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Year 2 - Excess > People and Illness > Flashcards

People and Illness Flashcards

1
Q

What are the main clinical features which define ADHD?

A
  • Inattention
    Lacks of persistence in activities requiring concentration
    Selected attention - distraction
    Sustained attention - problem-solving
  • Impulsivity
    Inappropriate/defective filtering of information
    Poor awareness of risk makes individuals accident-prone
    Social disinhibition, excessive talking
    Poor peer relationships, aggression, emotional dysregulation
  • Hyperactivity
    Psychomotor agitation
    Restless, fidgety, disorganised, ill-regulated
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2
Q

Discuss the influence of genetics on the development of ADHD

A

Candidate ADHD susceptibility genes: those involved in reward pathways, dopamine regulation
Associated learning disorders: Fragile X, Klinefelter & Williams syndromes
Genetic-environment interactions - genes can increase or reduce the impact of the environment on the development of ADHD

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3
Q

Which characteristics might be present in an fMRI of an individual with ADHD?

A

Reduced frontoparietal volume
Right dorsolateral prefrontal lobe reduced
Smaller basal ganglia
Smaller cerebellar vermis
Attentional systems involved: anterior fronto-striatal networks
Posterior parieto-cerebellar circuits

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4
Q

Which co-morbidities is ADHD associated with?

A
  • Mood disorders
  • Tic disorders e.g. Tourette syndrome
  • Insomnia
  • Anxiety
  • Learning disorders
  • Behavioural difficulties: ODD/CD (oppositional defiant disorder/conduct disorder)
  • Social communication difficulties
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5
Q

Describe the process of development of attention in children

A
  • 0-12 months: fleeting; focus very briefly, quickly distracted
  • 1-2 years: rigid; can attend to task of their own choosing
  • 2-3 years: single-channelled; can only focus on one thing at a time
  • 3-4 years: focus; attention is single-channelled but child can control this
  • 4-5 years: dual-channelled; can do task & listen to someone at same time
  • 5+ years: integrated; mature attention control
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6
Q

Briefly outline the process of assessment of ADHD

A
  • No specific diagnostic test, so assessment includes:
  • Direct observations in >1 setting: ADHD must be pervasive
  • Structured questionnaires given to reliable informants
  • Psychoeducational assessment
  • Identifying co-morbid mental health problems
  • Developmental history
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7
Q

Which structured questionnaires are commonly used in the assessment of ADHD?

A
  • SNAP-IV Teacher and Parent Rating Scale
  • Conners Scale for ADHD Assessment
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8
Q

What type of information would be relevant when taking a history for assessment of ADHD?

A
  • Past history
    Pregnancy/delivery (any alcohol/illicit drugs?)
    Patterns of feeding, sleeping, play
    Activity levels, impulsivity, inattention
  • Medical history
    Head injury
    Hearing problems
    “Tics”/funny turns/seizures
  • Family history
    Learning difficulties in the family
    Stressors in the family
    Child’s care history
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9
Q

Discuss the use of behavioural parent training in the management of ADHD

A
  • Encourage consistency in managing less desirable behaviour
  • Do not personalise behaviour problems
  • Routines, countdowns, reminders
  • Planned ignoring, time-outs, quiet time
  • Positively reinforce appropriate behaviour
  • Clear rules with consequences
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10
Q

Discuss the use of behavioural training in schools to manage ADHD

A

Management of the environment
* Provide a calm environment, reducing background noise
* Avoid too many distracting stimuli when wanting a child to concentrate
* Initially avoid situations that require quiet, still behaviour for long periods of time
* Maintain structure & supervision longer than you think necessary
Behavioural management
* Do not give instructions without first gaining the child’s attention
* Give clear, direct, short instructions & provide visual aids if needed
* Ask child to repeat back instructions
* Improve concentration skills with activities the child enjoys
* Plan ahead for problem situations
* Model good listening skills

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11
Q

Outline the mechanism of action of methylphenidate, including different preparations & dosages

A

Methylphenidate aka ritalin, concerta, equasym, medikinet
Blocks dopamine and noradrenaline reuptake by blocking transporter: increases NA and DA
Immediate release tablets: 5mg 3-4x a day
Modified release/sustained release preparations available, 8-12h duration
Usually give long-acting in the morning and short-acting in late afternoon
Drug holidays required

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12
Q

Outline the mechanism of action of dexamphetamine, including different preparations & dosages

A

Dexamphetamine acts to release dopamine stored in presynaptic vesicles, whilst blocking reuptake via transporter, increasing dopamine
Dexedrine 5mg: immediate release; max dose 20-40mg
Elvanse: lisdexamphetamine dimesylate, sustained release, 13h duration
* Increases available NA and DA
* Max dose 70mg
* Pro-drug, converted to dexamphetamine via first-pass metabolism
* Less susceptible to abuse

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13
Q

Outline the mechanism of action of atomoxetine

A

Noradrenaline reuptake inhibitor: enhances noradrenaline transmission in prefrontal cortex
Takes time to have an effect, approx 6 weeks, but no drug holidays required
Effective for co-morbid anxiety, depression

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14
Q

Outline the mechanism of action of guanfacine, including dosage and preparations

A

Selective central alpha 2a adrenergic receptor agonist
Stops the effect of noradrenaline at the synapse
Acts on prefrontal cortex, not nucleus accumbens, reducing the potential for abuse
Helpful with sleep & appetite issues; significant improvement within 3 weeks
Oral prolonged release tablet formulation
Basal metabolic rate is higher in children than adults, so dosage relative to body weight is higher/more frequent

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15
Q

Discuss the side-effects of psychostimulants and ways to manage them

A
  • Anorexia, nausea, weight loss, growth concerns
  • Sleep difficulties
  • Dizziness, headache, abdominal pain
  • Involuntary movements or tics
  • Dysphoria, agitation
  • Tachycardia, hypertension
  • Syncope suspected to have cardiac origin
    Stop medication & seek specialist advice
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16
Q

Discuss the side-effects of atomoxetine

A
  • Nausea/vomiting
  • Excessive tiredness
  • Insomnia
  • Abdominal pain, appetite suppression, weight loss, constipation
  • Headaches
  • Mood swings/rage, suicidal ideation
  • Hepatic impairment (monitor LFTs)
  • Tachycardia, hypertension
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17
Q

Discuss the side-effects of guanfacine and clonidine

A

Guanfacine
* Sedation
* Dizziness
* Hypotension: monitor BP and heart rate
* Precaution when combined with pscyhostimulants, reports of sudden death
Clonidine
* Paradoxical hypertension
* Paradoxical sleep disturbance

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18
Q

How would you manage side-effects like loss of appetite and insomnia?

A

Loss of appetite
* Caloric augmentation
* Administer medication with food
* Drug holidays
* Monitor height and weight
* Dietetic advice
Insomnia
* Administer medication earlier in the afternoon or reduce evening dose
* Sleep hygiene advice
* Melatonin

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19
Q

Discuss how ADHD medication monitoring is carried out

A
  • Height and weight: on a growth chart every 6 months
  • Heart rate and BP: repeat at every dose adjustment and every 6 months, ECG if treatment affects QT interval
  • Complete history
    Concomitant medicines
    Past, present medical history
    Psychiatric disorders
    Family history of sudden cardiac and unexplained death
  • Contraindications
    Depression, anorexia, suicidal tendencies, psychosis
    Pre-existing cardiovascular disorders
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20
Q

Discuss the legal status of psychostimulant medications

A
  • MPH and dex are schedule 2 controlled drugs (prescription only medicines)
  • BNF (British National Formulary)
    Prescription and requirements: form and strength of preparation
    Total quantity in words & figures
    Dose to be administered
    28 day validity - signed & dated by prescriber
    Signed on collection + proof of identity
    30 day supply - Good practice: pharmacist may supply more if requested but prescriber must state why
    After titration and dose stabilisation, prescribing and monitoring of ADHD medication is carried out under shared care protocol arrangements with primary care
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21
Q

Discuss the features which can influence the prognosis of ADHD going into adulthood

A

Prognosis depends on co-morbidity
* Organic disorders
* Psychiatric disorders e.g. ODD/CD
* Learning difficulties
* Which symptoms predominate & environment in which they predominate
Factors associated with persistence into adulthood
* Progressive reduction in cerebellar & hippocampal volumes
* Maternal depression, marital discord, negative parent-child interactions
* Family socioeconomic disadvantage
* Familial ADHD

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22
Q

Discuss the influence of arousal systems on the pathogenesis of ADHD

A
  • Deficiency in arousal mechanisms, defective inhibitory response
  • Neurons in prefrontal cortex are out of tune and can’t distinguish between important signals & background noise
  • Can’t focus as all the signals are the same - easily distracted
    Hypoarousal: low firing of NA and DA neurons
    Need to improve the “signal to noise” ratio; increase the drive of the arousal network to improve efficiency of information processing
    Hyperarousal: increased phasic firing of NA and DA neurons
    Excess NA and DA stimulate additional receptors and cause the signal-to-noise detection to deteriorate
    Need to downregulate neuronal activity to return to normal phasic firing
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23
Q

Discuss the anatomical changes in the cortical grey matter which take place during the development of the adolescent brain

A
  • Matures from back to front; increases and then decreases in volume as white matter increases
  • Maximum density of cortex is achieved in sensorimotor cortex first, while prefrontal cortex is last (superior temporal gyrus is last to change)
  • Massive synaptic proliferation in prefrontal area (early adolescence) followed by plateau phase
  • Then, reduction and reorganisation via neural pruning
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24
Q

Discuss the anatomical changes in the subcortical grey matter which take place during the development of the adolescent brain

A

Basal ganglia (involved in movement, higher order cognitive & emotional functioning) matures after limbic system
Limbic system is involved in emotional regulation, reward processing, appetite and pleasure seeking

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25
Q

Discuss the anatomical changes in the white matter which take place during the development of the adolescent brain

A

White matter tracts between the prefrontal cortex and subcortical areas develop in a steady non-linear way
White matter increases in all lobes simultaneously
The changes reflect ongoing myelination and increasing axonal diameter

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26
Q

Discuss the hormonal changes which affect adolescent brain development

A

Girls’ and boys’ grey matter changes in the same sequence, but girls’ grey matter peaks a year before
Corresponds to pubertal maturity, not age
Brain development and puberty are interrelated
Differential sensitivity to testosterone between boys and girls in limbic structures
> Greater risk of anxiety & depression in girls

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27
Q

Discuss the behavioural changes observed during adolescence

A
  • Novelty seeking
    Renders adolescents more susceptible to harm (boys especially)
  • Impulsivity
    Impulse control improves as prefrontal cortex and basal ganglia mature
  • Risk-taking e.g. drug-taking, unprotected sex
    Drive to try something new as subcortical structure development is outrunning that of prefrontal cortex
  • Reward seeking
    Nucleus accumbens and amygdala have increased activity in response to rewards; increases at onset of puberty, peaking at 15
  • Social behaviour: more sociable, form complex social relationships
    More sensitive to peer acceptance & rejection
    Skills in empathy, theory of mind, facial processing… develop, corresponding to grey & white matter changes in medial prefrontal cortex & temporoparietal regions
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28
Q

Describe changes in neurotransmitters during adolescence

A
  • Not all neurotransmitters develop at the same pace; serotonin systems develop fully earlier than noradrenaline and dopamine
  • Dopamine
    Sensitivity peaks during adolescence; dopamine receptors in striatum and prefrontal cortex increase in adolescence & then decline
    Neurocircuitry of reward seeking is determined by dopamine signals received by nucleus accumbens and basal ganglia
  • Oxytocin
    Receptors proliferate in limbic areas
    Adolescents show heightened response to emotional stimuli
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29
Q

List the different components of a mental state exam

A
  • Appearance and behaviour
  • Speech
  • Mood and affect
  • Thought
  • Perception
  • Cognition
  • Insight and judgement
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30
Q

What are the different features which should observed during the “appearance and behaviour” part of a mental state exam?

A
  • Age
  • Body mass
  • Personal care and hygiene
  • Distinguishing features
  • Signs of disease
  • Autonomic arousal
  • Personal objects
  • Psychomotor behaviour
  • Abnormal movements e.g. parkinsonism, tremors, dyskinesia
  • Level of cooperation and engagement
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31
Q

List the effects of alcohol on different body systems

A
  • GI: acute gastritis, chronic pancreatitis, carcinoma of the oesophagus/large bowel, diarrhoea & malabsorption
  • Cardiovascular: hypertension, arrhythmias (atrial fibrillation), cardiomyopathy, CHD
  • CNS: Wernicke-Korsakoff syndrome, alcoholic dementia, cerebellar atrophy
  • Liver: steatosis, hepatitis, cirrhosis, hepatocellular cancer
  • Muscle: acute and chronic myopathy
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32
Q

How do lymphatic capillaries absorb excess fluid from interstitial tissues?

A

Heart pumps blood along arteries under hydrostatic pressure
Blood pressure causes fluid to move out of the arterial end + move back in the venous end via osmotic pressure
However excess fluid and associated proteins remain in interstitial tissues > absorbed by lymphatic capillaries

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33
Q

Describe the structure of lymphatic capillaries

A
  • Very thin blind-ended tubes
  • Lined by a single layer of overlapping endothelial cells
  • Minimal basement membrane, no surrounding tissue
  • Special junctions: loosely attached so fluid passes between
  • Many vesicles of fluid & protein in cytoplasm (uptake of fluid via pinocytosis)
  • Fine anchoring filaments outside the cell stop collapse
  • 2 valves to prevent backflow of lymph
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34
Q

Describe the histology of the lymph node

A
  • Dense, collagenous outer capsule (extends into the interior via trabeculae)
  • Meshwork skeleton of reticular fibres
  • Densely packed cortex
    > Outer cortex: dominated by B cells in lymphatic nodules when active
    > Paracortex: transition zone dominated by T cells
  • Loosely arranged medulla
    > Contains sinuses within which lymph flows > subcapsular sinus > cortical sinus > medullary sinus > efferent vessels
  • Medullary cords dominated by B cells (plasma cells)
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35
Q

Describe the return of lymph to the venous system

A
  • Lymph of lower body returns to thoracic duct (left venous angle where internal jugular meets left subclavian)
    Thoracic duct located in posterior mediastinum (T5)
  • Cisterna chyli: most inferior part of thoracic duct
  • Lymph of right head, neck & upper limb: right lymphatic duct (union of internal jugular and right subclavian)
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36
Q

Name the primary lymphoid organs and describe their function

A
  • Red bone marrow:
    > Production & maturation of B lymphocytes & T cell precursors
    > Also granulocytic precursors, megakaryocytes & erythroblasts
  • Thymus:
    > Maturation of T cells - leave thymus as CD4+ “helper” or CD8+ cytotoxic T cells
  • Proliferation of clones
  • Development of immunological self-tolerance
    > selection of auto-reactive cells for removal (apoptosis) to prevent autoimmunity; export of repertoire of T cells for life
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37
Q

Which structures are located in the corticomedullary junction?

A

Post-capillary venules analogues to endothelial venules in lymph nodes in the thymus

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38
Q

What are Hassall’s corpuscles?

A

Characteristic regions of degenerating epithelial-reticular cells in the thymus

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39
Q

Which hormones are produced in the thymus?

A

Thymulin
Thymopoietin
Thymosins for T cell maturation

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40
Q

Describe the blood supply to the thymus

A

Inferior thyroid arteries and internal thoracic artery

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41
Q

Describe the development of the thymus

A

Develops from the endoderm of the 3rd pharyngeal pouch
Most active in childhood - increases in size until the first year of life
Remains the same size until 60, then decreases
In adulthood, involution occurs: fatty infiltration and lymphocyte depletion

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42
Q

Describe the structure of the lymph node

A
  • Small kidney bean-shaped aggregates of lymphoid tissue with fibrous capsule
  • Site of adaptive immune response activation; function is the filtration of lymph
  • Lymph node is compartmentalised
    > Germinal centre: B lymphocytes
    > Paracortical area: T lymphocytes
    > Primary lymphoid follicle: B cells
    > Medullary cords: macrophages & plasma cells
    > Medullary sinus: drains lymph to efferent lymphatic vessels
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43
Q

Which cells form the boundary between the sinuses and the dense lymphoid tissue of the cortex and medullary cords of the lymph node?

A

Littoral cells

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44
Q

Lis the locations of major lymph nodes

A
  • Cervical
  • Axillary
  • Lumbar
  • Pelvic
  • Inguinal
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45
Q

Large germinal centres develop light and dark poles - describe the differences between them

A

Light pole: towards capsule & source of antigen
> More active
> Greater content of tingible body macrophages
Dark pole: towards medulla
> Less active

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46
Q

Where are immature lymphocytes located in the lymph node?

A

Mantle zone / outer corona

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47
Q

Describe the location and function of stellate macrophages

A

Stellate macrophages line sinuses in the lymph node & are present on reticular fibres
> Stellate macrophages phagocytose foreign bodies & present antigens to lymphocytes

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48
Q

Describe the changes in the lymph node when an immune response is initiated

A
  • Humoral/antibody response (B cells)
    > Growth of lymphoid nodules/follicles in outer cortex - become secondary follicles
    > Enlargement of medullary cords (become populated with plasma cells)
  • Cell-mediated response (T cells)
    > Division and enlargement of discrete lymphocytes in paracortical area
    > High endothelial venules with cuboidal epithelium are specialised for the exit of lymphocytes
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49
Q

Which cells make up the filtration mechanism in the spleen?

A

Stave cells

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50
Q

Describe the blood supply to the spleen

A
  • Splenic artery branches into central arteries surrounded by T cell (periarterial lymphoid sheath)
  • Further branching at right angles into penicillar arteries (supply red pulp)
    > 3 regions
  • Pulp arteriole
  • Sheathed arteriole: surrounded by macrophages
    Terminal arteriole capillary (deliver blood to splenic cords)
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51
Q

Describe mucosa-associated lymphoid tissues

A

Lymphoid nodules underlying mucous membranes (GI, respiratory, urinary & reproductive tracts)
Diffusely scattered lymphocytes in the lamina propria - mainly T cells
Specialised overlying M cells (APCs) in microfolds
Peyer’s patches of the bowel predominantly produce IgA antibodies

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52
Q

List the 9 characteristics of cancer cells

A
  • Self-sufficiency
  • Insensitivity to growth-inhibitory signals
  • Evasion of apoptosis
  • Limitless replication potential
  • Sustained angiogenesis
  • Tissue invasion & metastasis
  • Avoiding immune destruction
  • Genome instability & mutations
  • Deregulating cellular energetics
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53
Q

List the steps involved in the metastatic cascade

A
  • Invasion
  • Intravasation
  • Transport
  • Extravasation
  • Colonisation
  • Angiogenesis
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54
Q

Compare the properties of epithelial and mesenchymal cells

A

Epithelial cells:
* Cohesive interactions among cells
* 3 membrane domains: apical, lateral and basal
* Presence of tight junctions
* Polarised distribution of cell components
* Lack of mobility
Mesenchymal cells:
* Loose/no interactions between cells
* No clear apical/basolateral membranes
* No cell-cell junctions
* No apicobasal polarised distribution of organelles
* Motile cells w/ invasive properties

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55
Q

Describe the epithelial-to-mesenchymal transition (EMT)

A
  • Epithelial cells lose typical characteristics & become migratory
  • In epithelial cells, actin is arranged cortically
  • Cells undergoing EMT rearrange their actin cytoskeleton to form thick strands (stress fibres)
    > Actin strands help movement
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56
Q

Describe the function of E-cadherin

A
  • Transmembrane protein which forms part of the adherens junction
  • E-cadherin binds w/ itself on adjacent epithelial cells via calcium-dependent homotypic binding
  • Mediate cell-cell adhesion via their extracellular domain & connect to actin cytoskeleton by associating with alpha and beta catenin via their cytosolic domain
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57
Q

Discuss the effects of aberrant E-cadherin expression in human tumours

A
  • E-cadherin becomes N-cadherin
    > N-cadherin is expressed in mesenchymal cells and promotes invasion and motility
  • Loss/induction of E-cadherin can result from
    > Upregulating mutations in transcriptional repressors e.g. snail
    > Silencing of CDH1 promoter by methylation
    > Mutations in beta catenin
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58
Q

Describe the role of altered integrin expression in the formation of tumours

A
  • Integrins form part of the cell-substratum junction
  • Composed of 2 non-covalently associated transmembrane glycoprotein subunits alpha and beta
    > Capable of bidirectional signalling
  • Found in basal epithelial cells (hemidesmosomes) and focal adhesions of migrating cells
  • Connect to actin stress fibres and altered expression promotes cell motility and invasion
    > Support oncogenic GFR signalling
    Extravasation and survival of CTCs
    Colonisation of metastatic sites
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59
Q

Describe the role of hepatocyte growth factor in metastasis

A

HGF or scatter factor can induce epithelial cells to dissociate and scatter
* HGF is a mitogen (growth factor) and a motogen (motility factor) produced by stromal cells in the tumour microenvironment
* Binds to c-met, a RTK on tumour epithelial cells
> Activation of c-met increases tyrosine phosphorylation of beta-catenin
> Results in disrupted E-cadherin-mediated cell-cell junctions

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60
Q

Increased proteolytic activity is necessary for invasion; which proteases are expressed in tumours?

A
  • Serine proteases: urokinase plasminogen activator (uPA)
    > Cleaves plasminogen to plasmin, which activates MMPs & degrades ECM
  • Matrix metalloproteinases (MMPs)
    > Require calcium/zinc to degrade matrix components
    > MMP-2 degrades type IV collagen
  • Cysteine proteases
    > Cathepsin K collagenolytic activity results in matrix degradation
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61
Q

Describe different modes of tumour spread

A
  • Lymphatic spread
    > Common in carcinomas, e.g. breast cancer travels to axillary nodes > thoracic duct > systemic circulation
  • Haematogenous spread
    > Common in sarcomas
  • Transcoelomic spread
    > Across peritoneal cavity
    > Incidence higher with tumours arising from peritoneal cavity e.g. ovarian
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62
Q

Describe intravasation and transport

A

Intravasation
> Attachment > degrade BM > diapedesis > new blood vessels are leaky facilitating entry
Transport
> Most tumour cells do not survive the shear stress of blood flow, immune detection & anoikis (cells initiate a form of apoptosis when detached from substratum)

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63
Q

Describe the process of extravasation

A

> Slow rolling by forming attachment with adhesion molecules on endothelial lining
Tumour cells express high levels of ligand for selectins
Cells roll until further interactions with cell surface molecules arrest the cell & facilitate diapedesis (integrins, cell adhesion molecules and junction adhesion molecules)

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64
Q

Describe the role of selectins in tumour formation

A
  • Selectins are carbohydrate-binding transmembrane molecules
    > P-selectin (platelets & endothelial cells)
    E-selectin: endothelial cells, ligand is a carbohydrate on tumour cells: sialyl-Lewisx antigen, associated w/ metastasis and poor prognosis
  • L-selectin: leukocytes
    Faciliate tumour cell dissemination and formation of tumour microenvironment
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65
Q

Describe the process of angiogenesis

A

As tumour cells become hypoxic, they produce a transcription factor - hypoxia inducible factor (HIF)
* Transcribes genes which promote angiogenesis such as VEGF
* Endothelial cells proliferate to produce sprouts
Neovasculature is leakier and facilitates extravasation

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66
Q

What is meant by the “angiogenic switch”?

A
  • Initiation of blood vessel formation is induced when angiogenic activators dominate over angiogenic inhibitors
  • Angiogenic inhibitors downregulated in cancer
    > Thrombospondin: antagonises VEGF
    > Angiostatin and endostatin inhibit epithelial cell migration
    > Tumstatin inhibits endothelial cell proliferation
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67
Q

List the cells of the tumour microenvironment

A
  • Cancer-associated fibroblasts (CAFs)
  • Endothelial cells
  • Pericytes (perivascular stromal cells)
  • Immune cells
    > Mast cells
    > Tumour-associated macrophages
    > Neutrophils
  • Mesenchymal stem cells
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68
Q

Describe the function of cancer-associated fibroblasts (CAFs)

A

Secrete MMPs, cytokines, IL-8 and VEGF

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69
Q

Describe the function of pericytes in the tumour microenvironment

A
  • Low pericyte coverage of vasculature - leaky vessel structure
  • Facilitates tumour cell invasion/extravasation
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70
Q

Describe the function of tumour-associated macrophages

A

Can polarise to
M1 - tumoricidal
M2 - promote tumour growth
> Chronic inflammation
> Immune suppression
> Angiogenesis
> Invasion/metastasis: CSF-1/EGF paracrine loop; EGF acts on tumour cells to promote invasive & proliferative capabilities
> Produce growth factors & MMPs to promote angiogenesis, cell invasion & intravasation

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71
Q

Explain the interactions between programmed death 1/programmed death ligand-1 (PD-1/PDL-1)

A
  • T cells are specifically activated by the T cell receptor
  • Binds to tumour antigen expressed on MHC on tumour cell
  • “On switch” for cytotoxic T cell response
  • PD-1 expressed on CD8+ T cell: off switch
  • PDL-1 expressed on tumour cell interacts with PD-1 to dampen immune response
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72
Q

Describe the MAPK cascade

A

Mitogen-associated protein kinase cascade
* Signalling molecule e.g. growth factor binds to receptor tyrosine kinase
* Relay protein Grb/Sos activates ras
* Ras activates Raf kinase
* Raf kinase phosphorylates & activates MEJ
* MEK activates ERK
* ERK goes to nucleus & alters gene transcription to produce response

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73
Q

Describe the pathophysiology and treatment of Chronic Myeloid Leukaemia (CML)

A
  • Philadelphia chromosome: reciprocal translocation between chromosomes 9 and 22
  • Forms a lethal recombinant gene: Bcr-Abl (strong kinase)
  • Tyrosine kinase is permanently switched on leading to rapid uncontrolled progression through cell cycle in myeloblasts
    Treatment: tyrosine kinase inhibitors (TKIs) e.g. imatinib
    > Bing to ATP-binding site in tyrosine kinase preventing functioning
    > Major improvement in survival but drug resistance can arise
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74
Q

Describe the use of target therapies for the treatment of non-small cell lung cancer

A
  • Non-small cell lung cancer with mutations in anaplastic lymphoma kinase: crizotinib
  • Non-small cell lung cancer with EGFR mutations: erlotinib
  • Both highly selective
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75
Q

Differentiate between predictive and prognostic markers

A

Predictive markers
> Predicts which patient will benefit from specific treatment, helping to choose a drug
> Basis of precision medicine e.g. Raf mutations in melanoma
Prognostic markers
> Inform about outcome regardless of treatment
> Helps in choosing which patients to treat, but not how to treat them
> E.g. circulating tumour cells in breast cancer
Oestrogen receptors are prognostic + predictive (high ER expression gives positive prognosis, ER+ve tumours benefit from tamoxifen)

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76
Q

Describe the mechanism of action of PARP inhibitors

A

E.g. olaparib, treats ovarian, breast & prostate cancer
* Targets PARP, which is involved in single-strand repair
* If single-strand break is not repaired, a double-strand break results
* Double strand breaks repaired via homologous recombination
> BRCA involved in double strand repair
Aberration in BRCA means double strand breaks are not repaired, resulting in cancer cell death

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77
Q

Describe the role of the innate immune response in eliminating nascent cancers

A
  • Innate lymphocytes - NK cells, NK T cells, gamma delta T cells - recognise aberrant cancer cells
  • NK cells recognise a change in MHC I expression, bind & release cytotoxic factors to kill cells
  • Bring other cells to the area like dendritic cells and macrophages
  • Release interferon gamma: initiates cytokine cascade
  • Trafficked to local lymph nodes or spleen generating adaptive immune response
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78
Q

Describe the process of immunoediting

A

Immunoediting produces low antigenicity tumour cells by selection; pressure from immune system + genomic instability enables evasion of immune response
* Elimination: removal of tumour by immune system
* Equilibirum: tumour does not growth further due to constant attack by immune system; latent
* Escape: tumour constantly generates new clones & variants
> Eventually heterogeneous tumour evades immune system
> Grows uncontrollably becoming clinical cancer

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79
Q

Describe the mechanism of action of checkpoint inhibitors (non-cellular therapy)

A

E.g. ipilimumab
Targets “off switch” on T cells: CTLA-4 (co-stimulatory for T cells), which interacts with B7 to suppress T cell proliferation
> T cells continue to be aggressive
Associated with adverse events like skin mucosa & gut problems, but they can be managed with steroids
Includes PD-1/PDL-1: nivolumab, pembrolizumab

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80
Q

Give examples of non-specific therapies (non-cellular therapy)

A
  • Using toll-like receptors e.g. imiquimod (TLR-8 agonist) mimics concentrated viral assault on skin, producing a localised inflammatory response > kills cancer cells
  • IL-2 immunotherapy
    > High toxicity & narrow therapeutic window but can be effective
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81
Q

Describe vaccination strategies (non-cellular cancer therapy)

A
  • Require that the tumour-associated antigen is only expressed in that tumour; brings strong immune response specifically towards tumour
  • Peptide therapy: single or multiple peptides (wide antigen panel)
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82
Q

Describe monoclonal antibody therapies

A
  • Administration of monoclonal antibodies which target either tumour-specific or over-expressed antigens
    Mechanisms:
  • Apoptosis induction
  • Complement-mediated cytotoxicity (CDC)
  • Antibody-dependent cell cytotoxicity (ADCC) - opsonisation
  • Conjugated to toxin/isotope
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83
Q

Discuss the role of haematopoietic stem cells in cancer treatment

A
  • Bone marrow donation, mobilise stem cells into peripheral blood using GCSF
  • Destroy immune system via total body irradiation/chemotherapy
  • Re-infuse HSC into clean system
  • Innate IR recovers first (primarily RBCs & platelets)
  • Potentially curative
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84
Q

List cellular immunotherapies used in cancer treatment

A
  • Haematopoietic stem cells
  • CAR (chimeric antigen receptor) T cells
  • NK cells
  • Gamma delta T cells
  • Tumour-infiltrating T cells
  • Dendritic cell vaccines
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85
Q

Define depression & describe the somatic signs and symptoms of depression

A
  • A pathological lowering of mood that has an impact on an individual’s day-to-day function
  • Somatic signs and symptoms: (every day > 2 weeks)
    > Fatigue
    > Insomnia / nightmares
    > Anhedonia
    > Loss of appetite, weight loss
    > Constipation, amenorrhoea
    > Loss of libido
86
Q

Describe the cognitive symptoms associated with depression

A
  • Loss of concentration (slowed thinking)
  • Negative thoughts
  • Lowered self-esteem, confidence
  • Guilt
  • Hopelessness
  • Suicidality
  • Memory loss/impairment
87
Q

Describe depressive psychosis

A
  • Delusions - mood congruent “nihilistic”
    > Guilt, poverty, hypochondriasis, persecutory
    > Cotard’s syndrome - self/part of self is dead
  • Hallucinations: auditory 2nd person voice
88
Q

Describe agitated depression

A
  • Rarer form of severe depression
  • Usual symptoms but patients tend to be highly restless
  • Often agitated, pacing, psychotic
    High risk for suicidality
89
Q

Describe depressive catatonia

A

State of stupor, inhibited motor activity
Seen in severe depression, schizophrenia
Presents:
* Altered GCS
* Abnormal speech (mute, repetitive)
* Abnormal posturing (rigidity, waxy flexibility)
* Life-threatening: patient stops eating and drinking

90
Q

Describe the mechanism of action of SSRIs including associated side-effects

A

Selective serotonin reuptake inhibitors (first-line) e.g. citalopram, fluoxetine, sertraline
* Block reuptake of serotonin, increasing the amount in the synapse
* 4-5 weeks to have an effect
- Side-effects
> Nausea, vomiting, dizziness
> Weight gain
> Discontinuation syndrome
> Paradoxically alerting: anxiety, suicidality, mania, serotonin syndrome: autonomic instability, prolonged QTc (risk of arrhythmia)

91
Q

Give examples of SNRIs and NASSAs

A

Selective noradrenaline reuptake inhibitors: venlafaxine, duloxetine
Noradrenaline and specific serotonin antagonists: mirtazapine

92
Q

Describe the mechanism of action of TCAs including associated side-effects

A

Tricyclic antidepressants: amitriptyline, imipramine, clomipramine
> Blocks 5HT and NA reuptake (second-line)
Side-effects:
> Anti-adrenergic (hypotension)
> Anti-cholinergic (dry mouth, blurred vision, constipation, QTc prolongation, arrhythmia)

93
Q

Describe the mechanism of action of MAOIs including associated side-effects

A

Monoamine oxidase inhibitors e.g. isocarboxazid, phenelzine
> Blocks MAO-A, MAO-B - breaks down 5HT, NA, DA in CNS
* Side-effects
> Hypertensive crisis: avoid foods with high tyramine content as MAO-A in GI tract breaks down tyramine

94
Q

Name novel biologics with potential uses in the treatment of depression

A
  • Ketamine
    > NMDA antagonist
  • Psilocybin (magic mushrooms)
    > Hallucinogenic, 5HT agonist
  • Lysergic acid (LSD)
    > Hallucinogenic, 5HT agonist
95
Q

Describe the use of electroconvulsive therapy (ECT) as a treatment for depression

A
  • Patient anaesthetised
  • Controlled seizure is induced
  • Rarely, memory might be affected
  • Used in cases of severe life-threatening depression
  • More effective than drugs
96
Q

Explain the biological causes of depression

A
  • Genetics
  • Medical comorbidities
    > Thyroid problems
    > Heart failure, stroke
    > Multiple sclerosis
  • Psychiatric comorbidities
    > Schizophrenia
    > Alcohol abuse
  • Pregnancy: post-natal depression
  • Medications: steroids
  • Neurochemical: monoamine hypothesis
    > Decreased 5HT, NA and DA
  • Neuroendocrine
    > Decreased T3 & TSH
    > Increased cortisol
97
Q

Explain the psychological causes of depression

A
  • Pre-morbid personality traits: predisposed personality
  • Coping skills
  • Adverse life events: kindling theory
    > Repeated stressors damage resilience
    > Every affective episode reduces resilience and increases likelihood of future spontaneous episodes
98
Q

Explain the social causes of depression

A
  • Social isolation
  • Socioeconomic disadvantage
  • Marginalised groups - LGBTQ+
  • Northern location
  • Modern western society
99
Q

Discuss psychological treatments for depression

A
  • Education: myth busting and reassuring they will get better
  • First principles
    > Socialisation
    > Routine/activity, exercise, diet, sleep
    > Avoid alcohol & drugs
  • CBT
    > Life stressor leads to altered thinking > altered emotional feelings/physical symptoms> altered behaviour
    > Breaking the cycle, examining thought patterns and changing behaviourHow can you calculate how many units of alcohol are in a drink?
100
Q

How can you calculate how many units of alcohol are in a drink?

A

Alcohol by volume (ABV) x volume of drink
Then divide by 1000
Examples: 1 unit in 1/2 pint or 1 unit in a single shot

101
Q

Outline current government recommendations for alcohol consumption

A
  • 14 units a week men & women
  • Men: 14-49 hazardous, >49 harmful, >8 binge drinking
  • Women: 14-35 hazardous, >35 harmful, >6 binge drinking
  • Keep alcohol-free days to recover
  • Amount of alcohol drunk on any one occasion should not be excessive
102
Q

Describe the effects of opiates on the CNS

A
  • All opioids act via opioid mu receptors in the CNS
  • Increase dopamine initially
  • Repeated use leads to system adaptation and downregulation of D receptors
    > Higher dose needed to get initial effect
  • Main effects: analgesia, euphoria, sedation
  • Results in impaired activity of prefrontal cortex
    > Lack of pleasure from other activities, lack of impulse control, emotional dysregulation
103
Q

Define opioid dependence according to ICD-10 criteria

A
  • Strong desire/compulsion to use opioid drug
  • Difficulties in controlling opioid use
  • Progressive neglect of alternative interests
  • Tolerance: increased doses of opioid required to achieve initial effect
  • Physiological withdrawal state when opioids seized/reduced
  • Persisting with opioids despite harmful consequences
104
Q

Describe the symptoms of an opioid overdose

A
  • Respiratory depression
  • Not moving & cannot be woken up (unresponsive)
  • Choking, gurgling, snoring
  • Skin is cold & clammy
  • Pinpoint pupils
  • Lips and nails are blue (peripheral cyanosis)
105
Q

Discuss the management of an opioid overdose

A
  • Naloxone kit (pre-filled syringe of injectable naloxone)
    > IM injection into deltoid/quadriceps
    > Quick onset of action (2-5 mins); another dose can be injected after 5 mins
    > Duration of effect is 30-90 mins
  • Naloxone spray (Nyxoid)
106
Q

Describe the symptoms of opioid withdrawal

A
  • Runny nose
  • Yawning
  • Sweating (treat autonomic symptoms with clonidine)
  • Insomnia (manage w/ trazadone, avoid benzodiazepines)
  • Anxiety (manage w/ seroquel, benzodiazepines at physician’s discretion)
  • Muscle aches: manage w/ ibuprofen
  • Increased tear production
  • Nausea and vomiting: manage w/ diphenhydramine, metoclopramide
  • Chills
  • Diarrhoea (manage w/ loperamide)
  • Dilated pupils
  • Stomach cramps
107
Q

Discuss substitute prescribing in opiate dependence

A
  • Methadone
    > Opioid analgesic, full agonist of mu-opioid receptors
    > Limited value in rapid relief of withdrawal
    > Slow initiation: risk of respiratory depression
    > Steady state reached in 5 days
  • Bruprenorphine
    > Espranol (oral lyophilisate) & buvidal (prolonged release solution for injection)
    > Partial opioid agonist: activates mu-opioid receptord producing analgesia, euphoria, constipation & respiratory depression
    > Can displace heroin from opioid receptors
    > Ceiling effect: increasing dose will not increase effect
108
Q

Compare methadone and bruprenorphine

A

Methadone:
* Cheaper, familiar
* Easier to supervise
* Less analgesic blocking
* More flexible dosing
* No precipitated withdrawal
* More sedating
Bruprenorphine:
* Less stigma
* Lower risk of diversion
* Less cardiac risk
* Greater reduction in effect of illicit opiates
* Less respiratory depression
* Quicker safe titration
* Less sedating

109
Q

Discuss safer drug consumption facilities and heroin-assisted treatment (HAT)

A
  • People can consume drugs, obtained elsewhere, under the supervision of trained health professionals
  • HAT involves providing prescribed heroin under supervised conditions to people with long-standing heroin addictions
  • Reaches a vulnerable group which doesn’t often engage with health services
110
Q

Discuss the uses of benzodiazepines

A
  • CNS depressants, predominantly act on GABA-A receptors
    Used for
  • Anxiety, panic attacks
  • Seizures/epilepsy
  • Skeletal muscle relaxation
  • Management of withdrawal syndromes
  • Insomnia
111
Q

Describe the different types of benzodiazepines

A
  • Ultra short-acting (T1/2 up to 3h)
    > Midazolam, triazolam
  • Short to intermediate-acting (T1/2 up to 40h)
    Lorazepam, temazepam, alprazolam
  • Long-acting (T1/2 up to 100h)
    > Chlordiazepoxide (librium), diazepam (valium), clonazepam
112
Q

Discuss dependence in the context of benzodiazepine use

A

Long term prescribing is not recommended as risks outweigh benefits
> Tolerance
> Dependence: psychological & physical, withdrawal seizures common
> Cognitive decline
> Respiratory depression & accidental overdose

113
Q

Discuss immediate and long-term complications of benzodiazepine use

A

Immediate
> Drowsiness, dizziness, sedation
> Calmness
> Confusion, slurred speech
> Blackouts, blurred vision
> Shallow breathing
> Decreased heart rate
> Overdose (loss of balance & coordination)
Long-term
> Dependence
If suddenly stopped, can cause fatal seizures

114
Q

Discuss the management of a benzodiazepine overdose

A

Caution with mixed overdoses with alcohol, opioids & other CNS depressants
* General supportive measures: maintain airways, breathing, circulation
* Specific benzodiazepine antagonist: flumazenil
> Given as a 1-2mg IV infusion over several minutes

115
Q

Discuss benzodiazepine withdrawal symptoms

A
  • Common
    > Sleep disturbances
    > Increased tension
    > Anxiety and panic attacks
    > Difficulty concentrating
    > Excessive sweating
    > Heart palpitations
    > Headache
    > Muscular stiffness/discomfort
    > mild/moderate changes in perception
    > Cravings
    > Hand tremors
  • Less common
    > Hallucinations
    > Seizures
    > Psychosis
    > Suicidal ideation
116
Q

Summarise the mechanism of action, effects & harms of cocaine use

A
  • Powerful stimulant from coca leaf; blocks dopamine reuptake
  • Effects
    > Happy/excited/alert/confident
    > Sick/anxious/paranoid
  • Harms (sympathomimetic)
    > Immediate: cardiovscular risk, psychosis
    > Long-term: cardiovascular including early MI and microvascular infarcts, cognitive deficits, addiction, blood-borne viruses, lung damage (COPD) due to hot vapours from crack
117
Q

Summarise the mechanism of action, effects & harms of methamphetamines

A
  • Psychostimulants which release dopamine & block reuptake
  • Effects
  • Harms
    > Immediate: CVS risks - sympathomimetic, overdose, chem sex, insomnia, psychosis
    > Long-term: addiction, CVS harms, meth mouth, depression, anxiety, psychosis, BBV
118
Q

What is meant by “meth mouth”?

A

Dry mouth, teeth decay/loss due to anticholinergic effects

119
Q

Summarise the mechanism of action, effects & harms of ecstasy/MDMA

A
  • Blocks serotonin and dopamine reuptake
  • Effects
    > Elevated mood, energised, alert
    > Anxiety/panic attacks/confusion/paranoia/pscyhosis
  • Harms
    > Immediate: CVS risks, liver & kidney problems, water intoxication: excessive drinking due to thirst, dehydration
    > Long-term: addiction, depression, anxiety
120
Q

Summarise the mechanism of action, effects & harms of khat

A

Leafy green plant w/ active ingredients cathinone and cathine
> Release ephedrine, a dopamine releaser
* Effects
> Elated, alert, appetite suppressant, calm
* Harms
> Immediate: CVS, increased sex drive, insomnia, anxiety, aggression, paranoia, psychosis
> Long-term: CVS, dependence, liver problems, oral cancer

121
Q

Summarise the mechanism of action, effects & harms of cannabis

A

> Cannabis CB1 receptor agonist
THC (tetrahydrocannabinol): anxiolytic and enforcing effects
CBD (cannabidiol): natural antipsychotic
Effects:
* Calm, happy, giggly
* Lethargic, unmotivated, paranoid
Harms:
Immediate: respiratory effects e.g. cough, memory impairment, insomnia, depression/anxiety, panic, aggression, psychosis
Long-term: increased risk of lung cancer, cardiovascular, mood/anxiety problems

122
Q

Summarise the mechanism of action and effects of LSD

A

Lysergic acid (LSD)
* Agonist at serotonin 5HT2A receptor
Effects
> Euphoria, warmth, enlightment
> Detachment from the world around
> Hallucinations

123
Q

Summarise the mechanism of action, effects & harms of ketamine

A
  • Hallucinogenic dissociative drug; NMDA glutamate receptor antagonist
  • Effects
    > Dream-like, detached, chilled, relaxed, happy
    > Confused, nauseated
  • Harms
    > Immediate: CVS risk, confusion, agitation, muscle paralysis, injuries, bladder problems
    > Long-term: depression, psychosis, memory & attention problems
124
Q

Describe novel psychoactive substances (NPSs)

A

Group of drugs created to produce similar effects to drugs like cocaine, cannabis and ecstasy but legal
Structurally different in order to avoid being controlled under the Misuse of Drugs Act
* Began appearing around 2008-2009 but UK Psychoactive Substances Act May 2016 made it an offence to produce a substance used to get high

125
Q

Summarise the mechanism of action, effects & harms of mephedrone

A

Novel psychoactive substance (stimulant)
- Releases dopamine & blocks reuptake
Effects:
* Energised, active, alert, fast-thinking, confident, euphoric, sexually aroused
* Anxious, agitated, dizzy, hot
Harms:
> Immediate: CVS, psychosis, seizures, overheating, overdose, insomnia
> Long-term: insufficient data, CVS, addiction, mental health

126
Q

Summarise the mechanism of action, effects & harms of GHB and GBL

A

GHB: gammahydroxybutyric acid
GBL: gammabutylrolactone
GHB and GABA-B receptor agonist
* Effects
> Euphoria, relaxed, sleepy, sexually aroused
* Harms
> Immediate: overdose, death, sexual assault, burns, confusion
> Long-term: addiction, severe withdrawal

127
Q

Summarise the mechanism of action, effects & harms of synthetic cannabinoid receptor agonists (SCRAs)

A
  • Full agonists at CB1 and CB2, more potent than traditional cannabis
    Effects
    > Relaxation, altered consciousness, happy, giggles
    > Disinhibition, energised, euphoria
    > Paranoid, psychotic, panic attacks
    Harms
    > Immediate: dizziness, confusion, agitation, aggression, anxiety, paranoia, suicidal ideation, nausea, vomiting, hot flushes, psychosis, CVS, numbness, seizures, serotonin syndrome, death
    > Long-term: withdrawal, renal injury, precipitated psychosis
128
Q

Describe pharmacological management of acute withdrawal involving downers, uppers and SCRAs

A

Downers: delirium tremens, seizures; treat with diazepam/chlordiazepoxide reducing regimes, add baclofen for GHB
Uppers: wellbeing medications, sedating antihistamine (promethazine), loperamide, antiemetics, chlordiazepoxide if severe
SCRAs: symptomatic relief + wellbeing medications + chlordiazepoxide reducing regimes

129
Q

Describe how public health measures can impact alcohol-related liver disease

A
  • Minimum unit pricing
  • Multi-buy discount ban (decline in total per adult off-trade alcohol sales)
  • Increased investment in alcohol treatment & care services
  • Increased delivery of alcohol brief interventions
  • Legislation to ban irresponsible promotions in the on-trade
  • Introduction of lower drink drive limit to 50mg per 100ml of blood
    Impact: reduction in alcohol-related death, especially in men in most deprived areas
130
Q

Discuss the consequences of metabolism of alcohol in terms of
* Acetaldehyde production
* Acetate production
* Increased NADH/NAD ratio

A
  • Acetaldehyde production: binds to proteins and DNA: immunogenic as protein adducts on cell surface stimulate immune response with cytotoxic T cells; also stimulates collagen production by stellate cells
  • Acetate production: increased acetyl CoA promotes inflammation by histone acetylation
  • Increased NADH/NAD ratio:
    > Reduced gluconeogenesis & increased glycolysis, risk of hypoglycaemia
    > Increased pyruvate converted to lactate: lactic acidosis
    > Reduced lipolysis and increased lipogenesis: fatty change of the liver (steatosis)
131
Q

Discuss the consequences of metabolism of alcohol in terms of reactive oxygen species (ROS) production

A
  • Largely through MEOS but catalase activity may contribute
  • Production of hydrogen peroxide and superoxide ions
  • Activate redox sensitive transcription factors such as Nf-kB which leads to increased TNF-alpha
  • Promotes lipid peroxidation which promotes inflammation and damages mitochondrial membranes leading to apoptosis
132
Q

Describe the effects of increased intestinal permeability in the context of alcohol-related liver disease

A

Intestinal permeability increase leads to portal circulation endotoxaemia
Promotes activation of Kupffer cells which promote liver injury through production of TNF-alpha and ROS
TNF-alpha production promotes apoptosis, necrosis & pyroptosis, also activates stellate cells to produce collagen leading to fibrosis

133
Q

Define pyroptosis

A

Highly inflammatory form of lytic programmed cell death
Occurs upon infection with intracellular pathogens

134
Q

Describe the 2 pathways which lead to programmed cell death

A
  • Intrinsic pathway
    > Stimulated by oxygen free radicals (oxidative stress)
    > Leads to leakage of pro-apoptotic factors from mitochondria e.g. cytochrome C
    > Proteolytic caspase activation
    > Breakdown of cellular cytoskeleton & budding broken down organelles into apoptotic bodies which are phagocytosed
  • Extrinsic pathway
    >Stimulated by TNF-alpha binding to NF receptor (also activated by cytotoxic T cells)
    > Proteolytic caspase activation via FADD (Fas-associated death domain) protein or TRADD (TNF receptor associated death domain) protein
135
Q

Describe the process of autophagy

A
  • Lysosomal degradation pathway that controls the disposal of intracellular waste (damaged organelles/invading pathogens)
  • Adaptive to a number of stressors
    > Starvation, growth factor depletion, oxidative injury, chemicals
  • Alcohol acutely increases autophagy but reduces it with chronic use - build-up of damaged structures within cell leads to fibrosis, cirrhosis and malignancy
  • Generally, autophagy blocks the induction of caspase-dependent apoptosis
136
Q

Discuss the impacts of malnutrition on alcohol-related liver diseae

A
  • Depletion of trace elements e.g. zinc may exacerbate ROS production and promote apoptosis
  • Vitamin deficiency (folate, vitamin B6 & B12) may lead to impaired methionine metabolism, increase in homocysteine & reduction in glutathione
  • Less protection of cell from oxidative stress
137
Q

Outline the consequences of disrupted methionine metabolism

A
  • Reduced SAM:SAH ratio
    > Reduced transmethylation
    > Impaired gene expression
  • Increased caspase-3/8 expression: apoptosis
  • Increased TNF-alpha (reduced IL-10): inflammation
  • Reduced cystathione beta-synthase activity
  • Reduced trans-sulfuration: reduced glutathione production, oxidative stress
138
Q

Outline the effects of obesity on alcohol-related liver disease

A
  • Alcohol induces a lipdystrophy: increased visceral fat & reduced peripheral fat
  • Induction of CYP2E1 by increased free fatty acids, insulin resistance & alcohol
  • Increased ROS & further insulin resistance
  • Obesity induces a pro-inflammatory state (esp in response to endotoxaemia)
  • Risk increased in patients with raised BMI
139
Q

Describe non-invasive tests used in screening for alcohol-related liver disease

A
  • Blood tests
    > Composite scores e.g. FIB-4 index
    > Specialised: enhanced liver fibrosis test (ELF)
  • Measures hyaluronic acid, procollagen III amino terminal peptide, tissue inhibitor of metalloproteinase 1
  • Transient elastography (FibroScan)
    > Imaging is more sensitive & specific for diagnosing cirrhosis
    > Offer to men who drink >50 units and women who drink >35 per week for several months
140
Q

Outline the clinical features of alcohol-related liver disease

A
  • Incidental: malaisea, nausea, hepatomegaly, fever
  • Decompensation: jaundice, sepsis, variceal haemorrhage, hepatic encephalopathy, ascites, hepato-renal failure, hepatocellular carcinoma
  • Chronic liver disease: spider naevi, foetor hepaticus, synthetic dysfunction (hypoalbuminaemia + prolonged PT)
  • Portal hypertension: caput medusae, splenomegaly, thrombocytopaenia
141
Q

Describe the assessment of severity of chronic liver disease

A
  • Childs-Turcotte-Pugh score
    > Includes scores for encephalopathy, ascites, bilirubin, albumin, PT prolongation
  • Models for End-stage Liver Disease (MELD)
    > Uses bilirubin, INR & creatinine
  • MELD-Na includes sodium (low sodium > poor prognosis)
  • UKELD score for liver transplant
142
Q

Discuss the diagnosis of alcoholic hepatitis

A
  • Onset of jaundice within prior 8 weeks
  • Ongoing consumption of >40 (female) or 60 (male)g alcohol/day > 6 months + <60 days abstinence before onset of jaundice
    AST > 50
    AST:ALT ratio >1.5
    Both values < 400 IU/L
    Serum bilirubin >3.0mg/dL
143
Q

Discuss the treatment of alcoholic hepatitis

A
  • Assessed with discriminant function (DF) using prothrombin time + bilirubin levels
  • Glasgow alcoholic hepatitis score (GAHS) is preferred
    > 5 variable score: age, urea, white cell count, PT ratio, bilirubin
  • Survival benefits w/ corticosteroids (prednisolone) + intensive enteral nutrition
  • Liver transplant improves survival rates bur alcoholic hepatitis is not an indication for transplant in the UK
144
Q

Outline the causes of alcohol dependence

A
  • Social learning model
  • Disease model
  • Genetic vulnerability
    > Chromosome 4 alcohol dehydrogenase polymorphisms mildly protective
    > Chromosome 12 aldehyde dehydrogenase polymorphism significantly protective
    > Polymorphism in 5HT transporter gene
    > Locus on chromosome 16 associated with severe alcohol dependence
145
Q

Discuss the effects of alcohol on the brain

A
  • CNS depressants; GABA-A receptor agonist
  • Acutely: anxiolytic, slurred speech, disinhibition, sedation, reduced consciousness
  • Dopamine release, opioid, cannabinoid & serotonergic receptors also implicated
  • NMDA glutamate receptor antagonist; reduced calcium influx, reduced excitation
  • Chronic use: upregulation of receptors, hyperexcitable state in withdrawals
146
Q

List psychological harms related to regular heavy drinking

A
  • Insomnia
  • Depression and anxiety
  • Attempted suicide
  • Changes in personality
  • Amnesia and dementia
  • Delirium tremens
  • Alcohol hallucinosis
  • Other addictions
147
Q

Describe inpatient alcohol detoxification

A

-Benzodiazepines: chlordiazepoxide or diazepam
> Effective in preventing seizures and delirium
* Pabrinex IM: thiamine, prophylaxis against Wernicke-Korsakoff syndrome
* Forceval: multivitamin and mineral supplement

148
Q

List symptoms of alcohol withdrawal

A
  • Anxiety, insomnia, headache, palpitations
  • GI upset, anorexia
  • Alcoholic hallucinosis (usually visual)
  • Withdrawal seizures: generalised tonic-clonic convulsions
  • Delirium tremens: agitation, hallucinations, disorientation, tachycardia, hypertension, fever, diaphoresis
149
Q

Describe the mechanism of action and effects of acamprosate

A
  • Taurine derivate, structurally similar to GABA so enhances GABA neurotransmission
  • Inhibits NMDA glutamate receptor hyperactivity
  • Effects
    > Increased time to relapse + decreased number of drinks consumed
    > Maintains abstinence if given early w/detox and combined with CBT
150
Q

Describe the mechanism of action and effects of disulfiram

A

Acetaldehyde dehydrogenase inhibitor: acetaldehyde accumulates if alcohol is consumed
Effects
* Nausea
* Flushing, palpitations, postural syncope, circulatory collapse
* Headache, visual disturbances

151
Q

Describe the mechanism of action and effects of naltrexone and nalmefene

A

Both are opioid receptor antagonists
Block pleasurable effects of alcohol by blocking natural opioids released by alcohol / mesolimbic dopamine reward pathway
Effective in reducing relapse in alcohol dependence; nalmefene has a longer half-life and less liver toxicity

152
Q

Discuss non-pharmacological interventions used in the prevention of alcoholic relapse

A
  • CBT: relapse prevention, enhances capacity to maintain abstinence
  • Contingency management
  • Social behaviour & network therapy
  • Behavioural self-control training
    > Limits, alter rate of drinking
    > Drink diary, non-alcoholic spacers
    > Assertiveness, reward, alternative coping skills
  • Motivational interviewing
    > Based on transtheoretical model of change by Prochaska & De Clemente
    > 4 principles: reflective listening, develop attitude discrepancy, roll with resistance without confrontation, support self-efficacy for change
  • 12 step programmes/AA
153
Q

Discuss alcohol-drug interactions with illicit, prescription and over-the-counter drugs

A

Illicit:
> Cocaine: cocaethylene is formed, longer-lasting & more euphorigenic, increases CVS risk
> Heroin: respiratory depression
Prescription:
> Benzodiazepines/barbiturates: respiratory depression
> Metronidazole: inhibits aldehyde dehydrogenase, similar effects to disulfiram
Over-the-counter
> Paracetamol: alcohol-acetaminophen syndrome
> Potential fulminant hepatic failure requiring emergent transplant or death

154
Q

Discuss Lishman’s hypothesis for alcohol-related brain damage and list different types

A
  • Non-alcohol related forms of Wernicke-Korsakoff syndrome due to thiamine depletion alone: full recovery
  • Alcohol neurotoxicity alone: slowly reversible dementia
  • Combination of both: irreversible cognitive impairment
    Types:
  • Neuropathies (peripheral neuritis)
  • Cerebellar degeneration
  • Dementia
  • Amnestic syndrome
155
Q

Describe the clinical features of alcohol amnestic syndrome (formerly Wernicke-Korsakoff syndrome)

A
  • Syndrome associated with chronic prominent loss of recent memory
    > Remote memory impaired
    Immediate recall preserved
    Disturbances of time sense & ordering of events
    Difficulties in learning new material
    Confabulation: fill memory gap with story
    Procedural memory preserved
    Amnesic defects out of proportion with other disturbances
156
Q

Differentiate between Wernicke’s encephalopathy and Korsakoff’s psychosis

A
  • Wernicke’s encephalopathy: acute presentation which can progress to alcohol amnestic syndrome
  • Korsakoff’s psychosis: chronic mental disorder linked with alcoholism + thiamine deficiency, sometimes preceded by Wernicke’s encephalopathy
157
Q

Describe the structures which are damaged in alcohol amnestic syndrome + signs

A
  • Thalamus
    > anterior principal nucleus
    > dorsomedial thalamic nuclei
  • Mamillary bodies
  • Cortical atrophy
    If under stress, neuronal death & haemorrhage
    Signs:
  • Confusion
  • Eye symptoms: gaze paralysis & nystagmus
  • Gait ataxia
  • Problems with spatial skills
158
Q

Describe the presentation of alcohol dementia

A
  • Decline from previous level, memory loss + one of the following:
    > Agnosia: cannot recognise familiar things
    > Aphasia: circumlocution, cliches
    > Apraxia: senses intact, understand what was asked but physically unable
    > Loss of executive functioning
  • Poor planning, organising, adaptability, cannot cope with change
159
Q

Describe the pathophysiology of hepatic encephalopathy

A
  • Ammonia and glutamate-glutamine cycle
  • Blood-brain barrier more permeable to ammonia w/ downregulation of glutamate receptors & uptake
    > Increase in astrocyte glutamine and osmotic stress
  • Indicates liver failure
160
Q

Give examples of precipitating factors for hepatic encephalopathy

A
  • Increased protein load e.g. upper GI haemorrhage
  • Decreased excretion of ammonia e.g. renal failure
  • Dehydration
  • Infection
161
Q

Describe the assessment and management of hepatic encephalopathy

A
  • West Haven criteria for grading mental state in hepatic encephalopathy
  • Treatment
    > Lactulose
    > Dietary measures to reduce nitrogen load
    > Removal of precipitants
    > General supportive measures
    > Reduction/closure of shunts
162
Q

Describe the effects of alcohol consumption during pregnancy

A
  • Increases risk of foetal growth restriction + miscarriage as alcohol freely crosses the placenta and is teratogenic
  • Results in foetal alcohol spectrum disorders:
  • Foetal alcohol syndrome (FAS)
  • Growth retardation
  • Microcephaly
  • Hyperactivity, irritability, seizures
  • Learning disabilities, mental retardation
  • Dysmorphic facial features: short palpebral fissures, smooth philtrum, thin upper lip
  • Alcohol-related birth defects (ARBD)
    > Features associated with FAS + anomalies in other organs e.g. cardiac, renal…
  • Alcohol-related neurodevelopmental disorder (ARND)
    > Behavioural abnormalities without dysmorphic features
163
Q

Name the areas of the brain responsible for calculation and the deficits which may arise if this area is damaged

A
  • Left hemisphere angular gyrus (parietal lobe)
  • Acalculia: inability to comprehend or write numbers properly
  • Anarithmetria: difficulty with arithmetic
164
Q

Name the areas of the brain responsible for praxis and the deficits which may arise if this area is damaged

A
  • Left hemisphere: parietal & frontal lobes
  • Errors of action conception (Knowledge of actions/item function) or action production (control of movement)
  • Includes ideational apraxia, orobuccal movemenets, imitation of gestures, using imagined objects…
165
Q

Name the areas of the brain responsible for visuospatial ability and the deficits which may arise if this area is damaged

A
  • Visual cortex (occipital lobe)
  • Parietal lobe: understanding of spacial relationships, orientation of objects
  • Temporal lobe: retrieve memory to identify/recognise what the object is
    Problems
  • Topographical disorientation: difficulty navigating a familiar environment
  • Dressing apraxia
  • Misreaching for objects
  • Visual neglect (parietal lesion)
  • Visual object agnosia
  • Prosopagnosia: do not recognise familiar faces
  • Constructional dyspraxia
166
Q

Define dementia and describe some general characteristics

A
  • Syndrome with chronic, progressive (usually irreversible) cognitive impairment due to brain disease
  • Deterioration from higher level of function
  • Multiple cognitive deficits
  • Chronic (>6 months)
  • Impact on social/occupational function
  • Personality change/disintregration
  • Decline in emotional control/motivation
  • No clouding of consciousness
167
Q

Discuss the causes of dementia

A
  • Parenchymal/degenerative
    > Alzheimer’s, vascular dementia, frontotemporal dementia…
  • Intracranial
    > Tumour, hydrocephalus, CVA…
  • Infection
    > Creutzfeldt-Jakob disease, neurosyphilis, HIV-associated dementia…
  • Endocrine
    > hypothyroidism, hyperparathyroidism, Cushing’s…
  • Metabolic
    > Uraemia, hepatic encephalopathy, hypoglycaemia…
  • Vitamin deficiency
    > B12, folate, thiamine…
  • Toxins
    > Alcohol, lead
168
Q

Discuss the main psychiatric differentials for dementia

A
  • Normal ageing
  • Delirium
  • Mild cognitive impairment
  • Amnesic syndrome e.g. Korsakoff’s
  • Chronic brain damage e.g. head injury, anoxia
  • Depression (pseudo-dementia)
  • Late onset schizophrenia/psychosis
  • Learning disability
  • Malingering presentations (pretending)
  • Dissociation
169
Q

Discuss the diagnosis of dementia

A
  • Clinical assessment
  • Corroborative history (family members)
  • General physical examination
  • Mental state examination
  • Standard + specialised bloods
    > FBC, ESR, CRP, glucose, U+E, LFTs, urinalysis (check UTI), consider HIV + syphilis serology…
  • Structured cognitive tests
  • Structural and functional imaging
    > CRX, LP, ECG, CT/MRI, EEG
    > SPECT: measures blood flow in brain, differentiates between types of dementia (dopamine FP-CIT used to diagnose dementia with Lewy bodies and Parkinson’s disease dementia)
170
Q

Explain the events taking place at the acetylcholine synapse during neurotransmission

A
  • Arriving AP depolarises presynaptic terminal
  • Calcium entry via voltage-gated Ca2+ channels
  • Intracellular calcium increases allows docking of synaptic vesicles containing ACh; released via exocytosis
  • ACh diffuses across synaptic cleft & binds to sodium channel receptors on post-synaptic membrane
    > Produces a graded depolarisation
  • Depolsarisation ends as ACh is broken down by acetylcholinesterase into acetate and choline
  • Pre-synaptic neuron reabsorbs choline to synthesise new ACh
171
Q

Explain the events taking place at the glutamate synapse during neurotransmission

A
  • Presynaptic AP causes the release of glutamate into the synaptic cleft
  • Glutamate acts on AMPA and NMDA receptors, but NMDA receptors are blocked by Mg2+ ions (& only NMDA receptors are permeable to calcium)
  • During a weak electrical stimulation, the EPSP is mediated entirely by AMPA receptors; slight depolarisation, few ions flowing through channels
  • During a stronger AP, AMPA receptors can depolarise the membrane sufficiently to expel Mg2+ from the NMDA channel, allowing a response to glutamate
  • Stronger depolarisation causes intracellular signalling cascades ; insertion of more AMPA receptors into postsynaptic membrane
172
Q

Explain the mechanism of action of cholinesterase inhibitors and their use in the treatment of dementia

A
  • Increase brain ACh levels by inhibiting CNS acetylcholinesterase, which breaks down ACh in the synapse
  • Donepezil, rivastigmine and galantamine are used
  • Used in mild-moderate Alzheimer’s, Parkinson’s disease dementia and dementia with Lewy bodies due to associated cholinergic deficits
    `
173
Q

Explain why cholinesterase inhibitors are not used in the treatment of frontotemporal dementia

A
  • No cholinergic deficits
  • More marked serotonergic deficits so SSRIs can be beneficial e.g. paroxetine, fluoxetine
174
Q

Antipsychotics should NOT be prescribed for a specific type of dementia - which is it?

A

Dementia with Lewy bodies
* can present with distressing visual hallucinations and secondary delusions
* Visual hallucinations are correlated with the depth of cortical cholinergic deficit

175
Q

Explain the role of glutamate in Alzheimer’s disease

A

Reduced glutamate clearance leads to chronic overactivity (excitotoxicity)
> disrupts memory formation via the NMDA receptor
However, in AD there is:
* Reduction of NMDA receptors in the hippocampus & neocortex
* Reduction of pyramidal (glutamate-containing) neurons in entorhinal cortex, CA1 & subiculum areas of hippocampus

176
Q

Explain the mechanism of action of memantine and its use in different types of dementia

A
  • NMDA receptor antagonist; blocks low-level glutamate NMDA activation
  • Targets frontal lobe
  • Improves memory by restoration of homeostasis in glutamatergic system
  • Improves agitation, aggression, psychotic symptoms
  • Licensed for moderate-severe Alzheimer’s disease, also used in severe vascular dementia
177
Q

List the clinical features of BPSD

A

Behavioural and Psychological Symptoms of Dementia (BPSD)
* Irritability
* Delusions
* Dysphoria/depression: reduced monoaminergic function
* Apathy/indifference
* Agitation/aggression
* Hallucinations
* Motor behaviours

178
Q

Discuss the management of agitation and aggression in BPSD

A
  • Associated with a greater cholinergic deficit and increased D2/D3 receptor availability in the striatum
  • SSRIs sertraline & citalopram reduce agitation
  • In severe cases (risk to themselves/others), atypical antipsychotics
    > Risperidone or aripiprazole used if not responding to donazepil, memantine & benzodiazepines
    > If stable for 3 months, cautiously withdraw
    > Do not use for insomnia, wandering or abnormal vocalisations
179
Q

Discuss the hallmark features of delirium

A
  • Acute onset of confusion
  • Impaired consciousness
  • Hyperactive/hypoactive subtype
  • Acute onset
  • Change in cognition/ fluctuation in mental state: worse nocturnally
  • Cognitive deficits
  • Visual hallucinations (& other psychotic symptoms)
  • Sleep-wake cycle disruption
  • Affect changes: mood instability, anger, elated
  • Underlying cause
180
Q

Compare delirium and dementia

A

Delirium:
* Rapid onset
* Acute medical cause
* Consciousness impaired
* Major sleep-wake cycle disturbance
* Considerable fluctuation in 24h period
* Agitation, restlessness
* Prominent visual hallucinations
* Prominent labile effect, distress
Dementia:
* Slow, progressive, insidious
* Chronic progressive cause
* Clear consciousness
* Relatively less disturbance
* Worse in evening “sun-downing”
* Relatively more settled
* Visual hallucinations less common
* Lability less common

181
Q

Discuss predisposing and precipitating factors for delirium

A
  • Predisposing factors: age, dementia, vascular disease, drugs
  • Precipitating factors:
    > Infection
    > Stroke
    > Drugs: opioid, steroids, digoxin…
    > MI & heart failure
    > Fractures
    > Cancer
    > Diabetes
    > Alcohol withdrawal
182
Q

Discuss non-pharmacological approaches to delirium

A
  • Noise control and lighting
  • Orientating influences: calendars, clocks, familiar objects, family
  • Fluid balance, diet, bowel habit, pain control
  • Regular communication/reassurance from staff (& limit variation in staff)
  • Encourage normal sleep cycle + side room if possible
  • Avoid ward transfers, recognise frailty
183
Q

Discuss the pharmacological management of delirium

A
  • Antipsychotics
    > Haloperidol, olanzapine
    > Risperidone, aripiprazole, quetiapine
  • Benzodiazepines (alcohol, post-seizure)
    > Lorazepam
    > Diazepam
  • Others
    > Treat underlying cause
    > Melatonin (normal sleep phase)
    > Trazadone: low-dose antidepresssant to manage agitation, stabilise affect + correct sleep cycle
184
Q

Describe the macroscopic pathological features seen in Alzheimer’s disease

A
  • Ventriculomegaly (+ hydrocephalus) due to tissue loss
  • Marked atrophy of medial temporal lobe and sulci
    > Also affects frontal and parietal lobes; relative sparing of occipital lobe
  • Shrinking of hippocampus & amygdala
    > Dilated temporal horns of lateral ventricles (surround hippocampus)
185
Q

Describe the microscopic pathological features seen in Alzheimer’s disease

A
  • Neurofibrillary tangle (primary biomarker)
    > Hyperphosphorylated tau accumulates in neuronal cell body
    > Synaptic & neuronal loss, reactive astrogliosis & microglial activation
    > Systematic progression of tau deposition
  • Beta amyloid plaques
  • Cerebral amyloid angiopathy (CAA): marked deposition of beta amyloid in vessel walls, predisposes to intraparenchymal haemorrhage
186
Q

Describe the stages of tau deposition and the Thal grading system for beta amyloid plaques

A

Tau deposition
> Stages I & II: entorhinal
> Stages III & IV: hippocampal
> Stages V & VI: isocortical
Thal grading system
> Phase I: cortex
> Phase II: hippocampus
> Phase III: diencephalic structures including basal ganglia
> Phase IV: brainstem
> Phase V: cerebellum

187
Q

List risk factors for the development of Alzheimer’s disease

A
  • Age
  • Family history: presenilin-2
  • Genetics: APOE-e4 (sporadic form)
  • Low educational attainment
  • Cardiovascular disease
  • Diabetes mellitus
  • High serum homocysteine
  • Head injury
188
Q

List protective factors for Alzheimer’s disease

A
  • NSAIDs
  • Oestrogens
  • Statins
  • Nicotine
189
Q

Describe the macroscopic and microscopic pathology of dementia with Lewy bodies (DLB)

A
  • Macroscopic: pallor of substantia nigra and locus coeruleus (pigmented nuclei around periaqueduct of pons)
  • Microscopic: primarily in cerebral cortex leading to dementia
    > Classical Lewy body: intracellular target lesion (alpha synuclein)
    > Accompanied by Lewy neurites (thread-like profiles)
    > Cortical Lewy body
190
Q

Classify frontotemporal dementias depending on protein pathology and clinical variants

A

Protein pathology:
* Tauopathies (FTLD-tau)
* TDP-43 pathology (FTLD-TDP)
* FUS pathology (FTLD-FUS)
* Ubiquitin pathology (FTLD-UPS)
Clinical variants
> Behavioural variant frontotemporal dementia (bvFTD)
> Progressive aphasia
- Semantic variant (svPPA)
- Nonfluent variant (nfvPPA)
- Lopogenic variant (lvPPA)

191
Q

Describe the macroscopic and microscopic pathology of progressive supranuclear palsy (PSP)

A
  • Subtype of FTLD-tau
  • Macroscopic:
    > Atrophy of frontal lobe, subthalamic nucleus, midbrain, pontine tegmentum & superior cerebellar peduncle
    > Pallor of substantia nigra
  • Microscopic
    > Globose neurofibrillary tangles mainly in globus pallidus, subthalamic nucleus & substantia nigra
    > Glial cells - tufted astrocyte s, abnormal accumulation of tau forming thick neurofibrillary threads around astrocytes (motor cortex + striatum)
    > Tau wrapped around oligodendrocytes forms coiled bodies
    > Neuronal loss & astrocytosis affecting basal ganglia, diencephalon & brainstem
192
Q

Describe the macroscopic and microscopic features of Pick disease

A
  • Subtype of FTLD-tau
  • Main pathological features
    > Macroscopic:
  • Severe atrophy of temporal & frontal lobes
    > Microscopic:
  • Pick bodies, Pick cells = large ballooned neurons
  • Glial tau inclusions
193
Q

Describe clinical features which can be used to distinguish different types of dementia

A
  • Alzheimer’s
    > Memory deficit
    > Aphasia, apraxia, agnosia
  • DLB
    > Memory deficit
    > Fluctuating attention
    > Extrapyramidal signs
    > Psychosis (hallucinations)
  • FTD
    > Memory deficit
    > Speech/language disorders
    > Disinhibition
    > Hyperorality
194
Q

Describe the primary and secondary structures of proteins

A
  • Primary: linear sequence of amino acids
  • Secondary: folding/coiling of the polypeptide due to H bonding
    > Alpha helices
  • H bonds form between carbon oxygen atom of each peptide bond with the amide H atom from an amino acid 4 positions towards C-terminus
  • Results in a periodic spiral (3.6 amino acids per turn)
  • Confers directionality on the helix
  • R groups face outwards, covering the helix
    > Beta pleated sheets
  • Each strand is 5-8 amino acids residues
  • Hydrogen bonding between strands of polypeptides forms the planar sheet
  • R groups project from both faces of the sheet
195
Q

Describe the tertiary, quaternary and supramolecular structure of proteins

A

Tertiary: overall conformation of protein/ 3D arrangement
- Stabilised by interactions between R groups
> disulphide bridges: covalent bonds between 2 cysteines containing sulphur
> hydrophobic interactions: non-polar R groups group together inside the molecule away from aqueous environment
> hydrogen bonds: polar groups on the outside, in contact with water
Quaternary: multimeric organisastion; formed by the addition of multiple polypeptides or the addition of prosthetic groups
Supramolecular: large-scale assemblies

196
Q

Describe the process of protein folding

A

Protein conformation is determined by its primary structure; proteins self-assemble into a 3D conformation
> Hydrophobicity is an important determinant of final conformation
* Nascent polypeptide is in a cellular environment w/ high macromolecular concentration
> neighbouring polypeptides will influence folding of nascent polypeptide
* Molecular chaperones interact help de novo proteins to fold & misfolded proteins to refold
> Selectively bind to short stretches of hydrophobic amino acids and provide a protective environment for folding

197
Q

Describe the different classes of chaperones

A
  • Hsp70 - 70-kilodalton heat shock protein
    > As a nascent polypeptide emerges from the ribosome, it is immediately coated with a chaperone
    > Eventually the whole polypeptide has been synthesised & coated with hsp70
    > Protects nascent polypeptide from molecular effects of surrounding proteins, allows folding
  • Chaperonin
    > Provide a protective environment by placing the polypeptide inside of the cavity of a cylinder-shaped chaperone
198
Q

Explain how misfolded proteins are identified in the ER and removed/corrected

A
  • Quality control in the ER: calnexin cycle: identification and removal of misfolded proteins
    Newly synthesised glycoprotein enters ER lumen w/ 3 sugar groups attached to reduce aggregation
    > glucosidases I and II cleave 2 sugar groups
    > single sugar group provides binding site for calnexin or calreticulin - chaperones
    > allow protein to assume correctly folded state
    > Glucosidase II removes final sugar group
  • Glucosyltransferase acts as a “folding sensor” by detecting domains of hydrophobicity in the protein
    > Hydrophobic domains should be on the inside to enable solubility in an aqueous environment + prevent aggregation
    > If none detected, allows protein to exit ER
    > If detected, it will reglucosylate it so it can repeat the cycle & possibly refold
    > if it continues to fold incorrectly: proteasomal degradation
199
Q

Describe the structure of the proteasome & how this relates to proteasomal degradation

A
  • Hollow cylindrical structures made up of a barrel-shaped proteolytic core
    > Subunits
    Alpha: non-enzymatic
    Beta: proteolytic
    > 2 caps
    Recognise & unfold protein before entering core
    Used for short half-life proteins: metabolic enzymes, nuclear proteins, misfolded proteins
  • Ubiquitin-proteasome system
    > Proteins tagged with at least 4 ubiquitins (polyubiquitination - added by ubiquitin ligase, requires ATP)
    > PolyUb-protein recognised by cap, removed & protein unfolded
    > Protein threaded through proteasome resulting in individual peptides
    > Expulsed by proteasome and further digested by cytosolic peptidases
200
Q

List risk factors and protective factors for Alzheimer’s disease

A

Risk factors
* Age
* Family history (presenilin-1, -2, components of gamma secretase)
* Genetics (apolipoprotein E e4 allele, sporadic)
* Low educational attainment
* Cardiovascular disease
* Diabetes mellitus
* Head injury
* High serum homocysteine
Protective factors
* NSAIDs
* Oestrogens
* Statins
* Nicotine

201
Q

Explain how amyloid beta peptide is formed

A
  • Amyloid beta peptide is an abnormal cleavage product of amyloid precusor protein (APP)
    > APP is a long transmembrane protein expressed in many tissues, including synapses
  • Beta amyloid is produced when 2 different enzymes cleave the protein
    > Normally APP may be cleaved by alpha secretases
    > In the pathogenic state beta secretase makes the first cut
    > Then gamma secretase cleaves the transmembrane domain, producing amyloid beta peptide (42 amino acids long & aggregates)
202
Q

Explain what is meant by the “amyloid hypothesis”

A
  • Amyloid beta peptide becomes harmful due to overproduction or reduced clearance from the brain
    > Forms oligomers, fibrils and plaques which aggregate
  • Secondary structure change: alpha helix-rich structure becomes beta pleated sheet-rich
    > Triggers a cascade of events:
  • Inflammation
  • Aggregation of tau
  • Synaptic & neuronal loss > cognitive decline & disability
203
Q

Discuss the pathological hyperphosphorylation of tau

A
  • Tau regulates microtubule dynamics, controlling processes such as axonal transport & neurite outgrowth
  • Pathological hyperphosphorylation: flame-shaped protein deposits
    > Kinases Cdk5 and GSK3-beta are implicated in phosphorylation
    > Downregulation of protein phosphatases (dephosphorylate tau)
  • Tau gene mutations + covalent modifications can lead to misfolding
  • Tau misfolding + formation of insoluble neurofibrillary tangles w/ increased beta pleated sheet content
    > microtubule dysfunction & disassembly, cell death
204
Q

Discuss the formation of Lewy bodies in DLB

A
  • Accumulation of alpha-synuclein
    > Maintains a supply of synaptic vesicles in the pre-synaptic terminal
  • Cortical Lewy bodies contain alpha-synuclein aggregates
    > Misfolding of secondary structure due to increase in beta-pleated sheets
    > Forms soluble oligomeric forms (proto-fibrils) which assembles into insoluble fibrils
    > building blocks for Lewy bodies
  • Commonly found in neurons of deeper layers of temporal & frontal cortices
205
Q

Transmissible Spongiform Encephalopathies (TSEs)

A
  • aka prionopathies, family of rare, progressive & fatal neurodegenerative disorders (inherited, sporadic or acquired)
  • Loss of motor coordination & behavioural changes
  • Infectious proteins (abnormal prion protein - PrPSc)
    > Can replicate without nucleic acids & transmit neurological disease
  • Seed the misfolding of normal prion protein (PrPc) & subsequent aggregation in normal cells
  • Prion protein becomes beta-pleated sheet dominated
    > Assembles into prion rods found in amyloid plaques
  • Characterised by spongiform vacuolation in the cerebral cortex
206
Q

List advantages & disadvantages of the MMSE (mini mental state examination) and state the cut-off scores for dementia

A

Advantages
* Short and easy
* High inter-rater reliability
* Screening tool & good for monitoring change
Disadvantages
* No frontal tests
* Insensitive to early impairments e.g. MCI
* Poorly covers executive function (weighted heavily towards memory/attention)
* Influenced by age, education, socioeconomic status
Cut-off scores
* Mild: 24
* Moderate: 20
* Severe: 9

207
Q

List advantages & disadvantages of the AMT (abbreviated mental test) and state the cut-off scores for dementia

A

10 items, cut-off 7-8/10
Advantages:
> Simple to perform and score
Disadvantages:
> Very limited validity data
> Culturally specific

208
Q

List advantages & disadvantages of the MoCA (Montreal Cognitive Assessment) and state the cut-off scores for dementia

A

out of 30, 24 is the cut-off for dementia
Advantages:
- Short & easy with frontal tests
Disadvantages
- Reliability is low in non-clinical populations

209
Q

List advantages & disadvantages of the ACE III (Addenbrooke’s Cognitive Examination) and state the cut-off scores for dementia

A

ou tof 100, the cut-off is 82-88
Advantages:
* More sensitive than MMSE in early disease
* Covers executive function
* More detailed, broader assessment than MMSE
Disadvantages: time-consuming

210
Q

List advantages & disadvantages of the FAB (frontal assessment battery) and state the cut-off scores for dementia

A

Cut-off is 12/18
Advantages
- Screening for frontotemporal dementia
> Used to differentiate between types of dementia e.g. patients with FTD score lower than those with mild Alzheimer’s
Disadvantages
- Limited use in other types of dementia

211
Q

List advantages & disadvantages of the 6CIT (6 Item Cognitive Impairment Test) and state the cut-off scores for dementia

A

Cut-off for dementia is 8/28 (8 or higher) - inverse scoring
Advantages
* High sensitivity and specificity even in mild dementia
* Performed quickly
* Easy to translate linguistically & culturally

Year 2 - Excess (6 decks)

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