Physiology Flashcards
1
Q
How are physiological systems controlled?
A
Homeostasis!
The ability to maintain a relatively stable internal state that persists despite changes in the external environment.
Achieved by control systems and negative (and sometimes positive) feedback systems.
Positive feedback:
- Haemostasis (thrombin generation)
- Oxytocin secretion in labour
2
Q
What is osmosis?
A
The net movement of water caused by a concentration gradient of water through a semi-permeable membrane.
3
Q
What forces determine fluid movement?
A
- Capillary pressure: pushes fluid out
- Interstitial fluid pressure: draws fluid in
- Plasma colloid oncotic pressure: albumin in blood draws fluid in
- Interstitial fluid colloid oncotic pressure: pushes fluid out
Also impacted by net endocrine influence of aldosterone, ADH, ANP, RAAS, relaxin and progesterone.
4
Q
What are the different anions and cations present intracellularly and extracellularly?
A
Cations:
Na extracellularly, K intracellularly and small amounts of Ca and Mg
Anions:
Cl extracellularly, PO4 intracellularly and smaller amounts of HCO3 (E), organic anions (I) and protein (I)
5
Q
What is the Anion gap?
A
Difference between measured cations (Na) and measured anions (Cl) and (HCO3).
Indicator of acid:base imbalance.
Normal can be different for different patients.
6
Q
What is Hyponatremia?
A
Low Na <135 mmol/L
Caused by dehydration (loop diuretics, ECF vol decreases) or overhydration (euvoleamic hyponatremia), or excess ADH which forces water to be drawn in.
7
Q
What is Hypernatremia?
A
High Na >145 mmol/L
Caused by dehydration through DI or excessive sweating or overhydration through excessive aldosterone secretion (may be due to tumour in zona glomerulosa).
8
Q
What happens to cells when you add isotonic, hypotonic and hypertonic solution to them?
A
- Isotonic (0.9% NaCl): EC volume expands, IC remains unchanged. Osmolarity remains unchanged. Little/no flux of water. Cell neither shrinks or swells.
- Hypotonic (<0.9% NaCl): More water in solution. EC and IC volume expands. EC and IC osmolarity reduced. Cells swells causing demyelination injury.
- Hypertonic (>0.9% NaCl): EC volume expands, IC volume reduces. EC osmolarity increased and IC osmolarity increased. Cells shrink.
9
Q
What is water intoxication?
A
Massive intake of water leading to hyponatremia, driving salts out.
Can lead to a coma or swelling of the brain.
10
Q
What do the cell’s organelles do?
A
Nucleus: Genetic information Ribosomes: Protein synthesis Rough ER: Protein synthesis and processing Smooth ER: Lipid synthesis Golgi apparatus: Protein processing and sorting Lysosomes: Digestion and recycling Mitochondria: ATP production Microtubules: Structure to cell Plasma membrane: Selective permeability
11
Q
What is the phospholipid bilayer permeable and impermeable to?
A
Phosopholipid bilayer’s fluidity is modified by cholesterol and temperature.
Freely permeable to water (aquaporins), gases (CO2, N2, O2), small uncharged polar molecules (urea, ethanol).
Impermeable to ions (Na, K, Cl, Ca), charged polar molecules (ATP, glucose-6-phosphate), large uncharged polar molecules (glucose).
12
Q
What are the different types of membrane transport?
A
- Simple diffusion: blood gases, water, urea, free fatty acids, ketone bodies.
- Facilitated diffusion: glucose, GLUT family e.g. GLUT4 for insulin.
- Primary Active transport: uses ATP to transport ions, water-soluble vitamins.
- Secondary Active transport: works by gradient set up by primary active transport. Transports glucose, symporters/co-transport.
- Pino/phago-cytosis: use of vesicles
13
Q
Why are membranes and membrane proteins needed?
A
- Signal transduction receptors: ion channels, membrane-bound steroid receptors, neurotransmission, growth factors and nuclear steroid receptors.
- Compartmentalisation: ionic gradients (membrane potentials) and membrane vesicles.
14
Q
How is epithelial integrity maintained?
A
Epithelia require polarisation of plasma membrane.
Allows for cell-specific function (secretion/absorption).
Allows for strong adherence to neighbouring cells (tight junctions) where only water can pass. Or integrated holes between cells for sharing of metabolites (gap junctions).
15
Q
What are the optimal conditions for enzymes?
A
Most enzymes like to work at pH 7 and 40 degrees.
Both pH extremes damage the protein and inhibit function.
Too cold - proteins slow down, membrane is less fluid.
Too hot - proteins denature, increased membrane fluidity.
16
Q
What are chromosomes?
A
Vehicles of genetic inheritance.
46 chromosomes (23 paternal and 23 maternal).
Numbered in order of decreasing size.
Diploid (2n).
17
Q
How might you describe chromosomes of different lengths?
A
Metacentric: p=q, centromeres in the middle
Submetacentric: p slightly shorter than q
Acrocentric: p is much smaller than q
Telocentric: no p (not in humans)
18
Q
What is the cell cycle?
A
G0: goes to sleep, not replicating anymore (quiescence, senescence or terminal differentiation)
G1: grows a bit
S: DNA synthesis - chromosome number doubled
G2: grows a bit more
M: Mitosis - physically divides, cytokinesis
19
Q
What is Mitosis?
A
Mitosis is a type of cell division in which one cell (the mother) divides to produce two new cells (the daughters) that are genetically identical to itself.
One diploid somatic cell (2n), one DNA replication (cell effectively tetraploid 4n), one cytokinesis, two genetically identical daughter cells (each one 2n).
20
Q
What is Meiosis?
A
Reductive cell division to produce gametes. A division process that takes us from a diploid cell—one with two sets of chromosomes—to haploid cells—ones with a single set of chromosomes.
One diploid germ cell (2n) undergoes one DNA replication (4n) - crossing over between homologous chromosomes and recombination or gene shuffling.
Two cytokinesis events.
Four genetically distinct daughter cells (n).
21
Q
What are the checkpoints in the cell cycle?
A
G1:S-phase checkpoint: stops cell cycle if poor environment/DNA damage (HPV E7 protein inhibits this checkpoint)
G2:M-phase checkpoint: stops cell cycle if errors detected in DNA. (Inactive damage sensors inhibit this checkpoint).
Spindle checkpoint: stops cell cycle if errors in mitotic spindle (checkpoint here leads to aneuploidy/polyploidy).
Anti-metabolite chemotherapy is only incorporated by rapidly dividing cells to stop the S phase. Includes methotrexate, fluorouracil and azacytidine.
22
Q
How is DNA used to make proteins?
A
Begins with DNA double helix
“Sense strand” is copied by RNA polymerase in transcription
New RNA molecule incorporating Uracil not Thymidine
mRNA translated into protein by cytosolic ribosomes and rough ER
23
Q
What are the different types of gene abnormalities?
A
- Chromosomal non-disjunction: failure of paired chromosomes to separate during cell division so both chromosomes go to one daughter.
- Chromosomal translocation: a chromosome breaks and a portion of it reattaches to a different chromosome
- Frame-shift mutation: caused by addition or deletion of base pair, shifting the way the sequence is read.
- Truncated mutation: point mutation that results in a premature stop codon.
- Tri-nucleotide repeat: mutation in which repeats of 3 nucleotides increase in copy numbers until they meet a threshold and become unstable.
- Splice-site mutations: inserts, deletes or changes a number of nucleotides in the specific site at which splicing occurs.
- Exon deletion: most commonplace. One or more pieces of coding gene are missing.
- Mis-sense mutation: a point mutation in which a single nucleotide change results in a codon for a different amino acid.
24
Q
What are the difference types of inheritance?
A
Autosomal dominant: disruption of 1 gene of a gene pair
Autosomal recessive: disruption of both, giving the option to be a carrier (1) or an affected (2)
X-linked recessive: mutation on X chromosome, males affected
X-linked dominance: severe in males, early neonatal death
25
What is the function of blood?
```
Heat exchange
Communication/endocrine
Immunity
Gas exchange and nutrient exchange
Fluid balance
```
26
What is the composition of blood?
45% cells (depends on size, sex and age)
RBC, platelets, WBCs (neutrophils, lymphocytes, monocytes, eosinophils, basophils).
55% plasma
Water, albumins, globulins, fibrinogen, lipids, glucose, aminoacides, water, ions.
27
What is diapedesis?
The passage of blood cells through the intact walls of the capillaries, typically accompanying inflammation.
Cytokines and other biochemical products of the inflamed tissue caused increased expression of selectins and ICAM-1. Adhesion molecules bind to complementary receptors on the neutrophils, causing it to adhere to the capillary wall where it then migrates to the site of injury.
28
How are RBC synthesised?
Kidney secretes erythropoietin which will activate hematopoietic stem cells which will become proerythroblasts which become RBCs.
29
What are the steps of haemostasis?
```
Tear to endothelial lining.
Vasconstriction induced by trauma.
Platelet plug formation by vWF secretion.
Formation of fibrin meshwork.
Cascade of enzymatic reactions.
Amplification of clotting factors.
```
30
What are the two pathways that lead to haemostasis?
Intrinsic: exposure of blood to collagen
Extrinsic: traumatised vascular walls (rapid activation)
Common end point: pro-thrombin activator complex leading to thrombin-catalysed cleavage of fibrinogen to fibrin.
31
How can a fibrin clot be dissolved?
The crosslinked fibrin multimers in a clot are broken down to soluble polypeptides by plasmin, a serine protease.
- Tissue plasminogen activator (tPA) is released from damaged cells to convert plasminogen to plasmin,
- Tranexamic acid (Lys analogue) prevents plasminogen activation by tPA.
32
What is the lethal triad?
The trauma triad of death is the combination of hypothermia, acidosis and coagulopathy. This combination is commonly seen in patients who have sustained severe traumatic injuries and results in a decreased plasma pH and core body temperature.
33
What drugs can be used for clot prevention?
Heparin: anticoagulant which removes activated thrombin
NSAIDs: inhibits prostaglandin synthesis
Warfarin/Diacoumarol-based drugs: inhibit hepatic Vit. K synthesis and abnormal prothrombin synthesied.
34
What are the functions of the colon?
Absorption of water (osmosis) and electrolytes (active transport)
Production of vitamins
Excretion of waste
35
What are the layers of the colonic wall?
```
Inner
Mucosa
Muscularis mucosae
Submucosa
Muscularis propria
Subserosa
Serosa
Outer
```
36
What is the unique feature of the muscular layer in the large bowel?
Continuous circular muscle
| 3 stripes of longitudinal muscle - taeniae coli
37
What is the histology of the colon?
Columnar epithelium
| With goblet cells
38
What is the colonic microbiome?
Loads and loads of appropriate bacteria present in the colon.
Some which you find in all of us, some which is unique to the individual
Produce gases (methane, oxygen, nitrogen) - dependant on diet and microbiome
Smell comes from small amount of hydrogen sulfide
39
What is the nerve supply to the colon?
Intrinsic: Meissners and Auerbach's plexus
Extrinsic: Parasympathetic (speed up) and sympathetic (slow down)
Presence of fecal material causes contraction back and forward to keep the poo in the colon so that there is maximal water absorption
40
What is the gastro-colic reflex?
Stomach stretching and food in the jejunum leads to mass movement in the colon
41
What is the anal sphincter?
Internal part: continuation of the smooth muscle of the colon
Pelvic floor hold bladder, rectum, anus up.
External part
42
What is the status of the muscle when the rectum is empty?
Both sphincters are contracted
| Puborectalis muscle is contracted
43
How do we know we need a poo?
Rectum fills - pressure sensors in the pelvic floor
Reflex relaxation of internal anal sphincter
Sampling reflex
44
How does defecation occur?
External sphincter relaxes
Puborectalis relaxes
Rectum contracts
Valsalva maneuver - pressure changes
45
How does posture affect defecation?
Sitting posture - Puborectalis muscle "chokes" rectum to maintain continence
Squatting posture - Puborectalis muscle relaxes and straightens pathway to anus
46
What causes constipation?
Consistency of stool - lack of water, lack of fibre
Bowel motility - slows down as you get older
Physical blockage to the bowel - scans/colonscopy
Pelvic floor disorders
47
What physiological issues can lead to diarrhoea?
Diseased bowel mucosa
Reduced rectal capacity
Pelvic floor disorder
48
What are the functions of bones?
```
Support
Protection
Blood cell synthesis
Calcium store
Movement
```
49
What is the epiphysis, metaphysis and diaphysis?
The epiphysis is the rounded end of a long bone, at its joint with adjacent bone(s). Between the epiphysis and diaphysis (the long midsection of the long bone) lies the metaphysis, including the epiphyseal plate (growth plate).
50
What is the functional organisation of bone structure?
Cortical (aka compact) - the outer compact, strong but heavy outer layer
Trabecular (aka Cancellous) - the spongy, strong and lightweight inside, large surface area (Ca2+, PO43- homeostasis)
Lots of fine meshwork at the points of major stress for the bone – transmits the force down the shaft
Reservoir of calcium – remodelling of the bone occurs here
51
How does bone develop?
Derived from somatic mesoderm
Osteogenesis begins sixth – seventh week of pregnancy
Two modes of formation:
Intramembranous ossification – within cartilagous tissue itself
Endochondral ossification
Same end point – mature bone
52
What are the different types of bone growth?
Appositional growth
Growth in diameter
Bone lamellae
Interstitial growth
Growth in length
Epiphyseal plate – small rich region of bone growth
53
What is Intramembranous Ossification?
Mesenchymal stem cells form clusters in early catilagous tissue, they then differentiate into osteoblasts and ossification centres form (random to a degree).
Osteoid secreted (rich strong protein matrix)
Traps osteoblasts
Differentiate into osteocytes
Trabecular matrix and periosteum form
Compact bone develops over trabecular bone
Blood vessels condense into red bone marrow
e.g. dermal bones - skull
54
What is Endochondral Ossification?
Mesenchymal cells form cartilaginous bone model
Chondrocyte hypertrophy then degradation.
Blood vessels enter central part
Perichondrial cells convert to osteoblasts
Oesteoid secreted
Bone secreted onto shaft
```
Epiphyses:
Blood vessels form secondary ossification centre
Compact bone externally
Spongy bone internally
Articular surfaces remain as cartilage
```
55
How do hormones control growth at the Epiphyseal Plates?
Growth hormone promotes chondrocyte expansion:
Mitosis (hyperplasia), get bigger (hypertrophy), degrade; osteoblast invasion, new bone added to diaphysis
Mitosis and expansion of chondrocytes maintains epiphyseal cartilage matrix, bone elongates
Balance between chondrocyte growth/degradation important – need to happen at the same rate
Steroids (testosterone) can close growth plates prematurely
56
What components make up the bone?
Osteoid matrix (90% collagen; 10% other proteins)
Also contains CaHPO4 mineral component (crystals)
Hydroxyapatite crystals - Ca10(PO4)6(OH)2
“reinforced concrete”
Three main cell types:
Osteoblasts (build bone)
Osteoclasts reabsorb bone
Inhibited by pyrophosphate
Osteocytes (sense and monitor mechanical strain to see whether bone needs to be added or removed)
57
What occurs during bone turnover?
Bone is continuously remodelled to maintain tissue integrity – trabecular bone sites most common
- Osteoclasts resorb old bone by eroding with secreted acid ~10 days
- After resorption macrophage-like cells recruited to remodelling site
- Osteoblast precursors recruited, proliferate and differentiate into mature osteoblasts
- Osteoblasts secrete osteoid which is then mineralised
New bone generated
Complete cycle - 90-130 days
58
What problems can occur with bone turnover?
Problems arise when Resorption predominates over synthesis
- Osteoporosis (~50% females; 20%males)
- Osteopenia – thinning but not quite as severe as osteoporosis
Problems arise when there is a reduced bone mineral density
- Endocrine imbalance
- Zero gravity (astronauts)
Fracture-prone – less force required to produce the same fracture
59
How does oestrogen and testosterone affect bones?
Oestrogen inhibits osteoclast function
Loss of oestrogen increases bone loss
Testosterone – provides bone strength
- Reduced testosterone (Hypogonadism) 20% male osteoporosis
- Menopause - loss of oestrogen increases bone loss
60
What is the effect of Bisphosphonates on bone?
```
Alendronic Acid (Fosamax)
Inorganic pyrophosphate analogue
Binds to hydroxyapatite minerals
- Inhibits osteoclast function
- Potentially induces apoptosis
- Reduces bone resorption
```
61
How does osteoporosis treatment affect the teeth?
Osteoporosis treatment like Fosamax (alendronic acid) can influence dental healing.
These drugs can inhibit remodelling of bone, meaning that there is slowing of dental healing, making it more prone to infection.
62
What is the process of fracture healing?
1. Initial response – fracture haematoma; acute inflammation
2. Macrophages accumulate at fracture site to phagocytose avascular bone fragments; haematoma; inflammatory exudates (3-5 days)
3. New vascular supply initiated
4. Induce significant bone repair and remodelling
activates periosteal and intraosseous osteoblasts at fracture site
5. Creates a callus between opposed bone ends -
Large bulge of osteoblastic tissue to stop it getting worse, will gradually go away
New organic bone matrix
63
What is Ca involved in?
```
Muscle contraction
Tooth formation
Enzyme co-factor (clotting factors)
Stabilises membrane potential
Second messenger (cell signalling)
Bone mineralisation (99%)
```
64
What are the normal Ca concentrations?
```
Total extra-cellular Ca
~ 2.2-2.6mmol/l (~9.4 mg/dl)
Ionised extra-cellular Ca2+
~ 1.0-1.25mmol/l
Intra-cellular Ca2+
~100 nmol/l
```
65
How are levels of calcium determined?
Obtained from diet
Absorbed throughout gut
Small intestine – 60-70%
Influenced by age, diet (lactose promotes; oxalates inhibit) and Vit. D availability.
66
What are the different types of calcium in the serum?
45% Free ionised Ca2+
Biologically active
55% bound
Not biologically active
45% bound to albumin
10% anions – phosphate; lactate active form
67
How can the ratio of serum calcium cause acidosis and alkalosis?
Acidosis: less Ca2+ bound to plasma proteins, H+ ions bound preferentially over Ca2+. renal Ca2+ excretion (distal convoluted tubule).
Alkalosis: more Ca2+ bound to plasma proteins
Decreased H and decreased renal Ca excretion.
Alkalotic patients more susceptible to hypocalcaemic tetany (characterized by spasms of the hands and feet, cramps, spasm of the voice box (larynx), and overactive neurological reflexes)
68
What occurs in Hypocalcaemia?
Causes tetany; occasionally seizures.
Nervous system progressively more excitable due to increased neuronal membrane Na+ permeability
Action potentials reach threshold more easily
If there is 50% reduction plasma Ca2+
- Peripheral nerve fibres discharge spontaneously
- Tetanic muscle contraction ensue:
Carpopedal spasm – prelude
Laryngeal muscle spasm… - can’t breathe
69
What occurs in Hypercalcaemia?
Depresses nervous system and muscle activity.
Decreases the cardiac QT interval
Reduced appetite
Constipation (reduced bowel peristalsis?)
Effects appear at ~12 mg/dl
>17 mg/dl calcium phosphate crystals precipitate throughout the body – crunching sound during cannulation
70
How is calcium homeostasis controlled when there is decreased Ca?
Sensor: Parathyroid glands
Effectors: Kidneys and intestines
Reservoir: Bones
Decreased serum Ca, often has increased serum phosphate
Picked up by the parathyroid which release PRH, causes the release of Ca and phosphate
This increased Ca reabsorption and decreases phosphate reabsorption
Stimulate the enzyme 1alpha-hydroxylase which converts calcidiol (vit D precursor) to calcitriol (vit D active).
Calcitriol increases Ca and phosphate absorption
Effects on the gut too
Increased the level of Ca in the serum
Negative feedback mechanism
71
How is calcium homeostasis controlled when there is increased Ca?
If there is too much serum Ca, the thyroid release calcitonin
This turns off bone resorption and Ca release
72
What is primary hyperparathyroidism?
Frequent cause of hypercalcaemia
Third most common endocrine disorder
Defect in parathyroid glands – benign tumour – they get bigger, there is more tissue to secrete PTH from
(rarely – malignant tumour)
See: increased PTH, calcitriol, Ca2+, decreased PO43-
Normal feedback signals seen
BUT! Increased cell numbers mean PTH levels increased overall
73
What is secondary hyperparathyroidism?
Arises through defective feedback control compensation for hypocalcaemia
Usually associated with chronic kidney disease
Concept of Renal Bone Disease…
- No renal response to PTH causing…
- Poor renal Ca2+ reabsorption
- No vit. D activation
- Poor intestinal Ca2+ reabsorption i.e. hypocalcaemia
Bone is only site of PTH action
High bone demineralisation as Ca2+ released
Renal osteodystrophy
Negative feedback mechanisms fail; PTH levels remain elevated
74
How is calcium reabsorbed in the kidney?
Glomerulus: 55% filtered
About 99% reabsorbed along tubule
PCT: 60-70% reabsorbed, paracellular (80%), transcellular (20%). No PTH required.
TALH: 20-25% reabsorbed, 50% transcellular, 50% paracellular, PTH, calcitrol, calcitonin
DCT: 5-10% reabsorbed. Virtually all trans-cellular (PTH, calcitrol)
CD: 0.5-1% reabsorbed, active transport
Urine: 1-2% excreted
75
How is Phosphate Excretion regulated by the kidney?
```
Glomerulus: Absorption depends on glomerular fluid PO43- concentration
<1mmol/l most PO43- reabsorbed
>1mmol/l - excess is excreted
PCT: 75%-805 reabsorbed, majority via transcellular, no PTH required
TALH: Very little reabsorbed
DCT: Very little reabsorbed
CD: Very little reabsorbed
Urine: 10% excreted
```
76
What effect does PTH have on phosphate regulation?
PTH promotes bone resorption - Concomitant increase in extracellular fluid phosphate ions from bone salts
PTH decreases renal tubule phosphate transport maximum - More tubular phosphate now lost in urine
77
What are healthy and deficient vitamin D levels?
```
Vitamin D: "Normal” range: 50-100 nmol/l
Influenced by geography, ethnicity, ag
Insufficiency - <50nmol/l
Deficiency 0 <15-20 nmol/l
In deficiency, there is decreased bone mineralisation
Children - Rickets
Adults – osteomalacia
```
78
What happens to the bones in Rickets?
Can’t absorb the Ca
Elongated growth plate
Poor mineralisation
Bones bend/deform under load
```
Other deformities:
Soft skull bones (craniotabes)
Chest wall deformities
- Harrison sulcus
- Pigeon chest
Bone pain; teeth defects
```
79
What are the different types of muscle?
Roughly 50% off body is muscle:
~40%skeletal muscle
~10% cardiac and smooth muscle
80
How does the length of the muscles change during contraction?
Force of muscle contraction is a function of the overlap of actin:myosin filaments.
Normal resting length (~ 2.0 mm)
~maximum force of contraction at activation
(i.e. maximal active tension seen)
Stretched muscle (> 2.2 mm)
Reduced active tension seen
81
What are the different types of muscle contraction?
Isometric tension/contraction
muscle does not shorten during contraction
“static” contraction – muscle tone
E.g. carrying shopping
Isotonic contraction
muscle shortens but muscle tension remains constant throughout contraction
“Dynamic” contraction
82
What are the different types of muscle fibre?
Every muscle has fast and slow muscle fibres
~98% are fast muscle fibres
~2% slow muscle fibres
SLOW Twitch Fibers (Red muscle; Type 1) - Long latency period, Smaller than fast fibres, Innervated by smaller nerve fibres, Extensive vascular supply, Increased mitochondrial numbers for prolonged oxidative metabolism, Contains myoglobin “red muscle”
FAST Twitch Fibers (White Muscle; Type II)
Short latency period, Large - large strength of contraction, Extensive sarcoplasmic reticulum - rapid Ca 2+ release initiating contraction, Numerous glycolytic enzymes for rapid energy release via glycolysis, Less extensive vascular system and fewer mitochondria (reduced oxidative metabolism), No red myoglobin “white muscle”.
83
What are the energy sources of muscle contraction?
Storage of high energy phosphate bond in creatine phosphate:
ATP + Creatine = ADP + Creatine phosphate
By Creatine phosphokinase
Glycolysis of stored muscle glycogen to pyruvate
Aerobic (oxidative) mechanism - glucose, pyruvate, fatty acids
84
What is a motor unit?
All the muscle fibres innervated by a single nerve fibre – might have multiple projections but is still a singular nerve. Individual motor neuron from spinal cord innervate many muscle fibres
Muscle fibres in each motor unit interdigitate with other motor units – gives you an even simultaneous contraction across the muscle
85
How is fine and gross motor control different?
Fine motor control – low ratio of muscle fibres:nerve fibres (e.g. 2:1)
Gross motor control (larger muscles) high ratio of muscle fibres:nerve fibre (100:1)
86
What is summation?
Adding together of individual twitch contractions to increase the intensity of overall muscle contraction
1) Increasing the number of motor units contracting simultaneously - multiple fibre summation
2) Increasing contraction frequency - frequency summation, leads to tetany
87
What is multiple fibre summation?
Initial muscle contraction stimulus
Smaller muscle motor units stimulated preferentially over larger motor units (Smaller motor units are driven by small motor nerve fibres - more excitable therefore excited first)
Progressive increase in stimulus strength recruits larger and larger motor units
SIZE PRINCIPLE:
Permits gradations (steps) of muscle force during weak contraction to occur in small steps
Steps become progressively greater when large amounts of force are required.
88
What is frequency summation?
Initial strength of contraction may be weak
If muscle is stimulated before relaxation cycle has finished:
- Second contraction partially added to first
- Total strength of contraction increases
- Progressive increase in force of contraction with increased contraction frequency until plateau
- Tetanus will result
- Further stimuli do not increase contractile force
89
What is Bowditch Staircase?
Initial strength of contraction may be weak but…
…if muscle is stimulated after relaxation cycle has finished
Progressive increase in force of contraction seen
Strength of contraction increases to a plateau
Mechanism unclear
But could be due to progressive increases in [Ca 2+]i after each stimulation but failure to re-sequester all ions
90
What are the features of the nerve fibre and nerve terminal at the neuromuscular junction?
Nerve fibre:
Stimulates variable number of muscle fibres
Point of contact with muscle at neuromuscular junction
Nerve fibre remains outside sarcolemma
Nerve terminal:
Rich in mitochondria - requires ATP for ACh synthesis
ACh stored in synaptic vesicles (~300,000)
In the synaptic space, acetylcholine esterase (AChE) rapidly deactivates Ach (Choline and acetate)
91
How is an action potential transmitted across a neuromuscular junction?
Motor nerve impulse open synaptic voltage-gated Ca2+ channels
Increased Ca promotes synaptic vesicles migration to the pre- synaptic membrane
ACh released into the synaptic cleft
Two ACh bind ACh-gated Na+ channel (post-synaptic membrane)- Nicotinic cholinoreceptor (NAChR)
Increased Na depolarises the muscle fibre (end plate potential)
T-tubule system propagates EPP by release of Ca2+ from sarcoplasmic reticulum (excitation-contraction coupling)
EPP terminated by AChE
92
What is a depolarising blockade of the neuromuscular junction?
Prolonged activation of NAChR abolishes effector response.
Presence of nicotinic agonist inhibits post-synaptic membrane recovery.
Suxamethonium (Sux; succinylcholine) and rapid sequence induction (RSI) – given to paralyse muscles (general anaesthetic)
Sux not metabolised by AChE
93
What is a non-depolarising blockade of the neuromuscular junction?
Competitive inhibition of the NAChR - May block Na+ channel
e.g. d-tubocurare (curare)
(Chondrodendron tomentosum)
No depolarisation of the muscle
94
What effect do Organophosphates have on the neuromuscular junction?
Organophosphates (malathione, diisopropylfluorophosphate; DFP)
Potent AChE inhibitors
Prevent ACh hydrolysis
Promote prolonged end plate depolarisation
95
What is end plate potential depolarisation?
If stimulus is of sufficient magnitude, threshold is reached
Muscle fibre depolarises
-85mV - +40 mV
Magnitude of EPP proportional to amount of ACh released
96
What is excitation-contraction coupling?
EPP induces an action potential in the T tubule system
Voltage change sensed by dihydropyridine (DHP)-sensitive Ca2+ channels (L-type)
Ca2+ released from sarcoplasmic reticular cisternae
Increased [Ca2+]i - depolarisation now propagated deep into muscle belly
Muscle contracts
97
What are the basic requirements for control of muscle function?
Continuous feedback of sensory information from muscle (Afferent fibres)
Excitation of muscle by spinal cord anterior motor neurons (Efferent fibres)
98
What are the two types of sensory receptors?
Muscle spindles: Distributed throughout muscle belly
Monitor: Muscle length and Rate of change of length
Golgi tendon organs: Situated in muscle tendons
Monitor: Tendon tension and Rate of change of tension
Gives intrinsic muscle control - virtually subconscious operational level
Some transmission spinal cord, cerebellum, cerebral cortex - higher-level “conscious” regulation
99
What are the characteristics of a muscle spindle?
Made up of intra-fusal fibres – tiny skeletal muscle fibres
which are joined to extra-fusal fibres (main muscle fibres)
Central part lacks actin/myosin
No contraction
Only end section contract
100
What happens during a Patellar tendon Reflex (Knee-jerk)?
Dynamic stretch reflex
Quadriceps muscle stretched – stretches spindle receptor
Primary afferent activated
Alpha motor efferent activated – muscle contracts
Reflex functions to oppose sudden changes in muscle length
101
What are the functions of the kidney?
```
Excretes waste - urea, acid, drugs
Electrolyte balance (osmosis)
Facilitation of plasma Ca
Controls red blood cell numbers (EPO)
Gluconeogenesis
Controls blood pressure (renin)
Controls acid-base balance (pH)
Controls extra-cellular fluid volume
```
102
What are the different parts of the kidney?
```
The kidneys are paired organs found within fibrous renal capsule at the posterior abdominal wall
11cm long, 6cm wide, ~140g
Made up of:
Outer cortex
Inner medulla
Have a complex blood supply to nephrons
```
103
How does the renal blood supply work?
TWO CAPILLARY BEDS
- Glomerulus: high hydrostatic pressure and rapid fluid filtration
- Peritubular capillaries: lower hydrostatic pressure and rapid fluid reabsorption
Vasa recta are a specialised blood supply and allow for counter-current blood flow around Loop of Henle
104
What is the kidney nephron?
Functional unit of the kidney - 1 million per kidney
Tubule structure - 5cm long, wall of single epithelial cells, cell type reflects function of tubule at a given locus
Made up of:
Bowman’s capsule (Renal Corpuscle)
Glomerulus
Proximal convoluted tubule – high degree of reabsorbtion (increased SA)
Loop of Henle – losing water, thin layer of epithelial cells
Distal convoluted tubule
Collecting duct
105
What are the two types of nephrons?
Cortical nephrons (70-80%)
Glomeruli in outer cortex
Short-looped
```
Juxtamedullary nephrons (20-30%)
Help to concentrate urine
Glomeruli border on medulla
Long-looped
Paired with vasa recta (specialised blood supply)
```
106
What are the four basic processes of the kidney?
1) Filtration - glomerulus - water and solutes across the glomerular capillaries
2) Reabsorption - Removal of water and solutes from tubular filtrate into blood. Occurs in PCT, LoH, DCT
3) Secretion - Movement of solute from blood and peritubular fluid to tubular fluid. Occurs in PCT, DCT, CD
4) Excretion - Removal of substances from body in urine
107
How are different solutes/components treated in the kidney?
|nulin - filtration only
Nutrients (glucose, amino acids etc.) - filtration and total reabsorption
Electrolytes (Na+,Cl- etc.) - filtration and partial reabsorption
PAH, Creatinine clearance, Organic acids and bases - filtration and secretion
108
How to calculate renal clearance?
Concentration of substance in urine X Urine flow rate
| / Concentration of substance in plasma
109
How to calculate glomerular filtration rate?
Using inulin because it is freely filtered and not secreted or absorbed.
GFR = [Inulin]urine x urine flow rate (ml/min)
/ [Inulin]Plasma
110
What does GFR tell you?
Relative to inulin clearance
Indicator of renal function
Indicative of whether substance is absorbed or secreted:
- No absorption or secretion: Clearance = inulin clearance
- Secreted: Clearance > inulin clearance (creatinine; PAH)
- Net reabsorption: Clearance < inulin clearance (glucose)
111
What are the drawbacks of measuring GFR?
Can overestimate GFR due to tubular creatinine secretion (10-50%)
Creatinine metabolism reflection on lean body mass
Cimetidine, trimethoprim inhibit tubular secretion of creatinine
Not validated in pregnancy
112
How is renal plasma flow determined?
Renal plasma flow (measured using PAH; Para-AminoHippuric acid clearance)
113
How is filtration fraction determined?
Plasma fraction filtered through glomerular membrane
| Function of GFR / RPF
114
Why does so much filtration occur in the glomerulus?
More porous than other capillaries
Filtration inversely proportional to molecular size
Filterability of 1.0 means a substance is filtered as freely as water (Na, glucose, inulin)
115
How is filtration determined in the kidney?
Filtration = GFR X Plasma Concentration
116
How much does the kidney filter and reabsorb a day?
Filtered 180L
| Reabsorbed 179L
117
What is GFR affected by?
- Filtration coefficient (Kf) – thickness and SA of the membrane (Arteriolar endothelium and Glomerular podocytes)
- Net Filtration Pressure (NFP)
Arteriolar and Bowman’s capsule hydrostatic pressures
Glomerular and Bowman’s capsule colloid osmotic pressures
- Renal Blood Flow (RBF)
Autoregulation – small effect
118
What pressures affect the net filtration pressure in the kidneys?
Bowman’s Capsule fluid pressure (fluid in)
Glomerular hydrostatic pressure (fluid out)
Bowman’s Capsule colloid osmotic pressure
Glomerular colloid osmotic pressure (fluid in)
119
What is the Filtration Coefficient - Kf?
The ability of a membrane to filter solute
| Considers filtration surface area and ability to move water
120
How can the filtration coefficient be reduced in disease?
Fewer functioning glomeruli - decreased filter surface area, age-related
Chronic hypertension
Diabetes mellitus - thicken filter membrane and requires increased pressure
121
What is Glomerular Hydrostatic Pressure affected by?
- Systemic arterial pressure - tends to increase GHP and GFR but renal auto-regulation minimises major change
- Afferent arteriolar resistance - generally reduces GHP and GFR
- Efferent arteriolar resistance - increased GHP, variable response in GFR (increase then decrease)
122
How can efferent arteriolar constriction effect GFR?
Effect of efferent arteriolar constriction depends on severity of constriction
Mild efferent constriction increases GFR
Severe efferent constriction decreases GFR (>3X increase in resistance)
123
How is GFR auto-regulated?
Intrinsic feedback mechanisms maintains near constant renal blood flow and GFR
Minimises impact of systemic arterial pressure variations on RBF & GFR
(buffers small changes in pressure)
Without auto-regulation there would be a large increase in urine output (>40L)
124
How does the Renin-Angiotensin System help control GFR?
Decrease in arterial pressure
Decrease in GFR
Decreased NaCl recognised by Macula densa
Juxtaglomerular cells release Renin
Angiotensinogen - Angiotensin I - Angiotensin II
Negative effect on afferent pressure, positive effect on efferent pressure
GHP increased
GFR restored
125
What factors decrease GFR?
Decreased filtration coefficient - renal disease, hypertension, DM
Increased β-caryophyllene - kidney stones
Increased glomerular colloid osmotic pressure - decreased renal blood flow, increase in plasma proteins
Decreased glomerular hydrostatic pressure
Decreased efferent artery pressure - Angiotensin II drugs
Increased afferent artery pressure - NSAIDs
126
What happens in the proximal convoluted tubule?
Reabsorb:
~65% of filtered Na+, K+
~90% HCO3-
Virtually all glucose and amino acids
Secrete:
Organic acids, bases, H+
Drugs
Amounts of solute change along PCT
Osmolality remains roughly 300 mOsmol/L
Very water permeable
127
What happens in the Loop of Henle – Thin Descending Limb?
```
Highly permeable to water
~20% filtered water reabsorbed
Moderate permeability to other solutes
Increased Solute osmolarity (concentration)
- Tubular fluid most concentrated at tip of loop
- Counter-current exchange
Very few mitochondria
Little/no active reabsorption
```
128
What happens in the Loop of Henle – Thick Ascending Limb?
Reabsorb ~25% of filtered Na+, K+, Cl- via Na+-2Cl--K+ ATPase
Some Ca2+, Mg2+ via Paracellular route
Secretion H+ into tubular lumen
Highly impermeable to water
Counter-current exchange
Decreased solute osmolarity (less concentrated) - allows kidney to dilute or concentrate urine
129
What happens in the early distal tubule?
Similar characteristics to ascending loop of Henle
Initial part forms Macula Densa within juxtaglomerular apparatus
Reabsorbs Mg2+, Ca2+ and~5% of filtered Na+, Cl- load via Na+/Cl- co-transporter
Impermeable to water and urea
Fluid osmolarity (“diluted”)
130
What happens in Late distal and Cortical collecting tubules?
```
Sensitive to ADH
Impermeable to urea
Contain two distinct cell types
- Principal cells
- Intercalated cells
```
131
What are the principal and intercalated cells?
Principal cells - K secretion, reabsorb Na, sensitive to aldosterone
Intercalated cells - major role in acid-base balance (buffers acidosis), secrete H, K reabsorbed, NH3 secreted, HCO3 reabsorbed
132
What happens in the Medullary Collecting Ducts?
Final processing site for urine - actively reabsorbs Na+ and permeable to urea
Secretes H+ - role in acid-base regulation
Permeability to water governed by ADH
Increased ADH, increased Water reabsorption
133
How does the osmolality of the filtrate change as it passes through the nephron?
PCT: H20 and solutes reabsorbed, filtrate 300mOsmol/L
DL-LoH: H20 reabsorbed, filtrate 600mOsmol/L
AL-LoH: NaCl reabsorbed, filtrate 100mOsmol/L
DCT/CD: Na reabsorbed, K secreted filtrate 50mOsmol/L
134
What is the vasa recta in juxtamedullary nephrons?
Counter-current blood flow around Loop of Henle
Very low blood flow
Blood osmolarity reflects congruent segment of medullary interstitium
Prevents dissipation of interstitial hyper-osmolarity
135
How is ECF volume regulated?
Sensors:
Baroreceptors
Stretch receptors
Osmoreceptors
Effectors:
Anti-diuretic hormone (ADH) (aka arginine vasopressin; AVP)
Renin/Angiotensinogen/Aldosterone system
Atrial Natriuretic Peptide (ANP)
136
What effect does ANP have on ECF volume?
```
Increased ECF vol, increased atrial stretch (heart)
Inhibits Renin secretion
Decreased Angiotensin II
Prevents water/NaCl reabsorption
Increased GFR
Decreased Tubular reabsorption of Na
Increased Water secretion
Increased Pressure diuresis/natriuresis
Decreased ECF volume
```
137
How does impaired renal function cause hypertension?
Reduced kidney mass/function
Immediate response: increased NaCl/water intake, increased blood vol, ECF, CO, slow increase in arterial pressure, decreased peripheral resistance (compensation)
Delayed response: decreased CO, ECF (autoregulation), increased peripheral resistance, increased arterial pressure (Hypertension)
138
What is the function of the nervous system?
Constant processes incoming information from sensory nerves and sensory organs
Integrates this information
Produces an appropriate bodily response via muscle contraction, hormone secretion etc…
139
What are the two types of nerve cells?
Neurones - Information transfer
Neuroglia
Supporting cells
Maintain blood:brain barrier, fluid regulation
Include astrocytes, oligodendrocytes, microglia, ependymal cells
140
How does a nerve cell receive and send information?
Sensory info arrives via dendrites and soma
Effector info leaves via the single axon (but axons may branch to provide collaterals, or differentiate between sensory and motor information)
141
What is convergence and divergence in the nervous system?
Divergence: Any individual neuron can make divergent connections to many different postsynaptic cells
Convergence: One postsynaptic cell receives convergent input from a number of different presynaptic cells
and
142
What is the membrane potential?
Differential ion concentrations across the cell membrane
143
What is the equilibrium potential?
Equilibrium between the ion ratio in the intracellular fluid and extracellular fluid which is dependent on membrane permeability and membrane voltage
144
What is the definition of the Nernst potential?
Diffusion potential across a membrane is a voltage that exactly opposes the net diffusion of a particular ion through that membrane, meaning there is no net diffusion of that ion.
Increased ion concentration means increased tendency for ion to diffuse in one direction.
Therefore larger Nernst potential required to prevent further net diffusion.
145
How does depolarisation and hyperpolarisation occur?
Depolarisation reduces trans-membrane potential difference (closer to 0mV)
Hyperpolarisation increases trans-membrane potential difference (more -mV)
Hyperpolarisation: Potential has -ve value if diffusing from IC to EC (K+)
Depolarisation: Potential has +ve value if diffusing from EC to IC (Na+) – becomes less neg
Hyperpolarisation: Potential has -ve value if diffusing from EC to IC (Cl-)
146
How does the action potential get started?
Sub-liminal stimulus: Membrane potential does not reach threshold (~-60mV), no Depolarisation
Phase 1 - Liminal stimulus, threshold reached (~-60mV)
Na+ channels open
Phase 2 – Threshold, upstroke, rapid Na+ influx
Membrane depolarises, Na+ channel then rapidly close
Phase 3 - K+ channel opens, Repolarisation starts
Phase 4 - Hyperpolarisation, Process repeats
147
What is the refractory period?
Na+ channels can’t open
Absolute refractory period - no depolarisation can occur
Relative refractory period - some depolarisation if there is a strong stimulus due to reduced inhibitory effect
148
How does action potential movement differ between myelinated and unmyelinated?
Unmyelinated axon: Slower transmission, 0.25m/sec (chronic pain fibres)
Myelinated axon: Saltatory conduction, depolarisation restricted to Nodes of Ranvier (action potential moves node to node)
Benefits: faster transmission and conserves energy (less ions used or exchanged)
149
What are the two types of synaptic transmission?
Electrical: cells share cytoplasm, gap junction proteins
Creates a functional syncytium (unit of contraction) e.g. used in heart, uterus
Chemical: most signalling in nervous system
Uses secretion of neurotransmitter to act on post-synaptic neurone
150
What are some of the common short-acting neurotransmitters?
Acetylcholine
Nitric oxide
Amino acids: GABA, glycine, glutamate
Monoamines: Noradrenaline, adrenaline, dopamine, serotonin
151
What are the neurotransmitters that are usually excitatory?
Glutamate: used throughout CNS – pain transmission
Acetylcholine: used in the pyramidal cells of motor cortex, basal ganglia, at the neuromuscular junction (NAChR) and in preganglionic autonomic fibres (NAChR) and post-ganglionic parasympathetic fibres (MAChR)
Noradrenaline: used in locus ceruleus (Pons) and in wakefulness (gets you up in the morning along with cortisol)
152
What are the neurotransmitters that are usually inhibitory?
GABA: used in the cortex, cerebellum, basal ganglia, spinal cord
Glycine: used in the spinal cord
Dopamine: used in the substantia nigra – damaged in Parkinson’s disease, basal ganglia (striatum)
Serotonin (5HT): used in the brain stem, spinal cord (dorsal horns). Inhibits pain pathways and influences mood (SSRIs)
153
What are some of the common long-acting neurotransmitters?
Hypothalamic-Releasing Hormones: GnRH
Pituitary Peptides: GH and Oxytocin
Peptides Acting on Gut and Brain: Gastrin, CCK, NGF
From Other Tissues: Angiotensin II
154
What are the two types of summation?
Discharge of single pre-synaptic neurone not sufficient to induce depolarisation so summation is needed.
Temporal summation: Initial sub-liminal stimulus summed with second or third sub-liminal stimuli
Spatial summation: Sub-liminal stimuli at different but close locations summed
155
How does synaptic transmission occur?
Nerve impulse open synaptic voltage-gated Ca2+ channels
Increased intracellular calcium promotes synaptic vesicles migration to pre-synaptic membrane.
NT released into synaptic cleft
- Ionotropic Receptor gates ion channels and has a short-term effect
- Metabotropic Receptor induces second messenger and has a longer-term effect
Excitation or Inhibition of post-synaptic membrane depending on the receptor
NT degraded or reabsorbed by pre-synaptic terminal
156
What is an EPSP?
An excitatory postsynaptic potential (EPSP) is the change in membrane voltage of a postsynaptic cell following the influx of positively charged ions into a cell (typically Na+) as a result of the activation of ligand-sensitive channels.
157
What is an IPSP?
An inhibitory postsynaptic potentials (IPSP) is a temporary hyperpolarization of postsynaptic membrane caused by the flow of negatively charged ions into the postsynaptic cell.
158
How does synaptic transmission ensures one-way directionality of the action potential?
At the axon hillock, there are very few Na channels so it is more difficult to depolarise. This reduces the reverse flow of signal.
However at the initial segment of the axon there are greater numbers of Na channels so the AP is propagated away from the soma.
159
What is Synaptic Fatigue?
Repetitive firing of excitatory synapses induces reduced firing in post-synaptic fibre. This is an adaptation in sensory receptors but can be detrimental.
160
What causes synaptic fatigue?
Exhaustion of presynaptic neurotransmitter stores (no time to restore resource pool)
Progressive inactivation of postsynaptic membrane receptors
Development of abnormal intra-cellular ion concentrations in postsynaptic neurones
161
Give some examples of drugs that the efficiency of synaptic transmission?
Benzodiazepines: enhance GABA fibre firing (stop seizures)
Atropine: inhibits muscarinic AChR (increase heart rate; cause pupil dilatation)
SSRIs: inhibit reuptake of serotonin (anti-depressants)
Strychnine: inhibits inhibitory glycine neurones in spinal cord and increases neuronal excitability muscle spasms
162
How does alkalosis affect synaptic transmission?
pH > 8.0 (alkalosis) can cause cerebral epileptic seizures
More Ca2+ bound to plasma proteins
Increased neuronal membrane Na+ permeability
Action potentials reach threshold more easily
Alkalotic patients more susceptible to hypocalcaemic tetany
163
How does acidosis affect synaptic transmission?
pH <7.0 (acidosis) can depress neuronal activity
Less Ca2+ bound to plasma proteins
Decreased neuronal membrane Na+ permeability
Depresses nervous system and muscle activity.
164
How are sensory nerve fibres classified?
Type A fibres large, myelinated and fast
Type C fibres small unmyelinated and slow
- all postganglionic autonomic fibres
- >one half of sensory fibres in peripheral nerves
165
What are some of the major sensory receptors?
Sensory Receptors allow perception of the environment
Mechanoreceptors in semi-circular canals - location
Nociceptors – pain
Thermoreceptors – temperature
Electro-magnetic receptors – light in the eyes (rods and cones)
Chemoreceptors – carotid bodies
166
What are the sensory modalities?
```
Chemical
Pain
Sight
Sound
Taste
Touch
Specific nerve fibres transmit only one sensory modality
```
167
What is Sensory Receptor Adaptation?
Sensory receptors adapt to any constant stimulus over time
Partially or completely
i.e. initially high impulse frequency – declines over time.
168
What are the two types of adapting sensory receptors?
Slowly adapting receptors (Tonic receptors)
Continually transmit info to brain while stimulus is present
Brain constantly appraised of bodily status e.g. muscle spindles and Golgi tendon organs
Rapidly adapting receptors (Phasic receptors)
Only signal when stimulus strength changes
Can’t transmit a continuous signal
React strongly while change is occurring e.g. skin Pacinian corpuscle
Appraises nervous system of rapid tissue deformations
NOT constant conditions in the body
169
What's the difference between white and grey matter?
White matter – contains nerve tracts (fasiculi)
Tract-specific function
High fidelity mapping of bodily structures
Grey matter – cell bodies
Organised into nuclei
Posterior grey horns (Sensory)
Anterior grey horns (Somatic motor control)
High fidelity mapping of bodily structures
170
What are the different Spinal Cord Pathways?
```
Fasiculus gracilis (nerve bundle to nucleus gracilis; medulla)
Dorsal column pathway
Spinothalamic Ascending (sensory)
Spinocerebellar Ascending (sensory)
Corticospinal Descending (motor)
```
171
How are sensory signals carried through the spinal cord to the brain?
Dorsal column pathway: Fast transmission of well-defined mechanoreceptive sensations
Spinothalamic pathway: Slower transmission of broad spectrum sensory modalities
172
What is the trajectory of the Dorsal column pathway?
Nerve fibres enter dorsal columns
Most pass uninterrupted to dorsal medulla
- Some form spinocerebellar tracts
- Some fibres initiate local cord reflexes
They synapse in medullary dorsal column nuclei
(cuneate and gracile nuclei)
They then decussate (crossover) to opposite side of brain stem
Continue through medial lemnisci to thalamus
They enter the brain stem from CN V, VII, IX, X which are incorporated into medial lemnisci
Sensation perceived in somatosensory cortex
173
What is the function of the dorsal column pathway?
FACILITATES THE RECOGNITION OF:
Touch sensations requiring a high degree of localisation of the stimulus and transmission of fine gradations of intensity (~100 gradations)
Phasic sensations (vibration)
Sensations of movement against skin
Position sensations from joints
Pressure sensations related to fine degrees of judgment of pressure intensity
174
What is the trajectory of the Spinothalamic pathway?
Nerve fibres enter dorsal columns
Synapse in dorsal horns of spinal grey matter
Decussate to the opposite side of cord
Then ascend via anterior and lateral white columns
Fibres terminate at all levels of lower brain stem and thalamus
175
What is the function of the spinothalamic pathway?
```
FACILITATES THE RECOGNITION OF:
Pain
Thermal sensations (warmth and cold)
Crude touch and pressure sensations
Tickle and itch sensations
Sexual sensations
```
176
How to the dorsal column and spinothalamic pathways differ in spatial orientation and transmission?
DORSAL COLUMN:
High level of spatial orientation in fibre origin
Fast transmission (30-110 m/sec)
SPINOTHALAMIC:
Low level of spatial orientation in fibre origin
Slower transmission (40 m/sec)
177
How does ascending sensory information reach the sensory cortex?
Ascending sensory information is projected to primary somatosensory area via thalamic ventral posterolateral nucleus.
178
How do motor commands from motor cortex reach the appropriate muscles?
Through two systems:
Voluntary commands - Pyramidal system
Involuntary commands - Extra-pyramidal system
179
What makes up the motor pyramidal system?
- Primary motor cortex – six layers
- Motor cortex neurones which have the following features:
Pyramidal cells
Axons to brain stem, medulla and pons, spinal cord
No intervening synapses
Rapid mechanism of skeletal muscle control
180
What is the Corticobulbar tract?
Function: Controls muscle of face, head, neck
Runs from the cortex to brain stem (medulla) and terminates in motor nuclei of CN V, VII,X, XII
Has both ipsilateral and contralateral sides for swallowing, speech, chewing and lingual movements
Except for part of the CN VII and CN XII which supplies muscles of facial expression in lower face
(exclusively contralateral projections)
181
What is the Corticospinal tract?
Made up of the primary motor cortex, ventral medulla surface and the pyramids which decussate in lower medulla (~85%) - lateral corticospinal tract
The remainder form Anterior corticospinal tract which decussate in anterior white commissure of spinal cord and synapse on motor neurones in anterior grey horns.
182
What is Brown-Séquard Syndrome?
Syndrome whereby the spinal cord is transected on only one side.
This stops the motor command on the side of the transection (through the corticospinal tract) – all motor functions blocked in all segments below transection level.
On that same side, you also lose the dorsal columns sensory function (Proprioception, vibration, fine touch, two-point discrimination) as well as the dermatomes below the level of that transection.
On the opposite side to the transection, you lose the spinothalamic pathway (Loss of pain, heat, cold sensation as well as all dermatomes two to six segments below transection).
183
What are the major functions of the cerebellum?
Oversight of postural muscle - modification of the red nucleus activity
Programming/fine tuning of voluntary and involuntary movement
184
What are some of the major cerebellar abnormalities?
Dysmetria - Subconscious motor control can NOT predict distance in movement leading to jerky movement
Ataxia - lack of voluntary coordination of muscle movements that can include gait abnormality, speech changes, and abnormalities in eye movements.
Dyspraxia - impacts an individual's ability to plan and process motor tasks, difficulty catching a ball/using a knife and fork
Past-pointing - the inability to place a finger or some other part of the body accurately on a selected point; seen esp. in cerebellar disorders (loss of inhibitory cerebellar motor command)
185
What are the two Spinocerebellar tracts?
```
Dorsal Spinocerebellar tract:
Terminates on same side as its origin
Vermis and intermediate zone
Ventral Spinocerebellar tract:
Terminates on both sides of cerebellum
```
186
What is the function of the dorsal spinocerebellar tract?
Transmits info from:
- Muscle spindles
- Some other large receptors (Golgi tendon organs)
Continually appraises cerebellum of status of:
- Muscle contraction
- Degree of tension on tendons
- Position and rates of movement of body parts
- Forces acting on body
187
What is the function of the ventral spinocerebellar tract?
Ventral Spinocerebellar tract provide the Efference Copy of anterior horn motor drive
The efference copy is continually appraising the cerebellum of the particular ongoing motor function.
Motor commands FROM higher brain centres excite ventral spinocerebellar neurones and the info relayed back to cerebellum.
188
What makes up the motor extra-pyramidal system?
Extensive interconnections with pyramidal (motor cortex) system
Made up of the cerebral nuclei, basal ganglia, cerebellum, red nucleus, vestibular nuclei, reticular formation, substantia nigra.
189
Which hormones regulate reproductive function?
Gonadotrophins: LH, FSH, hCG produced by gonatrophic cells.
Steroids: oestrogens, progestins, androgens
Cytokines: actinins and inhibins
190
Which cells are involved in the reproductive function of males?
Leydig cells - present in the interstitial space, sensitive to LH. Synthesise testosterone and progesterone from cholesterol.
Sertoli cells - present in seminiforous tubule, directly support spermatogenesis, sensitive to FSH.
Converts testosterone to oestradiol and dihydrotesterone
191
What is spermatogenesis?
Formation of spermatozoa
Diploid genome becomes haploid
Takes 64 days
192
What is Spermiogenesis?
Remodelling of spematid (round cell) into spermatozoan (propulsive cell)
193
What is Spermiation?
Release of spermatozoa from sertoli cells into the lumen of seminiferous tubules
194
Which cells are involved in the reproductive function of females?
Thecal cells: sensitive to LH, synthesise progesterone and testerone from cholesterol. Produce androgens which are precursors for oestrogen/estradiol.
Granulosa cells: sensitive to FSH, conversion of testerone to estadiol. FSH induces LH receptors on granulosa cells of dominant follicle.
195
What are the stages of the menstual cycle?
Decreasing levels of progesterone and oestrogen at the end of the cycle.
Small increase in FSH leads to release in follicle
As the follicle grows, oestrogen increases leading to negative feedback
FSH falls as dominant follicle arises (LH surge)
Ovulation occurs with a huge peak in LH and small peak in FSH and drop in oestrogen.
Becomes corpus luteum.
196
How does a blastocyst implant into the endometrial epithelium?
Usually non-adhesive for blastocyst
To survive it needs to signal its presence to the mother using a two-way communication system
hCG, oestrogens, progestins facilitate synchronisation between materal and blastocyst tissues.
Particularly hCG which is secreted by the trophoblast cells around day 6-7 post-fertilisation which prevents decline of corpus luteum, meaning that it continues to synthesise progestins until placenta forms.
197
What are the different types of oestrogens?
Oestrone (E1), 17b-Oestradiol (E2), Oestriol (E3)
Initially sourced from ovary
Derived from androgenic precursors
E3 is main oestrogen in pregnancy, indicator of fetal wellbeing, decline correlates with fetal distress
E2 signals endometrial epithelium proliferation/differentiation and increases number of endometrial progesterone receptors
198
What are progestins?
Pro-gestational hormones which are essential for a sucessful pregnancy
Initially come from corpus luteum, then placenta from 7-8 weeks
Prepares endometrium and uterus from implantation
Inhibition with mifepristone will terminate pregnancy
199
How does a blastocyst implant?
"Window of implantation"
Endometrium develops transient receptivity for an embryo usually between day 20-24
Blastocyst will undergo interstitial implantation
Decidua 'permits' invasion which is mediated by uterine stromal cell enlargement and the uterine natural killer cells
200
What are the stages of blastocyst implantation?
First interaction - blastocyst has looser adherence to the endometrial endothelium
Interstitial implantation in the endometrium
Interstitial invasion - extravillous trophoblast migrate from cell columns, anchoring villi, invasion of decidual glands, hypoxia becomes more hypoxic
Spiral artery remodelled
Endovascular invasion - driven by EVT and uNK
Taps into materal blood supply
201
What is placenta-mediated disease?
Endovascular invasion - EVT invade along artery into inner third myometrium, acquisition of maternal blood supply
Failed endovascular invasion: invasion localised to decidua, reduced acquitision of maternal blood supply
202
What are some of the complications of pregnancy?
Pre-eclampsia - only cured by birth, poor vasculation invasion
Premature birth
Placental abruption due to car crash
Fetal growth restriction due to poor environment
Recurrent miscarriage
203
What is an ectopic pregnancy?
An ectopic pregnancy is when a fertilised egg implants itself outside of the womb, usually in one of the fallopian tubes.
50% ampulla
20% isthmus
204
What is placenta accreta?
Placenta accreta is a serious pregnancy condition that occurs when the placenta grows too deeply into the uterine wall. Typically, the placenta detaches from the uterine wall after childbirth. With placenta accreta, part or all of the placenta remains attached.
Increased risk:
Previous C-section
Low-lying placenta
Risk of poor placenta separation or significant post-partum bleeding
205
Why is the blastocyst not rejected?
Differential gene expression
Increases in growth factors, proteolytic enzymes and inflammatory mediators - facilitates implantation
Change in expression of proteins needed for immune response preventing blastocyst rejection
206
How does the balance between Th1 and Th2 change during pregnancy?
Non-pregnant: Th1:Th2 balance - appropriate immune response
Normal pregnancy: Th2 bias observed, immune response modified. Placenta facilitates Th2 formation and Th1 regression.
Abnormal pregnancy: Th2 not observed, INFy increased, exaggerated inflammatory response
207
What is myometrial quiescence?
Myometrium is the smooth muscle of the uterus wall
Quiescence means it's non-contractile
This is determined by:
B2 agonists
PGE2 via EP2 receptor
Repression of acto-myosin ATPases activitity - relaxation
208
What are tocolytic drugs?
Anti-contraction
Used to suppress premature labour.
Provided when delivery would result in premature birth, postponing delivery for administration of glucocorticoids
209
What are the theories about why women go into labour?
Placental clock - increased levels of placental corticotrophin releasing hormone, stimulates fetal pituitary to release ACTH which causes secretion of DHEA (major oestrogenic precursor)
Oestrogens stimulate increase in myometrial gap.
Facilitates regular coordinated uterine contractions.
Fetal-induced signal - increased fetal surfactant proteins (SpA) activates amniotic fluid-dervied macrophages which migrate to the uterine wall and activate inflammatory gene expression
Infection (abnormal)
210
What are the 3 stages of parturition?
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Cervical dilation (remodelling)
Fetal explusion (myometrial contraction)
Placental delivery and haemostasis
Most of pregnancy, the cervix is hard and closed
Contraction act to remodel the cervix to open it around the baby's head.
```
211
What causes myometrial contractility?
Elevated Ca levels due to Ca-regulated contraction pathways
Extracellular sources via voltage-gated Ca channels
Intracellular souces - Ca store operated on sacroplasmic reticulum
212
What is Nifedipine?
Ca channel blocker
Usually treats hypertension
Inhibits premature myometrial contractions
213
What is Atosiban?
Oxytocin receptor antagonist
Can inhibit premature myometrial contractions
Doesn't impact prostaglandin levels
214
What is Carboprost?
Synthetic prostaglandin
| Used in obstetrical emergency of postpartum hemorrhage which reduces postpartum bleeding during these circumstances.
215
What is the effect of Oxytocin release in labour?
Elevates intracellular Ca by releasing intracellular stores
Increased OT receptors on fundal myometrium
Clinical analogues used to induce labour (Syntocinon)
216
What happens during placental delivery?
Rapid myometrial contraction
Physiological 'direct' pressure
Immediate fibrin deposition over placental site
217
What are the requirement of the changes in maternal physiology in pregnancy?
They need to precede fetal demands/growth
They need to be in excess of fetal requirements
They need to be dynamic
They need to enhance of nutrients/waste
218
What systems are affected in pregnancy?
```
Renal function and fluid homeostasis
Endocrine
Metabolic
Immune/defence
Cardiovascular
Respiratory
Gastrointestinal/hepatic
Reproductive
```
219
How does fluid retention change in pregnancy?
```
30-50% increase in total plasma volume
Significant extra-cellular fluid expansion (1-2 litres)
Net Na retention, water is dragged in too
Increased extracellular fluid volume
Decreased plasma osmolality
Decreased plasma oncotic pressure
Increased RBCs
'Dilution anaemia'
```
220
How is the kidney affected by pregnancy?
```
Increased kidney size
Decreased uretheral tone
Mechanical compression of uteters by abby
Hydronephrosis and urinary stasis
Increased blood flow to the kidney
Increase in GFR
Increase in Renin-Angiotension II
Increase in filter permeability
```
221
Why is eGFR not validated in pregnancy?
There is increased creatinine clearance and decreased plasma creatinine
222
How does pregnancy affect the blood?
Dilution anaemia - increase in RBCs but not enough, decreased haemoglobin and haemocrit
Blood is hypercoagulable - increase in fibrinogen, clotting factors, ESR
223
How does pregnancy affect the cardiovascular system?
Early phase - peripheral vasodilation, increased in CO, SV, HR
Changes in blood pressure, decreased BP and peripheral resistance in early/mid pregnancy and increased BP in late pregnancy
224
How does pregnancy affect the thorax?
Diaphragmatic elevation observed
Heart is displaced to an upward/left position
Apex of heart is moved laterally
Altered heard sounds (systolic/diastolic murmurs)
Altered ECG trace (inverted T wave, prominant Q wave)
225
How is maternal oxygen consumption facilitated by the respiratory system?
Maternal oxygen consumption is increased by 15-20%
Achieved by:
Diaphragmatic elevation - decreased TLC, FRC giving a reduced O2 reservoir, increased TV and MV
Progesterone-induced tracheo-bronchial smooth muscle relaxation
226
Why is there a state of compensated respiratory alkalosis in pregnancy?
Progesterone levels are increased during pregnancy. Progesterone causes stimulation of the respiratory center, which can lead to respiratory alkalosis. Chronic respiratory alkalosis is a common finding in pregnant women.
227
What are the changes to the stomach in pregnancy?
Delayed gastric emptying
Cardiac sphincter relaxation - heart burn
Anesthetic risk - aspiration pneumonitis
228
What are the changes to the liver in pregnancy?
Reduced secretion of CCK
Reduced gallbladder motility and gall stones
Execerable dyspepsia
Obstetric cholestasis
229
What are the changes to the bowel in pregnancy?
Gut transit time increased
Enhanced nutrient uptake in small bowel
Increased water reabsorption in large bowel (constipation)
230
What are the gastrointestinal symptoms of pregnancy?
Hyperemesis gravidarum - chronic pregnancy vomiting
Ptyalism - sensation of excess salivation
Altered appetite
Pica - ingestion of non-nutritive substances
231
How does glucose metabolism change in pregnancy?
Early pregnancy: maternal glycogen synthesis, fat deposition
Late pregnancy: maternal insulin resistance due to fetal hPL which is a diabetogenic agent - risk of diabetic ketoacidosis
232
How can the in utero environment influence adult diseases?
Affects subsequent physiological function in life
| May affect disease patterns and influence future progeny
233
How does pregnancy affect the uterus and cervix?
Uterus mass increases - smooth muscle hyperplasia and hypertrophy
Appearance of uterine natural killer cells
Cervix - increased softness and vascularity as gestation progresses
234
How does pregnancy affect the breasts?
Increase volume with gestation progression
Fat deposition around gland tissue
Increased gland duct numbers and serum prolactin
235
What is dextocardia?
Dextrocardia is a rare heart condition in which your heart points toward the right side of your chest instead of the left side.
236
When do the AV valves open and close?
As pressure builds in the ventricles the AV bulge and close.
As pressure builds and builds, they open to allow blood through.
After ejection, they then close again.
As pressure drops, AV valves open again and ventricles fill. Most filling is passive with the atria topping them up.
237
What is the membrane potential?
```
Differential ion concentrations across the cell membrane set up the membrane potential.
Direction of ion movement depends on:
Ion ratio
Membrane permeability
Membrane voltage
```
238
What is the diffusion potential?
Diffusion potential across a membrane is a voltage that exactly opposes the net diffusion of a particular ion through a membrane.
No net diffusion of that ion.
239
What is an inotrope?
An agent capable of altering the force or energy of a muscle contraction
240
What is positive and negative inotropism?
Positive inotropism - increase the force of a muscle contraction e.g. noradrenaline and digoxin
Negative inotropism - decrease the force of a muscle contraction e.g. B-blockers, Ca channel blockers
241
What is a dromotropic agent?
Alters the AV node conduction speed
| e.g. ACh is a negative dromotrope
242
How does sympathetic and parasympathetic stimulation affect SAN action potential?
Sympathetic - increases rate of reaching threshold
e.g. noradrenaline - increased SAN permeability to Na/Ca
Parasympathetic - decreases rate of reaching threshold e.g. ACh hyperpolarises SAN/AVN
243
What are the stages of the ventricular action potential?
Diastolic resting potential
Fast Na channels (Na in) - depolarisation
K leak into the cell - partial repolarisation
Slow Ca channels (L-type) open
Decreased K permeability - plateau/contraction
K efflux - repolarisation
244
What are the conducting cells of the heart?
Carry stimulus to atria and ventricles
Go in one direction
Specialised cardiac cells (not neural tissue)
245
Which leads make up Einthoven's triangle?
Lead I: activity between right upper chest to left upper chest
Lead II: activity between right upper chest and left leg
Lead III: activity between left upper chest and left leg
Gives 3 different views of the heart
246
Why is the aVR lead negative?
Negative wave reflection in aVR is normal due to a reversal of the polarity of the system.
247
How is voltage recorded on an ECG?
If a cardiac vector is directed at right angles or perpendicular to a particular lead axis, the net impression on that lead will be nil.
But as the angle between the cardiac and the lead vector increases, the voltage recorded in that particular lead will decrease and vice versa.
248
Why doe endocardial cells in the septum take slightly longer to repolarise than epicardial cells?
Epicardial cells have shorter action potential so repolarise earlier.
249
Why does ventricular repolarisation take longer than depolarisation?
Because it is carried out by cell-cell contact not through the purkinje system
250
How does ischemia after the action potentials?
Shorter endocardial action potential duration
Repolarisation begins before epicardial myocytes
ECG T wave -ve deflection
251
How is cardiac function regulated?
Local (intrinsic) - within vascular system (hormones, stretch)
Central - medulla and higher centres
252
What are the different cardiac volumes?
End diastolic volume - blood volume in ventricle at the end of relaxation
End systolic volume - blood volume in ventricle at the end of contraction
Stroke volume - blood ejected upon contraction
All variable - based on heart rate and filling time
253
What is the pre-load?
The degree of muscle tension as muscle starts to contract
| End diastolic pressure
254
What is the afterload?
The load against which the muscle exerts its contractile force
Pressure within aorta
255
How does sympathetic activation affect the heart?
Release of:
Noradrenaline from post-ganglionic fibres
Adrenaline and noradrenaline from adrenal medulla
Increased:
- Cardiomyocyte metabolism
- Force of contraction
- Stroke volume
256
What is the autonomic regulation of cardiac function?
Sympathetic stimulation - noradrenaline
Increases rate and force of contraction (positive inotropy and chronotropy)
Parasympathetic stimulation - vagus, ACh
Hyperpolarises SAN/AVN, slows rate of contraction, little effect on force
257
What is the Bambridge reflex?
Increased venous return
Stretches atrial baroreceptors and SAN
Afferent signals to medulla via vagus
Sympathetic efferent increases heart rate and force of contraction
Prevents blood 'traffic jam'
Ensures both ventricles eject similar volumes
258
How is blood pressure regulated?
```
Baroreceptors
- Aortic - aortic reflex
- Carotid - monitor blood flow to brain
- Atrial - bainbridge reflex
Chemoreceptors (plasma CO2/O2)
Aortic bodies
Carotid bodies
```
259
What are the reversible causes of heart failure?
```
4 Hs
Hyper/hypokalaemia/calcaemia
Hypoxia
Hypovolaemia
Hypothermia
```
```
4Ts
Thrombosis
Tension pneumothorax
Tamponade
Toxic substance
```
260
What is the function of the RAAS system?
Renin-Angiotensin-Aldosterone System
| To keep blood pressure and blood volume under control
