Inflammation

Rubor:  Redness
Calor:  Heat
Tumor:  Swelling
Dolar:  Pain
Loss of function

Stages of acute inflammation
Vascular:  Increased blood flow & permeability
Brief arteriole constriction, then constriction
Chemotaxis

Cell-derived materials that stimulate inflammation (see figure 6-11)

Cyclooxygenase (COX):  Increase prostaglandins
COX1:  Found in the gut
COX2:  Found near inflammation

Cytokines and leukotrienes are also products from most cells and basophils.  See figure 6-8

Tumor Necrotizing Factor is pro-inflammatory
IL-4:  Anti-inflammatory

Histamine constricts broncho smooth uscle, dilates vascular smooth muscle

See the complement and pathway picture

Hypersensitivity

Autoimmune Diseases

Systemic Lupus Erythematosis

Occurs i synovial membranes
Antibodies against IgG develop
Form Osteoclasts

#2 cause of death (25%)
Risk goes up with age
Men:  1:2 risk (prostate and lung are the most common)
Women:  1:3 risk (1/8 get breast; #2 is lung) 

Records of cancer go back 1,000s of years. 
Benign:  Resemble the tissue of origin
Normal cells:  Limited by cell membrane
Fibronectin:  Surface protein keeps cells from metastisizing
Tumor suppressors:  Stop cells from reproducing if there is an error in DNA
P53 Gene:  Stops cells from reproducing if there's an error.  It codes a protein to do this. 
Some carcinogens mark the P53 genes
51 known cancers are related P53 errors

Chinese moldy grain
UV radiation
Smoking

BRICA 1 & BRICA 2:  Breast-cancer suppressors

Proto-oncogenes:  Cause cells to divide
Oncogene:  Causes cancer

MYC:  "Go" gene

Herceptin:  Stops HER2 gene from working

Angigenesis:  "Blood making"  Tumors steal blood flow
Angiogenesis suppressors:  Doesn't work in people yet.  Mice get all the luck
Apoptosis:  Cancer cells don't do it. 
Tumor Necrosis Factor Alpha:  Most cancer cells don't listen
Many cancers have inflamatory components
Telomeres:  Cancers don't run out of them.  They constantly make telomerase

Cancer tends to screw up protein adhesion factors

Tumor Cell Markers

Human Coreonic Gonadotropin (HCG):  (Pregnancy test hormone)  Uterine cancer marker.  Called ectopic cancer. 
Some people's Prostate Specific Antigen will be too high
CA125:  Antigen produced abnormally by ovarian cancer cells
Carcinoma Embryonic Antigen (CEA):  Measures blood of colon cancer to see if disease is back


In situ:  Cancer hasn't reached the basement membrane

Tumors grow at different rates depending on:
Site
Cell type (thyroid cells divide faster)
Host characteristics (senescence affects cancer growth) 
Gender
Nutrition (anti-oxidants, stuff to make proof-reading enzymes) 
***Psycho-neuro immunology:  (Stress is bad for the immune system)  ***
Growth factors
Angiogenesis factors:  (thalidomides, angiogenesis inhibition) 
Vascular endothelial growth factors:  (cancer turns these on) 
Angiogenesis factor activated by inflammation

It takes about 3 doublings for one cancer cell to become a tumor 1 cm in size

Coliginase IV:  Breaks through capillaries.  Made by tumors to help metastasis

Cancer cells tend to attach to first blood vessel or lymph nodes they reach and exit the nearest site

Sentinal node:  first lymph node to be affected by cancer

Blood cycles to liver and lungs and that's why cancer metasizes there so often

Cancer hurts because tumors smoosh things. 

Multi-stage carcinogenesis:  Lots of accidents need to happen for cancer to occur

Mutations aren't usually inherited, but it's possible  

20% of cancer is caused by genetics

HPS disables P53
High-fat diet -> GI & reproductive cancer
Late childbirth -> breast cancer



Albert Albumin:  Albert is a good butler and always controls the volume at parties.  If people get out of hand at parties, he puts pressure on them.  Sort of like albumin controls blood volume and controls osmotic pressure. 

Globulin goblins are little creatures the bind insoluble proteins and make them soluble.  (In my handwritten notes, I point out that goblins can put things in chains, a form of binding.) 

Fibrinogen:  Fibers that make beaver-dam-like structures for clotting

Hematopoiesis:  Hema = blood; poiesis = to make

Erythropoietin:  Made in the kidney.  Stimulates creation of erythrocytes. 

Hematocrit:  Percentage of blood that is red blood cells.  Hema=blood; crit = analysis

Cytic:  Refers to red blood cell size
Chromic:  Refers to hemoglobin concentration

Normal blood values

Mean Corpuscle Volume (MCV):  87-103 fL/red cell or mcr m³/red cell
Viral Infection by Epstein-Barr
Most people are exposed as children
Swollen lymph nodes
Fatigue
Hepatic & Splenic tenderness
Need to know blood-flow direction

Three Layers to Blood Vessels
Tunica Intima:  Tunica = tissue; intima = close (to the blood)
Tunica Media:  Media = middle (Smooth muscle)
Tunica Adventitia: Adventitia = Foreign (farthest from blood)

Vasoconstriction:  Increases blood flow resistance
Vasodilation:  Decreases blood flow resistance

Veins=Capacitance Vessels:  Capacity to be a resavoir

Capillaries:  Just have an epithelial layer
BP:  Blood Pressure
CO:  Cardiac Output
TPR:  Total Peripheral Resistance, resistance by arterioles
CO:  Cardiac Output
HR:  Heart Rate
SV:  Stroke Volume
MAP /= BP
MAP ~ BP
MAP = ((2xdiastolic)+systolic)/3

Carotid Artery
Aorta
Kidneys (the arterioles)
Right artium

HR set by pacemaker/SA node in right atrium
Sympathetic nerves stimulate SA node to increase heart rate

Heart Rate set by pacemaker/SA node in the rigt atrium

Sympathetic nerves stimulate SA node to increase heart rate

Parasympathetic nerves slow SA node, heart rate drops
SV =mL/beat
SV depends on quantity of blood in the heart
EF = per cent of blood in the heart(also called endiastolic volume or pre-load: amount of blood in left ventricle before systole)/how much leaves
EF:  Ejection Fracture
Healthy EF ~ 80%
Tension/Length of myocardial fiber
At a certain length of myocardial fiber, the heart produces the most tension
Increase in pre-load leads to increase in stroke volume
Preload ~ venous return
Sympathetic nerve stimulation leads to an increase in stroke volume
Ionotropic response:  Increase in heart contractility leads to increase in stroke volume which leads to an increase in blood pressure
Chronotropic response:  Change in the number of beats
Anti-diuretic hormone (ADH or vasopressin)
Renin:  Hormoe from kidney
Blood pressure drop leads to increase of renin release from the kidneys leads to renin meeting with angiotensinogen producing angiontensin I which leads to a mixing with angiotensin Convertin Enzyme (ACE) to produce angiotensin II which goes to the adrenal gland and is converted to aldosterone with goes to the kidney and allows increased sodium reapsorption which leads to increased blood pressure
Posterior Pituitary releases anti-diuretic hormone (ADH) with BP drops
Intrinsic control:  Stretchyness
If a person is hypoxic, nitric oxide (NO) causes vasodilation
Endothelin:  Released by capillaries to cause constriction
Sympathetic nerves:  Release nor-epinephrine causing vasoconstriction increasing BP
Angiotensin:  Angio=blood vessel; tensin=pressure
Capillary Hydrostatic Pressure:  C_H = 18mm Hg (out of capillary)
Intersitial Hydrostatic Pressure:  I_H = 3 mm Hg (out of capillary)
Capillary Osmotic (oncotic) Pressure:  C_Pi = 28 mm Hg (into capillary)
Interstitial Osmotic (oncotic) Pressure:  I_Pi = 8 mm Hg (out of capillary)

C_H + I_H + I_Pi - C_Pi = Net Capillary Pressure
Breakdown of endothelial integrity
Inflammatory disease
Stress leads to increased cholesterol
Increased cholesterol leads to more cholesterol moving across capillaries which leads to increased O₂ free radicals which leads to increased inflammation
Increased iron also leads to increased coronary artery disease (Iron is oxidized)
-Chromic:  refers to amount of hemeglobin
-chromic = color
heme- = iron-containing/red
Hypertension is a blood pressure of >140/>90
Primary/Essential hypertension:  Unknown cause (most kinds)
Secondary hypertension:  Has a known cause
Odd of hypertension go up with age

Pathophysiology of Hypertension
BP = HR x SV x TPR
HR:  We didn't really go into this
SV:  Higher SV means the heart has to work harder
TPR:  Heart has to work harder for this too
    Increased sodium leads to increased calcium in vasculature which hardens arteries
    Africans have decreased sodium pumping ability

An example of secondary hypertension:
    Gestational hypertension (HTN during pregnancy)
    BP drop = HR increase x SV increase x TPR drop
        TPR drop due to increase in progesterone which is a smooth muscle relaxant
25% genetics
sodium intake
Men have higher BP than women
Race:  BP of blacks in USA > BP of blacks in Africa > BP whites in USA (stress is a factor) 
Chronic stress is worse for you than acute stress
BP:  <120/<80 = good
        121-140/81-90 = elevated
        >140/>90 = hypertension 
Signs:  Eye vasculature problems
            Kidney damage
            Atherosclerosis
Diet
Exercise
To lower heart rate:
    Beta blockers (slow SA node)
       Contraindicated for people with orthostatic BP problems and people with asthma
To lower stroke volume:
    Diuretics (like thiazides)
        Contraindicated for people with electrolyte balance issues
    Angiotensin Converting Enzyme (ACE) Inhibitors
        Possibly teratogenic
    Bradykinin (a vasorelaxant) 
To lower total peripheral resistance
    Calcium channel blockers
        Tend to lower heart rate too
Left ventricle hypertrophy
Stroke (CVA)
Myocardial infarction
Anything that impairs the heart's ability to pump
Causes 50% of deaths in US
There are three main arteries in the heart (two on the left, one on the right)
Controlled:
    Locally
    Neurally
    Hormonally
Risks Factors:
    Non-modifiable
        Gender
        Genetics
        Race (Africans & Asians at higher risk)
        Diabetes Type I
    Modifiable
        Stress
        Blood Pressure
        Obesity
        Diabetes Type II
        Smoking (causes issues with hypoxia, platelets and clotting)
Angina
    Stable (exertion)
        Sense of strangling, anxiety
        Felt during
            Uphill walks,
            Cold weather
            After meals
        Feeling goes away when at rest
    Prinzmetals (variant)/ unpredictable
        Wake up at night
        Happens during sitting
        Happens in women
    Unstable
        Starts out as stable, then stops being predictable
Occurs when O₂ demand > O₂ supply

Cells are hypoxic and do the anaerobic thing
O₂ demand > O₂ supply
O₂ delivery can't increase
Cortisol => Sympathetic increase
Sympathetic (up(TPR (up), SV(up), HR(up))) => Hypothalamus => Cortisol (up)

Apnea => Sympathetic (up)

Stress => Sympathetic(up) + Cortisol(up)

Sympathetic -> Hypothalamus -> Cortisol -> Sympathetic...

Therapy: 
    Prevention
    Nitroglycerin: Local vasodilator, lowers afterload and venous return
    Education
Different from angina as this kills cells
Infarct:  Dead cells
At 20 minutes of hypoxia = myo cell death
SV(down)
BP(down)
HR(up)
TPR(up)      (In that order; or...)
BP(2^nd) = HR(3^rd) x SV(1^st) x TPR(4^th)

Renin(up) => TPR(up) + BV(up)

Reflexes in these situations are bad for the O₂-less heart, but would otherwise be good for the body
Beta Blockers => HR(down)
ACE-I => TPR(down)
Diuretics => SV(down)
Morphine => Pain(down) + sympathetic(down) (also, it's a vasodilator)

Cell death affects neighboring cells ability to fire

Necrotic Zone:  Area of dead cells
Zone of injury:  Outside of necrotic zone
Zone of ischemia:  Outside of zone of injury

Sympathetic => stress => cortisol => increased free fatty acids

Manifestations
Pain in patients >60 years
    Not relieved by nitrates
    Radiates to jaw/neck/arm
Sympathetic
    Sweat
    Cold & clamminess
    Anxiety
SOB (low O₂)
Women experience fatigue and SOB
Enzymes from dead/dying cells (necrosis => lysis)
    Creatine phospho kinase (from heart and muscle)
    Lactic acid dehydrogenase (from heart)
    Troponin I
EKG changes
    Dysrhythmias:  New enzymes in blood change electrolyte balance
    Circus phenomena:  Heart with cell death and associated complications doesn't fire in the right order
Thromboembolisms:  Blood sits around, clots, clogs

Therapy: 
    Apirin:  Anti-clotting
    O₂
    Morphine (vasodilator)
    Digitalis (digoxin):  Increases contractility, but also O2 demand

Morphine
Oxygen
Nitro
Aspirin

TPA
Streptokinins }Two other drugs that do stuff
Heart loses ability to contract well
Heart unable to pump enough to meet metabolic needs of the body

80% > 65 years
Progressive disese
Lowers quality of life
Systile heart failure: 
    SV(down)
    O2 needs > O₂ available
    Post MI, contractility loss, increased preload, increased afterload
Cardiac myopathies
MI
Infection (myocarditis)
BP(down2^nd) = SV(down1^st) x TPR(up3^rd) x HR
Cardiac remodeling,
Collagen deposition in heart
Cathecholamines (NE) toxic to myocardium (cause apoptosis)
AAngiotensin
Endothelin
Atrionaturetic Peptide   

Diastolic failure more common in women
Systolic:  Low EF (poor pumper)
Remodeling lowers ventricular compliance
Toxins
Post MI
Idiopathic

Class I:  As heart stretches, SA node stretches, => pt. needs a pacer

Symptoms
Left ventricle
    Forward:   
        Fatigue
        Increased sodium reabsorption in kidneys
        Lowered urine
    Backward
        Left atria swelling
        SOB (w/ dyspnea)
        JVD
        Edema of extremeties
        PE
Right ventricle
    Forward
       Decreased blood flow to lungs
       Skeletal fatigue
       Less blood to brain and
CHF is basically the same as left heart failure

Therapy: 
    O₂
    Beta blockers (HR lowering)
    ACEI:  (TPR lowering)
    diuretics
    CPAP
        Apnea activats sympathetic
HTN
BP = HR x SV x TPR
Complicaions of HTN
CAD
MI
Angina
HF
Backward
    Swelling and edema
Combination of living tissue (30%) and mineral salts (phosphate and calcium)
Lining gives strength
Minerals give hardness
Very well vascularized
Constantly being remodeled
Ages < 20, formation > destruction
Ages 20-40, formation ~ destruction
Ages > 40, formation < destruction
Cell Types
Osteocytes:  True bone cells (ossus = bone, cyte = cell)
Osteoblasts:  Bone-making cells (ossus = bone, blast = creation (big bang/blast started creation)) stimulated by hormones, also stimulated by certain diets, exercise too
Osteoclasts:  Bone-destroying cells (ossus  = bone, clast = destruction (think of iconoclasts or the word clash, but not the band)), eat osteocytes

Cortisol/Corticosteroids lead to a loss of bone because they decrease formation by inhibiting growth hormones
Serum calcium drop => increase of parathyroid hormone (PTH) => increases Ca⁺⁺ absorption across gut, decreases renal Ca⁺⁺ secretion, increased bone destruction
This process also happens for phosphate. 
Too much PTH (hyper-parathyroidism,) leads to hypercalcemia
There are no receptors for PTH or estrogen on osteoclasts.  Nobody knows why this this process happens
Calcitonin from the thyroid causes a drop in blood Ca⁺⁺, decreases osteoclast activity

Vitamin D is required for gut CA⁺⁺ absorption
Pressure
Electricity (causes muscle activity which causes stress on the bones)
Exercise
Cytokine activity during an injury
Fractures:  Break in bone continuity.  In young males, most common at extremeties.  In elder people, most common at vertebrae and hips. 
Complete fracture:  Whole shaft
Green stick fracture:  Common in children.  Looks like what happens if you break a sapling
Open fracture:  Bone is exposed to the environment, may lead to infection, (great way to get necrotizing fasciitis) 
Pathological fracture:  No injury.  Caused by weakened bone (from infection, osteoporosis, tumor, or an old fracture)
Bleeding, swlling, inflammation
Fracture hematoma forms a mesh where new bone is formed
Callus:  Cartilage formation after a break

Problems can occur in children with breaks at epipheseal plates
The bone is normal, (not diseased,) but absorption outpaces formation
More in women than men, (men have thicken bones to begin with, (they bear more weight and men also have testosterone))
Family history
Thin people (less self-weight bearing)
Fair skin
Estrogen (related to bone creation and slowed bone destruction)
Lutenizing hormon (LH) and follicle stimulating hormone (FSH) increase osteoclast activity
Premature menopause
To increase  bone formation (a little different than the last list)
Weight bearing exercise
Estrogen-replacement therapy (slows osteoclast activity)
FosaMax
Menstrual dysfunction (low estrogen)
Eating disorders
BMI =< 18
Both diffuse and specific pain
Mostly affects women
Happens at 30-50 years old
Symptoms include fatigue and depression
Affects high achievers, (believed to be a point where they become stressed out)
Victims can identify when condition began, (they got the flu and it became fibromyalgia
Vitamin D deficiency in kids
Low gut Ca⁺⁺ abosrption, PTH takes Ca⁺⁺ from bone, lack of Vitamin D from diet and skin, kidneys don't activate the D
Complications:  Abnormal bone deformation, lack of bone mineralization, lack of height
Partially reversable
OJ had it
Risk factors:  Dark skin, breast feeding (without a D supplement,) northern latitudes (>35 degrees latitude)
Motor-Nervous System
Normal Neuron
See this video (yes, I made it myself, no I didn't take that picture.  It's from Google Image Search)

Channels in cell allow ions to move in and out
Na- moves into cell (depolarizes it, making it less negative)
K- goes back into cell (repolarizes)
Neurons are more permeable to Na-
Once threshold happens, (-55 mv) depolarization happens

Myelin forms sheathes around axons to speed up the depolarization process.  Rather than traveling down the whole axon, it skips along different nodes of Ranvier.  (Places where the myelin coating gets thin) 
Progressive neurological disorder.  Degeneration of neurons in a region of the brain that controls movement
Degeneration of dopaminergic neurons in substantra nigra and other areas of the brain. 
Signs:  Hyperexcitability, termor, rigidity, loss of cognitive function, tremor at rest (begins unilaterally), "pill rolling", poverty of movement, chewing and speech issues, poor balance, depression
Records of it go back to 5,000 B.C. in India by Sai's great³⁴⁹ grandfather
Common in people over the age of 60
Primary:  No cause
Secondary:  Has a cause
Dopamine (Inhibits movement)
GABA (Inhibits movement)
Acetylcholine (ACh) (Excites movement)
Not-clearly inherited
Possible genetic links (I realize it doesn't make sense if you look at the one above it.) 
Protein accumulation
Genes that dispose of proteins  do too much/not enough
Possibly environmental
Drugs (schizophrenia drugs)
Tumors
Toxins
Clusters
Trauma
Treatments
Dopamine precursor (Levadopa) (Given early)
Monamine antagonists:  Stop dopamine breakdown.
Anticholinergic drugs
Neurotropic factors:  Get people to develop new neurons (glial cells)
Cell transplants
Adrenal...  (the room was really hot and I started falling asleep)
1 in 1,000 people have MS
Women more than men
Shows up when people are 20-40 years
May be genetic
Prevalence varies
People from higher latitudes
Etiology:  Unknown
Consists of an autoimmune attack against the myelin on your neurons
Axons may come under attack
Signs:  One-sided weakness, loss of peripheral vision, incontinence, inability to walk, spastic, cognitive issues, ear-ringing, pain
If MRI is positive with the first episode, prognosis is worse, (disease progression will be faster)
Has a sudden onset
In pregnant women, MS goes into remission (because of the anti-inflammatory response)
After parturition, low estrogen starts pro-inflammatory stuff and MS comes back (like that proverbial cat)
Stress => Immune response => MS+ (pro-inflammatory response triggers it)
Fever => MS+
MS is a T-Cell-driven response
B-Cells also make one antibody
Dx: Monoclonal antibodies are high, MRI shows brain lesions
Tx:  Glucocorticoids (steroids, to stop inflammation), Interferons (ex interferon beta (betaseron))
Avoid hot temperatures, (saunas, hot tubs,) as they may inflame
Chorea:  Wild dance
Rare, degenerative disease of the basal ganglia and cerebral cortex
Either parent to either sex kid (autosomal dominant)
Occurs at 30-50 years
Chromosome IV
Expanding gene codon leads to destruction of the brain and general cell death
Lots of jerky movements

Use 5,000-6,000 calories a day

Dementia

Mitochondria are affected

Loss of GABA (inhibitory hormone)

Manifestations:

Jerkiness

Depression

Dementia

Diagnosis:  Genetic analysis

Therapy:  Death (approximately five years after onset)

Myasthenia Gravis

Progressive failure of pulses at neuromuscular junctions

Motor neurons => acetylcholine (ACh) => Muscle

ImG:  Antibodies develop against acetylcholine receptors

Symptoms

Muscle fatigue

Reduced contractability

Slurred speech

Drooping eyelids

Worsening of symptoms with fatigue

Improvement of symptoms with rest

Therapy

Drugs that block breakdown of ACh

Plasmapheresis

Drugs

Thymectomy

Diagnosis: 

If Tensilon ACh-esterase inhibitor IV, (anti-ACh-ase,) makes patient perk up

Death:  Diaphragm stoppage

Amyotropic Lateral Sclerosis (ALS)

Degenerative disease of upper and lower neurons

Cranial nerves III, IV, VI exempt

Occurs without obvious inflammation

Ideopathic

Five year life span

No direct genetic link

Clinical manifestations:  Starts with one muscle group and progresses.

Death:  Respiratory failure

Endocrine system

Function:  Maintain steady-state homeostasis

Negative feedback loops:  Hormones stimulate foreign tissues to remove negative stimulus

Daily circadian rhythm

Pregnancy & growth have non-standary steady states

Works to ensure reproduction (pass on DNA)

Large fluctuations not the norm

Cells can up & down regulate receptors (grow more/shed)

Up regulate to maximize stimulus

Down regulate to avoid overstimulation

Hormone Types

Proteins:  Large (too large to cross cell membrane.)  Needs a cell-surface receptor to activate a 2^nd messenger

Steroids:  Get into cell plasma via membrane

Amines:  Small, usually enter via receptors

The hypothalamic-pituitary hormonal system

Negative

Affective disorders
Lack of vocal inflection
Poor eye contact
Elosia (poverty of speech)
Antidonia (lack of pleasure)
Apathy
Family
No single gene found (thought to be many genes)
Environment exposure
    Pre-natal viral infections (Finnish influenza)
    2^nd trimester neuron migration in brain goes wrong
    Dutch low caloric mothers
    Babies born during certain months of the year
    Hypoxia at birth
Neurological-anatomical abnormalities
Brain structural changes

Change in neurotransmitters
GABA (inhibitory)
Dopamine (inhibitory)
Excess dopamine can lead to schizophrenia
Serotonin can change dopamine binding
5-10% resond 100%
Side effects totally suck
Tardive diskinesthia
8-20% of people have major depression
Poor mood
Unable to feel pleasure
15% mortality rate (suicide)
Women get it more than men
Occurs at any age
Rates are higher in teens, middle-aged adults and elderly
Clinical manifestations
(Need two week of five of these)
Weight gain or loss
Insomnia, hypersomnia
Psychomotor agitation or retardation
Fatigue or energy loss
Worthless or guilty feelings
Decreased ability to think/act/concentrate
Recurrent thoughts of death or suicide
25% of indviduals will experience a manic episode
Increased mood
Irritability
Inflated self esteem
Decreased need for sleep
Flight of ideas
Increased physical or pleasurable behaviors
Poor impulse control
Genetic
Environment (trigger, often stress)
(Both are needed) 
Biochemistry of depression
Serotonin abnormalities
Hypersecretion of cortisol (30-70%)
Blunted response to TSH (20-30%)
Treatment:  Increased monoamines (serotonin and norepineprine)
Mania:  Excess monoamine
Treatment takes time
Prescriptions:
Monoamine oxidase inhibitors (MAO):  High side effects
Tricyclic antidepressants:  Stops uptake, (I think of serotonin,) has side effects
Selective Serotonin Reuptake Inhibitors (SSRI):  Few side effects, prolongs serotonin
Treatment
Lithium:  Cell membrane stabilizer.  People might miss the mania
Hypercortisolemia can lead to depression
Hypocortisolemia can lead to depression
Hypothyroidism can lead to depression, (why it spikes in the elderly)