Week 3 Sem 2 Med1022 Flashcards
Variation- 2 types of genetic mutation producing polymorphism
Single base mutation Variable length insertion/deletion
Pharmacogenetics
Study of how genetic differences influence the patient-drug interaction
Beta-2 adrenoreceptors
Receptor for salbutamol to cause bronchodilation n vasodilation Receptors may be mutated so become hyperresponsive (= initially great response but then becomes desensitised wit long term treatment ) Have to stop takin beta-2 agonists in long term
Metabolism of drugs
Metabolised by liver enzymes eg those part of CYP450 family Biotransformation Then leave the body
Gene for CYP450 r very polymorphic, thus can get these variations:
Deleted gene -no enzyme, no metabolism of drugs SNP-eg unstable enzyme (reduced metabolism) Normal enzyme Duplicated genes (higher enzyme levels, faster metabolism)
Some patients r CYP2D6 deficient
Slow metabolism Drug levels too high No prodrug activation
Some patients r CYP2D6 duplicants
Metabolism too fast
HER2
Human epidermal growth factor receptor 2 Tyrosine kinase receptor overexpressed in breast cancer Herceptin (monoclonal antibody) effective for this form of cancer, but not forms caused by other genetic mutations
Pharmacogenomics
Use of genetic info to guide drug therapy-dif in responses can be predicted if genetic makeup is known
Prospective efficacy
Using pharmacogenetics to select patients who r predicted to b responders/non-responders/hyper-responders to particular drug
Skeletal muscle
Regeneration: limited Voluntary movement Many nuclei peripherally Striated (due to sarcomeres)
structure of skeletal muscle
whole muscle (surrounded by epimysium) fascicles=bunches of muscle fibres (sur. by perimyiusm) each muscle fibre (sur. by endomysium) each muscle fibre has many myofibrils each myofibril has many myofilments myofilaments arranged into sarcomeres
sarcomere
segment bw 2 neighbouring Z-lines
I band
actin only
A band
entire length of myosin
H zone
myosin only
M line
proteins that form attachment site for myosin, half way through A band
Thin filaments
actin (+ tropomysin + TROPONIN)
tropomysin
long strand thingy that covers the active site on actin
troponin
has Ca2+ binding site
Thick filaments
myosin
myosin
globular heads are cross bridge projections each head has actin binding site n ATPase site
cross bridge cycle
- ATP splitting- BASICALLY ATP STUCK TO MYOSIN HEAD N IS CHOPPED IN HALF TO ADP AND PI 2. Attachment- BASICALLY CA2+ STICKS TO TROPONIN, CAUSING TROPOMYSIN TO EXPOSE ACTIVE SITES ON ACTIN 3. Power stroke- BASICALLY HEAD OF MYOSIN BINDS TO ACTIN, PULLING IT IN, using ENERGY FROM CHOPPING UP ATP BEFORE 4. Detachment- BASICALLY ADP AND Pi ARE RELEASED FROM MYOSIN HEAD. ANOTHER ATP ATTACHES TO MYOSIN HEAD. MYOSIN HEAD DETACHES FROM ACTIN. (THEN ATP IS SPLIT –CYCLE STARTS AGAIN)
notes for cross bridge cycle
ATP splitting occurs before any attachment to actin -to get myosin head ready to go. Need ATP to bind to myosin head before myosin head can let go off actin (STEP 4) otherwise, myosin head would get stuck on actin= cycle locks after step 3 hence Rigor Mortis (body becomes stiff after death)
other notes for cross bridge cycle
the faster u split the ATP the faster the cycle can keep going/repeat (i.e. faster rate of cycle) the faster the muscle can contract/shorten ie myosin ATPase activity is a determinant of muscle speed
isometric contraction
muscle stays same length tension mite be fluctuating, e.g. holding weights still the invisible chair
isotonic concentric contraction
u overcome the force n the muscle shortens muscle contracts against a load that it is able to move eg lifting up dumbell
isotonic contraction
tension stays the same length of muscle changes energy required by muscle changes
eccentric contraction
the opposing force is greater than the force created by the muscle and the muscle lengthens e.g. putting down dumbbells walking down steep hill if u keep doing this u get DOMS (Delayed Onset Muscle Soreness)
antagonist muscles
muscles with opposing actions one muscle is flexing and one is extending the joint eg bicep n tricep
agonist muscles
muscles doing same action two muscles which work in conjunction with one another to perform the same movement across a joint
Passive Force
when a resting muscle is stretched Reflects passive elastic property of the muscle nothing to do wit contraction
Active Force
force generated by the crossbridges during a contraction depends on the length of the muscle
ryanodine receptors
channels that release Ca2+ on Lateral sac of sarcoplasmic reticulum
Length - Force Relation of Muscle ??
at optimal muscle length: all cross bridges attached
= max force is produced
??? at longer lengths less force less overlap bw thin n thick filaments less cross bridges ??? at shorter lengths less force but reason is complex Z-lines hit ends of thick filaments causing them to buckle
dihydropyridine receptors
‘voltage sensors’ on T-tubule
muscle wen contracts does WORK (moves a load through a distance)
work done= load x distance
______% chemical energy is converted to work, the rest is dissipated as heat (muscles produce heat when they contract)
20 - 25%
2 important features of isotonic contractions
1.amount by which the muscle shortens: lighter the load the further the muscle can shorten?? 2. velocity, or speed, at which it shortens lighter the load the faster the muscle can shorten
velocity
Distance Shortened/ time
Force – Velocity Relation
relationship between load and the velocity of muscle shortening fastest velocity of shortening (Vmax) occurs with zero load (determined by its myosin ATPase activity bc this determines how quickly the crossbridges can cycle) lowest velocity of shortening = zero wen muscle cant move the load (i.e. isometric contraction)
Power def
rate at which work is done
formulas for power
Power= work done/time power= load x distance/time load=force, distance/time=velocity => power= force x velocity
power
determined by the force muscle is generating and the velocity at which it is shortening
max power
wen muscle is contracting wit 1/3 max force and 1/3 max velocity
Twitch contraction
Response to a single action potential contraction lasts much longer than the AP that triggered it also a latent period bw AP and contraction (cos takes time for EC-coupling (excitation-coupling) to occur)
SUMMATION of the contractions
wen a second contraction builds on the first, producing an overall higher force occurs wen a 2nd AP produced while muscle still contracting to 1st AP.
TETANIC CONTRACTIONS/tetanus
Response to repetitive stimulation if stimulation not very frequent, get unfused tetanic contractions if stimulation very frequent, get fused tetanic contractions
max force generated by muscle wen
optimal muscle length + force in a fully fused tetanic contraction
each muscle fiber
only recieves
Smll motor unit
large motor unit
RECRUITMENT OF MOTOR UNITS
wen we vary the number of motor neurons going to a whole muscle so that we can get different numbers of muscle fibers being contracted
(btw, wen there is an AP in a motor neuron, ALL of the muscle fibers innervated by that neuron (ie motor unit) will contract
notes for RECRUITMENT OF MOTOR UNITS
generally smaller motor units r recruited first befor bigger ones (cos they have smaller cell bodies, hence, lower thresholds for excitation)
Functional importance of motor units
- _Contractile strength gradation _: the more motor units recruited, the stronger the overall contraction will be (each motor unit can also grade its own contraction by varying the frequency of AP firing)
- Fatigue reduction: allow the contractile work 2 b shared bw muscle fibers (fanks to asynchronous activation of different motor units)
Grading the Strength of Contraction
(summary)
- Varying muscle length
Length - Force Relation of Muscle
- Varying the frequency of excitation
varying the rate of firing motor nerves
- Varying the number of motor units activated
Recruitment
Glycolytic =
Oxidative=
anaerobic
aerobic
Muscle gets E from 3 pathways
- The Creatine Phosphate (CP) immediate energy pathway
- Anaerobic metabolism (ie glycolysis)
- Aerobic metabolism (aka Oxidative Phosphorylation)
The Creatine Phosphate (CP) immediate energy pathway
basically creatine phosphate + ADP -> ATP + Creatine
very fast but limited (depends on availability of creatine phosphate
ANAEROBIC GLYCOLYSIS
Relatively insufficient-only get 2 ATP per glucose molecule
Need glucose as fuel (from blood or muscle glycogen stores
vERY fast
don’t need oxy- but lactic acid produced
AEROBIC ENERGY PATHWAY
very efficient (get 38 ATP per glucose
but slow
can use glucose, fats or proteins
low intensity exercise
mainly use FATS
high intensity exercise
mainly use CARBO
the more muscle glycogen u have
the longer it takes to exhaustion (aka
” carbo loading “)
3 types of muscle fibers
- Type I fibers/slow fibers/slow-oxidative fibers/slow motor units
- Type IIA fibers/fast-oxidative fibers/ Fast fatigue-resistant motor units
- Type IIB fibers/fast-glycolytic fibers/Fast fatigueable motor units
Type I fibers/slow fibers/slow-oxidative fibers/slow motor units
- Mainly does oxidative phosphorylation
- Fibers r small in diameter
- Motor units r small
- Lots of capillaries (cos need 02) n mitochondria present
- Myoglobin content high (red muscle)
- For prolonged contractile activity with high endurance (e.g. maintaining posture)
Type IIA fibers/fast-oxidative fibers/Fast fatigue-resistant motor units
- Mainly does oxidative phosphorylation
- Fibers r intermediate in diameter
- Motor units r intermediate
- Lots of capillaries n mitochondria present
- Myoglobin content high (red muscle)
- For relatively fast movements with medium endurance
Type IIB fibers/fast-glycolytic fibers/Fast fatigueable motor units
- Mainly does glycolysis
- Fibers r large in diameter
- Motor units r large
- Few capillaries n mitochondria present
- Myoglobin content high (red muscle)
- For rapid, powerful movements
muscle fibers
decrease in ability to generate force during prolonged activity
Type I fiber
Type IIA fiber
Types II B fiber
very resistant to fatigue
moderately resistant to fatigue
fatigues most rapidly
some facts bout muscle fiber activity
- speed of contraction cant change
- slow fibre cant change to fast fibre
- transition bw type II fibres possible
- proportion of type I and type II fibres genetically determined
Endurane trainign
increases oxidative capacity of all muscle fibres involved (doesnt matter type)
mito, oxidative enzymes + capillaries increase
can increase diameter of type I fibers (makes them stronger)
some type IIB fibers may change to type IIA fibers
Strength (Resistance) training
increases capactiy of anaerobic pathways in fibers involved
increases conc of glycolytic enzymes
type IIA to type IIB transitions
increase muscle fiber size (diameter) in all muscle types
(greater increase achieved than with endurance ttraining)
muscle hypertrophy
more actin n myosin laid down= get bigger cells
btw testosterone promotes synthesis of actin n myosin
never get MORE muscle cells
Sarcopenia
age related decrease in skeletal muslce mass n strength
exercise as treatment strategy
Erikson’s Stages of Early Psychosocial Development
(3 main stages)
stage 1
Basic Trust vs. Mistrust (Infancy) (0-1 yr)
basically, kid is dependent on n looked
after by caregiver (usually
mother) consistantly
the care of caregiver develops basic sense of trust n openess in kid
Erikson’s Stages of Early Psychosocial Development
stage 2
(mainly 3 stages)
Autonomy vs. Shame and Doubt (1-3 years)
- children starts to have control over own action n does ‘cool stuff’ eg run around, manipulate objects
- but if fail, there is shame n doubt
- eg ‘i willcarry my lego by myself’, then drops it
Erikson’s Stages of Early Psychosocial Development
stage 3
(mainly 3 stages)
Initiative vs. Guilt (3-5 years)
- Children develop imagination for possibilities
- kids’ imagination in play flourishes
- if they want to play somethin, but someone else doesnt, guilt comes in for the child who’s at odds with other children,
the challenge here is being able to cooperate with others - get support from parents=
initiative and cooperation are developed
The Growth of Attachment
- basically, attachment (human behaviour) is a evolutionary survival advantage
- attachment= security + need for physical closeness with someone
- usually attachment to mother, but could b any caregiver
Steps Toward Attachment
- Preattachment Stage (Birth to 6-8 weeks)
- Attachment in the Making (6-8 wks to 6-8 mnths)
- True Attachment (6-8 months to 18 months)
- Reciprocal Relationships (18 mnths on)
Preattachment Stage (Birth to 6-8 weeks)
in this stage, newborns will
attach to anyone, not picking who’s who yet
Attachment in the Making (6-8 wks to 6-8 mnths)
starts to work out who mother is
thinks mothers do it better
can select out mum
eg at party, kid passed around but kid cries, wen back to mum, stops cring
True Attachment (6-8 months to 18 months)
gives the infant a secure base to explore the world eg kid crawls forward, then
looks back to mother 2 check if its ok
Reciprocal Relationships (18 mnths on)
the infant has basic capacity to care for the parent eg kid wants to go to the park, so gets sneakers n gives them to parent
(so parent can help him tie on his shoelaces
Father-Infant Relationships
- usually its attachment to mum first, then father relationship development follows
- dad tends to spend more time playin kid, while mum more for comforting eg dad plays with kid, but wen kid falls n hurts himself, calls mum first to care
Forms of attachment
(found through experi. where kid n mom goes into unfamiliar room then mum leaves. focus is on wen retursn, how does kid react)
- SECURE ATTACHMENT
- wen mum returns, kid is comforted/cryin stops. kid explores again
- AVOIDANT ATTACHMENT
- kid just ignores/turns away fr mum, continues wat kid was doin
- child doesnt get much from mother- there is this expectiation that kid should be independent
- RESISTANT ATTACHMENT
- kid is upset n remains upset
- stress n ambivalence present
- ‘i need u to be here n u werent here!’ ‘im really not happy bout this situation’
- DISORGANIZED ATTACHMENT
- kid is confused-not sure how to react
- most concerning type
- seen where there is abuse/neglect
- ns wat’s gonna happen next/wat mother can provide
other notes bout step towards attachment
- most kids r in secure attachment, least % of kids in disorganised attachment
- this attachment is kindof 2 way: not just kid but
also parent has effect.- ESSENTIALS FOR PARENTING
- warmth
- sensitivity
- responsiveness
- dependability
Consequences of Attachment
- basically kids wit more secure attachments= better social relationships later on, more confident and successful with peers, better mental health etc
- children use early attachments as prototypes (ie the internal workin model) for later relationships and interactions
internal working model
expectations derived from early caregiving experiences (concerning the availability of attachment figures and one’s interaction with those figures)
Play
- 1 year= kids play alongside each other without much interaction
15-18 months= kids do similar activities (eg most play lego) + smile at each other in simple social play , but no intergrated play yet
2 years=kids play togez eg lets play chasey, or build this structure etc interactive play
Gender Differences in Play
- bw ages 2-3, boys tend 2 play wit boys, girls play wit girls for all types of activities
Girls tend to support girl peers in enabling
boys tend to compete/contradict/threaten boy peers in activity known as constricting
Prosocial behavior
any behavior that benefits others
Altruism
- behavior that does not benefit oneself but does benefit others, such as helping and sharing
- kids as young as 18 mnts show altruism
- skill underlying altruistic behaviour is empathy
study design- basic terms:
case
someone wit disease/condidtion that we’re interested in
study design-basic terms:
control
someone who doesnt have the disease/condition that we’re interested in (opposite to case)
study design-basic terms:
exposure
anything that influences the likelihood of someone getting the disease/condition we’‘re interested in
study design-basic terms:
outcome
descriptive studies
- eg ideas/editorials/opinions, case reports (wen ppl have seen something unusual n they’ve written it up), case series (=series of those observations)
2.
ecological studies
- observations made on GPS not INDIVIDUALS (hence not on flow chart)
- can suggest that something is associated wit somethin =good for makin hypothesis
- problem: ecological fallacy: eg info collected about alcho. consump. n liver cirrho. was not collected from the same ppl>so cant assume cause n effect
cross sectional studies
- basically ask ppl about themselves (ie the exposure) n their health (ie the outcome) at the same time but bc of this we have a problem: cant tel which caused which
- eg end up with:
people who report cannabis use are more likely to be depressed
BUT we dont noe whether:
cannabis caused depression
or depressed ppl choose to use cannabis more
case control studies
we start wit the disease state: whether they’ve got the disease (
hence they’re a case) or if they didnt have the disease (=the control)
then we go bak in time n see if
they were exposed to something we’re interested in
- good for finding causes of RARE DISEASES
- use ODDS RATIOS
odds ratio
to find relationship bw exposure n disease
to calculate odds ratio,
its pretty much
wat r the odds of exposure in the cases
vs the odds of exposure in the controls
odds ratio= odds of exposure in cases [(disease + exposure)/(disease+ no exposure)] / odds of exposure in controls [(control + expos.)/(control + no exp.)]
the outcome (11.6) shows that the disese was much more likely to happen with those that were exposed
cohort studies
- basically u start with the exposure (or no exposure) then u follow ppl through til some ppl get the disease n some dont
- 2 types: PROSPECTIVE= u start the study tday n u expose/dont expose the patients today to the future
RETROSPECTIVE= u identify the exposure that occured in the past and u follow ppl up, to the present (maybe useful inthings like cancer causation. BUT often need very good/unbiased documentation of exposure from past=difficult to get)
- always move forward in time
- gud for estimatin risk of developin disease due to a particular exposure
- outcome is risk ratio aka relative risk
nested case control study
HIGHLIGHT bout these is that
- u get documentation of exposure BEFOR devel. of outcome
- dont need to assess all blood samples in cohort
basically, there’s a large gp of
eg women.
then u follow them through
til eg some of them get breast
cancer. these will be called
‘cases’. those that didnt,
we take a subgroup of them
n call them ‘control’.
At the beginning, u mite have
collected all their blood samples
and looked at something of interest
eg blood oestrogen levels.
Now u mite say ‘i wonder if their
blood eostrogen levels yrs n yrs
before hand had something to do wit
their breast cancer
BC now that u have ur two little gps,
u only need to check their blood
samples ( rather than all samples from the
the originial gp) to see if
blood eostrogen levels had something
to do with the breast cancer
randomized controlled trial
Gold-standard study design for findin causation
- but cant do RCT all the time (eg cant expose ppl to somethin dangerous eg smokin vs non smoke, just to see wat happens
can answer simple questions such as in the ASPREE trial (eg ‘
is it better for people who are otherwise well and over the age of 70 years to take a low dose of aspirin daily or not? (n~20,000) “)
- commonly used to show treatment works/doesnt eg drug trials, vaccine trails, behavioural interventions
ususally every1 is blinded as to who is in gp A wit the
tablet or who is in gp B with the placebo /double blinding
cluster randomized trials
not getting randomization of individuals, rather we’re getting gps randomized.
eg gps were randomised to say different things to all their patients
NOT gp say different things to each of THIER patients (since not possible)
meta analysis
- combo of trials n data from them to get the bigger pic
and also get more stable results than if it were just from
1 trial by itself - thing about meta is that it is only as free of bias as the individual studies that contributed to it
cranial nerves for eye muscles/movement
CN 3,4,6
cranial nerves for face muscle/expression
CN 7
cranial nerve for neck muscles (SCN n trapezius
cranial nerve for tongue movement
CN 12
pattern of weakness in musculoskeletalness if upper motor neurons affected
- UL(upper limb) flexors are stronger; LL(lower limb) extensors are stronger
- spasticity(increasedmuscletone=unusual “tightness”, stiffness, or “pull” of muscles)
- hyperreflexia (reflex overactive/overresponsive, get eg twitching
- extensor plantar reflex
pattern of weakness in musculoskeletalness if lower motor neurons affected
- weakness of all innervated muscles of the affected nerve (ie extensors n flexors r equally affected)
- atrophy (muscle wasting)
- fasciculations (smll muscle twitch)
- hypotonia (decreased tone)
- hyporeflexic or areflexic (below normal or absent reflexes, opposite of hyperreflexia
Parkinson’s disease
substantia nigra neurones degenerate, so not enough dopamine provided to the basal ganglia
“underactive” movement disorder
huntington’s disease
“Overactive” movement disorder
autosomal dominant
Involuntary movements, ie couldnt keep still (constantly fidgeting)
lateral sacs of sarcoplasmic reticulum
pumps Ca2+ from cytoplasm to inside.
releases ca2+ without atp to cytoplasm wen action potential comes etc etc
sarcolemma
plasma membrane
sarcoplasmic reticulum
bags of ca2+
has LOTS of Ca2+ (compared to cytoplasm)
(so must PUMP Ca2+ from cyto back into sarcoplasmic ret)
process from action potential to ca2+ release from sarcoplasmic reticulum
- AP runs down sarcolemma n depolarise T tubule
- dihydropyridine receptor on T tubule tells
ryanodine receptors on lateral sac of sarcoplasmic reticulum to open
- Ca2+ released from SR down its conc gradient
3 ways to grade strength of contraction
- vary muscle length (length-force relation)
- vary rate of firing neurons
- vary number of motor units recruited
