Goodbye

Hello everyone,

Since the summer is coming to a close and the semester is almost over, I will no longer be posting any new material on my blog. I hope everyone has enjoyed all of the information I have presented and learned a lot about various topics we have covered in infectious disease as well as sickle cell disease. I have had a good time writing about these topics and hope that everyone has learned something new and found them as interesting as I have. Thank you all for taking the time to not only read, but also comment on my posts.  I hope everyone has a nice, relaxing break and I will see you again soon!
Thanks,

Eden

Hydroxyurea Treatment

Hydroxyurea was first synthesized in 1869 and is presently being used to treat a multitude of conditions, including sickle cell disease. Hydroxyurea reduces the severity of sickle cell disease by stimulation the production of fetal hemoglobin, or HbF.

HbF is the form of hemoglobin present in the fetus and small infants. Although some may persist, most HbF disappears early in childhood. Fetal hemoglobin is able to block the sickling action of red blood cells and 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 a mild form of the disease.

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

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, called neutropenia, and clot-forming platelets, or 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. 

Here's a case study using hydroxyurea in sickle cell disease 

Rabies Virus

The rabies virus is a bullet shaped, nonsegmented, negative stranded RNA genome that belongs to the order Mononegaviralesiruses and the Rhabdoviridae family. Rhabdoviruses are approximately 180 nm long and 75 nm wide. The rabies genome encodes five proteins: nucleoprotein, phosphoprotein, matrix protein, glycoprotein and polymerase. All rhabdoviruses have two major structural components: a helical ribonucleoprotein core and a surrounding envelope. In the ribonucleoprotein, genomic RNA is tightly encased by the nucleoprotein. Two other viral proteins, the phospoprotein and the L-protein are associated with the RNP. The glycoprotein forms approximately 400 trimeric spikes which are tightly arranged on the surface of the virus. The matrix protein is associated both with the envelope and the RNP and may be the central protein of rhabdovirus assembly. The arrangement of these proteins and the RNA genome determine the structure of the rabies virus.

When a human or animal is injected with infected saliva, the rabies virus replicates at the site of inoculation. Aided by the glycoprotein protein, the viral envelope attaches and fuses with the host cell membrane. The plasma membrane folds inside itself with clathrin-coated pits which allow cytoplasmic absorption via pinocytosis. The virions aggregate with the large endosomes, and after fusion with their membranes, they initiate the uncoating and release of the viral RNP into the cytoplasm. Since the rabies virus has a linear, single stranded RNA genome, messenger RNAs are produced to permit virus replication using the host cell machinery. Translation of the genome occurs on the free ribosomes in the cytoplasm, and some posttranslational processing occurs in the endoplasmic reticulum and golgi apparatus.

Once infected, the rabies virus travels to the brain by following the peripheral nerves. The incubation period of the disease is usually a few months in humans, depending on the distance the virus must travel to reach the central nervous system. Once the rabies virus reaches the central nervous system and symptoms begin to show, the infection is effectively untreatable and usually fatal within days.

Early-stage symptoms of rabies are malaise, headache and fever, progressing to acute pain, violent movements, uncontrolled excitement, depression, and hydrophobia. Finally, the patient may experience periods of mania and lethargy, eventually leading to coma. The primary cause of death is usually respiratory insufficiency. Overall, roughly 97% of human rabies cases result from dog bites. In the US, animal control and vaccination programs have effectively eliminated domestic dogs as reservoirs of rabies.

The real zombie virus? 

Sickle Cell Symptoms

Since sickle cell disease is a blood disorder, it has many signs and symptoms. These symptoms may present after 4 months of age. The most frequently seen symptom is anemia. Sickle cells are fragile and break apart easily and die, leaving you chronically short on red blood cells. Red blood cells usually live for about 120 days before they die and need to be replaced; but sickle cells die after only 10 to 20 days. The result is a chronic shortage of red blood cells, known as anemia. Without enough red blood cells in circulation, your body can't get the oxygen it needs to feel energized. That's why anemia causes fatigue.

Another symptom is periodic episodes of pain, called crises. Pain develops when sickle-shaped red blood cells block blood flow through tiny blood vessels to your chest, abdomen and joints. Pain can also occur in your bones. The pain may vary in intensity and can last for a few hours to a few weeks. Some people experience only a few episodes of pain while others experience a dozen or more crises a year. If a crisis is severe enough, patients may be hospitalized.

Hand-foot syndrome is another sign of sickle cell disease. Swollen hands and feet may be the first signs of sickle cell anemia in babies. The swelling is caused by sickle-shaped red blood cells blocking blood flow out of their hands and feet.

Sickle cell disease causes frequent infections. Sickle cells can damage your spleen, which fights infections, and may make you more vulnerable. Doctors commonly give infants and children with sickle cell anemia antibiotics to prevent potentially life-threatening infections, such as pneumonia.

Delayed growth is seen in sickle cell disease patients. Red blood cells provide your body with the oxygen and nutrients you need for growth and a shortage of healthy red blood cells can slow growth in infants and children and delay puberty in teenagers.

A final symptom of sickle cell disease is vision problems. Tiny blood vessels that supply your eyes may become plugged with sickle cells. This can damage the retina, which is the portion of the eye that processes visual images.

Play this word search!

Tuberculosis Treatment

Mycobacterium tuberculosis is a very slow-growing organism that requires the use of multiple drugs for several months for treatment. With the appropriate antibiotics tuberculosis can be cured in most individuals. Treatment usually combines several different antibiotic drugs that are given for at least 6 months and sometimes for as long as 12 months. However, many M. tuberculosis strains are resistant to one or more of the standard TB drugs, which complicates treatment greatly.

Currently, there are 10 drugs approved by the U.S. Food and Drug Administration for the treatment of TB. Of the approved drugs, isoniazid, rifampin, ethambutol, and pyrazinamide are considered first-line antituberculosis agents. These four drugs form the foundation of initial courses of therapy.

Drug-resistant TB is major problem for the treatment of the disease. Multidrug-resistant TB, is defined as disease caused by TB bacilli resistant to at least isoniazid and rifampicin, the two most powerful anti-TB drugs. Mulitdrug-resistant tuberculosis is resistant to drugs but its resistance can be intensified by inconsistent or partial treatment. When patients do not take all their medication regularly for the required time period, drug-resistant bacteria can arise. While drug-resistant TB is generally treatable, it requires extensive chemotherapy with second-line anti-TB drugs. These second line drugs produce more severe adverse drug reactions more frequently than the preferred first line drugs. There are six classes of second-line drugs used for the treatment of TB including aminoglycosides, fluoroquinolones, polypeptides, thioamides, cycloserine, and p-aminosalicylic acid. 

Within the last few years a new form of TB has emerged, extensively drug-resistant TB. Whereas regular TB and even multidrug-resistant TB progress relatively slowly, extensively drug-resistant TB progresses much more rapidly and can be fatal within months or even a few weeks. Extensively drug-resistant TB is defined as TB that has developed resistance to at least rifampin and isoniazid, as well as to any member of the fluoroquinolone family and at least one of the aminoglycosides or polypeptides. The emergence of extensively drug-resistant TB, particularly in settings where many TB patients are also infected with HIV, poses a serious threat to TB control.

Currently, short course Direct Observation Therapy (DOTS) is a key component of the World Health Organization's campaign to stop TB. DOTS involves patient case management by trained health professionals who ensure that the patient is taking their TB drugs. Because TB has such a long course of treatment, many patients stop their medications prematurely. DOTS sends health professionals to the patient to ensure they are taking the medication and may also supply the medicine to the patient. In some areas, patients come to the DOT clinic instead of the health worker traveling to them. Often, DOTS provides enablers or incentives to ensure patients continue their treatment, such as transportation or free meals. 

History and Discovery

Although sickle cell disease has been present in Africa for over five thousand year, the first documented case of sickle cell disease in the United States occurred in 1910. Walter Clement Noel, a dental student from the island of Grenada studying in Chicago, went to Dr. James B. Herrick with symptoms of anemia and episodes of pain. Herrick, a cardiologist, did not show much interest in the case and assigned a resident, Dr. Ernest Irons, to look farther into Noel’s condition. When microscopically examining Noel’s blood, Irons discovered red cells he described as "having the shape of a sickle". This regained the attention of Herrick who became interested in the discover of a potential new, unknown disease. He consequently published a paper in a medical journal and used the term "sickle shaped cells".

　

As more cases began to surface it was clear that, for whatever reason, it occurred only or primarily in persons of African origin. In 1927, Hahn and Gillespie discovered that red blood cells from people with the disease could be made to sickle by removing oxygen. The trouble was that there were people whose red cells had this trait of sickling when deprived of oxygen but who did not have the disease. This condition became known as "sickle trait".

　

In 1949, two articles appeared independently showing conclusively that sickle cell disease was inherited and that people with sickle trait were heterozygous for the gene whereas people with the disease were homozygous. One was published by a military doctor in what was then known as Portuguese East Africa, now Mozambique, named Col. E. A. Beet. His article was in an African medical journal. The other was by Dr. James V. Neel, Chairman and founder of the Department of Human Genetics at the University of Michigan. Neel published his article in the prestigious American Journal of Science. As a result of the much wider readership of that journal, Neel usually gets the credit for the discovery although most authors are careful to cite both and many people think that Neel and Beet worked together.

　

Two years later, in 1951, the famous Nobel Prize-winning chemist, Dr. Linus Pauling and his colleague Dr. Harvey Itano, discovered that the red, oxygen-carrying protein, hemoglobin, had a different chemical structure in people with sickle cell disease. The details of the abnormality were worked out by Dr. Vernon Ingram in 1956. In the 1970’s, more details of how this abnormal structure affects the red blood cells were revealed and better tests for the detection of the disease were developed. In the years following, better ways of treating sickle cell patients and potential treatments appeared. The life span and the quality of life of patients were improved. Genetic counseling became an important tool for informing people about the risks of having a child with sickle cell disease. The goal of a total cure has not been reached but great progress has been made.

Antibiotic Replacement?

Since bacteria are ever changing and evolving, many have become resistant to the antibiotics that were originally developed to treat the infections that they cause. With more and more bacteria developing resistance faster than new antibiotics can be developed, previously treatable infections may become more serious. Bacteriophages and phage therapy may provide a solution to antibiotic resistant antibiotics.

Bacteriophages are viruses that invade bacterial cells and disrupt bacterial metabolism and cause the bacterium to lyse. Phage Therapy uses lytic bacteriophages to treat pathogenic bacterial infections. Bacteriophages do not generally cover as wide a range of bacteria as antibiotics. Most phages are specific for one species of bacteria and many are only able to lyse specific strains within a species. Because phages can be so specific, phage therapy results in less harm to the normal body flora than commonly used antibiotics, which often disrupt the normal gastrointestinal flora and result in opportunistic secondary infections by organisms such as Clostridium difficile. 

Bacteria also develop resistance to phages, but it is much easier to develop new phages than new antibiotics. A new phage may be obtained for a new strain of resistant bacteria in a few weeks compared to a few years for the development of a new antibiotic. As bacteria evolve and become resistant, the corresponding phages naturally evolve alongside. Phages have special advantage for localized use because they penetrate deeper as long as the infection is present, rather than decrease rapidly in concentration below the surface like antibiotics. The phages stop reproducing once the specific bacteria they target is destroyed and do not develop secondary resistance. With the increasing incidence of antibiotic resistant bacteria and a deficit in the development of new classes of antibiotics to counteract them, there is a need to apply phages in a range of infections.

Here is a case study describing an effective phage treatment