deficiency of GAA.  The onset can be as early as the first decade of childhood or as late as the sixth decade of adulthood.  The primary symptom is muscle weakness progressing to respiratory weakness and death from respiratory failure after a course lasting several years.  The heart may be involved but it will not be grossly enlarged.  A diagnosis of Pompe disease can be confirmed by screening for the common genetic mutations or measuring the level of GAA enzyme activity in a blood sample — a test that has 100 percent accuracy.  Once Pompe disease is diagnosed, testing of all family members and consultation with a professional geneticist is recommended.  Carriers are most reliably identified via genetic mutation analysis.

A diagnosis of Pompe disease can be confirmed by screening for the common genetic mutations or measuring the level of GAA enzyme activity in a blood sample — a test that has 100 percent accuracy.  Once Pompe disease is diagnosed, testing of all family members and consultation with a professional geneticist is recommended.  Carriers are most reliably identified via genetic mutation analysis.”

“…Individuals with Pompe disease are best treated by a team of specialists (such as cardiologist, neurologist, and respiratory therapist) knowledgeable about the disease, who can offer supportive and symptomatic care.  The discovery of the GAA gene has led to rapid progress in understanding the biological mechanisms and properties of the GAA enzyme.  As a result, an enzyme replacement therapy has been developed that has shown, in clinical trials with infantile-onset patients, to decrease heart size, maintain normal heart function, improve muscle function, tone, and strength, and reduce glycogen accumulation.  A drug called alglucosidase alfa (Myozyme©), has received FDA approval for the treatment of infants and children with Pompe disease.  Another alglucosidase alfa drug, Lumizyme©, has been approved for late-onset (non-infantile) Pompe disease. ..”

“…Without enzyme replacement therapy, the hearts of babies with infantile onset Pompe disease progressively thicken and enlarge.  These babies die before the age of one year from either cardiorespiratory failure or respiratory infection.  For individuals with late onset Pompe disease, the prognosis is dependent upon the age of onset.  In general, the later the age of onset, the slower the progression of the disease.  Ultimately, the prognosis is dependent upon the extent of respiratory muscle involvement. …”

 It is interesting that even when the Acid Alpha-glycosidase is only involved in the degradation of about 3 % of the Glycogen, its deficit provokes such important damages. Since this enzyme is not related to the main pathways of degradation of glycogen, its deficit does not produce hypoglycemia or a direct lack of metabolic energy. Cellular damage is caused mainly by accumulation of glycogen in the cytoplasm and the lysosomes.

As describe above, nowadays the treatment is based on the use of a recombinant human acid Glycosidase as a replacement of the normal enzyme.  “Extraordinary Measures” describes, in fact, the events that triggered the development of the enzyme for the treatment of this disease.

My favorite quotes of this movie:

John Crowley (Looking at the college-aged kids hired to work under Dr. Stonehill):

-These guys make me feel old.
Dr. Robert Stonehill:

- Scientists get all sensible & careful when they get old. Young ones like risk, not afraid of new ideas… and you can pay ‘em less.

John Crowley (talking with Dr. Stonehill after an argument):

-  ”Fine, spend the rest of your life dreaming up great ideas that don’t get funded. Draw your diagrams on the wall that cure diseases in theory but never help a single human being in reality.”

John Crowley (arguing with a corporate executive about drug research):

-  ”This is not about a return on an investment, it’s about kids. Kids with names, dreams, families that love them.”

Recommended articles and links:

NINDS Pompe Disease Information Page

Ibrahim, J.; McGovern, M. M.

Glycogen Storage Disease Type II

Some pictures of the Crowley family

Of course, there are many different apple pies, and many different serving portions  too!!!

So…let’s do the calculations with a “standar” apple pie…certainly not the best but it is standard, so standard that it is the same all around the world!

Of course, I am talking about the MacDonald Apple pie!

Nutrition facts of the Macdonald baked Apple pie (taken from the label):

Proteins 2g

Fat 13 g

Carbohydrates 32 g

Sodium 170 mg

How many calories are obtained when you eat 1 serving size of this pie?

Cells recognize one another because of the saccharides attached to cell surfaces. 

They  are present usually as oligosaccharides associated through covalent links to lipids and/or proteins forming Glycoconjugates. The lipid or protein part is integrated into the cell membrane structure, with the saccharide part towards the external membrane surface.

Membrane carbohydrates  (2-10% of the membranes) are on the extracellular surface bounded to lipids or proteins of the membrane, forming glycoconjugates that serve as docking sites in cell recognition, adhesion and receptor action. These sugars include mainly glucose, galactose, mannose, fucose, N-acetyl galactosamine and  N-acetyl glucosamine.

The different kinds of Glycoconjugates include:

Proteoglycans: In the Proteoglycans, the Glucosaminoglycan moety forms the greater fraction of the molecule (tipically a proteoglycan consists of 95 % of carbohydrates) and is the main site of biological activity, providing multiple binding sites. They are found mainly in the extracellular matrix. They are major components of connective tissue.

Glycoproteins: Membrane bound glycoproteins participate in a wide range of cellular phenomena, including cell recognition, cell surface antigenicity, etc. In the glycoproteins, the majority of the molecule consist of proteins; they have one or more oligosaccharides attached to a protein, and they usually are branched and do not have serial repeats, so they are rich in information, forming highly specific sites for recognition and high affinity binding by other proteins

Glycolipids: are membrane lipids in which the hydrophilic head groups are oligosaccharides.

 As in glycoproteins, glycolipids  act as specific sites for recognition by carbohydrate binding proteins.  The four types of human RBC have different oligosaccharides (antigens) in their cell membranes. Blood groups depends on the gangliosides (a kind of sphingolipid) in the surface of the RBC .

Where do the visits come from today?

The Dietary Reference Intake can be defined  a system of nutrition recommendations that estimates the amounts of nutrients required to prevent deficiencies and maintain optimal Health.

The DRI includes some concepts that sometimes are used as equivalents, when they are not. In other cases, the same concept receive different names, depending of the source of the article you are reading.

DRIs consists of four dietary reference standards:

1.- Estimated Average Requirement (EAR): Average daily nutrient intake level estimated to meet the requirement of one half of the healthy individuals in a specific age and gender group.

 2.- Recommended Dietary Allowance (RDA): Average daily Dietary intake level that is sufficient to meet the nutrient requirements of nearly all (97-98%) individuals (EAR+2DS) on each life state and gender group. It is approximately 20 % higher than the EAR. RDA are printed in food labels in the United States and Canada.  (The definition of RDA is similar to the definition of  Recommended Nutrient Intake (RNI)  used by the World Health Organization and other international organizations).

 3.- Adequate Intake (AI): Estimation of nutrient intake in healthy people (used when EAR and RDA are not known)

 4.- Tolerable Upper Intake Level (UL): Highest average daily intake level from food, water and supplements that is likely to pose no risk of adverse health effect from excess in almost all apparently healthy individuals in an age and gender specific population group. (This concept is important mainly in relation to nutritional supplements, since the ingestion of natural foods is regulated in the body through mechanisms of absorption and excretion), In absence of observations of known adverse effects, it is used a default value of 10 times de Recommended Dietary Allowance.

More information about these reference standards can be found at:

Dietary Reference Intake

Reference dialy Intake 

 Interactive DRI for health care professionals

 Yates, A.A.: Dietary Reference Intakes –What is new and how to use them (Power point presentation)

Who Experts Committee:

Vitamin and Mineral requirements in human nutrition

World Health Organization, 2004

A 70 year-old English lady that lives alone is admitted to the hospital for evaluation of a leg wound that is not healing properly. The patient also complains of pain in muscle and bones. On the examination, you find some hemorrhagic lesions in the skin, including ecchymosis in buttocks and both legs and petechiaes in other areas of the skin. The nails show splinter hemorrhages. When asked about her dietetic habits, the patient refers that she is too old to eat so much, so she has a very frugal lunch and dinners based mainly in tea and toasts.

Laboratory examinations show normal blood coagulation tests and Hemoglobin of 9.8 g/dL

The treatment for the condition described above should consist mainly in the administration of the following vitamin:

a)     Ascorbic Acid

b)     Biotin

c)      Folic Acid

d)     Pantothenic acid

e)     Niacin

f)       Vitamin B1

g)     Vitamin B2

h)    Vitamin B6

i)       Vitamin B12

j)       Vitamin D

k)     Vitamin E

l)       Vitamin K

Platelet aggregates

Platelet membrane is rich in glycoproteins organized as receptors of very different types: tyrosine kinase receptors, integrin family receptors, receptors rich in Leucine (LRR), protein G linked transmembrane receptors, immunoglobulin super family proteins, lectins and others.

Many of these receptors play an important role in the haemostatic function of platelets, participating in the interaction among platelets, between platelets and vascular tissue, and among platelets and coagulation factors and other agonists (ADP, epinephrine, thromboxane A2, and others)

Other platelet membrane receptors are involved in the participation of platelets in processes such as inflammation, tumor growth, metastasis and immunologic type reactions.

From the medical point of view, GPIIb-IIIa and GPIb receptors are particularly important.

[GP] IIb-IIIa is the most abundant receptor in the platelet surface, representing almost 15 % of all the proteins in the cell surface. This receptor is a member of the Integrin receptors family and is also called Integrin αIIb-β₃. This is an important receptor in platelet aggregation, since it binds Von Willebrand factor and fibrinogen.  The relevance of this kind of receptors for an appropriate hemostasis is obvious if we consider that genetic mutations which provoke the absence or formation of lesser quantities of these receptors give rise to platelets that are not able of binding to fibrinogen and aggregate (Glanzmann Thromboasthenia).

Another important medical issue related to these receptors is the fact that nowadays antagonists of these receptors have been developed for inhibiting platelet aggregation, so we can use anticoagulant drugs that inhibit platelet aggregation regardless of the agonist. Examples of these drugs are Abciximab: a human monoclonal antibody, Eptifibatide, a cyclic hexapeptide derived from the venom of a snake) and Tirofiban, a synthetic non-peptide molecule.

GPI-b (GPIb-GPIX-GPV) is a Leucine Rich Receptor (LRR) formed by a multiprotein complex of 4 different types of glycoproteins: GPIb alfa and GPIb beta, (linked through disulfide bonds) and GPIX and GPV (associated by non covalent forces).

This receptor is crucial for the platelets initial attachment to the extracellular matrix of the damaged vessel. This attachment is made through the Von Willebrand factor, which acts as a bridge between the sub endothelial collagen (exposed as a consequence of the vessel damage) and the GPI-b receptors in the platelet membrane.

The Bernard-Soulier syndrome is an autosomal recessive disorder which appears as a consequence of an absence or decrease of the glycoproteins that form the GPIb-GPIX-GPV receptors.

Excellent reviews on these issues can be found at the following links:

Platelet function defects.

Platelet function disorders 

Platelet receptors and signaling in the dynamics of thrombus formation

 Inherited Disorders of Platelets 

 Blood coagulation 

 Thromboasthenia of Glanzmann and Naegeli 

 Giant Platelet Syndrome

Mouse Islet of Langerhans immunostained for Glucagon

Assume that you find a patient with a glucagon-secreting pancreatic tumor (glucagonoma). Which one of the following is most likely to result from hyperglucagonemia?

a)     Decreased lipolysis

b)     Hyperglycemia

c)      Increased muscle protein synthesis.

d)     Increased liver glycolytic rate

e)     Increased glycogenesis

Source of platelets.

Platelets are formed from their precursors in the hematopoietic tissue. 

Platelets, like other blood cells, are formed from Hemocytoblast that under certain conditions, and mainly under the effects of thrombopoietin, may be converted in a megacarioblast. Megacaryoblast is transformed into Promegacariocyte, and this cell in Megakaryocyte.

During Megakaryocyte maturation process,   DNA replication continues, and the nucleus suffers many divisions, but the cell continue undivided. While this process is going on, a large amount of cytoplasm accumulates.

Platelets are formed by the development of demarcation membranes in the cytoplasm, with subsequent release of the formed fragments to the venous sinusoids of the marrow bone.

A Megakaryocyte can release thousands of platelets, leaving the parenchyma cell with virtually only the nucleus and residual cytoplasma.

General structure:

Platelets are very small (1 to 4 microns in diameter) and circulate between 4 and 10 days, as flattened disks without nucleus. Platelet membrane is very rich in phospholipids and contains various glycoproteins that perform a fundamental role in the reception and transduction of intracellular signals. The cytoplasm of platelets contains a microphylament system and an actin/myosin contractile structure, called thrombosthenin, which, when activated, modify the conformation of the membrane. The cytoplasm also contains microtubules, which together with the microfilaments form an internal cytoskeleton responsible for the platelets conformation, but at the same time flexible enough to allow the conformational changes that occur during the platelet activation.

Platelet cytoplasm contains also residual endoplasmic reticulum(forming the so-called dense tubular system), mitochondria, glycogen and three different types of granules: Alpha granules, dense granules and lysosomal granules, containing biologically active substances that are released during the coagulation process The energy for platelet processes (aggregation, secretion and others) derive from the aerobic metabolism  in the mitochondria and anaerobic glycolysis (recall that the cytoplasm contains glycogen granules)

Platelet receptors and granules are particularly interesting from the physiological and medical point of view, so they will be discussed in more detail in future posts.

Recommended articles:

Flaumenhaft, R. et al:

The actin cytoskeleton differentially regulates platelet (alpha)granule and dense granule secretions.

The Online Metabolic and Molecular Bases of Inhereted Diseases.

The inhereted disorders of platelets

Wikipedia:

Platelet.