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BMS3052 > WEEK 10 COMORBIDITIES > Flashcards

WEEK 10 COMORBIDITIES Flashcards

1
Q

What are the nine National Health priority areas (NHPAs)?

A
  • Cancer control (added 1996)
  • Cardiovascular health
  • Injury prevention and control.
  • Mental health
  • Diabetes mellitus
  • Asthma
  • Arthritis and musculoskeletal conditions.
  • Obesity (added 2008)
  • Dementia (added 2012)
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2
Q

At least how long dochronic health conditions have to last?

A
  • At least 1 year
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3
Q

What is chronic disease defined as?

A
  • Lasting a year or more.
  • Requiring ongoing medical treatment or limits daily activities or both.
  • Is the number one cause of death and disability in Australia.
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4
Q

What is the global burden of disease expected to cost by 2030?

A
  • $47 trillion
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5
Q

In 2018, what was the Global burden of disease estimate?

A
  • 71% of deaths (41 million people)

- With 85% of these deaths in low and middle income countries

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6
Q

In Aus, what % of people have one or more chronic conditions?

A
  • 47% (1 in 2 Australians)
  • 80% >65 yrs have one or more chronic conditions
  • 20% have two or more conditions (1 in 5 Aussies)
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7
Q

Are males or females in Aus more likely to have comorbidities?

A
  • Females
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8
Q

What cost do comorbidities contribute to Aus?

A

-More than 27 billion per year

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9
Q

What are the social impacts of multimorbidity?

A
  • Employment slightly down by 15% compared to normal people
  • Disability up by 42.1%
  • Psychological distress increased by 30.7%
  • Pain increased by 33%
  • Increased fair on poor health by 26.7%
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10
Q

Adults with asthma are ___times more likely to be ___ .

A

Adults with asthma are 1.4 times more likely to be obese .

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11
Q

What % of people with asthma have heart, stroke and vascular diseases?

A

-15% versus 11% in non asthmatics

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12
Q

What % of people with COPD have one or more comorbidities?

A
  • 90%
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13
Q

What are examples of underlying socio economic, cultural, political and environmental determinants that are causes of chronic diseases?

A
  • Globalization
  • Urbanization
  • Population ageing
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14
Q

What are common modifiable risk factors that contribute to causing chronic disease?

A
  • Unhealthy diet
  • Physical inactivity
  • Tobacco use
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15
Q

What are non modifiable risk factors that contribute to the cause of chronic disease?

A
  • Age

- Heredity

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16
Q

What are the intermediate risk factors that contribute to the cause of chronic disease?

A
  • Raised blood pressure
  • Raised blood glucose
  • Abnormal blood lipids
  • Overweight/obesity
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17
Q

What are the main 5 chronic diseases that have underlying socioeconomic, cultural, political, and environmental determinants + common modifiable risk factors + non modifiable risk factors + intermediate risk factors contributing to main chronic diseases?

A
  • Heart disease
  • Stroke
  • Cancer
  • Chronic respiratory diseases
  • Diabetes
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18
Q

What is the aim of the national strategic framework for chronic conditions and what have they moved away from ?

A
  • They have moved away from a disease specific approach.
  • It recognises that there are similar underlying risk factors for several chronic conditions.
  • Similar management and prevention principles apply to multiple chronic conditions
  • Emphasises coordinated care
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19
Q

What is the vision for the National strategic framework for chronic conditions?

A
  • The vision is it all Australians live healthier lives through effective prevention and management of chronic conditions.
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20
Q

In what three main ways is the vision for the National strategic framework for chronic conditions going to be achieved?

A
  1. Focus on prevention for a healthier Australia.
  2. Provide efficient effective and appropriate care to support people with chronic conditions to optimise quality of life.
  3. Target priority populations.
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21
Q

Who are the partners, what are the principles and who are the enablers for the National strategic framework for chronic conditions?

A
  • The partners are basically everyone
  • The principles are equity and person centred approaches
  • The enablers are evidence based information and health literacy
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22
Q

What types of measurable indicators have been identified from the National strategic framework for chronic conditions?

A
  • Heart disease risk

- Salt intake per capita

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23
Q

In terms of the 9 voluntary global NCD targets for 2025, is an aim for Diabetes/obesity to have a 0% increase, an improvement?

A
  • Yes it is still an improvement because the cases will have 0% increase, meaning they will not be increasing
  • However 5 years may not be a long enough timeframe to achieve this.
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24
Q

In terms of the 9 voluntary global NCD targets for 2025, is an aim for physical inactivity to have a 10% reduction valid?

A
  • Yes as it may seem like a small change BUT it all adds up and can result in a large population health improvement
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25
Q

What are the 9 voluntary global NCD targets for 2025?

A
  1. To have a 25% reduction in premature mortality from NCDs (non communicable diseases)
  2. To have a 10% reduction in harmful use of alcohol.
  3. To have a 10% reduction in physical inactivity.
  4. To have a 30% reduction in salt/sodium intake.
  5. To have a 30% reduction in tobacco use.
  6. To have a 25% reduction in raise blood pressure.
  7. To have a 0% increase in diabetes/obesity.
  8. To have a 50% coverage in drug therapy in counselling.
  9. To have an 80% coverage in essential NCD medicines and Technologies.
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26
Q

How do we make the 9 voluntary global NCD targets for 2025 happen?

A
  • Must have cooridnated interventions to allow for change. Also population wide to allow for prevention. E.g. If we improve exercise and diet, then we will have an improvement in LDL cholesterol levels.
  • Comprehensive interventions
  • Integration of interventions
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27
Q

What are examples of areas to target in making the 9 voluntary global NCD targets for 2025 happen?

A
  • Laws/regulations
  • Taxes/price increases
  • Built environment improvement.
  • Advocacy
  • Community, school and workplace interventions.
  • Screening
  • Clinical prevention (trying to make sure something doesn’t get worse e.g. high BP)
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28
Q

What is an example of a comprehensive community based intervention?

A
  • Lifestyle modification program to try and reduce risk factors that was designed in Hawaii with community involvement
  • Reducing weight, BP, cholesterol. Nutrition education, support groups
  • Did NOT have an emphasis on weight loss
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29
Q

In terms of effective strategies for implementing health change in AUs, what is an example of an issue where two effective strategies were implemented?

A
  • Smoking (Tobacco control)

- Two effective strategies were: Increase in price through taxation and mass media campaigns

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30
Q

With Australia adhering to the WHO target of a 30% reduction in salt intake by 2025, how many lives will that save (also how much money roughly)?

A
  • Will save approx 3, 400 lives and save ‘millions’ of $
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31
Q

With Australia adhering to the WHO target of a 10% reduction in physical inactivity by 2025, how many lives will that save (also how much money roughly)?

A
  • 6 000 fewer cases of disease
  • 2 000 fewer deaths
  • Fewer DALYs, better productivity
  • $ 96 million reduction in healthcare costs
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32
Q

What is the number one risk factors for stroke?

A
  • Hypertension
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33
Q

What does uncontrolled hypertension increase the risk of?

A
  • Stroke
  • Heart attack
  • Kidney failure
  • Blindness
  • Other complications
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34
Q

What is a high systolic BP in Aus and US defined as respectively?

A
  • At least 140 in Aus and at least 130 in US
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35
Q

Is the aetiology for primary/ essential hypertension (90%) known?

A
  • NO
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36
Q

What are 5 risk factors for primary/essential hypertension?

A
  • Genetics
  • Smoking
  • Stress
  • Environment
  • Diet
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37
Q

What are two main Qs that are asked with relation to diet and Primary/essential hypertension?

A
  1. Does diet affect intestinal bacteria?

2. Does intestinal bacteria contribute to elevated blood pressure?

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38
Q

Diet affects ____ bacteria and ___ integrity.

A

Diet affects INTESTINAL bacteria and GIT integrity

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39
Q

What are 4 main areas that can impact on the intestinal gut bacteria/integrity in the human?

A
  1. Dietary intake (protein fat carbs, polyphenols)
  2. Altered gut bacteria (changes in Lactobacilli etc)
  3. Biologic effects (Alters host metabolism, immune system production of pro and anti inflammatory metabolites)
  4. Host disease (CVD, DM2, Obesity, Metabolic syndrome, Autoimmune disease)
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40
Q

Can Polyphenols impact on the microbiota?

A
  • YES
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41
Q

What impact does having too many carbs or fats have?

A
  • They alter the gut bacteria e.g. Increase in bad bacteria. A decrease in Lactobacilli or bifidobacteria (healthy)
  • This can lead to complications (decrease in GI integrity)
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42
Q

What are two examples of healthy bacteria?

A
  • Lactobacilli and bifidobacteria
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43
Q

What effect does a change in bacteria have on the immune system?

A
  • The immune system will recognise this change and this can lead to CVS complications
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44
Q

What has a Gluten Free diet shown to have an increase in?

A
  • Enterobacteria
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45
Q

Has the Mediterranean diet shown to promote a good gut integrity in those that follow it?

A
  • YES
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46
Q

Gut microbiota promote _______ and ________.

A

Gut microbiota promote HYPERTENSION and VASCULAR DYSFUNCTION

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47
Q

In a study by Karbach et al 2016, what were mice that were conventionally raised (compared to germ free) shown to do overall, and also with specific BP and immune cells and what does this indicate?

A
  • The conventionally raised mice (CONV) were shown to promote AngII vascular dysfunction, increased in BP and decreased relaxation (more constriction)
  • There was an increase in CD45.2+ cells which are indicative of B and T cell transduction, thus possibly a heightened immune response.
  • Thus conclusion was that gut microbiota facilitate AngII induced vascular dysfunction, by supporting immune cell inflammation and infiltration
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48
Q

What is the central role that the microbitoa play in terms of Angiotensin II?

A
  • They play a central role in modulating the plasma and fecal metabolomes in response to AngII
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49
Q

In a 2019 study (Cheema & Pluznic), did any metabolites change in germ free mice with AngII treatment, and did any change in the conventional mice?

A
  • NONE of the metabolomics changed in germ free mice
  • There was a SIGNIFICANT change in the metabolites of the conventional mice: A decrease in 71 good fecal metabolites, increase in 4 bad plasma metabolites and an increase in 25 BAD metabolites
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50
Q

What is an important determinant of microbiota?

A
  • Fecal matter
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51
Q

What type of metabolite has been shown to decrease hypertension and how does this occur?

A
  • SCFAs (short chain fatty acids)
  • Commensal bacteria produce these
  • They are absorbed through the intestinal lumen into the portal vein. This goes to the liver and distributed to the body where it leads to a decrease in BP
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52
Q

What are examples of SCFAs and which type of bacteria produces them?

A
  • Acetate, Propionate, Butyrate

- Commensal bacteria produce these via fermentation

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53
Q

Which special role does Butyrate have in the digestive tract?

A
  • It is a SCFA that feeds colonocytes and decreases local inflammation
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54
Q

Why is it important to have a high fibre diet in terms of bacteria?

A
  • Because the SCFAs produced by commensal bacteria could increase neuroprotection and improve the CVS
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55
Q

What effect does Acetate have on BP?

A
  • It decreases BP via the GPR41
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56
Q

Via which receptor does the SCFA Propionate decrease BP through?

A
  • GPR41
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57
Q

Via which receptor does the SCGA Propionate increase BP through?

A
  • Olfr78
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58
Q

What effect on BP does Butyrate have?

A
  • The effect on BP is unknown
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59
Q

In summary, what are the two main ways to prevent/reverse systemic hypertension?

A
  • Mediterranean/high fibre diet OR

- Short chain fatty acids (SCFAs) -via tablet, injection or adding to bread

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60
Q

What are the 5 first line treatment options for resistant hypertension?

A
  1. Control weight
  2. Physical activity/exercise
  3. Diet
  4. STOP smoking
  5. Decrease alcohol
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61
Q

What are the pharmacological treatment options for hypertension?

A

Angiotensin converting enzyme inhibitors & antgitensin antagonists
Beta blockers
Calcium channel blockers (NOT FOR HF)
Diuretics (thiazides, loop, K+ sparing)

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62
Q

What is resistant hypertension defined as?

A
  • Blood pressure not under 140/90
  • 3 blood pressure lowering drugs are used (including one diuretic) and if the BP is STILL NOT CONTROLLED there is a 3 fold risk of a cardiac event occurring
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63
Q

What % of people with resistant hypertension are obese?

A
  • 50%
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64
Q

What % of people with resistant hypertension jave sleep apnea?

A
  • Approx. 74%
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65
Q

What are some of the other factors addociated with resistant hypertension?

A
  • Female sex
  • Diabetes
  • Black race
  • Older age
  • High alcohol intake
  • High salt intake
  • Kidney disease
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66
Q

What are 4 patient related causes of resistant hypertension?

A
  1. A high salt diet.
  2. Medications that raise blood pressure.
  3. Lifestyle choices
  4. Not adhering to blood pressure medication plan.
67
Q

What are three physician related causes of resistant hypertension?

A
  1. Unsuspected secondary cause
  2. Inadequate use of diuretics.
  3. Progressive renal insufficiency.
68
Q

What are 7 types of medications that can interfere with blood pressure control?

A
  1. NSAIDS and asprin
  2. Sympathomimetic agents (decongestants)
  3. Diet pills (diuretic tablets)
  4. Excessive alcohol
  5. Licorice (mineralocorticoid effect- retention of sodium)
  6. Oral contraceptive pills
  7. Erythropoietin (EPO–> RBCs–> thicker blood–> increase in vascular resistance)
69
Q

What effect can having licorice have on the system?

A
  • It can have a mineralcorticoid effect, causing you to retain sodium.
70
Q

What effect can taking erythropoietin have (EPO)?

A
  • Leads to thicker blood–> increase in vascular resistance and thus increase in BP
71
Q

What are the 5 treatment options for Resistant Hypertension?

A
  1. Optimise the current treatment Plan.
  2. Treat identifiable cause if found
  3. Mineral corticoid receptor antagonists i.e. spironolactone.
  4. Minoxidil (K+ agonist –> Opens up K+ ATP channels)
72
Q

What is the mechanism of action for Minoxidil (i.e. K+ATP channel opening/ K+ channel agoinst)?

A
  • Overall, it leads to vasodilation of resistance arteries and lowering of blood pressure (in resistant hypertension)
  • Specifically, Minoxidil allows the K+ channel to open, which allows for hyperpolarisation and this leads to a lowering of calcium as the VOCC channel closes (Ca2+ can’t enter-due to hyperpolarisatoin)
  • This then leads to RELAXATION
73
Q

What are four examples of Future options for resistant hypertension in terms of pharmacological treatments?

A
  1. Novel aldosterone antagonists
  2. Aldosterone synthase inhibitors.
  3. Endothelin antagonists (potent vasoconstrictor, pulmonary hypertension)
  4. Direct renin inhibitors
74
Q

What are three examples of Future options for Resistant hypertension that are NON-pharmacological?

A
  • Renal denervation – especially for patients in which kidneys contribute to the cause (high radio frequency supplied to artery supplying the kidney- lead to decrease in resistant hypertension)
  • Neurovascular decompensation
  • Implantable pulse generators (like the carotid bodies in neck and act as a baroreceptor to sense changes within BP to help maintain homeostasis in CNS)
75
Q

Which part of the brain can high BP damage in the context of ALzheimers?

A
  • High BP can damage small arteries in the frontal lobe (memory and emotion)
76
Q

Have potassium (K+) sparing diuretics reduced the risk of Alzheimer’s disease?

A
  • Yes, by about 75%

- Other antihypertensive medication lowers the risk of Alzheimers disease by about 30%

77
Q

Would the reduced risk of potassium (K+) sparing diuretics come from managing blood pressure or if antihypertensiveness interferes with otehr processes relating to Alzheimer’s?

A
  • We are not sure but it is suspected that it is due to the managing of BP
78
Q

What are 4 ways you can control blood pressure via lifestyle changes to reduce risk of Alzheimer’s disease?

A
  • Eat a healthy diet
  • Maintain a healthy weight
  • Stop smoking and reduce alcohol
  • Check blood pressure at home!!
79
Q

Which way does O2 diffuse from?

A
  • Across the alveolar wall and it enters the bloodstream
80
Q

Which way does CO2 diffuse from?

A
  • FROM the blood across the alveolar wall to enter the alveoli
81
Q

What is a stroke defined as?

A
  • A “Brain attack”
  • Sudden disruption of the blood supply to a part of the brain
  • Loss of blood supply= decrease in oxygeni= cerebral ischaemia
82
Q

What is the infarct damage of a stroke caused by?

A
  • Immediate necrosis and/or delayed apoptosis (also cytotoxicity)
  • Lack of glucose to brain
83
Q

What are some examples of possible pathways linking lung and CVD diseases?

A
  • Inflammation driving up pressure (RV hypertrophy)
  • Bacteria leaking out from gut to lungs (microbiota_
  • HIV
  • Systemic or local inflammation
84
Q

What is the % of people that have a recurrent stroke out of the people that survive the first one?

A
  • Approx. 10%
85
Q 
What is the: 
i. Pharmacological 
ii. Surgical 
iii. Endogenous repair/regeneration
treatment for Stroke?
A

i. t-PA or Asprin
ii. Endovascular surgery (but must be clots in a large artery, availability of devices)
iii. Rehabilitation (re-wire the brain to re-gain mobility)

86
Q

What was the cause of death for both men and women following an initial stroke where they survived and why is this the cause of death?

A
  • A recurring stroke (cerebrovascular disease)
  • This is only 10% chance in those that survive the initial stroke but it is typically a MUCH larger stroke (more severe)
87
Q

What is the most common acute post stroke complication in a hospital setting?

A
  • increased intracranial pressure
88
Q

What do many people die from in hospital following a stroke they survived and why is this the case?

A
  • Pneumonia
  • Because following stroke, you get depressed immunity.
  • There is initially an inflammatory storm and the brain recognises this and therefore shuts down the immune system. Thus at greater risk of pneumonia and the death rate is about 10%
89
Q

What are 6 areas of the body that Stroke can cause pathophysiological complications in?

A
  • Brain
  • Lung
  • GI tract
  • Heart
  • Lymphoid tissue
    (also can cause skeletal muscle wastage and dysphagia)
90
Q

In a study by Prass et al 2003, what occurred in mice that were subjected to a stroke in terms of the lungs?

A
  • The ischaemic stroke (via MCA occlusion) caused a time dependent increase in the bacteria in lungs, peaking at 12 HOURS (important time point)
  • Also causes an increase in bacteria in blood
  • It also causes a thickening of alveolar walls and neutrophil infiltration
  • Evidence of E.coli pneumonia as well!
91
Q

What evidence suggests that bacteria that is present in the lungs after stroke is coming from the animal itself?

A
  • Stanley et al. 2016
  • Germ free (GF) mice were subjected to a stroke
  • After 24 hours, there were NO bacteria present in the lungs
  • This suggests that because there was no ‘external bacteria’ that may have entered, the bacteria was coming from the conventional mice themselves.
92
Q

What was done to try and work out where bacteria was coming from in humans?

A
  • Stroke patients were taken and had a sample of lungs and mapped out the bacteria.
  • The bacteria was very similar to those found in the GI tract
  • So this suggests that the bacteria is possibly coming from the gut (Enterococcus spp.)
93
Q

What is a proposed mechanism of increasing bacteria in the lungs?

A
  • After a stroke, there is an increase in the sympathetic output
  • Brain—> nerves of gut allow for NA release which alters microbiota composition and this then allows for bacterial molecules to be produced (FAs, GABA. 5-HT precursors)
  • The bacteria that is produced as a result of altered microbiota composition from NA can then leak into the lungs
94
Q

What is a potential target for trying to decrease the bacteria in the lungs following a stroke?

A
  • Targeting the INCREASED sympathetic output
  • Propanolol (beta adrenoceptor antagonist) 6-OHDA which destroys sympathetic nerve terminals
  • Harsh drug BUT reduces the number of bacteria
95
Q

What is a downside of using a MCA model to look at intestinal bacteria in the lungs following stroke?

A
  • There is 60% mortality
96
Q

What was another option that was looked into for decreasing the number of bacteria in the lungs following stroke?

A
  • Antibiotic treatment, specifically Moxifloxacin was used in the experiment
97
Q

What was the experimental protocol for looking at whether Moxifloxacin could reduce lung infections following stroke?

A
  • 7 week old MALE mice
  • MXFX was given every 2 hours.
  • In the diagram it has that it was given from 0-1 hrs, then again at 12 hrs to 22 hrs. Then the treatment was stopped
  • They then had functional tests every day and brain removal at day 4 or 7.
98
Q

Has antibacterial therapy (antibiotics) been shown to reduce functional deficits and infarct volume 4-7 days after MCAO IN ANIMALS?

A
  • YES
99
Q

Has antibacterial therapy (antibiotics) been shown to reduce mortality and lung infections after MCAO IN ANIMALS?

A
  • YES

- In the lung and blood there were 0 CFU/ml of bacteria

100
Q

Did 3 CTs show that pneumonia was improved with broad spectrum antibiotics in patients following stroke?

A
  • NO!

- It was NOT improved

101
Q

In the PASS trial, did the Ceftriaxone antibiotic provide a beneficial effect on stroke outcome in humans? -

A

NO

- BUT it did improve the UT infections and pneumonia

102
Q

What is the issue with antibiotics for improving post stroke lack of immune responses?

A
  • Using antibiotics is targeting the endpoint BUT need to be focused on the upstream mechanisms suc has stopping bacteria from getting out of the lungs.
  • The switch from pro inflammatory to anti inflammatory is day 4 to day 7. In patients it is generally day 7.
103
Q

How long does the switch from pro to anti inflammatory take in patients following stroke?

A
  • Switch from pro inflammatory to anti inflammatory response in brain is day 4 to day 7.
  • In patients it is generally by day 7.
104
Q

Does stroke cause lung infections in BOTH animals and humans?

A
  • YES
105
Q

True or False: Lung infections are caused by increased sympathetic output following stroke

A
  • TRUE
106
Q

Does antibiotic treatment decrease lung infections in BOTH animal and human models of stroke?

A
  • NO- only animal models. Doesn’t work in human models.
107
Q

How can gut dysbiosis lead to cardiac dysfunction following stroke?

A
  • Dysbiosis leads to an increase in the intestinal permeability
  • This then leads to bacterial translocation and Endotoxemia
  • This then leads to Atherosclerosis and thrombosis which in turn leads to cardiac dysfunction
108
Q

Is it true that there is a “leaky gut” post stroke?

A
  • YES
109
Q

How does the increase in sympathetic output following stroke lead to cardiac dysfunction?

A
  • It leads to a catecholamine surge (NA) which leads to cardiomyocyte necrosis, hypertrophy and fibrosis hence cardiac dysfunction
110
Q

Post stroke, what is the general pathology occurring in the blood vessels in terms of inflammation?

A
  • There is an inflammatory response both systemically and in the brain
  • This involves T cells, neutrophils etc. (i.e. immune cells).
  • These enter via the leaky BBB which is damaged 2-5 days post stroke
111
Q

How do immune cells enter the brain to cause an inflammatory response following a stroke?

A
  • They enter via the leaky BBB and the blood vessels are damaged 2-5 days post stroke
112
Q

Does the increased sympathetic output following stroke activate lymphoid organs, thus releasing immune cells?

A
  • YES

- These immune cells migrate throughout the body, affecting systemic organs

113
Q

When neurons die, what do they release in terms of inflammation?

A
  • They release cytokines that attract immune cells to the brain
114
Q

Which immune cells contribute to the neuronal and non neuronal cell death following stroke?

A
  • T cells (CD4 and CD8) (cytokines released: IL-1 IL-22 IL-17 TNF FAS ROS IFN-y)
  • Activated macrophages and Activated microglia (ROS IL-1 IL-6 IL-18 TNF)
115
Q

What is a major factor that immune cells release to cause neuronal cell death?

A
  • ROS
116
Q

What is Evans blue?

A
  • It won’t cross the blood brain barrier (BBB) if there is an intact blood vessel but does if there is a leaky blood vessel. This is useful for determining when there is a stroke causing leaky blood vessel
117
Q

Roughly how long following stroke will the immune system be shut down to prevent any further inflammation?

A
  • Roughly 5 days

- Thus systemic immunosuppression occurs which links with increased pneumonia (nosocomial) etc.

118
Q

At 24 hours following stroke, which immune cells peak at high levels?

A
  • Microglia and macrophages (but more so microglia because this is a local inflammation in the brain unlike macrophages that come from systemic circulation)
  • Also a rise in neuts (but doesn’t peak at 24 hours)
119
Q

What is the order of the different immune responses following stroke?

A
  • Local immune response
  • Innate immune response
  • Adaptive immune response
120
Q

At what timepoint do T cells increase and peak at post stroke?
Is this a large number of T cells to peak?

A
  • They increase and peak at about 3 days post stroke

- Not a large number of T cells to peak but they still have an impact.

121
Q

Do B and T cells play a large role in infarct damage within 5 days following stroke and if so, how was this demonstrated?

A
  • YES
  • Demonstrated by subjecting T and B cell deficient mice to an MCAO. These mice showed a LOWER infarct volume than the T and B cell mice, meaning that T and B cells play a significant role in infarct damage within 5 days post stroke
122
Q

In terms of the stroke damage timeline visual, which cells are involved in the initiation phase (local), the innate immune response phase, the adaptive phase and the recovery/resolution phase, and which timepoints do these occur in?

A
  • INITIATION: Damaged neurons and Astrocytes- Hours
  • INNATE: Microglia, Infiltrating myeloid cells (M1/M2), Innate lymphocytes (neutrophils?)- Hours
  • ADAPTIVE: Pro-inflamm lymphocytes (T and B cells) and T regs (anti-inflamm)- Days
  • RECOVERY/RESOLUTION: Recovering neurons and oligodendrocytes - Weeks
123
Q

Does the spleen size increase, decrease, or stay the same post stroke, and what does this suggest?

A
  • It decreases following stroke
  • This suggests that the spleen contributes to neurodegeneration following stroke and it was producing systemic immune cells that may contribute post stroke
124
Q

Until what timepoint does the spleen weight decrease following stroke and what does this suggest?

A
  • Does not decrease until 72 hours following stroke
  • Suggests that the adaptive immune system is producing B and T cells (mainly the T cells that cause the damage) as they peak at about 3 days post stroke. - May also suggest that there is some apoptosis occurring
125
Q

Is macrophage infiltration into the brain coming from the spleen?

A
  • NO

- The macrophages are probably coming from other lymphoid tissues

126
Q

Where do the infiltrating B and T cells come from when the get into the brain following stroke?

A
  • From the spleen
127
Q

Is there an increase in the spleen weight at 24 hours following stroke, and which other factor is increased at this timepoint (&why)?

A
  • NO it does not increase significantly
  • BUT there is an increase in Caspase 3
  • This is because the cells have NOT died yet. They are in the process of being killed but haven’t actually been killed hence no weight gain
128
Q

At 24 hours, why is there a decrease in the size of the spleen?

A
  • It could be due to the increased sympathetic output leading to increased apoptosis (increase in Caspase 3)
129
Q

Where are most of the anti-inflammatory drugs in the process of the drug pipeline, and why is this the case?

A
  • Many of them made it to stage 4 CTs but have all failed

- Due to lack of evidence, perhaps because the drugs may have been crossing the BBB or it was the type of treatment

130
Q

What are 5 things that are immune system-CVD related?

A
  • Systemic and pulmonary hypertension
  • Myocardial infarction
  • Atherosclerosis
  • Aortic aneurysm
  • Atrial Fibrillation
131
Q

What is the brain-immune system-CV axis?

A
  • Central stimuli affecting sympathetic outflow–> increase in sympathetic outflow–> T cells produced from spleen/lymph nodes–> activated T cells –> Sodium/volume retention and also increase in vessel ROS which decreases the vessel NO–> hypertension
132
Q

In a study looking at hypertension and immune cells (via flow cytometry), did the B and T cell deficient mice have an increase or decrease in BP, and what does this suggest?

A
  • They did not have a huge increase in BP (not as large as the +B and +T cell mice)
  • Thus immune cells are contributors of CVD
133
Q

Does ischaemic stroke increase BP?

A
  • YES (but also increased BP is common regardless of whether stroke is hemorrhagic or ischemic)
134
Q

Is high BP common in stroke patients and does it decrease following stroke?

A
  • Exists in more than 3/4 of patients, where 1/2 have a history of hypertension
  • Declines spontaneously in 2/3 of cases returning to pre-stroke levels over first week
135
Q

What may be driving elevated blood pressure following stroke?

A

-Brain autoregulation- hyperperfusion followed by hypoperfusion in the brain. Waves of blood flow going up and down. Not sure why (initially thought it was immune cells)

136
Q

What was done to determine what is causing elevated blood pressure post stroke?

A
  • They gave 13-15 week old male rats ischaemic stroke (MCAO) and then removed the mesenteric vascular bed at 24 hours post stroke
137
Q

What did the team (Martinez-Revelles et al.) find that was perhaps contributing to the increased blood pressure following stroke, and what does this mean?

A
  • The ischaemic stroke mice (in terms of the mesenteric artery relaxation %) was lowered compared to the normal mice
138
Q

What is the most important factor released by blood vessels to control vasodilator tone and what is the mechanism behind it?

A
  • NO-
  • The increase in the concentration of Ach leads to eNOS (enztyme that activates) NO-
  • NO- then enters the the vascular smooth muscle cell to cause relaxation from converting soluble guanylate cyclase (sGC) into cMGP, thereby relaxing the smooth muscle cell
139
Q

Does ischaemic stroke alter sodium nitroprusside- (SNP) mediated dilation in the mesenteric artery and why is this/what does this mean?

A
  • No it does NOT
  • This tells us that the problem is not with the NO receptor, but it is more upstream, hence an issue with Ach possibly
  • SNP comes into the sGC at the Vascular smooth muscle, not the endothelial cell
140
Q

What is SNP (Sodium nitroprusside)?

A
  • It is a Nitric Oxide (NO) donor

- Comes into the vascular smooth muscle and donates a NO-

141
Q

Does decreased nitric oxide (NO) result in endothelial dysfunction, and if so, how does this occur?

A
  • YES
  • Occurs when Leukocytes adhere to the endothelial cells and release ROS
  • Increased ROS causes scavengers NO
  • NO then forms a highly damagin oxidant (ONOO- better known as Peroxynitrite)
  • This ONOO- is one of the MAIN factors causing endothelial dysfunction
142
Q

What is one of the main factors causing endothelial dysfunction?

A
  • ONOO- better known as Peroxynitrite

- This is formed from NO and O2- via ROS

143
Q

Does ischaemic stroke increase the superoxide levels in systemic blood vessels such as the mesenteric artery?

A
  • YES
144
Q

Which scavenger abolishes stroke induced increase in superoxide levels, and what is the mechanism of action (also what effect on Ach did it have) ?

A
  • PEG-SOD (Polyethylene glycol- superoxide dimutase)
  • It breaks down superoxide and converts into H2O
  • The diminished Ach effect had returned to normal levels
145
Q

Do infiltrating leukocytes cause endothelial dysfunction following stroke, and if so, why is this the case?

A
  • YES
  • This is the case because the leukocytes adhere to the endothelial cells
  • There are elevated ROS and inflammatory cytokines produced
  • The ROS and cytokines lead to a apoptotic endothelial cell thus leading to many leukocytes adhering and endothelial dysfunction after a stroke
  • So increased ROS is causing endothelial vascular dysfunction
146
Q

How long does it take for immune cell infiltration to reach the brain after a stroke?

A
  • Roughly 6 hours after onset
147
Q

What does stroke trigger the release of and via what mechanism?

A
  • Stroke triggers the release of immune cells from lymphoid tissue via increased sympathetic output
148
Q

Does ischaemic stroke of endothelial vascular dysfunction and if so how does it do this?

A
  • YES it does

- Does this via increased superoxide production

149
Q

Does anti-inflammatory treatment improve post stroke outcomes?

A
  • NO
150
Q

Can stroke cause epilepsy?

A
  • YES
151
Q

Why do seizures happen in those that have epilepsy?

A
  • Seizures happene because of a disruption to electrical activity in the brain, leading to a change in the person’s movement, behaviour, level of awareness and/or feelings.
152
Q

How many unprovoked seizures does a person have to have to be diagnosed with epilepsy?

A
  • 2 unprovoked seizures
153
Q

What is epilepsy?

A
  • A medical condition that affects the brain and causes for reoccurring unprovoked seizures.
154
Q

What is the most common identifiable cause of epilepsy in people above the age of 35 years?

A
  • Stroke
155
Q

In the elderly, wat % of seizures is stroke the cause of?

A
  • > 50% of cases
156
Q

At what time frame do seizures typically occur in in terms of stroke is well?

A
  • Typicaly occur within 24 hours of the stroke
157
Q

Are you most likely to have a seizure if you have a haemorrhagic stroke or ischaemic?

A
  • You’re most likely to have a seizure if you have had a hemorrhagic stroke.
  • This is possibly due to irritaton of byproducts
158
Q

If you have a seizure following an ischaemic stroke (less likely than haemorrhagic), then why may this be the case?

A
  • May be the case due to lower threshold in response to hyperperfusion inujury
  • There is no precise mechanism though
159
Q

In which situations is having a seizure most likely in terms of stroke?

A
  • Haemorrhagic stroke
  • Severe stroke
  • Stroke in the cerebral cortex
160
Q

Can a small proportion of people that are epileptic suffer a stroke, and if so, how does this occur?

A
  • YES
  • Thought to occur via the GABA A receptor drug to enhance inhibitory effect OR Ca2+ channel targets to increase the excitation
161
Q

What is Phenytoin and how does it contribute to stroke?

A
  • It is a drug used to reduce excitation for those with Seizures
  • It targets the Na+ channels to reduce excitation and this could be leading to atherosclerotic plaques to cause an embolus to cause stroke OR build up of fatty tissue to cause a thrombus
162
Q

Is prophylactisc administration of antiepileptic agents (e.g. Phenytoin) recommended following stroke?

A
  • NO
  • Not recommended as it is associated with an increased risk of atherosclerosis
  • Also associated with increased blood levels of total cholesterol atherogenic (non-HDL) cholesterol. and trigylcerides
163
Q

Compared to two cohorts who did not have any comobidities, were the patients in the epilepsy cohort at an increased risk of stroke?

A
  • YES
  • They were at s 3-fold increased risk for having a stroke as it is thought that their medication may contribute to the risk (e.g. Phenytoin)

BMS3052 (14 decks)

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