IM FUCKED GOD PLS HELP Flashcards by New a

Q

Lofexidine

A

non-substitute detoxification, central ⍺2-agonist, suppresses some components of withdrawal syndrome

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Q

Methadone

A

substitution method of detoxification, long-acting drug, no euphoria to morphine

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Q

Naltrexone:

A

opioid antagonist, prevents euphoria to opioids, given daily to addicts to prevent relapses, reduces alcohol-induced reward

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Q

Buprenorphine

A

partial agonist, substitution method of detoxification

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Q

Clonidine:

A

⍺2-adrenoceptor agonist inhibits excessive transmitter release happening during withdrawal

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Q

Propranolol

A

β-blocker blocks excessive symp

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Q

Acamprosate

A

weak NMDA antagonist interferes with synaptic plasticity, reduces crave

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Q

Disulfiram

A

causes accumulation of acetaldehyde making alcohol consumption unpleasant

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Q

Nicotine replacement therapy:

A

relieves psychological + physiological withdrawal syndrome + reduces cigarette consumption but not nicotine abstinence

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Q

Bupropion

A

Antidepressant blocking monoamine reuptake so NA + DA
Nicotinic antagonist, ↑[DA] in nucleus accumbens
induce seizures, eating disorders, mania (bipolar disorder)

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Q

Varenicline (Champix):

A

partial α4β2 nAChR agonist, full agonist for α7 nACHR, more effective than NRT

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Q

Withdrawal syndrome

A

physical characterised by abstinence syndrome (LC) sweating, gooseflesh (cold turkey), irritability, aggression
psychological characterised by craving to avoid withdrawal effects

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Q

Chronic drug administration

A

homeostatic adaptive changes to oppose drug action, withdrawal –> rebound effect
eg alcohol causes convulsions
amphetamine causes sedation

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Q

Mechanism of dependence (DA)

A

Less frontal cortex activity + less striatal D2 binding

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Q

Mechanism of dependence (α4β2)

A

Upregulation of α4β2 + rapid development of tolerance – desensitisation of nAch receptors

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Q

Impulsive control disorders

A

cycle of tension/arousal
impulsive acts
pleasure/relief/gratification
regret/guilt/self-reproach
REPEAT via positive reinforcement (natural reward)

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Q

Compulsive disorders:

A

cycle of anxiety/stress
repetitive behaviours
relief of anxiety/stress
obsessions
REPEAT via negative reinforcement (anti reward)

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Q

Positive reinforcement:

A

social drug-taking
drug induces pleasurable effect
triggering further drug administration via natural rewards

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Q

Negative reinforcement:

A

drug
tolerance
escalating compulsive
dependence
negative emotional state triggers craving
drug administration via aversive, dysphoria experience of withdrawal NOT high

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Q

Opioids target

A

Agonist at μ (δ, κ) opioid receptors

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Q

Cocaine target

A

Dopamine transporter blocker – indirect DA agonist

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Q

Amphetamine target

A

Dopamine releaser – indirect DA agonist

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Q

Alcohol target

A

Facilitates GABAA + inhibits NMDA receptor function

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Q

Nicotine target

A

Agonist at nACh receptors

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Cannabinoids target

Agonist at CB1 receptors

Phencyclidine target

NMDA receptor antagonist

Hallucinogens target

5-HT2A agonists

Cocaine

Blocks catecholamine reuptake so↑DA, stimulant effect

Amphetamine

Release cytosolic monoamines (DA)

MDMA (ecstasy)

-Inhibits monoamine transporters -Large ↑5-HT -depletion ↑5-HT --> psychotomimetic effects ↑DA --> euphoria followed by rebound dysphoria

Alcohol

- Potentiates GABA-mediated inhibition like Bz - Inhibits presynaptic Ca2+ entry - Inhibits transmitter release - Disinhibits mesolimbic DAergic neurons (↑ reward) - Induces release of endogenous opioid peptides

Nicotine/tobacco

-nACh receptors, α4β2 subtype Receptors, ligand-gated cation channels (pre- + post-synaptic) -↑NT release + neuronal excitability including opioid peptides -Cortex + hippocampus (↑cognitive function) -Ventral tegmental area VTA (where DAergic neuron project to nucleus accumbens reward pathways via DA release)

Barbiturates

Positive allosteric modulators - ↑Affinity of receptor for agonist - ↓GABA required for same response - GABA receptor channel opened for longer --> ↑Cl- in less time

Benzodiazepines

- Positive allosteric modulators binding at alpha-gamma interface of pentamer but only bind to alpha 1, 2, 3, or 5 - Stabilise GABAa receptors in open state so ↑binding of GABA

Flumenazil

competitive antagonist at BZD binding site used for OD

Z-drugs

Bind at alpha-gamma interface on GABA-A receptors

5HT1A receptors

metabotropic,presynaptic membrane, auto-inhibitory

Buspirone

For GAD - 5HT1A agonist - increased activity of receptors - body downregulates receptors - buspirone still inhibits serotonin release but to a smaller extent than before - overall increase in serotonin release in synapse

α1:

on postsynaptic membrane couples Gq to activate phospholipase C

α2

on presynaptic membrane couples Gi to inhibit adenylate cyclase

β1

on postsynaptic membrane couples Gs to activate adenylate cyclase - ↑HR, impulse conduction, contraction, ejection fraction - ↑Renin release by juxtaglomerular cells - ↑Ghrelin release by stomach for hunger

β2

on postsynaptic membrane couples Gs to activate adenylate cyclase - SM contraction of bronchus, bronchioles, detrusor muscle, uterine muscle - Contract urethral sphincter - ↑Renin release by juxtaglomerular cells - Glucose metabolism: inhibits insulin release, stimulates gluconeogenesis, glycolysis, lipolysis - Thickened salivary secretion

Venlafaxine

- 5HT + NA reuptake inhibitor (SNRI) - Serotonin transporter > NA transporter - ↓appetite due to activation of adrenoceptors

Trazodone

- 5HT2 receptor antagonist blocks reuptake of serotonin - α2 antagonist - 5HT reuptake inhibitor - 5HT2, 5HT3, H1 antagonist

Mirtazapine

- α2 antagonist | - ↑5HT + NA release in synapse

Mianserin

α2, 5HT2A, α1 antagonist – cause bone marrow depression

Estrogen

treat postpartum depression via monoamine system, GABA system, glutamate system

TCA Amitriptyline

- NA + 5-HT reuptake inhibitor - Block Mus so anticholinergic + antimuscarinic --> constipation, blurred vision, dry mouth, drowsiness (reversible) - Block H1 --> weight gain + sedation - Block α adrenoceptors --> ↓BP, postural hypotension, tachycardia, dizziness

Reversible MAOi

Moclobemide | -Accumulation of NA displaces RIMA so degradation of excess NA

MAOA

breakdown of 5-HT > NA > DA + tyramine – in cheese + wine

MAOB

breakdown DA

Aneuploidy

- Nondisjunction - Misscariages - Extra chromosome maternal

Sex chromosome aneuploidy

Lives :)

Trisomy 21

Downs MOST nondisjunction Robertsonian translocation Mosaic

Trisomy 18

Edwards Maternal meiotic nondisjuntction MOST trisomy Die

Trisomy 13

``` Patau MOST trisomy from maternal nondisjunction Translocations Midline defects Eyes close together ```

45XO

``` Turners Paternal meiotic errors Can be mosaic Hands/feet oedema Webbed neck Underdeveloped female ```

47XXY

``` Klinefelters Non disjunction paternal/maternal meiosis Mosaic Phenotypically MALE Female fat distribution ```

47XYY

Paternal meiotic non disjunction | Tall

DiGeorge

De novo | Commonest deletion syndrome

Williams syndrome

De novo + autosomal dominant Microdeletions 100% penetrant ELN gene elastin --> CVS disease

Chondrocytes

secrete collagen, proteoglycans, hyaluronan

Hyaluronan

Tethers aggrecan which is held together by collagen type II fibres GAG High viscosity Highly hydrated Low load + high velocity (hydrodynamic lubrication)

Aggrecan (GAG):

Proteoglycan induces osmotic gel swelling pressure inflates cartilage by creating negative charge

Avascular articular cartilage

nutrients from synovial fluid

Type II collagen fibrils:

hold it together, resist gel swelling tendency

eg Glycosamino-glycan chain (GAG):

chondroitin sulfate, keratan sulfate, hyalauronan

Proteoglycan

= GAG + core protein Has core protein surrounded by GAG chains fixed negative charge + huge osmotic (swelling) pressure from attracted cations – Gibbs-Donan effect

Achieve stability

- Congruity - Fibrous capsule + its thickenings into extra-articular ligaments - Intra-articular ligaments - Packing improves congruity by: menisci: semilunar cartilages, knee, fat pads - Muscles acting across joint

Pannus

releases metalloproteinases

TIMPS

released to inhibit activity of metallopeptidases but low conc to make diff

Collagenases

metallopeptidase | cleave collagen type II cleaved + unwind triple helix structure

Metallopeptidases

cleave collagen leaving 1/4 + 3/4 fragment | 1/4 fragment reveals antibody binding site (neoepitope)

Aggrecanases

cleave aggrecan at several points in chain

ADAMTS

Aggrecanase | cleave aggrecan at certain points revealing antibody binding sites

DNA ligase

attaches Okazaki fragments by forming phosphodiester bonds via complementary nature of “sticky” ends ATP driven

G-banding

Few days Chromosome number Translocations LARGE deletions/dup

FISH

``` Few days Suspect gene/region Chromosome number Translocations Deletions/dup ```

Q-PCR

Quick Suspect trisomy Chromosome number

aCGH

Suspect gene | Point mutations

NGS

Point mutations

Gel electrophoresis

separate DNA fragments by size

Regulatory factors

recognise their target sequence | by interacting through major groove because greater bond variation

TATA box

promoter element which allows the binding of RNA polymerase (TBP, TFII, RNAPII)

Telomerase

Brings RNA fragment to | restore length of lagging strand

Topoisomerase II

molecular clamp unlinks tangled chromosomes using ATP to work clamp

Robertsonian chromosome

Fusion of acrocentric chromosomes 45 chromosomes is stable karyotype 46 chromosome is unstable

Deletion:

Breakage + loss of acentric fragment | Detected by array CGH/FISH

Haploinsufficiency

Deletion in monosomic region

Non-disjunction

failure of separation of chromosomes

Mosaicism

Presence of 2 genetically different cell lines, derived from same zygote eg production of trisomy

EEG awake

HIGH FREQUENCY Low freq Desynchronised

EEG sleep

Low freq HIGH AMPLITUDE Synchronised

Awake

- photoreceptors converge onto retinal GANGLION cell - thalamic cells RELAY - primary visual cortex

Falling asleep

- thalamic cells DONT RELAY - insensitive to retinal input via inhibitory neurone - automatically DEPOLARISE - fire AP w low frequency synchronously - repeat - disconnects primary visual cortex from sensory inputs

Serotonin pathway origins/projections

Raphe nuclei: projects throughtout CNS --> analgesia

Ach pathway origins/projections

- Pontomesencephalic tegmentum of brainstem projects to thalamus + cerebellum - Basal forebrain projects to neocortex + hippocampus

DA pathway origins/projections

- Substantia Nigra projects to basal ganglia | - Ventral Tegmental Area projects to frontal cortex, limbic areas: amygdala, nucleus accumbens

H1 pathway origins/projections

Hypothalamus projects throughout cerebral cortex + thalamus

Orexin pathway origins/projections

Hypothalamus projects to CNS

NA pathway origins/projections

Locus Coerulus of brainstem projects throughout CNS

Extradural haemorrhage

- MMA rupture - unconcious - lucid as dura takes time to stretch - symptoms

Subdural haemorrhage

-Trauma Blood clot between arachnoid + dural meninges -Rupture of veins crossing subdural space

Subarachnoid haemorrhage

- External brain vessels rupture - Berry aneurysm - Blood below pia/arachnoid following brain contours - Cerebral spasm --> stroke

Multiple petechial haemorrhage

-Obstruct small arterioles + capillaries

Watershed zone infarction

- profuse haemorrhage - low BF at arterial territories boundaries - no O2 to adjacent periphery territory tissue - infarction

Cerebral contusion

trauma

Microaneurysm

- hypertensive cerebral arteries rupture | - intracerebral haemorrhage

Aortic dissection

- elderly w medial wall degenration | - marfans

Berry sacular

- circle of willis bifurcations rupture | - subarachnoid haemorrhage

AAA

- post atheroma - rupture - intraperitoneal haemorrhage - thromboembolis - ischamia + gangrene

cingulate gyrus

empathy

mamillary bodies

episodic memory

parahippocampal gyrus

environmental scenes

amygdala

danger detector

orbitofrontal cortex

memory + reward | inhibits inappropriate

AMPA receptor

- Ligand gated Glu - Activated - Allows Na in, Glu binds

NMDA receptor

- Ligand + vg Glu - Remains closed - Blocked by Mg

Corticospinal tract pathway

- subcortical white matter passing via corona radiata - posterior limb of internal capsule - bottleneck - crus cerebri - anterior cerebral peduncle - basilar pons - pyramid of medulla - 90% decussate lowest medulla border - 10% no decussation

Lateral crossed tract

control distal limb for manual dexerity

Anterior uncrossed tract

decuss at spinal segment controls proximal limb

UMN cell body

in motor/premotor cortex of frontal lobe

UMN axon

- extends spinal cord - spinal level muscle - synapses LMN

LMN cell body

in anterior horn of grey or CN motor nucleus

LMN axon

run in peripheral nerve to muscle

M1

Voluntary contralateral body | Precentral gyrus, frontal lobe anterior to central sulcus

Premotor cortex

Movement plan + preparation | Anterior to M1

Corticospinal

voluntary contralateral lib/trunk

Medial surface

lower limb supplied by ACA

Lateral superior

upper limb + hand

Lateral inferior

face + tongue

Corticobulbar

CN motor nuclei in brainstem controls jaw, face, tongue, larync, pharynx

Neural tube

spinal cord meninges

Neural tube lumen

ventricle

Neural epithelial cells

cells making up neural tube makes radial glial cell

Morphogen

ON/OFF genes in newly formed neuroblast

Microcephaly

- loss - uncontrolled mitosis - less neuroblast - less nerve cells - smaller brain learning difficulty

Neurogenesis

- neural plate - neural groove - neural tube

Ach pathway function of pontomesencephalic tegmentum

DESYNCHRONISES thalamus Inhibits automatic AP firing Increases thalamic response Restores connection to world

Ach pathway function of basal forebrain

RESPONSE STRENGTH + SELECTIVITY PLASTICITY Awake, attentive COGNITIVE, LEARNING, MEMORY

Ach pathway dysfunction

Damaged basal forebrain in Alzheimer Gets damaged affecting cholinergic system Lose cortex cells + Ach which tunes system and aids memory

Aricept

Treat Alzeimers | AchE INHIBITORS increase ACh in presynaptic cleft

DA pathway function of substantia nigra

voluntary movements

DA pathway function of ventral tegmental area

Awake + alert to damaging/rewarding stimuli | ADAPTS BEHAVIOUR towards rewarding stimuli

Ach pathway dysfunction of ventral tegmental area

OVER-ACTIVITY SCHIZOPHRENIA (due to amphetamine)

Dopamine Antagonists

treating scizophrenia symptoms

NA pathway function of locus coeruleus

``` AMPLITUDE + SELECTIVITY Plasticity Awake + vigilant to new stimulus Learning + cognitive Memory consolidation Mood Analgesia ```

NA pathway dysfunction of locus coeruleus

ANXIETY + DEPRESSION

Serotonin pathway function of raphe nuclei

Quiet waking - zoned out MOOD + HAPPINESS Raphe Nucleus Magnus suppresses ascending pain pathway Impulse-control, patience, relaxing, responses to reward

Serotonin pathway dysfunction of raphe nuclei

ANXIETY + DEPRESSION

H1 pathway function of hypothalamus

WAKE-PROMOTING circuits | Awake + alert

Orexin pathway function of hypothalamus

regulation of sleep/wake cycle, appetite + alertness

Describe wake up

- in HYPOTHALAMUS, HISTAMINE + OREXIN cells activated - projections towards BRAINSTEM - activate brainstem ARAS (Ascending Rrticular Activating System) - includes nuclei of 5-HT, ACH, NA - activate basal forebrain - projecting to thalamus - relay again connecting cortex to world - wakefulness - DESYNCHORNIZE EEG

Big brainstem lesion

COMA since damaged ARAS nuclei so thalamus not desynchronised

promotes sleep

Circadian rhythm (SUPRACHISMATIC NUCLEUS) Tiredness from increased brain activity (ADENOSINE) Illness (increased IMMUNE BY-PRODUCTS)

Damage to hypothalamic ventrolateral preoptic nucleus

damaged GABA cell lesion so insomina

adenosine

turns the hypothalamic GABA centre on = sleepy

caffeine

ADENOSINE RECEPTOR ANTAGONIST

how to dream

-activation of PONTOMESENCEPHALIC TEGMENTUM + BASAL NUCLEUS -ON cholinergic system: Higher cortical activity ON skeletal muscle paralysis

addiction

- enhance DA in | - nucleus accumbens (VT area projects here) = PLEASURE CENTRE

Microglia

engulf, digest, destroy pathogens + dead cells

Astrocytes

``` produce sheath wrapping around nerve cells maintaining ECF at optimal conc for Na+K+ by AT Remove used NT Transport nutrients Waste products to capillaries Forms BBB ```

Electrotonic potential

Small Slow depolarisation Exponential decay Graded

De-inactivate

reset to original position when at RMP

Absolute refractory period:

no AP can be fired as RMP being restored

Relative refractory period:

more depolarisation needed to reach threshold so AP firing controlled

Refractory membrane:

part of axon in refractory period after AP fired

SM contraction

- Ach binds to M3 Gq in GI, eye, bronchi SM - ↑PLC: breaks PIP2 --> DAG + IP3 - IP3 binds to calcium stores (SR) so calcium release inside cell - DAG acts on Na+ channels to depolarise sarcoplasmic membrane so vgcc open, Ca2+ influx - Ca2+ binds to calmodulin forming Calcium-calmodulin complex - activates MLCK: phosphorylates myosin light chains - contraction

Para on eye

- Ach stimulate M3 Gq - contracts contrictor pupillae SM - miosis - opens canal of Schlemm behind pupil - drains aq humour - reduce intra-ocular pressure

Para on heart

- Ach stimulate M2 Gi - ↓SAN freq of pacemaker potentials - ↓Conduction

Para on bladder

``` Symp -relax detrusor for filling -contract sphincter to hold Stretch receptors activate micturtion reflex -contract detrusor -relax external spinchter ```

Para on lungs

- M3 Gq - contract bronchi SM cells - bronchoconstriction

Ipratopium

anti-mus bronchodilator in COPD

Para on GI

- Ach on M3 Gq - contract circular + longitudinal SM in GI - motility

DAT blocking

blocking dopamine transporter so accumulation in synapse eg cocaine

Selegiline

selective MAOB inhibitor so no peripheral effect

MAOB inhibitor

-block DA metabolism -protect against MPTP toxicity: preventing conversion of MPP+ (not neuroprotective) to ↑DA in synaptic bouton -DA leaks out into synapse

Entacapone

COMT inhibitor | slows elimination of L-dopa

Bromocriptine

D2 agonists mimic dopamine effect 1st line young Parkinsons

Ropinirole

Newer D2 agonist Longer duration of action Lower tendency for dyskinesia

Pramipexole

Newer D2 agonist | Antioxidant effects + protective effect on mitochondria

Amantadine

antiviral drug, but ↑DA release

Benzatropine

For resting tremors Antimus Stimulate DA release since Mus receptors inhibits DA nerve terminals

Prochlorperazine:

for vestibular dysfunction | Mus, H1, DA antagonists

Promethazine:

for vestibular dysfunction | Mus, H1 antagonist

Hyoscine hydrobromide (scopolamine)

for vestibular dysfunction | Mus antagonist

Zine, diphenyhydramine (Benadryl):

for vestibular dysfunction | H1 antagonists

Monoamine theory FOR

- Overall reduced activity of central NA/5HT systems - Reserpine depletes brain of NA +5-HT induces depression - Antidepressants increase [amines] in brain

Monoamine theory AGAINST

- Difficult to show deficits in brain [NA] + [5-HT] - Plasma responds better to diff AD - AD take weeks for effect but in amines acute (secondary adaptive changes more important) - Some AD weak on amine uptake (trazodone) so no increase in 5HT + NA - Cocaine blocks amine uptake but no AD effect - Decrease in 5HT in bipolar linked to aggression not depression

Neuroendocrine theory

- NAergic + 5HT neurons input to hypothalamus - hypothalamus releases corticotropin-releasing hormone (CRH) - CRH acts on pituitary - releases adrenocorticotrophic hormone (ACTH) - cortisol release from adrenal cortex in response to ACTH in blood

Neuroendocrine theory FOR

- CRH – mimic depressive behaviour - ↑[cortisol]plasma in depressed - ↑[CRH] in CSF - Genes + environment affect HPA axis hyperactivity

Robertsonian translocation

- Chromosomal rearrangement between chromosomes 14 + 21 - Short arms of 2 chromosomes break + lost - Long arms fuse into single chromosome - Produces 3 copies of long arm 21 - Carrier of robertsonian translocation offspring w Downs

Balanced rearrangements

Due to translocations, insertions, inversions No genetic material lost/gained No disease Gametes less likely to have a normal karyotype

Unbalanced rearrangements

Due to deletions, duplications, isochromosomes, ring chromosomes, marker chromosomes DNA gained/lost Abnormal phenotype

Angelman syndrome

Microdeletion Developmental delay Speech impairment

Prader-Willi syndrome

Microdeletion Hypotonia in infancy Small hands + feet Obesity

Penetrance:

proportion of people who will go on to develop a disease if they carry a mutation in a gene - Marfans

Anticipation:

worsening of disease severity in successive generations which only occurs in triplet repeat disorders - Huntingtons

Expressivity:

variation in severity of a disorder between individuals with same mutation

Imprinting:

only maternal or paternal alleles expressed

Autosomal recessive inheritance

Genders equally affected Siblings not parents/offspring Recurrence risk is 1/4 for each sibling of an affected person Carrier probability of 2/3 for normal siblings of an affected person All offspring are carriers

Mosaicism mechanisms

- Post-zygotic nondisjunction: mitotic non-disjunction | - Anaphase lag

Metacentric:

p = q | 1-3, 16-18

Submetacentric

p < q, 4-12, 19-20, X

Synaptonemal complex:

lattice of proteins between homologous chromosomes forms at specific locations then spreads to cover entire length of chromosomes

Bivalent:

alignment of homologous chromosomes + crossing over

Synapsis

tight pairing of homologous chromosomes

Phenylketonuria

LOF Metabolic disorder lack of phenylalanine hydroxylase (PAH) Homo lack PAH to convert phenylalanine --> tyrosine SO PKU

De Vivo syndrome

Haploinsuffiency GLUT1 deficiency Dominant

Marfan’s syndrome

Dominant-negative FBN1 encodes fibrillin-1: forms elastic fibres in connective tissue Mutant fibrillin-1 forms complex with normal fibrillin-1 blocking normal fibrillin-1

Achondroplasia

GOF Overactive FGFR3 encodes fibroblast growth factor receptor 3 Skeletal development Dominant

Marfan’s syndrome

Dominane-negative FBN1 encodes fibrillin-1: forms elastic fibres in connective tissue Mutant fibrillin-1 forms complex with normal fibrillin-1 blocking normal fibrillin-1

Non-synonymous SNP

Missense | Nonsense

Synonymous SNP

Silent mutation

Promotor SNPs:

Changes in the gene promoter may alter level of gene expression eg TATA

Slicing SNPs:

Lead to creation/deletion of splice donor, acceptor, branch sites, affecting final mRNA so protein

Terminator SNPs

Affects termination + polyA of mRNA

Euchromatin:

extended state dispersed through nucleus, allows gene expression

Heterochromatin

highly condensed, genes not expressed - centromere

Osteoblasts

Synthesise + secrete collagen fibres

Osteocytes

mature bone cells that have stopped making bone and have become buried inside bone tissue

Osteoclasts

breakdown bone + degrade collagen

canaliculi

Minute channels in compact bone allow osteocytes to connect throughout bone

Osteogenesis imperfecta

``` Mutated type I collagen gene Skeletal abnormalities Blue sclera Autosomal dominant Glycine --> cystine disrupts α helix ```

TGFβ

decreases metalloproteinase production + stimulates production of TIMP metalloproteinase inhibitor

Achondrogenesis

Mutated type 2 collagen | Abnormal development of cartilage + bone

Cytokine interleukin-1 (IL-1)

Inhibits proteoglycan synthesis Stimulates metalloproteinase activity Promote matrix degradation Stimulates fibroblast growth + bone resorption by osteoclasts

Tight junctions:

seal sheet, define membrane domains

Desmosomes

Linked to filaments → high | tensile strength

DNA Polymerase

Synthesises new DNA strands in 5’ to 3’ direction

Primase:

catalyses short RNA | primers synthesis on single stranded DNA templates

DNA Polymerase

Synthesises new DNA strands in 5’ to 3’ | direction

Capped at 5’ end

methyl CAP regulates mRNA chain length ensures its stability during translation

Polyadenylated tail at 3’ end

protect mRNA from degradation by enzymes

Capped at 5’ end

methyl CAP regulates mRNA chain length and ensures its stability during translation

Polyadenylated tail at 3’ end

→ to protect | the mRNA from degradation by enzymes

splicesome:

made of 5 snRNA proteins

initiation of translation

assembly of ribosome on | mRNA together with 1st aminoacyl tRNA (mettRNA)

Streptomycin

Antibiotic Acts on small ribosomal subunit Inhibits initiation Misreads genetic code

termination of translation

-link between last AA + tRNA broken -polypeptide released from ribosome

``` Streptomycin Erythromycin Large Ribosomal Subunit Inhibits translocation Neomycin Multiple Sites Several effects ```

Antibiotic Acts on small ribosomal subunit Inhibits initiation Misreads genetic code

Tetracyclines

Antibiotic Acts on small ribosomal subunit Inhibits amino-acyl tRNA binding

Neomycin

Antibiotic Acts on multiple sites Several effects

Class I anti-arrhythmic

Na+ channel blockers | In non-nodal tissue so atria/ventricles ↓upstroke

Class II anti-arrhythmic

β blockers | nodal + non-nodal tissue

Class I anti-arrhythmic

Na+ channel blockers in non-nodal tissue so atria/ventricles ↓upstroke

Class II anti-arrhythmic

β blockers (nodal + non-nodal tissue)

Class III anti-arrhythmic

K+ channel blockers | (non-nodal tissue) not repolarising quickly, ↑AP length increases refractory period

Class IV anti-arrhythmic

Ca2+ channel blockers | (nodal + non-nodal tissue) affects upstroke in nodal + plateau in non-nodal

Duchenne muscular dystrophy:

mutated dystrophin gene Xp21 | X linked condition so young men severely affected

Myasthenia gravis:

Autoimmune autoantibodies attack nic Ach receptors on muscle so Ach has nothing to bind to on muscle muscle weakness

Radiculopathy:

nerve root damaged, caused by arthritis, prolapsed disk (slip disk) weakness, wasting, radicular nerve root pain

Mononeuropathy:

nerve damaged distally from trauma or entrapment (compression of nerve)

Pyridostigmine:

Ach inhibitor blocks Ach breakdown in synaptic cleft to ↑availability

Plexopathy:

post-infective/traumatic, symptoms dependent on location + extent

Erb’s Palsy:

during delivery when upper brachial trunk C5 + C6 compressed so lose muscles controlled by upper trunk: - Arms adducted - Elbows extended - Wrist remains pronated - Wrist remains flexed

Regulatory step in kidney:

1α-hydroxylase regulates production of active vitamin D calcitriol

Type 1 muscle fibres

``` ENDURANCE slow contraction small motor neuron = red many mitochondria resistant to fatigue ```

Type 2a muscle fibres

SHORT HIGH INTENSITY fast contraction large motor neuron some mitochondria

Type 2b muscle fibres

``` SHORT MAX INTENSITY fastest contraction largest motor neuron - white low mitochondria fatigues ```

Marathon runner

small muscles fatigue resistant dense strong muscles from high oxidative capacity

Sprinter

rapid powerful contractions easily fatigues at max efforts high force per cross-sectional area of muscle low oxidative capacity via mitochondria

Powerlifter

muscles hypertrophied highly glycolytic fatigue easily

Strength training

↑type 2 myosins IGF-1 release muscle fibre hypertrophy glycolytic pathway capability

Endurance training

``` low impact CVS training ↑mitochondrial replication myoglobin content oxidative metabolic capability fatigue resistant type I slow myosin ```

IGF-1 (insulin like growth factor):

initiates skeletal muscle growth activates satellite cells for muscle fibre growth ↑protein synthesis by activating transcription factors

Growth cone in muscle development

attracted by high density of AChR clusters | secretes Agrin

Satellite cells:

- muscle resident stem cells express Pax7 | - postnatal growth + regeneration of muscles

Early limb bud:

ectodermal jacket surrounding a mesenchymal core

Dermatome:

subdivision of differentiating somite + skin area supplied by a single spinal nerve + its ganglion forms dermis, subdermal connective tissue

Intramembranous ossification:

no cartilage intermediate forms flat bones of face, most cranial bones, clavicles

Epimere:

small dorsal portion formed from somite’s dorsomedial cells EXTENSOR SPINE innervated by dorsal primary ramus

Hypomere

larger ventral portion formed by somite’s dorsolateral cells FLEXOR SPINE outer, intermediate, muscles of limbs, inner layers in thorax + abdomen innervated by ventral primary ramus

How somites formed

from proliferating pre-somitic mesoderm

Somites:

mesodermal derivates from paraxial mesoderm

Dermomyotome forms

Myotome + dermatome

Sclerotome forms

bones – vertebrae, neural arches, proximal ribs

Syndetome forms

tendons

Myotome forms

epimere, hypomere, limb muscle

Dermatome forms

dorsal dermis

Stratum spinosum

many desmosomes (junctions) between cells – strong bonds holding epidermis together

Stratum basale

Stem cells constantly proliferate

Stratum granulosum

Cells differentiating to form outermost layer Lamellar bodies contain lipids ‘Keratohyalin’: precursor of keratin

Stratum corneum

Thick Squamous cells w/o nuclei Cornified squamous cells – full of keratin (from keratohyalin granules) so resistant to injury Nonpolar lipids (waterproof) between cells – from lamellar bodies

Melanocytes:

synthesises melanosomes, transfers them to basal keratinocytes via long dendrites for UV protection –

Keratinocytes:

arrange melanin pigment in a cap distal to nucleus especially in basal layer (stem cells)

Langerhans cells:

immune system, antigen-presenting cells like macrophages, dendritic cells forming network

Subsynovium (loose areolar connective tissue):

lymphatic drainage of H2O + proteins

Type B cell:

fibroblastic synoviocyte secretes hyaluronan + lubricin

PTH:

Stimulates osteoblasts to produce M-CSF + RANK ligand for ↑bone resorption -↑Ca2+ reabsorption in DCT -↑Phosphate excretion ↑1-α hydroxylase in PCT

Calcium:

-Bone growth/remodelling -Controls PTH secretion muscle contraction blood clotting co-enzyme stabilization of membrane potentials second messenger/stimulus response coupling

Primary hypoparathyroidism

Congenital DiGeorge Autoimmune

Secondary hypoparathyroidism

parathyroid damage

Mg hypoparathyroidism

co-factor in PTH production

Primary hyperparathyroidism

``` tumour HIGH Ca2+ single adenoma diffuse hyperplasia multiple endocrine neoplasia MEN ```

Secondary hyperparathyroidism

-hypocalemia/PTH resistance -compensatory hyperfunctioning parathyroids -LOW Ca2+: renal disease vit D def

Tertiary hyperparathyroidism

glandular hyperfunction DESPITE correcting abnormality | HIGH Ca2+

Biphosphonates

for hyperparathyroidism | maintain existing bone mineralisation

Calcimimetics

for hyperparathyroidism | Ca2+ too high to active calcium sensing receptor inducing processes to lower Ca2+

Granulomatous diseases:

characterised by immune responses | cause of hypercalcemia

1-alpha hydroxylase:

enzyme activates vit D

response to hypercalcaemia

- inhibition of 1-alpha hydroxylation of vit D (regulatory step in kidney) - PTH production compensates for high Ca2+ - calcitonin production from thyroid’s C-cells - action on bone inhibits PTH action - calcitonin reduces Ca2+ - ineffective

hypercalcaemia symptoms

``` CNS depression RENAL disease renal STONES abdominal PAIN short QT - arrhythmia ```

Frusemide:

hypercalcaemia treatment | loop diuretic for insufficient to flush Ca2+ out

Bisphosphonates:

hypercalcaemia treatment | stop osteoclasts

Prednisolone:

hypercalcaemia treatment | suppress immune since osteoclast is immuno-stimulated cell

Saline rehydration

hypercalcaemia treatment | lets Na/Ca exchanger

how immobility causes hypercalcaemia

- less osteoblast movement - osteoblast slow - osteoclast normal - BREAKDOWN > filling - more Ca2+

how thiazide diuretics cause hypercalcaemia

increase Ca2+ reabsorption

Familial hypocalciuric hypercalcaemia

- Defective calcium sensing gene encodes bone receptor | - HIGH PTH

Osteoclast-activating factor

produced by lymphoma, multiple myeloma HIGH PTH HIGH Ca2+

how cancer causes hypercalcaemia

lung cancer releases PTH, PTH-RP

response to hypocalcaemia

- ↓Ca2+ - PTH release stimulated - ↑activation of 1α-hydroxylase - active vit D - ↑FGF23 - ↑phosphate loss in kidney - encourages Ca2+ retention - ↑vit D increase as intestinal Ca2+ absorption - ↑bone resorption - ↑serum Ca2+

hypocalcaemia symptoms

``` Paresthesias Laryngospasm Bronchospasm --> SOB Seizures, confusion, hallucinations Chvosteks sign Trousseau’s sign Long QT Acute: syncope, congestive HF Chronic: dry skin, coarse hair, pruritis ```

Pseudohypoparathyroidism

produce PTH but defected receptor HIGH PTH, PO4 low Ca2+, vit D teddy bear

response to vit D def

- ↓Vit D - ↓Ca2+ intestinal absorption -↓Ca2+ in blood - response is to ↑PTH - ↑Ca2+ reabsorption from kidney + ↑bone resorption - raise serum Ca2+ normal - FGF23 ↓serum phosphate conc

FGF23

- produced in bone when high phosphate - ↑phosphate excretion from kidney + inhibits activation of vitD by inhibiting 1α-hydroxylase to stop absorbing phosphate from gut - ↓serum phosphate conc

dietary vit D

Take in ergosterol --> ergocalciferol (vit D2)

light vit D

Hits skin so cholesterol reduced --> cholecalciferol (vit D3)

how vit D3 does calcium homeostasis

- ↑Ca2+ absorption in the gut - Stimulates CaBP synthesis - Synergises with PTH on bone - Inhibits PTH synthesis - Inhibits 1a-hydroxylase

processing location + movement

- magnoceullar input - primary visual cortex - superior temporal cortex - parietal cortex - motor/ssc to interact w environment

control of saccadic + pursuit movement

motor controlled by III, IV, VI nuclei

pursuit movement

Voluntary - pontine nuclei - cerebellum - vestibular nuclei - CN nuclei

involuntary saccadic movement

- retina | - SUPERIOR COLLICULUS

voluntary saccadic movement

- frontal - parietal - SUPERIOR COLLICULUS

ipsilateral monocular scotoma

PARIETAL RETINAL | detach, tumour, infection

ipsilateral monocular anopia

optic NERVE | tumour, cranial fracture

contralateral homonymous hemiaopia

optic TRACT | tumour, stroke

contralateral homonymous hemiaopia w macula sparing

CALCARINE SULCUS | tumour, stroke

tunnel vision

bilateral retina GLAUCOMA intraocular p compresses optic nerve edge

central scotoma

RETINA | optic nerve, choroid disorder - macular degeneration

contralateral homonymous central scotoma

bilateral VISUAL CORTEX of macular fibres at occipital cortex

bitemporal hemianopia

optic CHIASM | pit tumour affects inferior 1st

contralateral superior homonymous quadrantopia

TEMPORAL

contralateral inferior homonymous quadrantopia

PARIETAL

presbyopia

- ageing - sclerosed crystalline STIFF lens - ciliary weak - less accommodation - fixed focus

vitreous degeneration

- jelly proteins - clump - low clarity

vitreous detachment

- vitreous shrink - pulls from retina - retinal tear

cataract

opaque lens proteins

type 1a afferent

Velocity of muscle STRETCH | spasticity

extrafusal fibres

driven by α-motor neurones

intrafusal fibres

driven by γ-motor neurones

nuclear bag fibres

Type Ia afferents - Velocity dependant - Monosynaptic - Thick fast axons - Corrects rapid unintended movements

rapid stretch of nuclear bag fibres

central portion change length and activate the type Ia afferent

nuclear chain fibres

Type II afferents - Thin slow axons - Indirect via excitatory interneurons - Maintains limb position

type II afferent

muscle LENGTH | hypertonia

type 1b afferent

TENSION | tendon tension from active muscle contraction

Golgi tendon organs

- Inhibit rising tone when standing | - Excite muscles when walking (contact α-motor neurone via excitatory interneurone)

reciprocal inhibition

OFF antagonist α-motor neuron Gly QUICK, weak, short lasting

presynaptic inhibition

OFF antagonist REFLEX arc GABS slow, POWERFUL, long lasting

Baclofen

↑GABAb mimics presyn inhibition

GABAa

inhibitory + ionotropic | no specific inhibition ALL motor neurons

GABAb

inhibits spindle fibre REFLEX

Tizanidine

α2 suppress interneurons ↑NA transmission

medial pain pathway

- nociceptors - midbrain ALERTNESS - non-specific thalamic nuclei - anterior cingulate FEAR DISTRESS AVOIDANCE - higher cortical areas PERCEPTION

lateral pain pathway

- nociceptors - VPL nucleus - SSC LOCALISE DISCRIMINATE - higher cortical areas PERCEPTION

delusion

A false, unshakeable belief that is out of keeping with the patient’s social and cultural background

chemical guidance signals

form gradient eg neuroreglin + semaphorins | attract/repel migrating cells

marginal zone cells

produce reelin via cajal retizius cells

reelin

Ensure cortical development deep to superficial tissues | Acts as a guidance chemical telling cells to move to the pial surface

subplate cells

make guidance signals to migrating nerve cells

ganglionic eminence

becomes inhibitory neurons + oligodendrocytes

big pyramidal cells

from deep layer long dendrites to surface big axons to subcortical structures

stellate cells

from middle layer | receive info from deep thalamus

pyramidal cells

from superficial layer | axons to cortical structures

lissencephaly

mutated reelin | learning difficulties + epilepsy

heterotopia:

``` mutated cytoskeleton disrupted cortical development lose doublecortin protein in females X linked unmigrated cell clusters normal intellect to severe learning difficulties epilepsy ```

growth cone in axon guidance

growth tip of neurites lamellipodium supported by actin meshwork fliopodia

fliopodia

seek guidance signals attracts actin bundle growth repels actin bundle shrinkage

floor plate signalling proteins

attract axon to spinal cord floor + move it to opposite side

integrin

matching binding molecule

laminin

ECM

cross linking

neuroligin-1 + β-neuroxin binds to flipodia forming test synapse

active synapses

- ↑Ca2 --> ↑AMPA - Dendrite spine grows via cytoskeletal changes - Synaptic bouton grows via dendritic signals

VPL nucleus

info from limb/trunk

VPM nucleus

info from head/neck | trigeminothalamic pathway

dorsal column pathway

- 1st cell body dorsal root ganglion - axon enters dorsal root + joins medial/lateral dorsal column - 2nd cell body in gracile/cuneate medulla nuclei - dessucates internal arcuate fibres at medulla - medial lemniscus - PON - midbrain - 3rd cell body thalamic VPN - posterior limb of internal capsule - SSC

medial dorsal column

lateral dorsal column

>T6 CUNEATE fasiculus upper limb/chest

spinothalamic pathway

- 1st cell body dorsal root ganglion - axon enters dorsal root ganglion + synapses - 2nd cell body in dorsal root - decuss VENTRAL WHITE COMMISSURE: - spinothalamic tract some neurons synapse brainstem reticular formation sloww - anterolateral medulla - pons lateral to medial lemniscus - midbrain - 3rd cell body thalamic VPN - posterior limb of internal capsule - SSC

lateral inhibition

↑spatial discrimination

smaller receptive field

↑innervation density

↓temporal resolution

- receptive field stimulated quick succession - mechanoreceptor CANT DEPOLARISE FAST ENOUGH to produce 2 separate potentials - potentials SUMMATE - LOSE HIGH FREQ INFO

all-in-one receptors

receptor = afferent no synapse somatosensory + olfactory

frontal eye fields

VOLUNTARY attention, gaze

lateral spinothalamic lesion

cant localise noxious stimuli

stimulate VPL nucleus

somatotopically organised | parasthesia

descending pain pathway

- orbitofrontal cortex - periaqueductal grey - nucleus raphe magnus releases 5HT + enkephalin - inhibits pain transmission in dorsal horn

insular cortex

represents body + VISCERA

hyperalgesia

↑sensitive pain | lose descending inhibitory input

allodynia

pain w/o noxious | reorganisation

neurogenic pain

pain independent of tissue damage | long term potentiation between 1st + 2nd

anterior cingulate cortex

connected to hypothalamus ANS amygdala, frontal cortex (emotion + motivation)

anticonvulsant

block high freq AP during seizures | ↓NT release at potentiated synapses

perceptual threshold

Minimum stimulus strength that will generate enough action potentials to be detected

phantom limb syndrome

Afferents innervate stump as though they are the peripheral areas that were previously painful

drug dependence

Adaptive state due to repetitive drug use resulting in withdrawal symptoms

Which pathway is inhibited in addiction

Prefrontal cortex and anterior cingulate gyrus to orbitofrontal cortex

neuroepithelial cells divide in the vertical plane forming

Neuroblast cells

REM initiation

“higher” cortex produces meaningful but internally generated activity

which layer are the bipolar cells found

Inner nuclear layer

which cone receptors in central vision

red blue

drusen

Fatty plaques form in the retina pigment epithelium

Magnocellular cells

fast movement and broad outlines

associative agnosia

Occipito-temporal lobe | lesion

Meniere’s disease

tinnitus, dizziness, ‘’fullness’’ of ears

stereocilia tips are pulled in the direction of the taller one

Depolarisation as more ion channels open so more positive charge inside the cell

joint

Transmit loads

odontoid peg

pivot joint

decrease in Pj

after synovial fluid formed

aspirin poisoning

Hypokalaemia

Why is there a higher concentration of ionised aspirin in the blood

Aspirin unionised is polar and lipophilic so it can cross the border to donate protons to plasma

Where is melanin stored

Basal keratinocytes

why SNVs arise

One base is swapped for another and the mismatch repair system fails to repair this

From which layer does the primitive node arise

Mesoderm

how the clock-wavefront model allows for Somitogenesis

Triggers opposing gradient thresholds of signalling molecules stimulate the negative feedback loop of somite protein translation

How does thalidomide cause shortened limbs

All of the cells in PZ see FGF instead of only half so all re-specify into distal cells

Pax7

satellite cells allow post-natal growth + regeneration of muscles

atopic eczema treatment

Dermovate | Ropical calcineurin inhibitors

At what point does Actinic Keratosis become Bowen’s

Once it involves the full thickness of the epidermis

Reciprocal Translations

NHEJ

how muscles grow

Quiescent muscle cells are simulated to divide into myoblast cells that differentiate into muscle cells and fuse with the injured region

pharmacokinetics

what the body does to the drugs

22q11.2 deletion syndrome

cleft palate several immune deficiency + hypocalcaemia

myopathy

Proximal weakness Normal reflexes High CK Less prominent wasting

accuracy of movement

muscle increases excitation of the muscle to contract at the same speed as the intrafusal end poles to correct the length of the centre

substantia nigra

Has cell bodies of dopamine neurones here to control basal ganglia

alar plate

forms the motor/anterior root

anterolateral laminae

innervates distal extensors

Pyramidal weakness

upper limb flexion, lower limb extension and circumduction

phase 2 of drug metabolism

Makes the metabolites less reactive so that it is removed from the plasma quicker

ossicle bones

hammer/maleus anvil/incus stirrup/stapes

oval window

membrane covers bone bole

middle ear

AMPLIFIES

conductive hear loss

outer/middle ear dysfunction

sensorineural hearing loss

inner ear

endolymph

inside cells K+ fills membranous chamber/cochear duct

perilymph

surround cells Na+ fills scala vestibuli + tympani

scala vestibule

perilymph

cochlear duct

endolymph seprated by vestibular + basilar membrane

scala tympani

perilymph

tectorial membrane

covers + attaches to spiral organ | roof fixed

tip links

transduce

inner hair cell

detects

outer hair cell

amplifies

vibrations on ear drum

``` tip links pulled K+ influx K+ endolymph K+ into cell via electrochemical gradient depolarisation GLUTAMATE high f AP ```

basilar membrane

base vibrates

vestibular membrane

contact w scala vestibuli

stria vascularis

resorps + produces endolymph so normal p

endolymphatic hydrodrops

increase endolymph p leads to full ear, tinnitus, vertigo

outer ear

pinna -> tympanic membrane

ototoxic drugs

fuck stereocilia so less AP NSAID cisplatin aminoglycosides - gentamicin

acoustic neuroma/vestibular schwannoma

tumours on same nerve diff branches vestibular + facial nerve run in same meatus unilateral tinnitus dizzy + faint

presbycusis

lose high freq w age

Discriminative hearing pathway

- inner hair cells - DORSAL cochlear nuclei - inferior colliculi - thalamic MEDIAL GENICULATE NUCLEUS - auditory cortex

sound localisation pathway

- inner hair cells - VENTRAL cochlear nuclei - lateral (high f) / medial (low f) - inferior colliculi - MEDIAL GENICULATE BODY - auditory cortex

lateral vestibulospinal tract

otolith system LINEAR movement postural control

medial vestibular tract

semilunar canal | ANGULAR head rotation

otoconia

crystals in saccule + utricle membrane increases inertia + sense gravity

utricle

horizontal acceleration

saccule

vertical acceleration

cupula

gelatinous membrane | bulges towards utricle --> long stereocilia to ON vestibuloreceptors

medial longitudinal fasiculus

connects ocular CN nuclei to vestibular nuclei | controls ocular muscles

vestibulo-ocular reflex

- semicircular canals - vestibular nuclei - CN nuclei - pupil movement

purkinje cells

large inhibitory GABAergic neurons | inhibits vestibular nuclei so BLOCKS connection between vestibular nuclei + CN nuclei

pontine nuclei pathway

SHORT TERM POTENTIATION - retinal ganglion cell - ACCESSORY OPTIC SYSTEM - pontine nuclei - mossy fibre - granule cell - parallel fibre - purkinje cells -ve - vestibular nuclei - BLOCK CN

olivary nuclei pathway

LONG TERM POTENTIATION - retinal ganglion cell - THALAMIC GENICULATE BODY - olivary nuclei - climbing fibre - purkinje cell -ve - vestibular nuclei - BLOCK CN

voluntary motor loop

SMA in medial frontal loop to putamen

non motor loop

cognition, motivation, addiction

caudate-prefrontal connection

COGNITION + behaviour | vision attention gaze via projection to frontal eye fields

overactive caudate-prefrontal connection

OCD

limbic loop

ventral striatum/nucleus accumbens | opiate receptors = motivation, reward learning, addiction

parkinsons

substantia nigra pass compacta bradykinesia = less movement rigidity = UMN + stretch reflex

MPTP heroin metabolite

enters via DA transporter | converted to MPP+ via MAOb

MPP+

oxidative stress on mitochondria

retenone pesticide

block mitochondria | parkinson symptoms

lewbys bodies

- mutated α-synuclein | - protein aggregate ppt

why use Domperidone

anti-emetic adminstered with L-dopa

why ON/OFF parkinsons?

rapid oscillations in mobility | rely on L-dopa since all neurons dead

dyskinesia

sustained contraction via L-dopa from OD

akinesia

cant initiate movement

paradoxial kinesis

projections from amygdala to ventral striatum

Atropine

anticholinergic

huntingtons

chorea + rigidity

Carbidopa

DOPA decarboxylase inhibitor | inhibit peripheral metabolism of L-dopa so more can cross BBB

cerebellar lesion

``` intention tremor ataxia nystagmus hypotonia slur ```

direct pathway to increase planned movement

- striatum - globus pallidus internus - ACTIVATE thalamus - disinhibits ventral anterior thalamus - prefrontal cortex signals

indirect pathway to inhibit unwanted movements

- striatum - globus pallidus exturnus - SUBTHALAMIC NUCLEUS - globus pallidus internus - BLOCKS THALAMUS - BLOCKS frontal cortex

disinhibition of subthalamic nucleus

- activates globus pallidus internus - inhibits ventral lateral thalamus - inhibits unwanted movement

spinocerebellum

vermis + anterior lobe GAIT, POSTURE, TONE receives PROPRIOCEPTION info CORRECTS movement error

cerebrocerebellum/pontocerebellum

posterior lobe + tonsils ACCURATE smooth movement SPEECH articulation

vestibulocerebellum/flocculonodular lobe

BALANCE control occular reflexes receives CN vestibular nerve input

dentate nucleus

cerebellum outflow pathway

granule cells

excitatory glutamate neurons

basket cells

interneurons around purkinje cell bodies

golgi cells

inhibitory interneurons

higher cerebellar functions

cognition | language processing

how cerebellum receives constant info about intended movement

frontal lobe to contralateral cerebellum via pons

how cerebellum sends corrective orders

brainstem + cerebral motor cortex via thalamus

cerebellum role

movement INTENT ACTUAL movement COMPARES command signals w sensory impulses sends CORRECTIVE orders

lateral cerebellar lesion

ipsilateral voluntary extremities

medial cerebellar lesion

truncal ataxia so broad gait nystagmus head tilting

hyaline arteriosclerosis

damage kidney arterioles plasma protein exudes into intima narrows lumen PINK histology

heart response to hypertension

LV hypertrophy Heart dilates + fails Atrial fibrillation

why LV hypertrophy unsustainable

STIFFENS myocardium ↑diffusion distance atherosclerosis in intima

chronic kidney disease

ischaemic nephron atrophy from hypertension narrowing arteries small atrophied kidney

how does tubulo-interstital inflammation arise from hypertension

- narrow arteries - low nephron mass - glomerular capillary hypertension - ↑glomerular permeability - ↑filtration of plasma proteins - proteinuria - excessive tubular protein reabsorption

how fatty plaques form?

- shear stress + Ang II - endothelial dysfunction - express adhesion molecules - activates endothelium - recruit infiltarting monocytes + inflammatory cells

early hypertensive retinopathy

nick retinal veins by overlying arterioles

moderate hypertensive retinopathy

straight wide capillaries flame shaped haemorrhage cotton wool spots hard exudates around macula

late chronic/malignant acute retinopathy

optic disc swelling + haemorrhage

baroreceptors

carotid sinus | STRETCH

chemoreceptors

carotid/aortic bodies | low O2, ↑CO2, ↑pH

what activates RAAS?

low perfusion HIGH Na sensed by macula densa OR symp via juxtaglomerular apparatus in nephron

renin

angiotensinogen -> ang I

ACE

ang I -> ang II

11β-hyfroxysteroid dehydrogenase type 2

metabolises cortisol -> inactive cortisone

how ang II ↑BP?

``` peripheral vasoconstriction of resistance vessels aldosterone release posterior pit release ASH thirst heart hypertrophy symp negative feedback via ANP, BNP ```

baroreceptor reflex

vasoconstricts when low BP except brain

autoregulation

cerebral arteries have tight control w UNCHANGED BP

↑PCO2

asphyxia ↑cerebral BF vasodilation

↓PCO2

hyperventilation ↓cerebral BF vasoconstriction

↓PO2

local hypoxia ADENOSINE vasodilators ↑cerebral BF

defective areas of BBB

area postrema brainstem hypothalamic subfornical organ hypothalamic periventricular osmoreceptors

regional hyperaemia

activityyy depolarisation freq K+ efflux into environment vasodilation

postural hypotension

compliant veins dilate ↓CVP + EDV ↓cerebral BF

cerebral spasms

UNCONTROLLED vasocontriction -> cerebral ischaemia

5HT as local vasoconstrictor

from perivascular nerves

neuropeptide Y as local vasoconstrictor

from perivascular nerves

endothelial-1 as local vasoconstrictor

from vascular endothelium

K+ as local vasoconstrictor

from damaged cells

Vasospasm treatment

Ca2+ channel blocker | ETA blcoker

Amlodipine

Ca2+ channel blocker for vasospasm act on VSMC

Bosentan

ETA blocker | for vasospasm

cushings

bradycardia + HIGH BP

space occupying lesion

``` lesion push brain foramen magnum press on RVLM - symp control HIGH BP, TPR, HR stimulate baroreflex more vagal so bradycardia ```

stroke treatment

thrombolysis 4.5hrs evacuate clot aspirin Clopidogrel/Ticagrelor

cystic space

macrophage clears liquefaction necrosis