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Michaellis 10-year-old black male child who was admitted to the hospital because he was experiencing severe chest pain.

Michaellis 10-year-old black male child who was admitted to the hospital because he was

experiencing severe chest pain. He had been hospitalized on several previous occasions for vasoocclusive

episodes that caused him to experience severe pain that could not be managed with nonprescription

drugs such as ibuprofen. He was slightly jaundiced, short of breath and easily tired, and

feverish. A chest x-ray was taken and was abnormal. An arterial blood sample showed a pO2 value of 6

kPa (normal is 10-13 kPa).

1. You suspect that Michael has sickle cell anemia and you have ordered an isoelectric focusing

electrophoretic analysis of the chil's lysed red blood cells. (Lysing the red blood cells releases

the hemoglobin.) Draw a diagram of the predicted results.. Why will this test allow you to

diagnose this child's disease?

2. In the emergency room, oxygen (100%) was administered to the patient. (Inspired air normally is

about 20% oxygen.) Why was this an effective treatment?

3. You recall reading in the medical literature about a dramatic new drug treatment for sickle cell

anemia, and you'd like to try it on this patient. The drug is hydroxyurea, and is thought to function

by stimulating the afflicted person's synthesis of fetal hemoglobin. Exactly how hydroxyurea

stimulated fetal hemoglobin synthesis is unclear, but it is believed that hydroxyurea is metabolized

to Nitric Oxide (NO), which binds to a soluble guanylate cyclase enzyme which catalyzes the

synthesis of a second messenger, cyclic GMP (cGMP). The cGMP interacts with transcription

factors in a manner that is not completely understood to induce the transcription of the fetal

hemoglobin gene.

a. In a clinical study, patients who took hydroxyurea showed a 50% reduction in frequency of

hospital admissions for severe pain, and there was also a decrease in the frequency of fever and

abnormal chest x-rays. Why would increasing the synthesis of fetal hemoglobin result in

alleviating the symptoms of sickle cell anemia?

b. Medical practioners who used hydroxyurea as a treatment for sickle cell anemia noted that their

patients seemed to benefit from the administration of the drug long before the synthesis of fetal

hemoglobin had time to take effect. It has recently been determined that hydroxyurea can react

directly with the iron ion of oxy- and deoxyHb to form iron nitrosyl hemoglobin (HbNO). Why

would this be of benefit to the sickle-cell anemic patient?

c. In addition, hydroxyurea has been shown to produce NO directly, in less than an hour after

hydroxyurea administration. It's also possible that HbNO could produce free NO, either directly

or indirectly. NO is an mportant second messenger which, even in nanomolar amounts,

stimulates vasodilation. How could production of NO help the sickle-cell anemic patient?


4.A year ago, at a conference, one of your colleagues told you that she had “cured” a patient of sickle

cell anemia by performing a bone marrow transplant. Why would this procedure “cure” sickle cell

anemia?

5. At the same conference, you attendedaa talk describing the discovery of a novel mode of

action of NO:

NO might be involved in oxygen delivery to the cells in a more direct manner–through reacting

with hemoglobin, for example. This hypothesis was confirmed when the investigators showed that

NO can react with hemoglobin to form S-nitrosohemoglobin. The NO reacts with the sulfhydryl

group on Cys93 on the β chain of hemoglobin to form the S-nitrosohemoglobin. The reaction is

readily reversible, with SNO-Hb releasing NO under certain conditions.


a.  A purified sample of hemoglobin is subjected to a chemical modification experiment in

which an alkylating agent is added to the hemoglobin. The alkylating agent Nethylmaleimide

(NEM) reacts with sulfhydryl groups as shown in Fig. 1. The NEM has the

ability to react with the Cys β93 in oxy-Hb but not deoxy-Hb. What does this tell you about

the environment of Cys β93?


Figure . Reaction of NEM with cysteine thiols.


Top Answer

Hyperbaric oxygen therapy can be done in a number of ways. It can be given in a special type of room called a hyperbaric... View the full answer

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