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Body in Motion: Neuroscience By Dan SandlerStructure of the Nervous system ▶ Q: What cell type is most abundant in the Central Nervous System (CNS)? ▶ As: 1) Oligodendrocyte 2) Astrocyte 3) Shwann cell 4) Neuron 5) Microglial cellStructure of the Nervous system ▶ Q: What cell type is most abundant in the Central Nervous System (CNS)? ▶ As: 1) Oligodendrocyte 2) Astrocyte 3) Shwann cell 4) Neuron 5) Microglial cellBasic Structure of CNS ▶ CNS: - Neurons : Conduct Action Potentials - Oligodengrocytes : Myelin - Astrocytes : Nutritional support, BBB, (+synapse regulation) - Microglia : Immune cellsBasic Structure of PNS ▶ PNS: - Neurons : Conduct Action Potentials - Schwann cells : Myelin - Satellite cells : Cell body support (ganglions) Fibre Types: A-alpha, A-beta, A-delta, C fibres Mechanosensation organsAction Potentials Q: Which membrane channels are open at 3? A: 1) Na, K, Na/K pump 2) Na only 3) K only 4) None 5) K, Na/K pumpAction Potentials Q: Which combination of ion channels is present at 3? A: 1) Na opening, K open 2) Na open, K closed 3) Na open, K closing 4) Na closed, K closed 5) Na closing, K openSending a signal: Action Potentials ▶ 3 ions: Na, K, (Cl important for inhibitory neurotransmitters) ▶ Ion Channels – resting potential maintained by Na/K pump and leak K channels ▶ Action Potential due to voltage sensitive Na and K channels ▶ Nernst Equation describes the measurable electrical difference across the membrane these ions make (do not learn it) ▶ Saltatory conduction – faster with myelin because you can ‘skip’ across (A-delta vs C fibres)Sending a signal: Neuro Transmission Q: Which ion is required to enter the presynaptic bouton to initiate exocytosis of neurotransmitters from presynaptic vesicles into the synaptic cleft? A: 1) Calcium 2) Potassium 3) Sodium 4) Cholride 5) PhosphateSending a signal: Neuro Transmission Q: Which ion is required to enter the presynaptic bouton to initiate exocytosis of neurotransmitters from presynaptic vesicles into the synaptic cleft? A: 1) Calcium 2) Potassium 3) Sodium 4) Cholride 5) Phosphate Sending a signal: Neuro Transmission 1. Docking - vesicle binds to membrane, before AP invades terminal 2. Action potential invades the presynaptic terminal 3. Membrane depolarisation occurs 4. Voltage-gated calcium channels open 5. Increase in calcium promotes vesicle fusion 6. Exocytosis - Vesicles release neurotransmitters into the synaptic cleft via snare proteins *Botulinum Toxin* 7. Endocytosis - new vesicle membrane “pinched” off & reuptake of neurotransmitter/degradation products 8. Loading - new vesicle is filled with neurotransmitter 2+ 2+ 2+ 2+Neurotransmitters & information encoding ▶ Excitatory - leads to +ve Postsynaptic membrane potential - Glutamate, serotonin, Ach, Noradrenaline ▶ Inhibitory - leads to -ve Postsynaptic membrane potential - GABA, Glycine ▶ Ionotropic (fast – receptor is an ion channel) vs Metabotropic (slow – receptor is G protein coupled to ion channel/secondary messenger) ▶ Autonomic Pathways are commonly asked about ▶ Summation and encoding - Lots of excitatory can push next neuron over the threshold and cause one or more APs - Inhibitory can decrease AP frequency but depends where along a dendrite it the synapse is. -Resultant AP pattern/frequency is what ultimately carries information Control of Movement ▶ CNS - Brain & Spinal cord (Upper Motor Neurons) ▶ PNS – eg Musculocutaneous n. (Lower motor Neurons) ▶ NMJ ▶ Effector - (eg Biceps Brachii)Excitation, Contraction & Reflexes Q: What in a skeletal myocyte conducts the membrane depolarisation from the sarcolemma to the terminal cisternae of the sarcoplasmic reticulum to facilitate calcium release to initiate muscle contraction? A: 1) Z Disc 2) T-Tubules 3) Troponin 4) Tropomyosin 5) Actin filamentsExcitation, Contraction & Reflexes Q: What in a skeletal myocyte conducts the membrane depolarisation from the sarcolemma to the terminal cisternae of the sarcoplasmic reticulum to facilitate calcium release to initiate muscle contraction? A: 1) Z Disc 2) T-Tubules 3) Troponin 4) Tropomyosin 5) Actin filamentsMuscle Contraction ▶ Action potential down peripheral nerve via alpha motor neuron ▶ Acetylcholine release at motor end plate via exocytosis ▶ Stimulation of Ach Receptor ion channel allows Na in causing depolarisation of sarcoplasm ▶ Depolarisation propagated down T-Tubules ▶ Dihydropyridine Calcium Channel and Ryanodine Receptor type 1 convert the depolarisation in the t-tubule to calcium release from the terminal cisternae of the sarcoplasmic reticulum ▶ Therefore Calcium is released from SR into sarcoplasm ▶ Calcium required for actin and myosin to interact and cause contraction – sliding filament theory ▶ Myosin head moves to its starting high-energy ‘cocked’ configuration Muscle Contraction (ATP is hydrolysed leaving ADP+Pi bound) like cocking a gun ready to fire ▶ Ca2+ binds to troponin complex (Troponin T, C & I) which induces a conformational change, moving tropomyosin out the way, allowing myosin to bind for the power stroke & Repeat ▶ Power stroke: myosin releases bound ADP + Pi, causing the head to move and pull on the actin filament ▶ ATP binds, cross-bridges break and myosin head moves to its low energy configuration (unbound + uncocked) ▶ Myosin head hydrolyses ATP leaving ADP+Pi bound and moves back to its starting high-energy ‘cocked’ configurationReflexes ▶ Q: In regards to the flexor muscle, which of these statements the correct order of information flow in the Patellar Myotatic (stretch) reflex arc? ⇧ ▶ A: 1) Muscle spindle fibre, efferent sensory neuron, ⇩afferent motor neuron, flexor muscle relaxation 2) Muscle spindle fibre, efferent sensory neuron, ⇧ efferent motor neuron, flexor muscle contraction 3) Muscle spindle fibre, afferent sensory neuron, interneuron, ⇩efferent motor neuron, flexor muscle relaxation 4) Muscle spindle fibre, afferent sensory neuron, interneuron, ⇧ efferent motor neuron, flexor muscle contraction 5) Muscle spindle fibre, afferent sensory neuron, ⇩efferent motor neuron, flexor muscle relaxationReflexes ▶ Q: In regards to the flexor muscle, which of these statements the correct order of information flow in the Patellar Myotatic (stretch) reflex arc? ⇧ ▶ A: 1) Muscle spindle fibre, efferent sensory neuron, ⇩afferent motor neuron, flexor muscle relaxation 2) Muscle spindle fibre, efferent sensory neuron, ⇧ efferent motor neuron, flexor muscle contraction 3) Muscle spindle fibre, afferent sensory neuron, interneuron, ⇩efferent motor neuron, flexor muscle relaxation 4) Muscle spindle fibre, afferent sensory neuron, interneuron, ⇧ efferent motor neuron, flexor muscle contraction 5) Muscle spindle fibre, afferent sensory neuron, ⇩efferent motor neuron, flexor muscle relaxationReflexes ▶ Definition: An involuntary, nearly instantaneous movement in response to a stimulus (does not require the brain) ▶ Myotatic (stretch) Reflex: eg: patellar, biceps, triceps, achilles ▶ Clinically important to testReflexes – Crossed Extensor ▶Response to mechanical stimulus ▶Allows for coordinated movement so you don’t fall over due to one reflex ▶Complicated compared to Myotatic but follows the same prinicplesReflexes ▶ Turn head to the right eyes go left ▶ Semicircular canals -> CNVIII Nucleus -> CNVI & CNIII (& CNIV in up/down) -> ocular muscles ▶ Split into 2 then focus one eye at a time ▶ Turn head to the right eyes go left Reflexes ▶ Semicircular canals -> CNVIII Nucleus -> CNIII & CNVI (& CNIV in up/down) -> ocular muscles ▶ Here: the eyes sort themselves out becuase otherwise you’d never see anything very well. The vestibular system just stimulates this.Neuromuscular Disorders ▶ Q: A 24 y/o female presents to her GP with a concerning loss of power in her left hand getting progressively worse over the last two weeks. She was seen in secondary care and given a course of corticosteroids. Her symptoms improved. Which one of the following factors was most important in making MS a more likely diagnosis than ALS? A: 1) Age 2) Sex 3) Affecting the left hand only 4) No sensory deficit 5) Responded to CorticosteroidsNeuromuscular Disorders ▶ Q: A 24 y/o female presents to her GP with a concerning loss of power in her left hand getting progressively worse over the last two weeks. She was seen in secondary care and given a course of corticosteroids. Her symptoms improved. Which one of the following factors was most important in making MS a more likely diagnosis than ALS? A: 1) Age 2) Sex 3) Affecting the left hand only 4) No sensory deficit 5) Responded to CorticosteroidsALS – Amyotrophic Lateral Sclerosis ▶ Degenerative disease of all motor neurones (upper+lower) ▶ Inability to initiate and control voluntary movements. Starts in 20s & 30s with weakness peripherally and eventually leads to inability to speak, eat, move and, finally, breathe ▶ Does not affect cognition ▶ No known cure – life expectancy 2-5y from diagnosis ▶ Unknown eitiology but involves abnormal protein folding & aggregation leads to oxidative stress and cell death. Environmental and genetic (eg. SOD1, C9orf72) factors. ▶ Main treatment strategy is symptom management: - physical, occupational, speech & respiratory therapies - exercise in moderation - hot sauna/steam rooms to relax muscles • Riluzole/Rilutek - 1st drug to prolong survival (by 2-3 months)MS – Multiple Sclerosis ▶ Demylinating disease that can effect any part of the CNS ▶ Presents (normally) in the 20s & 30s, associated with females and being further from the equator (UV/Vitamin D related?) ▶ Wide range of symotoms blurred vision, uncontrolled voluntary movement, loss of sensation & balance. Common cause of monocular blindness due to optic neuritis. ▶ 3 flavours: Clinically isolated syndrome (CIS) - first episode that causes inflammation & damage to nerves (myelin) (Demyelinating) Relapsing-remitting MS (RRMS) - follows a predictable pattern where symptoms worsen and then improve Secondary-progressive MS (SPMS) - RRMS can develop into a more aggressive and progressive form of the disease if left untreatedMS – Multiple Sclerosis ▶ formation of lesions in the CNS (called plaques) where there is inflammation due to autoimmune response causing destruction of myelin ▶ No cure, symptom management: Managing relapses (avoiding nerve damage due to inflammation) - corticosteroids reduce inflammation - plasmapheresis (plasma exchange) Disease modifying treatments (DMTs) - variety of approved drugs available - Betaseron, Avonex, Copaxone…. - all drugs reduce relapses & inflammation Rehabilitation - exercise programme to address physical challenges associated with MS Psychosocial support - chronic, debilitating disease can affect mental health, support groups provide support structureBody in Motion: Clinical Pharmacology By Dan SandlerPain Pathways ▶ Q: At which point in the pain pathway do afferent second order sensory neurons decussate? ▶ As: 1) In the Peripheral nerve 2) In the Spinal cord 3) In the Medulla Oblongata 4) In the Thalamus 5) In the CortexPain Pathways ▶ Q: At which point in the pain pathway do afferent second order sensory neurons decussate? ▶ As: 1) In the Peripheral nerve 2) In the Spinal cord 3) In the Medulla Oblongata 4) In the Thalamus 5) In the Cortex Pain Pathways ▶ Pain is a distressing sensation that is associated with with actual or potential tissue damage, and is often coupled with a strong emotional response. ▶ Pain can be useful as seen when pain sensation is lost in SEPA or diabetic neuropathy and end up damaging themselves unknowingly leading to further damage. It can also be pointless and debilitating such as in Complex Regional Pain Syndrome or any chronic pain (eg unexplained back pain is a huge burden on GPs). Types of Pain: ▶ Nociceptive – A-delta (fast) + C fibres (slow) ▶ Neuropathic – Neuronal injury from surgery, trauma or disease Allodynia – Non-painful stimuli become interpreted as painful Hyperalgesia – Painful stimuli are more painful than they should be ▶ Inflammatory - Chemical sensitisation from: prostaglandins (PLA2 releases arachidonic acid that gets converted to inflammatory prostaglandins by COX1); 5HT; bradykinin; histamine; DAMPS (ATP, NO); H+ etc. Pain Pathways ▶ First stage: pain sensing by nociceptors ▶ Second stage: nociceptive stimuli are transmitted to the dorsal horn of the spinal cord via afferent neurons ▶ Third stage: transmission to the brain via ascending tracts in the spinal cord. Decussation (crossing) of the second-order neuron to ascend up the spinothalamic tract, through the medulla oblongata, to the third-order neuron in the thalamus. The dorsal horn synapse can be inhibited or amplified by local spinal circuits and descending tracts from higher brain centres. ▶ Final stage: transmission of the signal from the thalamus to the somatosensory cortex where pain is perceived. There are also connections from the thalamus to the prefrontal cortex where a complex cognitive and motor response can be coordinated, and to the limbic system which is responsible for the affective or emotional experience of pain. Dorsal Horn Synapse ▶ Site of modulation and reflexes (eg crossed extensor reflex) ▶ Excitatory to second order: - Glutamate via NMDA + AMPA Receptors - Substance P (+CGRP) at Neurokinin A Receptor ▶ Inhibitory to second order: -General: Beta-Endogenous Morphine (Endorphin) & Enkephalins at GPC Opioid receptors (mu, delta, kappa) inhibit by blocking presynaptic Ca2+ channels -Local: GABA, Glycine, cannabinoids -Descending: 5HT, NA ▶ Gate Control Theory of Pain: -If you’re feeling something else you won’t notice pain. Eg, you’ve been on the floor with a broken leg for 30 mins, there’s now a deadly spider crawling on your leg…which one is more important in the next 10 seconds? Brain/spinal reflex modulate cognition of pain, dorsal horn acts as a ‘gate’ influenced by mood and local factors etc.Pain Medication ▶ Analgesics: - Paracetamol, Opioids ▶ Anti-inflammatories: - NSAIDS (COX inhibitors), Corticosteroids ▶ Anti-Neuropathics: - Gabapentinoids, Anti-epileptics, Certain Antidepressents Inflammation (Galen) ▶ Clinically:Calor, Heat Rubor, Redness Tumor, Swelling Dolor, Pain (Functio Leesa)(LoF) Aulus Cornelius Celsus Inflammation ▶ Inflammation increases blood flow and capillary leakiness leading to these signs. Inflammatory pain comes from the release of chemicals that sensitise nociceptors. ▶ Macrophages recognise DAMPS (DNA, ATP) or PAMPS (LPS) using TLR and release various mediators: eicosanoids, chemokines, cytokines (TNF-alpha), NO. ▶ Mast cells degranulate releasing: Histamine, bradykinin, eicosanoids ▶ Neutrophils extravasate by rolling along the vessel wall and using selectins and integrins that bind to ICAM-1 to leave the vessel ▶ Lymphocytes leave the vessel too and interact with APCs to generate specific immune responses both T-cell and antibody mediatedPathways ▶ Q: Decrease production of which molecule causes the antiplatelet action of Aspirin? ▶ As: 1) PGE2 2) Bradykinin 3) Leukotrienes 4) PGI2 5) Thromboxane A2Pathways ▶ Q: Decrease production of which molecule causes the antiplatelet action of Aspirin? ▶ As: 1) PGE2 2) Bradykinin 3) Leukotrienes 4) PGI2 5) Thromboxane A2Pathways Arachidonic Pathway: ▶ Is converted to proinflammatory prostaglandins as well as beneficial housekeeping prostaglandins that protect the kidneys and stomach ▶ COX Inhibited by NSAIDS: Aspirin, Ibuprofen, Naproxen, Celecoxib, Diclofenac ▶ Corticosteroids decrease PLA2 activity but lots of side effects ▶ Montelukast is a LRA so can affect part of this pathway without so many side effects – useful in asthma ▶ COX produces Thromboxane A2 – a platelet activator – which is why we give 300mg aspirin as an antiplatelet in acute MI etc.Pathways Coagulation Cascade ▶ Extrinsic pathway activated by cells not normally in the vascular space so normally the vessel wall has been compromised ▶ Intrinsic activated by endothelial damage but also acts as amplification loop as Thrombin activates Factor XI ▶ Kept in regulation by protein S and protein C which are also activated by Thrombin as a self regulation mechanism. Antithrombin III also present. ▶ Converts Fibrinogen to Fibrin to cover defects in combination with platelets ▶ Over activation can lead to bleeding due to consumption coagulopathy eg. DIC, TTPPathways Complement ▶ 3 initiation pathways: Mannose binding lectin or C1q binds molecular patterns on bacteria, C1q also binds to antibodies on the surface if present, leading to a series of events that creates a C3 convertase generating C3a &C3b ▶ The alternative pathway involves spontaneous cleavage of C3 to C3a & C3b ▶ All pathways lead to C3b bound to a surface (can be on own cells too) ▶ C3b acts as an opsin on cell surfaces ▶ C3b also binds C3 convertase to make C5 convertase forming C5a & C5b ▶ C5b associates with C6,7,8 to form an anchor complex that multiple C9 units can associate with and form a pore in the cell membrane – this is the MAC which lyses cel10-165b6789 ▶ C5a>C3b are very strong chemoattractantsMedications ▶ Q: For which of these medication overdoses would you treat with N-Acetylcysteine? ▶ As: 1) Ibuprofen 2) Paracetamol 3) Morphine 4) Prednisolone 5) WarfarinMedications ▶ Q: For which of these medication overdoses would you treat with N-Acetylcysteine? ▶ As: 1) Ibuprofen 2) Paracetamol 3) Morphine 4) Prednisolone 5) WarfarinSpecific Analgesics - Paracetamol ▶ Para-acetylaminophenol (paracetamol/acetaminophen) ▶ Simple analgesic - MOA uncertain but thought to act centrally either via COX or serotonin in descending pathways ▶ Antipyrexial but also an analgesic ▶ Metabolised by conjugation but also by CYP2E1 into NAPQI so ethanol can prevent toxicity but so can glutathione and N-Aceytlcysteine (chronic alcohol abuse might reduce capacity for paracetamol but the evidence isn’t great) ▶ 500mg-1g every 4-6h up to 4g per day ▶ Relatively few adverse effects other than hepatotoxicity when taken as a deliberate overdose or accidental like in co-codamol abuse (Lean trend) when too much paracetamol overwhelms the normal metabolism mechanism forcing CYP2E1 degradation and formation of NAPQI that depletes glutathione and causes hepatocellular necrosisSpecific Analgesics - Opioids ▶ Endogenous: Beta-endorphin, enkephalins, dynorphins ▶ Weak opioids: codeine, dihydrocodeine ▶ Strong opioids: Morphine, diamorphine, fentanyl, carfentanyl etc. ▶ Act via GPCR (mu, kappa, delta) in CNS and PNS to inhibit presynaptic Ca2+ channels and increase K+ capacitance in post synaptic to lower resting potential ▶ Indicated for acute severe pain eg MI, fractures ▶ 5-10mg IV slowly ▶ Can cause respiratory depression and death ▶ Other adverse effects include drowsiness, constipation, N&V (should be co-prescribed antiemetic), hypotension, urinary retention ▶ Many drug interactions – be very aware of alcohol and benzos as well as neuro/psych drugs ▶ Monitor for dependency and watch for drug seeking behaviourSpecific Analgesics/anti-inflammatory - NSAIDs ▶ Started with willow tree bark containing salicin, then aspirin was made ▶ Main ones: Aspirin, Ibuprofen, Naproxen, Diclofenac, Celecoxib ▶ Indicated for inflammatory pain and MSK: RA, OA, Back pain etc. ▶ Aspirin also used in CV events eg. Stroke/MI due to antiplatelet activity from decreased thromboxane A2 – 300mg stat dose PO. ▶ Cause upper GI ulcers due to decrease housekeeping prostaglandins - particularly bad with GCs too as that PLA2+COX inhibition leaving basically no prostaglandins to protect from ulcers ▶ Can protect with PPIs but further kidney problems with this ▶ Celecoxib less GI sensitive as COX2 specific ▶ Avoid in pregnancy – patent ductus and labour issues. ▶ Asthma can be exacerbated due to overflow from COX pathway to LOX pathway, increasing leukotriene production ▶ Ibuprofen: 200-400mg tds PO Specific Anti-inflammatory-Corticosteroids ▶ Produced in the adrenal cortex and raise blood glucose – Glucocorticoids ▶ Steroid hormones with classic genomic (slow powerful) effects via nuclear receptors and newly appreciated non-genomic (quick weaker) effects ▶ VERY powerful drugs – broad immunosuppressive properties with anti- inflammatory effects too – Loads of indications (asthma, rheumatic diseases, COPD, vasculitis) ▶ Cautions: Infection, CHF, Osteoporosis, diabetes, HTN, latent TB etc. ▶ Lots of doses and preparations that reflect their varied use. Commonly inhaled for asthma/COPD and given PO. Physiological diurnal pattern can be matched if given as a course eg 20mg in the morning, 10mg at night. ▶ If given long term in high dose: iatrogenic Cushing’s, GC induced diabetes, skin thinning, infection risk, HTN, peptic ulcer, weight gain, osteoporosis, anxiety, myopathy, adrenal suppression ▶ Should take more if patient develops intercurrent illness to avoid Addisonian Crisis due to adrenal surppression ▶ Interactions include hypokalaemic drugs eg thiazides, live vaccines (BCG)Body in Motion: Locomotor By Dan SandlerPain Pathways ▶ Q: The major protein constituent of cortical bone is formed from the following repeat unit [n-X-Y] . What is A? ▶ A: 1) Glutamine 2) Methionine 3) Ascorbic Acid 4) Glycine 5) ProlineConnective Tissue ▶ Q: The major protein constituent of cortical bone is formed from the following repeat unit nA-X-Y] . What is A? ▶ A: 1) Glutamine 2) Methionine 3) Ascorbic Acid 4) Glycine 5) ProlineConnective Tissue ▶ Epithelia, Neural, Muscular, Connective ▶ Connective tissues – more about the non-cellular function ▶ = Cells + ECM + Ground substance + interstitial fluid ▶ Resident cells – fibroblast, osteocytes, chondrocytes – collagen & PGs & enzymes ▶ Immigrant cells –cells derived from haemopoietic cells lines eg macrophages, lymphocytes, mast cells Extracellular Matrix (ECM) ▶ Major Components: Collagens, Elastins, (PGs) ▶ Collagens are a very diverse group of proteins that combine in different permutations of alpha chains to achieve desired structural outcome ▶ Bone - contains collagen types I, V, XII, XIV Cartilage - contains collagen types II, VII, IX, X, XI Skin - contains collagen types I, II, III, V, XI BM – Type IV ▶ General sequence: [Gly-n-Y] repeating unit X/Y are often 3/4-hydroxyproline but can be others ▶ Elastin provides elasticity as shown by exhalation Lungs very high in elastin which is why alpha1-antitrypsin inhibition by cigarette smoke (peroxynitrite) leads to uncontrolled loss of elastin and alveoli causing emphysema (COPD) ▶ Proteoglycans are big molecules that draw in water and form the ground substance, a kind of gel which has properties dependant on the ratio of various PGs for example in cartilage you want shock absorbing, low friction properties: glycosaminoglycan (chondroitin sulphate) + core protein backbone = aggrecan multiple aggrecans + hyaluronic acid backbone = major PG in cartilageBones ▶ Q: Osteoprotegrin (OPG) binds to a signalling molecule attached to which of the following cell types to inhibit bone resorption ▶ A: 1) Osteoblast 2) Osteoclast 3) Chondrocyte 4) Osteocyte 5) Thyroid C-cellBones ▶ Q: Osteoprotegrin (OPG) binds to a signalling molecule attached to which of the following cell types to inhibit bone resorption ▶ A: 1) Osteoblast 2) Osteoclast 3) Chondrocyte 4) Osteocyte 5) Thyroid C-cellBones ▶ Bones: ~20% Collagen (Type I), 70% Salts (Ca, Mg, Al…), 10% Water (PG+Cells+Salts) ▶ Collagen + Hydroxyapatite = Reinforced Concrete (compressive+shear forces) ▶ Together with cartilage from the skeleton and joint surfaces ▶ Cortical (80%) vs Cancellous (Trabecular) (20%) ▶ Contain Bone Marrow which is Erythropoietic and produces RBCs, WBCs, Platelets ▶ Contain Osteogenic precursor cells, Osteoblasts, Osteocytes (15-20% of OBs), Osteoclasts ▶ Formed by Intramembranous Ossification and Endochondral Ossification ▶ Long bones: Epiphysis, (Physis), Metaphysis, Diaphysis, Metaphysis, (Physis), EpiphysisBone Development ▶ Intramembranous vs Endochondral Ossification ▶ Intramembranous (IO): 1) Mesenchymal stem cells proliferate and differentiate into osteoblasts in fibrous tissue 2) (Woven) Osteoid put down, calcified and Osteoblasts trapped to form Osteocytes 3) Trabecular matrix forms around the blood vessels and periosteum forms 4) Cortical bone forms under periosteum, blood vessels condense into red marrow - Flat bones in foetal development, Reduced fracture healing ▶ Endochondral (EO): 1) Starts with cartilage scaffold with its own perichondrium which becomes periosteum 2) In the diaphysis periosteal collar forms and chondrocytes in nearby chondrocytes enlarge and die as they deposit matrix, their surrounding cartilage then disintegrates 3) Blood vessels move in the gaps and bring osteogenic cells 4) Ossification front forms with cartilage forming at the front and dying at the back then ossifying – leads to growth (SOCs form) ▶ Eventually ossification catches up to the new cartilage formation and the bone is fully ossified and no longer grows.Bone Remodelling ▶ Adapting to stresses and Calcium homeostasis – 14-18% of bone replaced per year ▶ 4 Stages: Quiescence; Resorption; Reversal; Formation ▶ Quiescence is resting (90% of bone) ▶ Activation from PTH, other Hormones, mechanical load triggers turnover Osteoblasts release RANK-L and OPG in response that activates Osteoclasts ▶ Resorption: Osteoclasts bind to bone surface and form ruffled border releasing HCl and proteases that degrade bone. ▶ Reversal: Osteoprogenitors go to the resorption pit and are stimulated by osteoclasts to become osteoblasts. Osteoclasts then apoptose. ▶ Formation: The new Osteoblasts now deposit osteoid and mineralise it ▶ Resorption controlled by many factors: PTH Oestrogen Calcitonin ▶ Formation controlled by many factors: PTH Oestrogen VitD Osteocalcin HGH PPi FGF23 OsteopontinFracture Healing ▶ Primary Healing in surgical fixation with no movement – IO Cutting cone of osteoclasts extends osteons leading to healing ▶ Secondary Healing – minor movement - Callus formation with cartilage – EO 1) Haematoma & inflammation/granulation 2) Primary soft callus 3) EO (if strain low) 4) Remodelling (IO type with cutting cones)Calcium Homeostasis ▶ Bones contain 99% of body calcium – Act as a reservoir ▶ Calcium levels are tightly controlled due to how important it is ▶ Major sites for control: Kidneys, Intestines, Bones, (Thyroid), (Liver & Skin)Structural Diseases of the connective tissues ▶ Q: Which of these structural diseases is associated with mutations in Fibrillin-1? ▶ A: 1) Osteogenesis Imperfecta Type 1 2) Osteogenesis Imperfecta Type 3 3) Scurvy 4) Marfan Syndrome 5) Ehlers-Danlos Type IVStructural Diseases of the connective tissues ▶ Q: Which of these structural diseases is associated with mutations in Fibrillin-1? ▶ A: 1) Osteogenesis Imperfecta Type 1 2) Osteogenesis Imperfecta Type 3 3) Scurvy 4) Marfan Syndrome 5) Ehlers-Danlos Type IVOsteogenesis Imperfecta ▶ Mutation in Col1A1&Col1A2 genes (Types 1-4) ▶ Amount (1) or Structural (2) defects ▶ Type 1 less severe than Type 2 - “Brittle Bones” vs lethal ▶ Type 1 associated with blue sclera and early fractures ▶ Type 2 associated with intrauterine fractures, perinatal death or death perinatally from respiratory compromiseScurvy ▶ Vitamin C deficiency (Ascorbic Acid) ▶ Causes decreased Proline Hydroxylation – no collagen [Gly-X-Y] X&Y both hydroxylated proline. ▶ Symptoms:Poor wound healing, hair and tooth loss, capillary weakness (bruises), glossitis, stunted growth ▶ At Risk: Food poverty (adults and children), Tea&Toast diet of the elderly, Eating disordersEhlers-Danlos ▶ Currently 13 Types each with a specific mutation and collection of symptoms ▶ Sometimes a gene mutation isn’t found that fits these types – clinical diagnosis including FHx Symptoms: Fragile skin which can split easily with minimal trauma. This leads to significant scarring usually starting from childhood. The common sites for scars are on the knees, elbows, shins, forehead and chin. Scars “like tissue paper”. Stretchy skin, often very stretchy! Joint hypermobility, which may cause dislocations or subluxations, and may be associated with chronic joint pain. Easy bruising, which may lead to permanent discolouration and is often visible on the shins. Fragile and extensible tissues can also result in hernias and prolapses Kyphoscoliosis/ScoliosisMarfan Syndrome ▶ Fibrillin-1 Mutations (~1300 known) ▶ Autosomal Dominant ▶ Fibrillin-1 is very important for the microtubules that support elastin molecules These microfibrils also sequester TGF-Beta ▶ Together these two issues explain the symptoms of Marfan’s: Increased linear bone growth (arachnodactyly) - Thumb/Finger/Wrist tests + Tall Joint hypermobility Aortic dissection/rupture Pectus excavatum Obstructive lung disease, pneumothorax Craniofacial abnormalities Lens dislocationLimping Child ▶ Q: A 14 year old boy is brought into A&E by his mother due to her son complaining of right hip pain over the last few days and has now developed a limp. On examination you notice the boy is overweight and check his BMI which you calculate to be 34. His right leg is externally rotated compared to the left. He is systemically well with no fever. Which of the following is the most likely diagnosis? ▶ A: 1) Perthe’s 2) SUFE 3) Developmental Dysplasia of the Hip 4) Septic arthritis 5) GoutLimping Child ▶ Q: A 14 year old boy is brought into A&E by his mother due to her son complaining of right hip pain over the last few days and has now developed a limp. On examination you notice the boy is overweight and check his BMI which you calculate to be 34. His right leg is externally rotated compared to the left. He is systemically well with no fever. Which of the following is the most likely diagnosis? ▶ A: 1) Perthe’s 2) SUFE 3) Developmental Dysplasia of the Hip 4) Septic arthritis 5) Gout Paediatric Hip Problems – Limping Kids ▶ DDH – Female predisposition Congenital - shouldn’t be missed as all babies checked Barlow Bad, Ortolani Good Treat with Harness or Cast in reduced position ▶ Perthes – AVN of femoral head Male predisposition 4-8 yo 60% recover without treatment – surgery to remodel hip can be done ▶ SUFE – slipped upper femoral epiphysis (external rotation) Male predisposition 13-16 yo Obese / Very tall and slender (rapid growth especially) Can be bilateral (40%) Treat with screw fixation ▶ Red Flags: Infection, back pain (discitis), Malignancy Older age ▶ Osteoporosis: After menopause decreased Oestrogen causes increased bone resorption Low energy fractures (falls) ▶ RA: Autoimmune disease against citrullinated proteins Morning Stiffness >30mins Hands are classic site (ulnar deviation) spares DIPJs can affect large joints (40%) Rh factor, CCP, Xray (narrow space, erosions) (?NSAIDs+PPI) + Short term GCs + Long term Methotrexate (ESR+CRP+DAS28) (Can’t use Mtx if pregnant, also can cause pulmonary fibrosis) ▶ OA: Wear & repair Morning stiffness <30mins Any but Spine, DIPJs, Knee, Hip Xray (narrow space, osteophytes, bone sclerosis + cysts) Obesity, Age, Genetics, Injury/Damage Analgesia (NSAIDs+PPI), SurgeryFeedback Please take a minute now before you leave to fill in a quick feedback form: Feedback Link AIM Facebook Page ▶ Give our Facebook page a like for updates and opportunities,just search @AIMEdinburgh Thank you for coming! ▶ If you have any more questions, feel free to email me at s1701952@sms.ed.ac.uk, or email accessibilityinmedicine@gmail.com