SICKLE CELL TRAIT

SICKLE CELL TRAIT

Sickle cell trait (or sicklemia) describes a condition in which a person has one abnormal allele of the hemoglobin beta gene (is heterozygous), but does not display the severe symptoms of sickle-cell disease that occur in a person who has two copies of that allele (is homozygous). Those who are heterozygous for the sickle cell allele produce both normal and abnormal hemoglobin (the two alleles are codominant with respect to the actual concentration of hemoglobin in the circulating cells).

Sickle cell disease is a blood disorder in which there is a single amino acid substitution in the hemoglobin protein of the red blood cells, which causes these cells to assume a sickle shape, especially when under low oxygen tension. Sickling and sickle cell disease also confer some resistance to malaria parasitization of red blood cells, so that individuals with sickle-cell trait (heterozygotes) have a selective advantage in environments where malaria is present.

HEMOGLOBIN GENETICS

Normally, a person inherits two copies of the gene that produces beta-globin, a protein needed to produce normal hemoglobin (hemoglobin A, genotype AA). A person with sickle cell trait inherits one normal allele and one abnormal allele encoding hemoglobin S (hemoglobin genotype AS).

The sickle cell trait can be used to demonstrate the concepts of co-dominance and incomplete dominance. An individual with the sickle cell trait shows incomplete dominance when the shape of the red blood cell is considered. This is because the sickling happens only at low oxygen concentrations. With regards to the actual concentration of hemoglobin in the circulating cells, the alleles demonstrate co-dominance as both 'normal' and mutant forms co-exist in the blood stream. It is interesting to note that unlike the sickle-cell trait, sickle-cell disease is passed on in a recessive manner.

The sickle cell gene has five haplotypes, which are named after its core geographical areas of distribution: Bantu, Benin, Cameroon, Senegalese and Saudi-Indian.

PREVALENCE

Sickle cell trait prevalence is highest in West Africa, where it is found in 25% of the population. The trait also has a high prevalence in South and Central Americans, especially those in Panama. However, it also very infrequently appears in Mediterranean countries such as Italy, Greece, and Spain, where it most likely expanded via the selective pressure of malaria, a disease that was endemic to the region.

SYMPTOMS

Sickle cell trait is a hemoglobin genotype AS and is generally regarded as a benign condition. However, individuals with sickle cell trait may have rare complications. For example, in November 2010, Dr. Jeffery K. Taubenberger of the National Institutes of Health discovered the earliest proof of sickle-cell disease while looking for the virus of the 1918 flu during the autopsy of an African-American soldier. Taubenberger's autopsy results showed that the soldier suffered a sickle-cell crisis that contributed to his death even though he had only one copy of the gene. There have been calls to reclassify sickle cell trait as a disease state, based on its malignant clinical presentations. Significance may be greater during exercise.

SIGNS, SYMPTOMS, AND PREVENTION

Because of the microcirculatory distress, a telltale sign or symptom of a potential sickling collapse is cramping. Specifically to sickle cell trait, cramping occurs in the lower extremities and back in athletes undergoing intense physical activity or exertion. In comparison to heat cramps, sickling cramps are less intense in terms of pain and have a weakness and fatigue associated with them, as opposed to tightly contracted muscles that lock up during heat cramps.

A sickling collapse comes on slowly, following cramps, weakness, general body aches and fatigue. Individuals with known positive sickle cell trait status experiencing significant muscle weakness or fatigue during exercise should take extra time to recover and hydrate before returning to activity in order to prevent further symptoms.

A collapse can be prevented by taking steps to ensure sufficient oxygen levels in the blood. Among these preventative measures are proper hydration and gradual acclimation to conditions such as heat, humidity, and decreased air pressure due to higher altitude.

CAUSES

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SICKLE CELL ANEMIA

Sickle cell anemia is caused by a mutation in the gene that tells your body to make the red, iron-rich compound that gives blood its red color (hemoglobin). Hemoglobin allows red blood cells to carry oxygen from your lungs to all parts of your body. In sickle cell anemia, the abnormal hemoglobin causes red blood cells to become rigid, sticky and misshapen.

The sickle cell gene is passed from generation to generation in a pattern of inheritance called autosomal recessive inheritance. This means that both the mother and the father must pass on the defective form of the gene for a child to be affected.

If only one parent passes the sickle cell gene to the child, that child will have the sickle cell trait. With one normal hemoglobin gene and one defective form of the gene, people with the sickle cell trait make both normal hemoglobin and sickle cell hemoglobin. Their blood might contain some sickle cells, but they generally don't have symptoms. But they are carriers of the disease, which means they can pass the gene to their children.

Risk factors

For a baby to be born with sickle cell anemia, both parents must carry a sickle cell gene. In the United States, it most commonly affects black people.

Complications

Sickle cell anemia can lead to a host of complications, including:

• Stroke. A stroke can occur if sickle cells block blood flow to an area of your brain. Signs of stroke include seizures, weakness or numbness of your arms and legs, sudden speech difficulties, and loss of consciousness. If your baby or child has any of these signs and symptoms, seek medical treatment immediately. A stroke can be fatal.
• Acute chest syndrome. This life-threatening complication causes chest pain, fever and difficulty breathing. Acute chest syndrome can be caused by a lung infection or by sickle cells blocking blood vessels in your lungs. It might require emergency medical treatment with antibiotics and other treatments.
• Pulmonary hypertension. People with sickle cell anemia can develop high blood pressure in their lungs (pulmonary hypertension). This complication usually affects adults rather than children. Shortness of breath and fatigue are common symptoms of this condition, which can be fatal.
• Organ damage. Sickle cells that block blood flow through blood vessels immediately deprive the affected organ of blood and oxygen. In sickle cell anemia, blood is also chronically low on oxygen. Chronic deprivation of oxygen-rich blood can damage nerves and organs in your body, including your kidneys, liver and spleen. Organ damage can be fatal.
• Blindness. Sickle cells can block tiny blood vessels that supply your eyes. Over time, this can damage the portion of the eye that processes visual images (retina) and lead to blindness.
• Leg ulcers. Sickle cell anemia can cause open sores, called ulcers, on your legs.
• Gallstones. The breakdown of red blood cells produces a substance called bilirubin. A high level of bilirubin in your body can lead to gallstones.
• Priapism. Men with sickle cell anemia can have painful, long-lasting erections, a condition called priapism. As occurs in other parts of the body, sickle cells can block the blood vessels in the penis. This can damage the penis and lead to impotence.

MEDICAL IMPLICATION OF SICKLE CELL:

Treatment

Treatment goals for sickle cell disease aim to relieve pain, prevent infections, and manage complications. Patients should seek care from a doctor who specializes in blood disorders (hematologist) or a clinic that is experienced in treating sickle cell disease.

Bone marrow transplantation is the only potential cure, but it is used in only a small number of cases as few patients are able to find donors who are suitable genetic matches. Blood transfusions are given to prevent worsening anemia and prevent stroke.

Drug treatments for sickle cell disease include:

• Antibiotics, usually penicillin, are commonly given to infants and young children, as well as adults, to help prevent infections.
• Pain relief medication ranging from nonprescription nonsteroidal anti-inflammatory drugs (NSAIDs) to opiods are given to control pain.
• Hydroxyurea is prescribed for patients with moderate-to-severe sickle cell disease to help reduce the frequency of pain episodes and acute chest syndrome. It is approved

Hydroxyurea

HbF, also called fetal hemoglobin, is the form of hemoglobin present in the fetus and small infants. Most HbF disappears early in childhood, although some HbF may persist. Fetal hemoglobin is able to block the sickling action of red blood cells. Because of this, infants with sickle cell disease do not develop symptoms of the illness until. HbF levels have dropped. Adults who have sickle cell disease but still retain high levels of hemoglobin F generally have mild disease.

Hydroxyurea (Droxia) is a drug that reduces the severity of sickle cell disease by stimulating production of HbF. It is currently the only drug in general use to prevent acute sickle cell crises.

Hydroxyurea is recommended as frontline therapy to treat adults and adolescents with moderate-to-severe recurrent pain (occurring three or more times a year). Hydroxyurea reduces the frequency of acute pain crises and episodes of acute chest syndrome. It is taken daily by mouth. Hydroxyurea can be taken indefinitely and the benefits appear to be long-lasting.

Hydroxyurea is not a cure-all. Not all patients respond to hydroxyurea, and the best candidates for the treatment are not yet clear. Many patients who can benefit from it are not receiving it. Hydroxyurea is still being investigated for younger patients. To date, the response to the drug in children with sickle cell disease is similar to the response in adults, and few severe adverse effects are being reported. Recent research also suggests that hydroxyurea is safe for infants.

Side effects include constipation, nausea, drowsiness, hair loss, and inflammation of the mouth. More severe side effects include reduction of white blood cells (neutropenia) and clot-forming platelets (thrombocytopenia). Hydroxyurea should not be taken by pregnant patients as it can cause birth defects. There have been concerns that long-term use of hydroxyurea may increase the risk of developing leukemia, but the significance of this risk remains unclear. Still, for some patients the risks of untreated sickle cell disease may outweigh the risks of hydroxyurea’s side effects.

Patients should handle hydroxyurea with care and wash their hands before and after touching the bottle or capsules. Household members who are not taking hydroxyurea (such as caregivers) should wear disposable gloves when handling the medicine or its bottle.

Transfusion

Blood transfusions are often critical for treating sickle cell disease. Transfusions may be used either as treatment for specific episodes or as chronic transfusion therapy to prevent life-threatening complications Ongoing transfusions can also help improve height and weight in children with sickle cell disease. Normal hemoglobin levels for patients with sickle cell disease are around 8 g/dL. Doctors will try to keep the hemoglobin level no higher than 10 g/dL after transfusion.

Episodic Transfusions. Episodic transfusions are needed in the following situations:

• To manage sudden severe events, including acute chest syndrome, stroke, widespread infection (septicemia), and multi-organ failure.
• To manage severe anemia, usually caused by splenic sequestration (dangerously enlarged spleen) or aplasia (halting of red blood cell production, most often caused by parvovirus). Transfusions are generally not required for mild or moderate anemia.
• Before major surgeries. Transfusions are generally not required for minor surgeries.

Chronic Transfusions. Chronic (on-going) transfusions are used for:

• Stroke prevention for first or recurrent strokes. Evidence shows that regular (every 3 - 4 weeks) blood transfusions can reduce the risk of a first stroke by 90% in high-risk children. In addition, studies indicate that as many as 90% of patients who have experienced a stroke do not experience another stroke after 5 years of transfusions. The U.S. National Institutes of Health strongly recommends that doctors do not stop regular transfusions for children with sickle cell disease who are at high risk for stroke.
• Pulmonary hypertension and chronic lung disease
• Heart failure
• Chronic kidney failure and severe anemia
• To reduce episodes of pain and acute chest syndrome

Chronic blood transfusions carry their own risks, including iron overload, alloimmunization (an immune response reaction), and exposure to bloodborne pathogens. Still, data from large-scale trials suggest that the risks for stroke outweigh the risks associated with transfusions. Researchers are working on ways to reduce the side effects associated with transfusion treatment.

Kinds of Transfusions. Transfusions may be either simple or exchange.

• Simple Transfusion. Simple transfusions involve the infusion of one or two units of donor blood to restore blood volume levels and oxygen flow. It is used for moderately severe anemia, severe fatigue, and nonemergency situations when there is a need for increased oxygen. It is also used for acute chest syndrome.
• Exchange Transfusion. Exchange transfusion involves drawing out the patient's blood while exchanging it for donor red blood cells. It can be done as manual procedure or as automatic one called erythrocytapheresis. Exchange transfusions may be used when there is any evidence that the patient's condition is deteriorating. It prevents stroke and also may be used in patients with severe acute chest syndrome. It reduces the risk of iron overload in patients who require chronic transfusion therapy. Studies suggest that it may improve oxygenation and reduce hemoglobin S levels.

Iron Overload and Chelation Therapy. Iron overload increases risk for damage to the liver, heart, and other organs. A liver biopsy accurately determines whether excess iron levels are present.

Chelation therapy is used to remove excess iron stores in the body. The drug deferoxamine (Desferal) is commonly used during such therapy. Unfortunately, deferoxamine has some severe side effects and must be used with a pump for about 12 hours each day. Many patients do not continue treatment. In 2005, the drug deferasirox (Exjade) was approved for the treatment of transfusion-related iron overload in patients ages 2 and older. It is taken once a day by mouth. Patients mix the pills in liquid and drink the mixture. This new treatment may make chelation therapy much easier and less painful for patients.

Other Complications of Transfusion Therapy.

• Immune reactions. An immune reaction may occur in response to donor blood. In such cases, the patient develops antibodies that target and destroy the transfused cells. This reaction, which can occur 5 - 20 days after transfusion, can result in severe anemia and may be life-threatening in some cases. It can be generally prevented with careful screening and matching of donor blood groups before the transfusion.
• Hyperviscosity. With this condition, a mixture of hemoglobin S and normal hemoglobin causes the blood to become sticky. The patient is at risk for high blood pressure, altered mental status, and seizures. Careful monitoring can prevent this condition.
• Transmission of viral illness. Before widespread blood screening, transfusions were highly associated with a risk for hepatitis and HIV. This complication has decreased considerably.

Bone Marrow or Stem Cell Transplantation

At this time, the only chance for cure for sickle cell disease is bone marrow or stem cell transplantation. The bone marrow nurtures stem cells, which are early cells that mature into red and white blood cells and platelets. By destroying the sickle cell patient's diseased bone marrow and stem cells and transplanting healthy bone marrow from a genetically-matched donor, normal hemoglobin may be produced. Clinical studies using a few carefully selected patients have reported very successful results.

Up to 80 - 85% of patients who meet criteria for receiving a transplant receive remain disease free. Unfortunately, only about 7% of patients with sickle cell meet the criteria for transplantation, including those who:

• Are age 16 or younger (generally considered the better candidates, but patients in their 20s have had successful transplants)
• Have severe symptoms but no long-term organ or neurologic damage
• Have a genetically matched brother or sister who will donate their marrow

Complications. Bone marrow transplant carries its own dangers and limitations, especially for patients who do not receive a bone marrow transplant from a well-matched brother or sister donor. About 10% of those who have bone marrow transplants die from the treatment. Some complications include:

• In patients who do not receive a bone marrow donation from a matched sibling, the transplanted cells from a donor (called allogeneic grafts) may attack the patient's own tissues, a potentially fatal condition called graft-versus-host disease (GVHD). Drugs that destroy bone marrow and suppress immunity must be administered before the procedure so that the body's immune system does not attack the transplanted tissue. Still, this does not always prevent the problem.
• Other very serious complications include bleeding, pneumonia, and severe infection.
• Those who live but are not cured face long-term problems caused by the drugs used in transplantation and by the disease itself.
• Even in those who are cured, long-term consequences may include a higher risk for cancer and infertility.

The use of umbilical cord blood and cells from placentas is showing promise for providing healthy stem cells to patients who do not have genetically matched donors for bone marrow transplant. Cord blood has certain advantages over stem cell transplantation, including the capacity to produce more cells quickly. Because immune factors in cord blood are immature, the risk and severity of graft-versus-host disease may be reduced.

Early clinical trials are also reporting some success with a process called partial chimerism, in which a mixture of the patient's and a donor's bone marrow is used. The procedure has far fewer side effects because all the bone marrow is not destroyed. Although some sickle blood cells remain, small studies indicate that the patients are still free of the typical infections and pain of the disease.

Investigational Treatments

Nitric Oxide. Nitric Oxide. Nitric oxide, a soluble gas, is a natural chemical in the body that relaxes smooth muscles and expands blood vessels. Patients with sickle cell disease are deficient in nitric oxide. This lack of nitric oxide constricts blood vessels and causes pain in sickle cell diseases. In adult patients, men may be more susceptible to this effect than women. Some studies indicate that inhaling nitric oxide may slow the disease process and improve symptoms in acute sickle cell crises. It is difficult to administer, however. More studies are needed. (Nitric oxide is not the same substance as nitrous oxide, the so-called laughing gas used in dentistry.)

Arginine. Arginine is involved in producing nitric oxide. Because a lack of arginine may contribute to the development of pulmonary hypertension, (a leading cause of death in patients with sickle cell disease), arginine is being studied as a potential drug treatment. Some research is also being conducted on arginine nutritional supplements. Patients should talk to their doctors before taking these or any other supplements.

Drugs To Prevent Dehydration. Researchers are studying various drugs, as well as mineral supplements such as magnesium pidolate and zinc sulfate, that may help prevent potassium loss and red blood cell dehydration.

Protein

A representation of the 3D structure of the protein myoglobin showing turquoise α-helices. This protein was the first to have its structure solved by X-ray crystallography. Towards the right-center among the coils, a prosthetic group called a heme group (shown in gray) with a bound oxygen molecule (red).

Proteins (/ˈproʊˌtiːnz/ or /ˈproʊti.ᵻnz/) are large biomolecules, or macromolecules, consisting of one or more long chains of amino acid residues. Proteins perform a vast array of functions within organisms, including catalysing metabolic reactions, DNA replication, responding to stimuli, and transporting molecules from one location to another. Proteins differ from one another primarily in their sequence of amino acids, which is dictated by the nucleotide sequence of their genes, and which usually results in protein folding into a specific three-dimensional structure that determines its activity.

A linear chain of amino acid residues is called a polypeptide. A protein contains at least one long polypeptide. Short polypeptides, containing less than 20–30 residues, are rarely considered to be proteins and are commonly called peptides, or sometimes oligopeptides. The individual amino acid residues are bonded together by peptide bonds and adjacent amino acid residues. The sequence of amino acid residues in a protein is defined by the sequence of a gene, which is encoded in the genetic code. In general, the genetic code specifies 20 standard amino acids; however, in certain organisms the genetic code can include selenocysteine and—in certain archaea—pyrrolysine. Shortly after or even during synthesis, the residues in a protein are often chemically modified by post-translational modification, which alters the physical and chemical properties, folding, stability, activity, and ultimately, the function of the proteins. Sometimes proteins have non-peptide groups attached, which can be called prosthetic groups or cofactors. Proteins can also work together to achieve a particular function, and they often associate to form stable protein complexes.

Sources of Protein

Proteins are used to rebuild and repair any tissue damage that happens to our bodies the kind that happens when we exercise. This guide will help you choose the healthy proteins.

1. Chicken. Chicken is low in fat and high in protein. You can grill or bake it while still keeping the fat content low. Frying will add a considerable amount of calories.

2. Beef. Beef is also a good source of protein. The problem with beef is that it is associated with a high fat content. If you stick to lean cuts of beef, you can minimize your intake of saturated fats.

3. Fish. Seafood is both high in protein and in unsaturated fats which are healthy for your heart. It will add some good variety to your diet.

4. Non-Meat Sources. Non-meat animal products are also high in protein. Products such as milk, cheese and eggs are all good examples. When eating these, try and use low fat versions since they can contain high amounts of saturated fats.

5. Soy. Soy protein has been found to reduce your risk of heart disease. It can be found in a variety of soy products such as nuts, milk and meat substitutes.

Proteins

Importance

Proteins are naturally occurring polypeptides. They:

• contribute to the mechanical structure of animals, including humans, e.g. keratin in hair and fingernails, and fibrous proteins such as collagen in tendons
• enable animals to move, e.g. myosin in muscle
• facilitate transport of smaller molecules around animals' bodies, e.g. haemoglobin
• control the types and rates of chemical reactions in living things; then they are called enzymes, e.g. amylase
• are important components of the human immune system, e.g. immunoglobins

Proteins make up about 15% of our body mass. They are the most abundant 'solid' substances in our bodies.

Each protein has its own precise function under the direction of its own gene. The shapes of proteins are of key importance. These are determined by the sequence of amino acids that make them up.

HYPERPROTEINEMIA:

Hyperproteinemia is defined as a much higher-than-normal amount of protein in the bloodstream, according to the Mayo Clinic. Usually, the blood is not a major protein carrier but certain conditions, like dehydration, inflammation, or infection, can cause an increase in the amount of detectable protein.

Under normal conditions, the human body metabolizes the protein in food, turning it into tissue or into glucose for energy. Human Kinetics notes that excess protein is usually stored as fat or excreted from the body in a number of different ways. A number of circumstantial and medical conditions, however, change how the body processes its protein intake.

In short, hyperproteinemia is a symptom, rather than an ailment in itself. Simple causes of hyperproteinemia include dehydration, in which a reduced amount of water in the body causes the blood content to become more concentrated than usual. More serious underlying conditions include: bone marrow problems, immune system disorders like HIV/AIDS, monoclona gammopathy, multiple myeloma, and amyloidosis.

Symptoms of hyperproteinemia can include: nausea, poor appetite, serious fatigue, digestive issues, inexplicable weight loss, continual fever, dizziness upon standing or sitting, and tingling in the fingers and toes.

A recent NIH-supported study found links between specific protein types and brain abnormalities found in Alzheimer's patients. In the future, the study results may be used to help doctors detect Alzheimer's disease, before major symptom onset, allowing them to create more effective patient treatment plans.

References

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