5P Flashcards
Bioavailability
Fraction of the administered dose of drug that reaches the systemic circulation
Apparent volume of distribution
theoreticalvolume in which the amount of drug would need to be uniformly distributed to produce
observed plasma concentration.
Clearance
volume of plasma from which a substance is completely removed per unit time
Half-life
time required for serum plasma concentration to decrease by half
Linear Pharmacokinetics
Concentration that results from a dose is
proportional to the dose
Double the dose, double the concentration.
Rate of elimination is proportional to the concentration
NonLinear Pharmacokinetics
plasma drug concentration changes either more or less than would be expected from a change in dose rate.
Rate of elimination is constant regardless of amount of drug present.
Therefore, drugclearancedecreases with increasing
drug concentration
Affinity
measure of the propensity of a drug to bind to its receptor; the attractiveness of drug and its receptor
Efficacy
(or Intrinsic Activity) – ability of a bound drug to change the receptor in a way that produces an effect
Antagonists have affinity but not efficacy
Potency
relative position of the dose-effect curve along the dose axis
Effects of Renal Disease on Pharmacokinetics and pharmacodynamics
Pharmacokinetics:
o Decreased elimination
o Decreased protein binding (plasma proteins lost in urine)
Pharmacodynamics:
o Altered sensitivity to drug effect
o Adverse effects
Increase dosage interval
Cystic Fibrosis and pharmacokinetics/dynamics
o Increased metabolism/elimination
o Larger VD
o Thus increase dosage, decrease dosage interval
Effects of Hepatic Impairment on Pharmacokinetics and pharmacodynamics
Pharmacokinetics o Decreased First pass metabolism o Decreased Activation of prodrugs o Decreased protein binding o Decreased elimination o Same/increased VD and slower rate of enzyme metabolism o Thus decrease dosage, increase dosing interval
Pharmacodynamics
o Altered drug effect
Which drug is contraindicated in renal impairment?
Naproxen
Core features of ADHD
1) inattention and lack of persistence
2) impulsivity (verbal and physical)
3) hyperactivity
Clinical features must be:
Apparent before the child is age 7 years
Excessive for the child’s age and development
Pervasive i.e. evident in more than 1 environment e.g. at home and in school
Steps of ‘Metastatic Cascade’
1) local invasion
2) angiogenesis
3) detachment
4) intravasation
5) transport
6) lodgement/arrest
7) extravasation
8) proliferation at ectopic site
vitronectin receptor
alpha-v-beta-3 = specific integrin that promotes invasion & metastasis. Found on metastatic melanoma cells
acts as a binding site for the enzyme MMP-2 from WBC in TME (solubel proteases can bind to integrins)
How does synthetic insulin compare to endogenous insulin
Analogues - different chemical structure to insulin, in aim to achieve faster onset of effects, or delayed effects.
Long-acting and short-acting analogues can be used as a combination.
Illness Behaviour
the way in which symptoms are perceived, evaluated, and acted upon by a person who recognises some pain, discomfort or other signs of organic malfunction
e.g. consulting behaviours adherence to treatment health-promoting behaviours avoidance unhelpful coping strategies - e.g. drugs, alcohol
Sick role
a term used in medical sociology regarding sickness and the rights and obligations of the affected
being sick means that the sufferer enters a role of ‘sanctioned deviance’.
Rights:
The sick person is exempt from normal social roles
The sick person is not responsible for their condition
Obligations:
The sick person should try to get well
The sick person should seek technically competent help and cooperate with the medical professional
Transition into the sick role may have some incidental secondary gains for patients = advantage that occurs secondary to stated or real illness.
Disease vs illness
Disease: disorder of structure and/or function
Illness: the expression and experience of ill health. Psychological, social and cultural factors are crucial
Locus of control
the degree to which a person believes that control to influence events resides with themself or others
Internal locus of control vs external locus of control
Internal locus of control vs external locus of control
Internal locus of control
believe that they have agency in their behaviour and ability to influence the world about them
Tend to adjust better to illness and have better management of illness → better health outcomes
NB: downside - can lead to feelings of guilt and safe blaming
external locus of control
believe that they have little control over events and that outcomes will be determined by others or by fate
Passive
Good coping with chronic illness
optimal functioning
self management strategies - good for adjustment to illness
reduced co-morbidity - prevent/minimise mental illness as a comorbidity
helpful coping behaviours - i.e. not drugs/alcohol
Successful adjustment
successful performance of adaptive tasks absence of psychiatric disorder presence of high positive affect adequate functional status satisfaction and wellbeing in various domains (quality of life)
Effect of psychiatric comorbidity on chronic illness
Increased morbidity and mortality Reduced adherence to treatment (x3) Reduced quality of life increased smoking reduced social and occupational functioning altered (poorer) illness behaviours
Barrier to Adjustment to chronic illness
Characteristics of the illness (e.g. pain, fatigue, unpredictability)
Characteristics of the treatment (e.g. dialysis)
Societal - stigma, rejection, discrimination
Comorbid psychiatric illness
personality, locus of control
social circumstances - finances, social support
Delirium
acute neuropsychiatric syndrome that has variable presentations.
Generally characterised by:
- Impaired consciousness (fluctuating level of consciousness)
- Acute onset
- Change in cognition
- Visual hallucinations (and other psychotic symptoms)
- Sleep-wake cycle disruption
- Affect changes
- In most cases, evidence of an underlying direct cause
Deririum vs dementia
1) delirium is acute, dementia is progressive
2) delirium is secondary to an underlying cause, dementia is a primary CNS disease
3) There are hallucinations and illusions in delirium, but less so in dementia
4) delirium causes fluctuation on levels of consciousness, but consciousness is not impaired in dementia
differential diagnosis for delirium
AV DEMENTIA A - alzheimers V - vascular D - depression, drugs, dementia E - ethanol M - metabolic E - endocrine (thyroid dysfunction, diabetes) N - neurological T - toxins I - infection A - autoimmune
Dementia
syndrome with chronic, progressive (usually irreversible) cognitive impairment due to brain disease
Characterised by a set of symptoms:
- Memory loss
- Deterioration from a higher level of function
- Multiple cognitive deficits
- Consciousness is preserved however
- Chronic duration > 6 months
- Impact on social/occupational function
Cognitive Tests
Addenbrooke’s Cognitive Examination (ACE)
MMSE (Mini-Mental State Examination)
Six-item Cognitive Impairment Test (6CIT)
Abbreviated Mental Test (AMT)
MMSE (Mini-Mental State Examination)
commonly used set of questions for screening cognitive function
24/30 = cutoff for dementia
Advantages
1) Ease and speed of administration
2) standardised
3) Screening tool and good for monitoring change
4) High inter-rater reliability
Disadvantages:
1) Insensitive to early impairments e.g. mild cognitive impairment (MCI)
2) Poorly covers executive function. Weighted heavily towards memory/attention → insensitive for frontal lobe dementia
3) Influenced by age, education, socio-economic status
Which memory is affected first in AD?
anterograde memory (episodic). Gradual transition to loss of retrograde memory working memory is preserved
Clinical Features of AD
- Failing memory - episodic memory is affected.
progressive loss of ability to learn, retain and process new information. - Cognitive decline (language, writing, reading, calculation, attention/problem solving)
- personality/mood changes.
- Neurological - primitive reflexes, postural abnormalities
- Frontal executive function - impairment of organising, planning and sequencing.
- visuospatial difficulties
Pathological hallmarks of AD
Deposition of β-amyloid (Aβ) in amyloid plaques in the cortex (especially hippocampus and medial temporal lobe)
Tau containing intracellular neurofibrillary tangles.
Amyloid may also be laid down in cerebral blood vessels, leading to amyloid angiopathy
Amyloid plaque and NFT formation in AD
Cleavage of APP by beta secretase leads to formation of β-amyloid , which is insoluble. β-amyloid aggregates to form plaques in the extracellular space, interrupting neuronal signalling. Plaques also initiate inflammtory reactions. Pro-inflammatorycytokines are believed to activate intracellular kinases, leading to hyperphosphorylation of tau protein. The hyper-phosphorylated tau collapses into twisted strands, which aggregate to form neurofibrillary tangles.
Hyperphosphorylation of tau causes microtubules to dissociate, interrupting neuronal transport.
Nutrients and other essential supplies can no longer move through the cells, which eventually die.
Results in widespread neuronal death and NT deficits.
As neurons die, large scale changes start to take place in the brain: Cortical atrophy Narrowing of gyri Widening of sulci Enlargement of ventricles
Vascular Dementia
multi-infarct dementia
effectively a series of mini-strokes, causing damage to the brain and thus memory.
Patient often has hypertension - Small vessel disease - subcortical - Large vessels disease - cortical multi-infarcts. Stepwise progression Memory impairment Lack of insight
Fronto-Temporal Dementia
group of neurodegenerative disorders characterised by frontal lobe and temporal lobe atrophy
Sporadic/Inherited
Often seen in younger patients: 45-65 year olds.
Frontal lobe dysfunction
- behavioural/personality changes
- Disinhibition, aggression
- Depression
- Agitation
Temporal dysfunction
- progressive impairment of language function.
- Progressive expressive aphasia
- Cognitive and memory impairment
Dementia with Lewy Bodies (DLB)
characterised by visual hallucinations, and fluctuating consciousness.
Progressive cognitive decline
strongly associated with Parkinsonism (may evolve later and is typically mild)
The lewy bodies formed are aggregates of the protein α-synuclein.
This is due to the protein misfolding into a β-pleated sheet structure.
These then further aggregate into higher-order insoluble structures (fibrils), which are the building blocks for Lewy bodies.
Avoid antipsychotic drugs in these patients!!
Parkinson’s Disease with Dementia
Classical lewy bodies
Bradykinesia, rigidity, tremor
Autonomic dysfunction
Cognitive impairment
When dementia develops after an established motor disorder, we call the disease Parkinson’s disease with dementia (PDD).
In contrast, when dementia develops prior to or at the same time as the motor disorder, we call the disease DLB.
Behavioural & Psychological Symptoms of Dementia
non-cognitive symptoms of dementia
symptoms of disturbed perception, mood or behaviour, frequently occurring in patients with dementia.
Confusion
Delusions
Hallucinations
Agitation and aggressive behaviour
medication options for patients with dementia
Symptomatic therapies
cholinesterase inhibitors
partial NMDA antagonist
Psychotropic medications for secondary symptoms
Cholinesterase Inhibitors
Donepizil, Rivastigmine and Galantamine
increase brain acetylcholine levels by inhibiting CNS acetylcholinesterase
Used in AD/PDD/DLB = all have marked cortical deficits of acetylcholine
not useful in frontotemporal dementia/vascular dementia
- FTD has a serotonin deficit
Partial NMDA Receptors Antagonist
memantine
acts on the glutamatergic system by blocking NMDA receptors
By binding to the NMDA receptor with a higher affinity than Mg2+ ions, memantine is able to inhibit the prolonged influx of Ca2+ ions, which forms the basis of neuronal excitotoxicity.
there is a buildup of glutamate in AD brains, thus Memantine is used to block NMDA receptors and stop the overactivity of the glutamatergic system.
Can be used alone or in combination with AChE inhibitors
used in moderate/severe AD or when cholinesterase inhibitors are not tolerated
Wernicke’s encephalopathy and Korsakoff’s psychosis
Wernicke’s encephalopathy is a serious acute medical illness
Korsakoff’s psychosis is a chronic mental disorder (= alcohol amnesia). amnestic syndrome with impaired recent memory and relatively intact intellectual
function
Two stages of the same disorder. Although the disorder is mainly linked with alcoholism it is due to a deficiency of thiamine.
Changes in the brain with alcohol dependence:
Cortical shrinkage and ventricular enlargement
Deeper, wider sulci in the cortex of the brain
Cerebellum is shrunken
hypofunction of parietal lobe
Approaches to Immunotherapy
1) Vaccination strategies
2) Nonspecific therapies (e.g. IL-2 therapies)
3) Antibody therapies (rituximab, bevacizumab)
4) Cell-based (e.g. HSCs for leukaemia)
Philadelphia translocation
specific genetic abnormality in chromosome 22 of leukaemia cancer cells
Chromosomes have misaligned during mitosis and repaired themselves incorrectly after a break
This chromosome is defective and unusually short because of reciprocal translocation of genetic material
between chromosome 9 and chromosome 22, and contains a fusion gene called BCR-ABL.
This gene is the ABL gene of chromosome 9 juxtaposed onto the BCR gene of chromosome 22, coding for a hybrid protein: a tyrosine kinase signalling protein that is constitutively active, causing the cell to divide uncontrollably.
Imatinib
a drug that inhibits Abl
binds to the amino acids of the BCR/ABL tyrosine kinase ATP binding site and stabilizes the inactive, non-ATP-
binding form of BCR/ABL
This prevents tyrosine autophosphorylation and, in turn, phosphorylation of its substrates.
VHL protein
classified as a tumour suppressor gene
VHL works by binding to hypoxia inducible factor
HIF results in transcription of growth factors for angiogenesis
HIF is kept in check by VHL -> tags HIF for destruction
molecular aberration in the VHL gene is common in renal carcinoma (HIF levels increase and cause very prolific blood supply to develop to the tumour)
critozinib
ALK = Anaplastic Lymphoma Kinase inhibitor
Prognostic marker
informs about the patient’s outcome regardless treatment
May help choose which patients to treat, but not how to treat them
Irrespective of treatment = prognostic
Predictive marker
predicts which patients will respond well to a particular treatment
Helps choose which treatment to use
forms the basis of precision medicine
Treatment-dependent = predictive
Enzalutamide
hormone therapy for men with advanced prostate cancer that has stopped responding to other hormone
therapy and chemotherapy treatments
AR signalling inhibitor that directly targets three stages of the AR signalling pathway
- blocks binding
- impairs nuclear translocation
- impairs DNA transcription
Enzalutamide is normally effective but splicing mutations can occur
Affect exon 5 of the mRNA, which codes for the ligand binding domain of the AR
results in constitutive activity, which cannot be inhibited by Enzalutamide as the AR does not even require androgen binding for action
psychiatry
medical speciality concerned with diagnosis, treatment
& prevention of mental health disorders
Organic Disorder
Change in mental function secondary to a physical process rather than psychiatric illness
Psychosis
altered relationship with reality
Delusion
fixed false belief held despite evidence to contrary, outwith sociocultural norms
Hallucination
sensory perception in the absence of external stimuli
illusion
misperception of real external stimuli
DEPRESSION: Core clinical features
pervasive low mood
+/- anhedonia
+/- fatigue
symptoms must persist for at least 2 weeks
Mood
subjective feeling of sustained emotion
Affect
objective immediate conveyance of emotion
blunt, flat, labile
Biological causes of depression
Genetics (60% MZT, 40% 1o)
Medical comorbidities (thyroid, HF, MS, CVA)
Psychiatric comorbidities (schizophrenia,)
Medications (steroids)
Neurochemical (↓ 5HT, NA, DA) = ‘Monoamine hypothesis’
Neuroendocrine (↓T3, TSH, ↑ cortisol)
Psychological contributors to depression
Personality traits - anxious, obsessive
Personality disorders
Coping skills
Adverse life events
Social contributors to depression
Poor social support
Socioeconomic disadvantage
Northernization
Biological features of depression
Indicate more severe depression
Diurnal variation (worse in the morning), insomnia, ↓ appetite,↓ weight, ↓ libido, constipation, amenorrhoea
Cognitive features of depression
↓ concentration, slow / negative thinking, guilt, loss of
self esteem, hopeless, suicidality
Cognitive distortions:
Minimizing, magnifying, arbitrary inference,
selective abstraction, personalization,
overgeneralization, catastrophizing
Psychotic features of depression
Delusions – mood congruent (‘nihilistic’)
Guilt, poverty, hypochondriasis, persecutory
Cotard’s syndrome – self / part of self is dead
Hallucinations – auditory 2nd person
”You’re stupid, you’re rubbish, you should die.”
Classifying severity of depression
Mild – >2 core + >2 associated, function ok
Mod – >2 core + >4 associated, function ↓
Sev – >2 core + >6 associated, function ↓↓
+/- psychosis
Depression assessment
Clinical history Risk assessment MSE (mental state exam) Physical exam Baseline blds
Treatment of depression
Moderate depression: Antidepressants
Severe depression: Antidepressants + Antipsychotics, ECT
Characteristics of dependence
1) Compulsion
2) loss of control
3) persistence despite understanding negative effects
4) withdrawal
5) tolerance
6) neglect of responsibilities
7) Repertoire narrows
8) Reinstatement
Disulfiram
used in treating alcohol dependence
pharmacologic action involves disruption of normal alcohol metabolism.
produces an irreversible inhibition of ADH enzyme activity, producing an adverse reaction with alcohol ingestion
flushing, headache, nausea and vomiting, sweating, hypotension and tachycardia.
unpleasant physiologic reactions deter continued drinking.
Acamprosate
used in treating alcohol dependence
enhances GABA signalling at GABAA receptors
used to manage withdrawal symptoms (unopposed
excitatory neurotransmission due to GABA-A receptor desensitization)
hepatic steatosis
adaptive lesion, not in itself harmful and reversible on abstinence
arises due to changes in hepatic fat metabolism due to excess H+ generation with ethanol oxidation
Develops in majority of heavy drinkers
What is the rate-limiting factor in alcohol metabolism?
ability of the liver to re-oxidise NADH
NAD+ is required for alcohol oxidation to acetaldehyde
Consequences of Metabolism of Alcohol: Acetaldehyde Production
Binds to proteins and DNA: immunogenic → provokes cellular response
Stimulates collagen production by Stellate cells → fibrous collagen produced (fibrosis)
Consequences of Metabolism of Alcohol
1) Acetaldehyde Production - immunogenic + stimulates fibrosis
2) Acetate accumulation - histone acetylation increases transcription of pro-inflammatory cytokines
3) ROS buildup - Activates redox-sensitive transcription factors such as NF-κB . Inflammation and mitochondrial damage
4) ↑ NADH/NAD ratio - increased FA synthesis
5) TNF-α production - apoptosis and fibrosis
6) increased intestinal permeability - endotoxaemia + more ROS formation
Apoptosis: Intrinsic pathway
triggered by free radicals (oxidative stress), leads to activation of cytochrome C and caspases
Apoptosis: Extrinsic pathway
receptor mediated. Activated by TNF-alpha, initiates caspase reaction
Malnutrition and alcoholic liver disease
Malnourished state can exacerbate alcohol damage
1) Depletion of trace elements e.g. zinc, exacerbates ROS
2) Impaired antioxidant production (glutathione not produced due to vitamin deficiency). Mitochondria are more susceptible to ROS
Depletion of natural antioxidants means there is no capacity to put a break on ROS damage
Causes apoptosis, inflammation and oxidative stress
Obesity and Alcoholic Liver Disease
clear association between obesity and developing alcoholic liver disease
If overweight, people are much more likely to metabolise alcohol via a pathway to form ROS
Obesity itself is an inflammatory state
Histological characteristics of hepatic steatosis
macrovesicular steatosis = swiss cheese appearance
mainly zones 2 and 3
Histological characteristics of alcoholic hepatitis
- mallory bodies
- hepatocyte ballooning
- macrovesicular fat globules
- collagen in zone 3
- neutrophil infiltration
Histological characteristics of alcoholic cirrhosis
Micronodular cirrhosis = nodular regeneration of hepatocellular tissue surrounded by surface of fibrotic scar tissue
fibrotic tissue (blue stained) surrounds regenerative nodules
macroscopically the liver is grossly deformed
FibroScan
Non-invasive method of visualising the liver
Measures “liver stiffness” = transient elastography
Sends sound pulse through liver and measures the speed of return
Fast in cirrhotic liver because it is hard and firm
Slow in normal liver because it is soft and spongy
Encephalopathy
altered level of consciousness as a result of liver failure
LFT Patterns of Alcoholic Liver Disease
Raised AST: ALT ratio – preferential AST elevation as mitochondrial disease
AST not >500 (ALT usually <300)
Neither exceeds 400 → if higher than this, it is not alcoholic liver disease; likely to be e.g. paracetamol overdose on a history of alcoholic liver disease
Alcoholic hepatitis may appear “cholestatic”
Glasgow Alcoholic Hepatitis Score (GAHS)
Score between 5-12 Considers: - age - INR - WCC - bilirubin - urea
Score >9 has a very high mortality rate despite treatment
Assessment of Severity of Chronic Liver Disease
Childs-Turcotte-Pugh Score
Considers:
- ascites
- encephalopathy
- bilirubin
- INR
Grade A = Compensated liver disease
Grade C = Decompensated liver disease
Features of advanced liver disease
Jaundice Variceal Haemorrhage Hepatic Encephalopathy Ascites +/- oedema Hepato-renal failure Hepatocellular Carcinoma
most commonly misused drug in Scotland
opiates
STIMULANTS
cocaine, amphetamines, ecstasy
Enhance transmission at the NA/ DA/ 5-HT synapses
o Increase behavioural and motor activity
o Increase alertness / disruption of sleep
o Euphoria
o Confidence
Central and peripheral sympathomimetic effects
Side effects of anxiety, insomnia and irritability
Associated with increased risk of stroke
Alpha adrenergic stimulation causes vasospasm and increases platelet aggregation
Stimulant Toxidrome
Effect at adrenergic receptors
THR- SHADE
T - tachychardia H - hypertension R - risk of arrhythmia - ECG may resemble STEMI S - sweating H - hallucination A - agitation D - dilated pupils E - elevated body temp
Serotonin Syndrome
Triad of:
1) Altered mental status – Agitation / confusion / seizures
2) Autonomic changes - Hyperthermia, diaphoresis (sweating), diarrhoea, tachycardia, hypertension,
salivation
3) Neuromuscular effects – Increased tone and rigidity, can elicit clonus
Hallucinations also common with serotonergic activation
Seen in many causes of stimulant toxidromes
Cocaine
Blocks DA, NA & 5-HT re-uptake
enhanced activity of these neurotransmitters
Exerts inhibitory effect on postsynaptic dopamine receptors
Blocks the presynaptic transporter protein for DA
o Dopaminergic pleasure effect
o Noradrenergic excess (readiness)
Amphetamines
Enhance release of DA & NA from pre-synaptic terminals
o Dopaminergic pleasure effect
o Noradrenergic excess (readiness)
Opiate Toxidrome
Pinpoint pupils Respiratory depression Sedates (low GCS) Bradycardia Hypotension Hypothermia Pulmonary oedema Seizures
Sedative / Hypnotic Toxidrome
Ataxia, altered gate Blurred vision Coma Confusion Delirium Sedation Pupils likely to be normal -> important for distinguishing with opioid toxicity
HALLUCINOGENS
Effects:
Serotoninergic (5-HT systems)
Noradrenergic (NE systems)
Cholinergic (ACh systems)
Cholinergic Toxidrome
Excessive PNS stimulation - DUMBBELS
D - defacation U - urination M - miosis (pupil constriction) B - bronchoconstriction B - bradycardia E - emesis L - lacrimation S - salivation
Ecstasy
Blocks 5-HT receptors and NA reuptake
o Can cause serotonin syndrome
Feelings of euphoria and social closeness
Stimulant toxidrome and perceptual effects
Thermoregulatory problems, hallucinations, CV complications
MarijuanaV
o Agonist at cannabinoid receptors
o Increases dopamine release
o Modulates opioid receptors
What type of dementia is characterised by visual hallucinations and fluctuating level of consciousness?
DLB
risk factors for AD
Increasing age
Genetics (APP, Presenilin, APOE4)
Downs syndrome
Female gender (2/3 with dementia are female)
Head injury
Rate limiting step in cholinergic transmission
reuptake of choline
dietary choline therefore will not help with cholinergic deficit
Botulinum toxin mechanism
acts by binding presynaptically and decreasing the release of acetylcholine, causing a neuromuscular blocking effect
nerve gases
inhibit AChE
Side effects of cholinesterase inhibitors e.g. donepezil
nausea, vomiting, diarrhoea, muscle
cramps, dizziness, fatigue and anorexia
Peptic Ulcers/GI Bleeding (increased acid secretion)
NMDA receptor
ionotropic receptor
permeable to calcium
ion channel is blocked by magnesium – Voltage dependent blockade
Involved in learning:
Long term potentiation – Slow gated kinetics (AP builds up and drifts off slowly). Causes long lasting enhancement of the effectiveness of synaptic transmission
Calcium activated Kinases:
– 1) Increase effectiveness of existing receptors
– 2) Increase the number of receptors
Glutamate in Alzheimer’s Disease
Reduced glutamate clearance in AD brains
Disrupts memory formation via the NMDA receptor
Excitotoxicity
However, there is global glutamate loss due to death of glutamate containing neurones
Too little activation is bad, but too much is even worse.
Memantine acts to restore homeostasis in the glutaminergic signalling pathways
- small beneficial effect in moderate to severe AD
what is cognition?
- Attention/orientation
- Memory
- Executive functioning
- Language
- Calculation
- Praxis - neurological process by which cognition directs motor action
- Visuospatial ability
Different components of attention
1) Arousal
2) Sustained Attention
3) selective attention
4) divided attention
How to test for attention deficits
• Observe the patient
Specific tests:
• Orientation in time and place (also depends on episodic memory)
• Digit span – forward/backward (also depends on working memory)
• Reciting months of the year (or days of the week) backwards
• Serial 7s
• Spell WORLD backwards
• The STROOP Test
Anterograde amnesia
loss of the ability to create new memories after the event that caused the amnesia, leading to a partial or complete inability to recall the recent past
long-term memories from before the event remain intact
retrograde amnesia
loss of memory-access to events that occurred, or information that was learned, before an injury or the onset of a disease
Ribot’s gradient
there is a time gradient in retrograde amnesia, so that recent memories are more likely to be lost than the more remote memories
i.e. older information is likely to be retained for a longer period of time
Alexia
inability to read
Agraphia
loss of ability to communicate through writing
Which part of the brain is involved in Calculation?
- Generally left hemisphere important
* Angular gyrus in parietal lobe crucial
Acalculia
inability to comprehend or write numbers properly
dyspraxia
Inability to move a body part despite normal physiological function
Usually left hemisphere function – parietal and frontal lobe. Errors of :
• Action conception (knowledge of actions/item function)
• Action production (production/control of movement)
agnosia
inability to interpret sensations and hence to recognize things
Visuospatial deficit
stratified medicine
medical care designed to optimize treatment by identifying subgroups of patients with similar disease profiles or drug responses
personalized medicine.
Wernicke’s Encephalopathy
Acute neuropsychiatric condition
Develops in problem drinkers who are thiamine-deficient
presents as a triad of:
○ Global confusion – apathy, disorientation and disturbed memory
○ Ataxia – affects trunk and lower extremities
○ abnormal eye movements - nystagmus, gaze palsies and paralysis of ocular muscles
Repeated episodes can cause damage to the limbic system and memory impairment (Korsakoff’s
psychosis).
Korsakoff’s psychosis
amnesic state in which there is profound impairment of memory but relative preservation of intellectual abilities in a setting of clear consciousness.
typically develops after an acute episode of Wernicke’s encephalopathy, however some patients develop the combined syndrome.
Immediate treatment with high-dose parenteral thiamine
Principles underlying brief intervention
FRAMES Model
● Feedback about personal risk & impairment
● Emphasis on personal Responsibility to change
● Advice (with permission) to cut down or abstain
● Menu of options for changing drinking/setting a target
● Empathetic interviewing: listening reflectivity without trying to persuade or confront
● Self-efficacy: and interviewing style that enhances people’s belief in their ability to change
4 Stages of ABI (Alcohol Brief Intervention)
- Raise the issue of alcohol
- Screening & Feedback
- Listening for readiness to change
- Select an approach
Brief interventions generally aim to moderate a person’s alcohol consumption to sensible levels and to eliminate harmful drinking practices
(RSLS = Really Should Lose Sugar)
MOTIVATIONAL CONSULTATION STYLE
method of producing behavioural change by helping patients to explore and resolve ambivalence, increasing motivation to change
Aims to increase internal motivation for change rather than impose change
Proteostasis
Steady state within the cell of all the proteins that are made, removed, processed, folded etc. in/out
of the cell
Molecular chaperone
any protein that interacts with, stabilises or helps another protein to acquire its functionally active conformation, without being present in its final structure
selectively bind to short stretches of hydrophobic amino acids
What is the role of glucosidases?
Glucosidases cleave off almost all sugar groups, leaving one behind
This provides a binding site for chaperone proteins, which bind to the end of the polypeptide and allow it to fold
After folding, glucosidase II removes the final sugar group, and the chaperone dissociates
What is the role of glucosyltransferase?
decides whether a protein is correctly folded by detecting stretches of hydrophobicity
If not, it transfers another sugar group back onto the polypeptide, so that it goes through the
folding process again
This process repeats several times. If the protein is still misfolded, it is targeted to the proteasome
Ubiquitin-Proteasome System
proteins are targeted to the proteasome by ubiquitination
A chain of ubiquitin is added to the faulty protein
This is an energy-requiring process
Long series of events involving a large group of molecules (ubiquitin ligases)
The polyubiquitin stretch is recognised by the cap on the proteasome and ubiquitin is removed
Protein is unfolded and threaded through into the proteasome and broken down into peptides/amino acids
Proteinopathies
accumulation of misfolded proteins resulting in aggregates, thereby gaining toxic activity or losing the normal function
Lymphoid organ
an organ where much of the organ contains a large collection of small lymphocytes (lymphoid tissue)
Lymphoid organs have a delicate skeleton consisting of reticular fibres (fine collagen fibres)
Mucosa Associated Lymphoid Tissue (MALT)
diffuse system of small concentrations of lymphoid tissue found in various SUBMUCOSAL membrane sites of the body, e.g. GI tract, oral passage, nasopharyngeal tract
lymphoid cells in these areas are able to respond to any bacteria or micro-organisms that get through the epithelium
Origin of the name B cells
Birds have an unusual organ in the hindgut, the Bursa of Fabricius
o Acts in a similar way to the thymus, but programmes B cells
o This is where the B for B cells comes from
“Lymphoreticular system”
Includes lymphoid organs and the bone marrow
Although it contains a large collection of small lymphocytes, bone marrow contains lots of other
populations of cells (megakaryocytes, immature erythrocytes, etc.)
This means that it is not strictly lymphoid tissue
what is the name for the first node reached by lymph?
First regional lymph node or sentinel node
this is where tumour cells are most likely to spread to (they reach it first)
Because lymph nodes are efficient filters and flow through them is slow, cells that metastasize from
primary tumours and enter lymphatic vessels often lodge and grow as secondary tumours in lymph
nodes.
Flow of lymph through the lymph node
Lymph flows in through an afferent lymphatic vessel into the subcapsular sinus. broad subcapsular sinus causes the rate of flow of the lymph to slow down
Then passes round the edge of the cortex and into the medullary sinuses
Drains through the efferent lymphatic vessel (converge at the hilum)
Filtration in lymph nodes
1) mechanical filtration - slow flow causes debris to settle
2) biological filtration - Stellate macrophages span the subcapsular, cortical and medullary sinuses. Phagocytose debris
Lymphoid nodule
spherical aggregates of B lymphocytes, seen in activated lymph nodes
indicate ongoing antibody response
sites of B memory cell and plasma cell generation.
Parts of the Lymphoid Nodule
corona (mantle): the region of the lymphoid nodule peripheral to the germinal center. Composed of a
dense accumulation of small lymphocytes that are migrating away from their site of origin within the
germinal centre.
dark zone: site of the intense proliferation of closely packed B cells
Light zone: Contains many macrophages with lots of cytoplasm, therefore stains paler
o Lies closer to the subcapsular sinus (source of the antigen)
Tonsil epithelium
non-keratinizing stratified squamous epithelium
(continuous with that of palatoglossal fold and tongue)
Mucosa invaginates into the substance of tonsil to form tonsillar crypts
Are tonsils MALT?
Palatine tonsils have a special feature, deep tonsillar crypts, that are not seen in MALT
These crypts are lined by non-keratinizing stratified squamous epithelium that is highly infiltrated by
lymphocytes
Debris (sloughed cells) builds up in these crypts, and acts as a trap for microorganisms
This gives the microorganisms a lot of exposure to the surrounding lymphocytes in the epithelium
Lymphocytes become activated and are released into the blood stream via tonsillar capillaries
apraxia
Loss of ability to execute skilled movements despite
having desire & physical ability to do so
Agnosia
Inability to recognise objects, shapes, people even
sounds despite an intact sensory system
Aphasia
Inability to produce (expressive) or understand
(receptive) language
Effect of Bilateral damage to the medial temporal
lobes/hippocampus
causes inability to learn new information – anterograde amnesia
hypaesthesia
a diminished capacity for physical sensation, especially of the skin.
mse vs mmse
MSE - structured way of observing and describing a patient’s psychological functioning at a given point in time
MMSE - a brief neuro-psychological screening test for dementia.
Which aspects does MMSE test?
1) orientation
2) registration
3) attention and calculation
4) recall
5) language
Frontal battery testing
brief assessment that can be used to distinguish between fronto-temporal dementia and AD type dementia
12 or below indicates frontotemporal dementia
Frontal battery testing: components
1) similarities (conceptualisation) - in what way are x & y alike?
2) lexical fluency (mental flexibility) - say as many words as you can starting with “s”
3) Motor series test (programming) - fist, edge, palm. Show patient and then get them to do it together, then alone
4) Conflicting instructions (sensitivity to interference) - tap twice when i tap once and tap once when i tap twice
5) Go - No go (inhibitory control) - tap once when i tap once and don’t tap when i tap twice
6) prehension behaviour (environmental autonomy) - “do not take my hands” and place hands on patient’s
Clock drawing test
measure of spatial dysfunction and neglect
Wernicke’s
Fluent, receptive dysphasia
Produce lots of language but makes no sense
Broca’s
Non-fluent, expressive dysphasia
Typically understand language, although they cannot express it.
Barriers to target therapy/precision medicine
1) oncogenes are easier to target than TSG (easier to break something overactive than to fix something broken)
2) cancer is usually a multiple mutation disease, and is complex and heterogenous (do you target each mutation?) How do you know you are targeting the ‘correct’ mutation?
3) do not have targets for every disease (not specific enough or unknown)
4) drug resistance - e.g. kinase mutations can limit the effectiveness of imatinib
