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Salivary Glands composed of...

and Secretions

Produce 1 to 2 litres per day
Composed of Parotid, submandibular, sublingual

Secrete:
        - amylase - starch digestion (minimal)
        - lysozyme - digest bacterial cell walls.
        - lingual lipase - lipid digestion (minimal)

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Rugae

Gastric Secretions

Ridges and folds, help grinding

2 litres
- Acid: HCl from parietal cells
- Mucous: Most abundant epithelial cell type and bicarbonate rich to coat and lubricate

- Proteases - Pepsin activation going to protein digestion
- Hormones - Gastrin increases acid and motility

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Small Intestine

~ 21 ft long (but surface area of a tennis court)

3 major segments:

• duodenum (short - 8 inches), liver and pancreatic secretions
• jejunum - (8 ft) 40% of small intestine
• Ileum - (12 ft) empties into large intestine

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Gastric emptying determined by feedback...

Feedback in the stomach:
Based on amt and fluidity of chyme, distention

Feedback in the duodenum:
By amnt of fat, acidity, tonicity, distention
And pancreatic exocrine excretion important:

• Secretin - released in response to increased acidity
• Released into blood and increases sodium bicarbonate release from pancreas and decreases gastric motility
• Cholecystokinin (CCK) - released in response to increased fat
• CCK released into blood to increase digestive enzyme release and decrease gastric motility

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Grapefruit inhibits....

CYP3A4, causing much higher amounts of certain drugs in the plasma (more bioavailable) because CYP breaks down the drug

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Bile acids important for...

1. Fats and fat soluble vitamins digestion
2. Waste products eliminated in bile
3. Bile acids re-circulate (secreted and reabsorbed)
4. Emulsifies lipid aggregates
5. Form micelles (lipid carriers)

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Pancreas and Digestion

1.5 litres per day

Proteases
   - trypsin and chymotrypsin
 

Lipase
   - triglyceride digested - monoglyceride + free fatty acid
   - only site of released enzyme for fat digestion

Amylase
   - hydrolyses starch to maltose

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Large Intestine

Important site for water and electrolyte reabsorption (10%)

Formation and storage of feces

Microbial fermentation:

• Digestion of carbohydrates not digested in small gut
• Synthesis of vitamin K and certain vitamin Bs

SF075

 Why is pain so different?

Pain is not a sensation but a...

Tissue injury vs. disturbed central sensory transmission (3)

Changes in pain over time... (3)

Pain is not a sensation but a perception:

It may be perceived in the absence of nocioceptor activation!

Tissue injury vs. disturbed central sensory transmission:

1. Paraesthesia: Abnormal sensation, such as of burning, pricking, tickling, or tingling, sometimes due to "central" pain syndrome following stroke

2. Phantom limb: Sensation that an amputated limb is still present, often with painful paraesthesia
3. Causalgia: Burning pain following nerve damage that persists long after tissue healing has occurred

Pain may change over time:

1. Hyperalgesia (an increased sensitivity to pain at pain receptors) and allodynia (painful response to a normally innocuous stimulus)

Receptors change, sensitization of afferents, spinal pathways etc

2. Plasticity - CNS may reorganize -> plastic as in changeable and not in a good way!
3. Psychological set - changes and pain may be minimized or focused on depending upon psychological state

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How does acute pain go to chronic pain?

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Immediate, soon and later pain

IMMEDIATE effects

1) local burn
2) action potentials in sensory fibres first awareness of pain

3) reddening, weal (swelling)

SOON AFTER

4) active compounds released from sensory nerves cause
histamine release etc

5) Flare occurs, further reddening and hyperalgesia (intense pain)

LONG TERM

6) Secondary hyperalgesia due to receptor sensitisation and changes in CNS transmission

7) Pain sensation lingers beyond tissue damage

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Gate theory of pain transmission

Activity in small diameter pain fibres (from nocioceptors) promotes ascending transmission by direct excitation (++)  and disinhibition (inhibition of inhibitory neuron).

Activity in large diameter fibres (non-nocioceptors) decreases ascending transmission by exciting inhibitory neurons. These in turn inhibit ascending neurons and reduces pain signal transmission to higher centres.

Thus, activity in large fibres can reduce transmission from small fibres…acupuncture, TENS (transcutaneous electrical nerve stimulation)

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Differences in pathways of pain and sensations of touch or vibration

Pain fibers are found in the spinothalamic tract:

The first order neurons of this tract originate in the periphery (sensory neurons) and synapse with second order neurons in the dorsal root of the spinal cord.  The second order neuron then crosses to the contralateral (opposite) side of the spinal cord at around the level where the peripheral nerve entered. Once on the other side the nerve fiber enters the spinal thalamic tract and ascends to the thalamus where it synapses with a third order neuron.  This third order neuron then projects into the cerebral cortex.  

Touch and vibration fibers travel through the dorsal column/medial lemniscus

The first order neurons of this tract enter the the dorsal root of the spinal cord and proceed immediately into the dorsal column where they ascend (on the ipsilateral side of the spinal cord) to the level of the medulla.  At the medulla the first order neuron synapses with the second order neuron. The second order neuron crosses to the contralateral side and projects to the thalamus where it synapses with the third order neuron. The third order neuron projects to the cerebral cortex.

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Endogenous Opioid Peptide System

Stimulation around the cerebral aqueduct (periaqueductal grey) causes release of endogenous opioids in the spinal cord descending pathways (via the Reticular formation). These bind to receptors in the CNS producing an analgesic effect.

Opioid receptors in CNS, mu, kappa, delta and various
subtypes.

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Referred pain from visceral pain receptors

The mixing of visceral and somatic afferents onto common neurons results in misinterpretation of the source of pain.

Ex The area where the pain is appreciated is innervated by the same spinal segment(s) as the deep structure.          Pain afferents from the arm enter in the same dorsal roots as visceral afferents from the heart.

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Thalamic pain syndrome

Deep brain stimulation for pain management has included
stimulation of the  thalamus via...

Rare neurological disorder (due to stroke involving thalamic nuclei in brainstem) in which the body becomes hypersensitive to pain as a result of damage to the thalamus

1. Sensory ventralis caudalis nucleus
2. Periventricular gray which appears to activate
3. The medial thalamic and cingulate cortex

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Cortical representation of pain is from the...

Pain information is not destined only for the...

Somatosensory cortex (the homunculus) but in
particular, near the lateral sulcus (Sylvian fissure). But this is somewhat plastic!

Deafferentation (human clinical studies and animal
models). Cortex representing the lost body part
develops inputs from adjacent areas.

Sensory cortex! It can go to the ...

1. Cinguate cortex
2. Parietal-insular cortex
3. Dorsalateral prefrontal cortex
4. Thalamus
5. Dorsal pons in brainstem

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2 changes associated with long term or chronic paIN

Chronic back pain

1. Long term or chronic pain is secondary hyperalgesia (primary being acute pain). Secondary hyperalgesia results from receptor sensitization and changes in CNS transmissions causing the pain sensation to linger beyond the actual tissue damage.
   
   
2. Chronic pain can result in plastic changes in the CNS.  Remember pain is not a sensation but rather a perception and as such may be perceived in the absence of nocioceptor activation.
   
   
   One study showed chronic back pain led to an enlarged representation of the back region of somatosensory cortex which may shrink after successful treatment.
   
   

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1. X-ray
2. Fluoroscopy
3. Computed Tomography (CT)
4. Magnetic Resonance Imaging (MRI)

1. X-ray
Produce x-rays by focusing high energy electrons on a tungsten target. While passing through the body, the x-rays are attenuated based on the density of the material they are passing through. The more dense the tissue, the more the rays are attenuated and the whiter the image. Contrast such as barium can be used to image soft tissues.

2. Fluoroscopy
Take multiple x-rays (video) of a single region of a patient’s body over a period of time. Inject iodine contrast into veins, which is filtered into the kidney, where it can be imaged by x-ray.

3. Computed Tomography (CT)

Multiple x-rays are taken of the patient from multiple angles. Patient lies on a bed, which is moved slowly through the CT machine. While the patient is moving, x-rays are taken from many angles around the patient.   Using computers, the data can be manipulated to show images in all planes of section. Data can also be assembled to show three dimensional images.

4. Magnetic Resonance Imaging (MRI) – Use a strong magnetic to align hydrogen nuclei. H atoms emit radio waves from the nuclei, which can be detected and used to assemble images. Useful for imaging soft tissue.

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Three main planes of section

1. Coronal – plane is perpendicular to the dorsal-ventral axis. Images viewed as if you were looking directly at the person
2. Transverse – plane is perpendicular to the cranio-caudal axis. Images viewed as if you looking from the feet upwards of a person in the supine position
3. Sagittal – plane is perpendicular to the medial-lateral axis. Images viewed as if you were looking at someone from the side

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Sampling Methods (5 types)

1. Surface masses – cell scrapings or surface biopsy
   
   
2. Deep Structure Biopsies – Use different types of needles depending on the type of sample needed
       Fine needle aspiration – 21-25 gauge needle
       Percutaneous core – 16-18 gauge needle
   
   
3. Endoluminal Sampling – Use a catheter to reach the inside of some organs (eg heart muscle). Use dilation and curettage to sample the uterus (dilate the cervix and allow the curette access to the uterus).
   
   
4. Laparoscopy – anesthetize patient and place at least three holes in the abdomen (one for camera, one for light, one for instrument). Inflate the chest cavity with carbon dioxide and perform surgery/sampling without opening the body cavity. Less invasive so patient can recover within a few days.
   
   
5. Laparotomy – anesthetize patient and cut open abdominal wall in order to perform procedure. Much more invasive so recovery takes longer (cut the muscle, requires six weeks to heal).

SF117

Define:

Hemostasis

Thrombosis

Primary hemostasis

Coagulation (secondary hemostasis)

Hemostasis
physiological process to stop bleeding
Thrombosis
abnormal formation of a clot within a vessel
Primary hemostasis
process leading to formation of a platelet plug
Coagulation (secondary hemostasis)
process leading to formation of a fibrin clot

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Mechanisms of Hemostasis

• Hemostasis is initiated by vascular injury
• Endothelial injury:
• vasospasm
• loss of antiplatelet and anticoagulant functions of endothelium
• exposure of subendothelial collagen and von
  Willebrand factor --> platelet adhesion and activation
• Exposure of extravascular tissue factor:
• initiation of coagulation cascade
• formation of fibrin clot

[image]

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Defects of primary hemostasis

Defects of coagulation (secondary
hemostasis)

Defects of primary hemostasis
= mucocutaneous bleeding
     nose, gums, teeth, bruising, menorrhagia, petechiae

Causes
1. Dec Platelet count
2. Dec von Willebrand factor
3. Dec Platelet function
Tests
CBC, bleeding time or closure time, vWF assays, platelet aggregation assays

Defects of coagulation (secondary hemostasis)
delayed bleeding
surgical bleeding
joint & muscle bleeds

Causes
1. Deficiency of one or more clotting factors:

congenital, esp. Factors VIII and IX

liver disease

vitamin K deficiency or warfarin

2. Inhibitors (e.g. heparin, dabigatran)

Tests
PT/INR, PTT (screening), factor levels

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Thrombosis Manifestations (2 types)

Virchow’s Triad

Arterial thrombosis - ISCHEMIA

• stroke, myocardial infarction, limb ischemia etc.
• occurs at site of high shear stress
• mostly platelets, some fibrin
• “White clot”

Venous thrombosis - EDEMA

• deep vein thrombosis (legs) (most common), pulmonary embolism
• occurs with stasis
• fibrin-rich, entrapped RBCs, few platelets
• “Red clot”

Virchow’s Triad
1. Abnormal Flow
2. Abnormal Coagulability
3. Abnormal Vessel Wall

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Arterial Thrombosis Mechanism (2)

Mechanism 1: thrombus formation in situ

• Abnormality of the vessel wall:
• atherosclerosis is the predominant Virchovian mechanism
• Plaque rupture triggers thrombosis:
• exposure of tissue factor expressed on
  macrophages and smooth muscle cells
• exposure of collagen in intercellular matrix
• thrombin generation and platelet activation
• formation of platelet rich thrombus

Mechanism 2: Embolization

Embolization may occur from:

• thrombus formation at a proximal site of vessel
• wall disease
• usual mechanism of TIAs
• heart valve
• heart chambers
• venous system
• clot goes to pulmonary artery

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Thrombosis and Atherosclerosis:
A vicious cycle?

Thrombosis and Inflammation
Two sides of one coin?

Thrombosis and Atherosclerosis:

• Atherosclerosis leads to loss of normal anticoagulant functions of endothelium
• we get enhanced thrombin generation and platelet activation
• Thrombin and platelet derived growth factor
  (PDGF) are mitogenic for smooth muscle
  cells
• subintimal hyperplasia
• development of foam cells

Thrombosis and Inflammation:

• Inflammatory stimuli are prothrombotic
• induce change from anti-coagulant to procoagulant phenotype in endothelial cells
• induce expression of tissue factor by
  monocytes/macrophages
• Thrombin is inflammatory
• activates leukocytes and induces adhesion
  molecules on endothelium -> recruit leukocytes
• Fibrin deposition is a hallmark of inflammation

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Venous Thrombosis: Mechanisms

Treatment of Thrombosis

• Stasis (condition of slow blood flow in the veins) and Hypercoagulability are the predominant Virchovian mechanisms
• Situational risk factors also important: surgery, immobility, pregnancy, oral contraceptives
  
  
  Treatment

• Arterial
• Antiplatelet agents
• ASA, clopidogrel etc.
• Fibrinolytic activators
• streptokinase, tPA etc.
• Venous (or cardioembolic)
• Anticoagulants
• Heparin and derivatives, Warfarin, Dabigatran, rivaroxaban, apixaban, edoxaban ...

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Hemorrhage

Loss of blood from the vascular compartment, usually as a result of trauma to or disease of the vessel wall. This can involve large vessels or small vessels

Where:

- outside of body (e.g. wound)
- body cavity (e.g. skull, GI tract, serous cavities)
- soft tissues (e.g. muscle, brain, skin)

Extent (size) or hematomas:

petechia - < 3 mm

purpura - 3 – 10 mm

ecchymosis - >1 cm (10 mm)

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Hyperemia

Increased amount of blood in an organ or tissue.

Active (= hyperemia): augmented flow of blood to tissues, e.g., exercise, inflammation

outflow normal, in flow high

Passive (= congestion): impaired outflow of blood, e.g., cardiac failure, obstruction to venous outflow, e.g.

• Left ventricular failure causing congestion of lungs and liver
• Right ventricular failure causing edema (swelling of lower extremities

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Thrombosis and 3 contributing factors

Embolism

Thrombus

   = intravascular blood clot, adherent to the vessel wall
Arterial: most common cause is atherosclerosis
Venous: deep veins of legs (DVT)

1. Endothelial Injury

2. Hypercoaguability

3. Abnormal blood flow

Embolus: a detached intravascular solid, liquid, or gaseous mass that is carried by the blood to a site distant from its point of origin. Most commonly thromboembolus.

Venous emboli:

origin - deep veins of legs

outcome - pulmonary embolism

Arterial emboli:

origin - heart (mural thrombi)

outcome - infarcts

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Infarction
and 2 types

Infarct: an area of ischemic necrosis in a tissue as a result of occlusion of the arterial supply/venous drainage

99+% are caused by a thromboembolus - almost all arterial occlusions

2 Types:

White infarct: parenchymal organs (ex kideny), arterial occlusion
Red infarct: organs with double blood supply (lungs)

Common sites (both): heart, brain, lungs

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Edema

due to (5 causes)

Increased fluid in the interstitial tissue spaces or body cavities (anasarca, hydropericardium, pleural effusion, ascites)

1. Increased hydrostatic pressure
Localized: vascular obstruction
Generalized: congestive heart failure

2. Dec plasma oncotic P (hypoproteinemia):
Nephrotic syndrome -> prod proteins, but lose them

Liver cirrhosis -> not synth enough proteins

3. Lymphatic obstruction: inflammatory, neoplastic…

4. Sodium (+ H2O) retention: renal failure

5. Inflammation: acute and chronic

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Shock

Systemic hypoperfusion (decreased blood flood through an organ) secondary to reduction in cardiac output or the effective circulating blood volume

Cardiogenic: myocardial pump failure (e.g. infarction, arrhythmias, tamponade)

Hypovolemic: loss of blood (e.g. hemorrhage, burn, trauma)

Septic (endotoxic): systemic bacterial infection (Gram negative bacteria)

A 3 year old child died of meningococcal meningitis. Her death was associated with severe clinical shock. Why? -> missed this? Why?