Stroke Week

Every week our class holds a rhetoric discussing, debating, and clarifying the role of inflammation in disease. During these discussions and accompanying readings on ischemic strokes I realized that it is largely accepted inflammation contributes to the tissue damage of stroke beyond the initial ischemic event; Inflammation causes more damage than necessary. However the mechanism of exactly how inflammation causes more damage than necessary is lacking.

Apparently hypoxia causes neurons to release excess glutamate which opens Ca2+ channels. The excess Ca2+ results in apoptosis of neighboring cells. This also results in free radical production which roams around causing more injury. Where does inflammation come in and cause extra damage? As far as I can tell inflammation is being activated properly in response to damaged tissue. For example damaged cells activate damage associated molecular pattern toll like receptors and the ensuing inflammation. It appears to me that inflammation is activated in response to damage. There does not seem to be any evidence that inflammation causes gratuitous damage.

I have questions for the experts. To what extent is the extra damage beyond the ischemic damage? How does inflammation cause extra damage after stroke? What evidence shows that inflammation causes extra damage and how is it possible to distinguish between ischemic damage and inflammatory damage?

HIV Vaccine?

The gold standard in HIV research has always been to find a preventive treatment, like a vaccine, which would thwart the virus before it could do harm. Many attempts at vaccines and chemoprophylaxis showed mixed and uninspiring results. These poor results caused many to feel that a successful HIV vaccine was impossible. However, results from a recent study in which two HIV vaccines were combined to give a synergistic effect showed moderate success in preventing HIV transmission to uninfected individuals in Thailand.
The trial combined two vaccines which previously failed in clinical tests, AIDSVAX and ALVAC, and resulted in only 51 of the 8197 HIV negative volunteers being infected with the virus (as opposed to 74 of the 8198 administered placebo injections). ALVAC contains three synthetic HIV genes attached to a bird virus vector, and is used to “prime” the human immune system, while AIDSVAX consists of an engineered protein present on HIV’s surface, which is thought to “boost” the immune response. While the 30% efficacy rate is encouraging, it is far from being clinic ready, especially since researchers do not fully understand the pharmacology of the two vaccines in tandem.
ALVAC is intended to activate the immune system by eliciting a T cell response (probably killer T cells), while AIDSVAX is designed to produce an antibody response to the synthetic epitope it presents. The combination can therefore seemingly stimulate the immune system to get ready for a fight (ALVAC) and then show the system’s competitor (AIDSVAX). However, many more experiments need to be done to show that this is indeed the pharmacological mechanism.
Additionally, a major concern is that the trial was down entirely with Thai people, with vaccines targeted at the virus mutation most often seen in that country. Before the vaccine can be world ready, it must be tested in different ethnic populations, and it must be shown that different region-specific virus mutations can be incorporated and be effective in the vaccines. Finally, although a 30% benefit is encouraging, the vaccine combination must be closer to 80 or 90% effective before it can be considered clinic ready.


Unfortunately, the article presenting this data has yet to be published (to my knowledge). Information and statistics taken from two online news articles: http://blog.newsweek.com/blogs/thehumancondition/archive/2009/09/24/good-news-from-the-hiv-vaccine-trial-the-maybe-cure-that-almost-wasn-t.aspx and http://www.startribune.com/lifestyle/health/61062722.html?elr=KArks:DCiUMEaPc:UiacyKU7DYaGEP7vDEh7P:DiUs

Differences in Response to a Hepatitis B Vaccine Booster Dose Among Alaskan Children and Adolescents Vaccinated During Infancy - A Summary

This blog is a summary of the article “Differences in Response to a Hepatitis B Vaccine Booster Dose Among Alaskan Children and Adolescents Vaccinated During Infancy, ” by Samandari et. al. (2007).

 

Since the duration of protection against the Hepatitis B virus (HBV), achieved by the both the HBV plasma vaccine, and the HBV recombinant DNA vaccine is unknown, Samandari et. al. (2007), conducted a study evaluating the  presence of  HBV immune memory in children in adolescents in Alaska. Immune memory can be indirectly determined through measuring the immune response to a vaccine booster dose.

 

Samandare et. al. (2007) measured 74 adolescents (aged 11.7 years – 14.9 years old) who had received the 3-dose plasma vaccine, 138 adolescents (aged 10.0 years - 14.7 years) and 166 children (aged 5.0 years -7.0 years) who had received the 3-dose recombinant DNA vaccine. All participants had been born to HBV surface-antigen negative mothers, and had received the starter dose of the HBV vaccine in the first 7 days of life.

 

Serologic immunity to the HBV virus is defined as a measure of antibody to HBV surface antigen of ³10mIU/mL. Of the children and adolescents who participated in this study, none had acquired chronic active cases of HBV. Upon receiving the booster dose of the HBV vaccine, 99% of the children and 83% of the adolescents who received the recombinant DNA vaccine had an anamnestic response to the booster dose. Comparatively, only 69% of the adolescents who received the plasma vaccine had an anamnestic response to the booster dose.

 

These results show that:

1.     The recombinant DNA vaccine may have a longer lasting immunological effect in protecting against HBV.

2.     There appears to be a relationship between increasing age and decreasing HBV vaccine protection.

 

This study indicates that it is necessary for individuals vaccinated as neonates to get an HBV booster during late childhood or early adolescence in order to prolong immunologic protection against this virus. (Samandari 2007)

 

References Cited

 

Samandari, Taraz., Anthony E Fiore., Susan Negus., James L. Williams., Wendi Kuhnert., Brian J. McMahon., Beth P. Pell

            2007   Differences in Response to a Hepatitis B Vaccine Booster Dose Among Alaskan Children and Adloescents Vaccinated During Infancy. Pediatrics 120:e373-e381.

 

 

Personality change is one of the most frequently complaints of carers after their friend or relative has had a stroke. Emotional disorder, disability, and cognitive impairment are likely to be important components of personality change. However, it also appears to be particularly important to consider the role of the carer factors such as emotional distress as potentially magnifying perceptions of personality change.

Although there is a substantial body of literature on the physical and psycho sexual consequences of stroke, there is a paucity of empirical studies on the experiences of rehabilitation professionals in addressing sexuality issues with patients during the rehabilitation process.The criteria used in determining positive outcomes for stroke patients have tended to focus on ‘functional ability’ which has led to an increasing neglect of the emotional and social consequences of stroke. While the goals of minimizing the functional effects of stroke and maximizing patient autonomy in stroke rehabilitation are clearly important, an area often neglected by professionals is the effects of stroke on sexuality and the sexual health of stroke survivors.

Leukocytes and Stroke

One of the earliest inflammatory responses to stroke identified in patients is an increase in peripheral leukocyte counts. Leukocyte increases have been observed within 24h of an ischaemic event and some studies report a sustained elevation, versus controls, for at least one week. It appears that neutrophils are the earliest leukocytes to respond, and their levels correlate with infarct volume. Selective labelling of neutrophils indicates that they are recruited to the brain within 24h of symptom onset. Increases in the levels of circulating monocytes are also observed, but this tends to be delayed compared to the neutrophil response, typically being seen more than three days post-stroke. Dendritic cells, which are key antigen presenting cells and immunregulators in the body, have also been shown to infiltrate into the brains of patients after cerebral ischemia, whilst circulating levels decrease.

Reference: Inflammation and brain injury: Acute cerebral ischaemia, peripheral and central inflammation 10.1016/j.bbi.2009.09.010

Correlation between strokes and hydrocephalus!!

Is there a correlation between strokes and hydrocephalus? I mean in a person who gets a stroke, is there is a possibility that he/she might develop a hydrocephalus? I ask because my father actually had several strokes, but they were not covering a large area of his brain so he recovered and remains on anticoagulants medication. When they performed the MRI for his last stroke, however, they found out that his brain ventricles were dilated. His doctor decided to insert a ventriculopertoneal shunt (VP shunt) to drain out the extra CSF from his ventricles to his abdomen. His condition has yet to improve though, and I was just wondering if you found any sort of relation between these diseases.

Another APC?

In class today we talked about three kinds of APCs (Antigen Presenting Cells): Dendritic Cells, B Cells, and Macrophages. In the following article researchers in Berlin, Germany found that the ito cells of the liver, also known as the hepatic stellate cells, have the same attributes as APC cells.
Normally ito cells, which account for anywhere from 5%-8% of liver cells, are calm and store vitamin A in the liver. However when activated, say by a period of alcohol abuse or another chemical toxin or a bout of hepatitis, the ito cells release collagen. As a result the normal liver tissue is replaced by fibrous scarring and can result in liver fibrosis and cirrhosis.
According to the article ito cells have another function too. "Upon bacterial infection, Ito cells elicited antigen-specific T cells and mediated protection." The researchers purified and isolated the ito cells. They then added a specific killer T cell antigen to them. The ito cells then presented the antigen to and activated the killer T cells. They behaved just as any other Antigen presenting cell would.

http://www.ncbi.nlm.nih.gov/pubmed/17239632?dopt=Abstract&holding=npg

Inflammation and Stroke

88% of all strokes are ischemic; an ischemic stroke results in a lack of, or reduced blood flow to the brain. When brain ischemia occurs, inflammatory responses are triggered in an attempt to heal the damaged tissue. However, these inflammatory responses are actually causing further tissue damage, leading to a greater amount of infarct, or dead tissue, in the brain. Reperfusion, the return of blood flow to the ischemic tissue, is the goal of most clinical therapies to treat ischemic brain injury. In spite of the benefit of returning blood to the ischemic brain, reperfusion also initiates inflammatory responses, such as the activation and recruitment of leukocytes, which may increase secondary injury to the brain. This secondary injury is called reperfusion injury.

Neutrophils are inflammatory responders to injury and disease. They are usually the first type of leukocyte to arrive at the injured site. After cerebral ischemia and reperfusion, neutrophils activate and adhere to the vascular endothelium where they contribute to cell death by producing cytotoxic substances and decreasing blood flow. Neutrophils increase injury by directly secreting deleterious substances or other inflammatory mediators. Several studies have shown that infarct volume is significantly reduced when neutrophil infiltration is inhibited.

It has been proven in experimental stroke that blocking various aspects of the inflammatory cascade reduces the amount of infarct. The problem is figuring out how to do this at the clinical level. This raises many questions on when and how to treat a patient who has had an ischemic stroke. At what point during brain ischemia and reperfusion is inflammation destructive? When is the inflammation beneficial and necessary for repair? What is the optimal time during an ischemic stroke to modulate the inflammatory responses? Clinically, the overall goal is to reduce the amount of dead tissue in the brain resulting from ischemia and the inflammatory responses so that the patient may retain as many neurological functions as possible. The greater the amount of infarct, the more neurological deficits that result. Understanding how and when these inflammatory responses play a role in stroke is essential for finding the best way to treat a stroke patient.

Gum Disease Linked to Stroke

When I read the title for this article from REDORBIT NEWS (http://www.redorbit.com/news/display/?id=1715005) I was interested in what they had to say. It took 3 minutes to read and with each line I was increasingly disenchanted with it. The article is about a study done based on data from 1,137 men who had full mouth X-rays and periodontal probing done at each tooth every three years. There were follow up exams for an average of 24 years. (I was impressed with the length of the study) The study concluded that periodontal bone loss was associated with the incidence of cerebrovascular disease. It is also stated that this association "was independent of cardiovascular risk factors and was much stronger among men younger than age 65."

They state the association was independent of cardiovascular risk factors but don't explain that any further. I would like to know what risk factors they looked at and compared.

They imply there is a strong association between periodontal disease and cerebrovascular disease, but I am not completely buying it. I find it hard to believe periodontal disease causes cerebrovascular disease. I wonder if an unhealthy lifestyle lead to both periodontal bone loss and cerebrovascular disease independently and it's just a coincidence they show up together.