About Aspirin Mechanism of Action (LM-01)


 

                                    Aspirin Structure

Several thousands of tons of aspirin (acetylsalicilate) are consumed  each year all over the world for the relief of headaches, inflammed joint, pain in general and fever. Also, at low doses, in the prevention of heart attacks. The relief caused by aspirin in these conditions is based mainly in aspirin effects on eicosanoid metabolism. Aspirin binds covalently (and so act as an irreversible inhibitor) to this enzyme of eicosanoid metabolism:

a) Lipoxygenase

b) Thromboxane Synthase

c) Prostacycline Synthase

d) Prostaglandin Synthase

e) Phospholipase A2

 

 

Answer

ANSWER TO I-01


Answer: (i)

The percentage of Hemoglobin A1c is the best indicator of the average levels of glucose in blood several weeks before the exam.

Hemoglobin A1c is formed through a non catalyzed reaction between glucose in blood and some amino groups in Hemoglobin A. This reaction is directly proportional to the concentration of glucose in blood. It means that hyperglycemic episodes in a  diabetic patient are registered in the blood as proportion of Hemoglobin A that becomes glycosylated. That is the connotation of the units used when this exam is reported: a report of  Hemoglobin A1c value equal  6 %, for example, means that 6 % of the Hemoglobin A of the patient is linked to glucose. The reference value of HbA1c for a non diabetic person is  4-6 %  .

An International study for a better standardization of the measurement and  report of HbA1c, including  the future use of  results as mmoles of Hb A1c per mol of Hemoglobin, is being developped in different countries. It also includes collecting and updating information to correlate the values of Hb A1c to the average values of glucose in blood for facilitating patient interpretation of HbA1c results.

In the following video, Dr. David M. Nathan summarize the presentation of the preliminary results of this ongoing investigation, in a recent American Diabetes Association meeting:

The value of Hb of HbA1c has shown a strong correlation to the average glucose level. Since the RBC has an average life span of 120 days, the proportion of glycosylated hemoglobin can reflect the glucose levels in previous months, but it mainly represents glycemia during the last month and is strongly influenced by glucose levels in the last two weeks.

This kind of glycosylation reaction is not exclusive of Hemoglobin, since other proteins also experiment it. As a consequence of repeated episodes of hyperglycemia over time, many proteins can become glycosylated with modification of their structure, functionality and solubility, producing complications seen in long term uncontrolled diabetes.  The concentration of glycosylated hemoglobin has shown a strong correlation with microvascular complications as retinopathies and nephropathies. 

 

Nowadays, the management plan of glycemic control for diabetic patients is based on Self Monitoring of Blood Glucose (SMBG) and measurement of Hemoglobin A1c. The American Diabetes Association (ADA) recommends to perform HbA1c determination twice a year in patients with controlled glycemia and every four months in patients that does not shows an appropriate glycemic control, or patients whose treatment have been changed.  (Standards of Medical Care in Diabetes, 2008)

The measurement of HbA1c is limited by the presence of concomitant conditions in the patient that affect the erythrocyte life, (like hemolytic anemias) or cases of Hemoglobin variants. Another limitation is related to the inability of this test to inform about hypoglycemic episodes in the patient.

 Recommended articles:

 

American Diabetes Association

Standards of Medical Care in Diabetes – 2008

Diabetes Care 31: S12-S54, 2008

 

Use of Glycated Hemoglobin and Microalbuminuria in the monitoring of Diabetes Mellitus.  Summary, Evidence Report/ Technology Assessment, Number 84. AHRQ Publication N o. 03-E048, July, 2003, Agency for healthcare, Research and Quality, Rockville, MD

American Diabetes Association: Care of Children and adolescent with Type I Diabetes. Diabetes Care, January 1, 2005 28 (sppl_1: S4-S36)

 Sacks, D. B. et al: Guidelines and recommendations for Laboratory Analysis in the Diagnosis and Management of Diabetes Mellitus. Clin Chem 48: 436-472, 2002

American Diabetes Association: Management of Hyperglycemia in Type 2 Diabetes: A Consensus Algorithm for the Initiation and Adjustment of Therapy  Diabetes Care:29, 1963-1972, 2006

 

Recommended Sites:

 

http://www.diabetes.org/home.jsp

 

http://care.diabetesjournals.org/

 

http://www.fda.gov/diabetes/

 

http://spectrum.diabetesjournals.org/

Diabetes Mellitus (I-01)


A 18-year-old male patient with type I diabetes mellitus (IDDM) feels nauseated and drowsy and has been vomiting for a few hours.  Clinical exam shows mild signs of dehydration and low blood pressure. You request lab tests and the results show the following significative results: 

Blood glucose:                350 mg/dL (Reference Range: 70-110 mg/dL)

Hemoglobin A:               12.8 g/dL    (Reference Range: 13.5-17.5 g/dL)

Hemoglobin A1c:           10 % of total Hb (Reference Range: < 6 %)

Urine ketones:                positive

Urine glucose:                positive

Blood pH                           7.30

Pa CO2 :                             Below reference range

Serum bicarbonate:     Below reference range

Which of the following best indicates that this patient has had hyperglycemia  over a period of weeks?

 a)     Ketonemia

b)      Ketonuria

c)       Glicemia

d)     Glucosuria

e)   Blood pH

f)  Partial pressure of CO2

g)  Serum bicarbonate

h) Hemoglobin

i) Hemoglobin A1c

 

Answer

 

Respiratory Distress Syndrome (L-01)


A premature baby, shortly after birth, presents with rapid breathing, intercostal retractions, and grunting sounds while breathing. A blood gas analysis reveals low oxygen and acidosis. A diagnosis of Respiratory Distress Syndrome is quickly made. This syndrome is seen in newborns with immature lungs whose pneumocytes do not synthesize enough:

a) phosphatidyl choline

b) phosphatidyl inositol

c) sphingosin

d) sphingomyelin

e) palmitoyl CoA

 f) palmitate

 

Answer

Answer to L-01


Answer: (a) 

Phosphatidyl choline or Lecithin is a phosphoglyceride, ester of a diacylglycerol with a phosphate linked to another alcohol. The phosphoglyceride group includes, among others, phosphatidyl choline, phosphatidyl serine, phosphatidyl ethanolamine, and phospathidyl inositol.   

Phosphoglycerides and sphingomyelin form the group of phospholipids. Phospholipids are amphipatic molecules: they have a hydrophobic part and a hydrophilic part.  It makes them very suitable for the structure of membranes and lipoproteins.

 Amphipatic molecules have surfactant properties: they decrease surface tension.

Normal lung functions depend on a constant supply of surfactants. Since in the case of a sphere, surface tension is inversely proportional to its radius (Laplace Law), the decrease of the radius of the alveolus during expiration increases the surface tension.

 In absence of a surfactant substance, small alveolus will collapse easily, and the newborn should make great efforts to continue breathing. It explains that some premature babies who show a deficiency of Pulmonary Surfactant develop Respiratory Distress Syndrome (RDS).  

Phospatidyl choline is the most abundant of the phospholipids in the extracellular fluid layer that lines alveoli of normal lungs, and is the main responsible of decreasing the surface tension of the fluid layer of the lung (surfactant properties), preventing atelectasia at the end of the expiration phase of breathing. 

Different lecithins (phosphatidyl cholines) are remodeled by enzymes in pneumocytes in such a way that the resultant product is dipalmitoyl phosphatidyl choline.

Dipalmitoylphosphatidylcholine  

Dipalmitoyl phosphatidyl choline is the most abundant phospholipid in adult surfactant. 

Composition of adult surfactant

         Lipids: 80-90 % by weight

              Phospholipids (80-90 % of the lipids)

            •         Dipalmitoyl-phosphatidylcholine (about 50 %)

                     Phosphatidyl glycerol (about 10 %)

                     Sphingomyelin (about 3 %)

                     Other lipids (10-20 %)

         Surfactant Proteins: 10-20 % by weight 

Once produced in the pneumocyte, surfactant migrates as “lamellar bodies” from the nucleus to the apical cell surface where the surfactant is released by exocytosis into the alveolus.

lamellar bodies exocytosis

Usually between 32 and 36 weeks of pregnancy occurs a notable increase in the synthesis of phosphatidyl choline, while the synthesis of sphingomyelin does not experiment significant changes. That is why the ratio L/S (Lecithine/Sphingmyelin) in amniotic fluid is used as a marker of lung maturation when this information becomes necessary, for example, in the schedule of a medical elective cesarean section.  Since the volume of amniotic fluid is very variable, it makes sense, for eliminating the influence of the dilution factor, to use the ratio of L/S instead of measuring just Lecithin concentration. 

About 30 000 infants present Respiratory Distress Syndrome (former called Hyaline Membrane), in the United States each year. Around 10 % of them die.

Corticosteroid treatment is used to increase lung maturity in cases of risk of premature delivery. The effects of corticosteroids in enhancing the production of surfactant have been related to the induction of palmitate synthase expression in the pneumocytes. It makes more palmitate available for the synthesis a remodeling of lecithins to dipalmitoyl phosphatidyl choline.

The treatment of premature babies with RDS includes the administration of surfactant substances into the tracheobronchial tree. During this process, the infant is turned from side to side to facilitate uniform acinar distribution of surfactant throughout both lungs. Natural and synthetic surfactant preparations have currently been approved by the U.S. Food and Drug Administration, including colfosceril palmitate, a synthetic formulation, and natural surfactants composed of modified bovine and porcine lung extracts. 

More information about surfactants and RDS can be found in:

Feng, A.; Stelle, D: Pediatrics, Respiratory Distress Syndrome

Pramanik, A: Respiratory Distress Syndrome