HIV and Hemophilia

Since we talked about HIV/AIDS a couple weeks ago in class, I wanted to remind everyone about HIV infection of hemophilia patients in the 80's. Patients with hemophilia often require frequent transfusions of clotting factors to control bleeding. This plasma-derived factor is made from pooled factor from many blood donors, which greatly increased the risk of HIV contamination in the 80s, when HIV screening of blood donors was not in place (and for some time they didn't even know about HIV). HIV transmission has not occurred from factor products since 1986, when they started viral inactivating blood products.

Unfortunately, about half of the hemophilia patients in the late 1970s and early 1980s in the United States were infected with HIV via blood products, and many have developed AIDS. Currently, 10-15% of the hemophilia population is HIV positive.

I think there is an important lesson from this story-even though we believe the blood supply is safe, it is only safe with respect to the infections we know about and can/do test for.

Rheumatoid Arthritis

Rheumatoid arthritis is an autoimmune disease that causes inflammation in the joints and it’s a type III response. There are many pain medications available for arthritis, because it is very painful and gets in the way of everyday life, since joints are used everyday in mobility. The way to determine if a patient has rheumatoid arthritis is by doing a blood test or x-rays, in which they search for rheumatoid factor. The treatments involve anti-inflammatory drugs. Based on the review articles it seems as though there are many factors that are involved, so there is a lot of research going into the causes of inflammation in the synovial area. There are also reactive oxygen species that play a part in the cause for inflammation, including O2¬¬-. Also, over expression of TNF-α reduces the activity of SOD, which is important in converting O2- into H2O2. Thus, as a treatment SOD mimetics are used to decrease peroxynitrite activity, influx of neutrophils at inflammatory site, and the release of proinflammatory cytokines. Researchers are also studies looking into supplements that can alleviate pain. However, it’s important to study the relationship between treatments and supplements, because they can affect each other.

When the immune system causes harm

As I have mentioned in my previous posts I am interested in Hepatitis C. There are currently over 170 million people infected with this virus worldwide. The long-term complication of Hepatitis C are cirrhosis and hepatocellular carcinoma. These complications often lead to liver transplant in the Hepatitis C patient.

As we learn more about HepatitisC and the immune response that is raised in attempts to clear the infection it becomes more clear that the inflammation intended to wipe out the virus is harming the liver and leading to cirrhosis and likely hepatocellular carcinoma.

Following viral infection there is activation of several pre-inflammatory mediators (chemokines -cytokines) that recruit immune cells into the liver. Once in the liver the immune cells are induced to generate an anti-viral immune response (T helper 1 cells secrete IFN-gamma and IL-2). If in the short-term the infection is not cleared the liver is set-up for a chronic inflammatory response (inflammation, regeneration and fibrosis). There is increasing evidence that different chemokines and receptors play roles at different stages in the infection.

Identification of serum markers for this inflammatory chemokine activity could help stage the chronic Hepatitis C viral process. Staging would assist with treatment options. Additionally, identification of an antagonist for this interaction would provide a treatment for liver inflammation, but would allow the virus to persist. Decreasing inflammation would potentially decrease cirrhosis and carcinoma. The concern is the cost of chronic Hepatitis C infection without the inflammation to hold it at bay.

There continue to be many unanswered questions for Hepatitis C, however the pieces of the puzzle continue to grow and fit into an explanation.

Reference -

Zeremski M, et al. The role of chemokines as inflammatory mediators in chronic hepatitis C virus infection. J Viral Hepat. 2007; 14(10): 675-87

Wald, O., et al. Chemokines in hepatitis C virus infection: pathogenesis, prognosis and therapeutics. Cytokine. 2007; 39(1): 50-62

DMARDS

Hi everyone! As you may have seen after reading the articles this week on arthritis there is no cure. But there are treatments that help with the symptoms. There was one that was mentioned but not really discussed and that was DMARD. The acronym was thrown out there, but not really explained. So DMARD stands for Disease-modifying antirheumatic drug. This is a family of drugs that are used to slow the progression of rheumatoid arthritis. Although RA was the disease it was propagated for, many other diseases have had a response to them. Interestingly enough, Crohn's Disease is included in this list along with lupus. Ulcerative Colitis was not included though.

DMARDS include a vast array of drugs used for different purposes. There are thirteen drugs, which are used by different mechanisms. There were three that really caught my eye and they were adalimumab, etanercept, and infliximab. The three of these drugs treat RA by TNF inhibitor. Tumor Necrosis Factor (TNF) is thought to be a major contributor to RA for TNF alpha causes both cell damage and inhibits superoxide dismutases in the cell (SOD1). TNF inhibitors eliminate abnormal B cell activity which cause the apoptosis trigger by TNF alpha.
For more information on DMARDs:

http://www.webmd.com/rheumatoid-arthritis/guide/dmard-rheumatoid-arthritis-treatment

SOD memetics showing promise as future treatment for inflammatory joint disease

In a disease such as RA where proinflamitory cytokines like TNF-a are being over produced and reactive oxygen species are overwhelming the bodies natural enzymatic defenses.  The use of superoxide dismutase mimetic to supplement the bodies natural defense is showing promises as a possible addition to future therapeutic strategies for fighting inflammatory joint disease.  Along with the article entitled “reactive oxygen species and superoxide dismutase: Role in joint diseases” I also learned of a study by a Italian pharmaceutical company which reported 56% reduction in inflammation and 70% decrease in joint erosion in arthritic rats.   Both studies used the same SOD mimetic M40403.  These reports appear very promising but there still needs to be more testing before human trials can start. 

Optimal Timing for Surgery

Within the article titled, "Optimal Timing of Surgery for Inflammatory Bowel Disease," it discusses how necessary surgery is when compared to having ulcerative colitis and Crohn's disease. Only 20% of people diagnosed with ulcerative colitis are required to have surgery at one point of their illness, while 80% of the patients with Crohn's disease are obliged to have surgery. For patients with ulcerative colitis, after surgery they are permanently cured. The surgery many surgeons suggest their patients get is total proctocolectomy because other surgeries such as partial proctocolectomy, ileoanal pouch anastomosis, and permanent stoma will not permanently cure them from UC. Thus, many surgeons it is better to perform surgery at an early stage of UC. As of today, there is no surgery that can sure Crohn's disease, but it can be to treat symptoms when the patient is not responding to medical treatment. Even then, about 20% of the patients have reoccurring symptoms after 2 years and 80% of them will show signs of symptoms again after 20 years. The surgeons have seen that if the surgery is for lessening the effects of fibrostenotic disease and not perforating or fistulizing disease there will be less frequency in how many times the symptoms reoccur. Overall, deciding when to have surgery must be a thoroughly thought-out decision for both the surgeon and the patient. Most of the time, by delaying the time of surgery can tremendously increase the suffering and pain the patient experiences and reduce the chances of having a good outcome. In contrast, while delaying other medications could continue to improve the situation and eventually eliminate the need for surgery. In addition, if during the delay time the symptoms such as infections could be reduced and as a result lessening the risk of morbidity.
In a study done in England, it showed that the rate of mortality for patients who received surgery compared to ones who had not elected for surgery in either ulcerative colitis or Crohn's disease patients lived longer. Three years after surgery only 3.7% of patients with UC died after having surgery while the mortality for patients without surgery was 13.6%. Same with Crohn's disease patients, it increased significantly from patients that had surgery to patients who had not, 3.3% and 10.1% respectively. On the other hand, patients who had a emergency colectomy versus patients who elected themselves for the surgery had higher mortality rates. The study was done in the Oxford region with 23,464 patients from 1968 until 1996.

Sources:

"Threshold for Elective Colectomy Called Too High." Medical News.


Hodin R.S. "Optimal Timing of Surgery for Inflammatory Bowel Disease." SpringerLink.