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Case 1 SBA based teaching  TJ Pinchemain  All the notes you’ll ever need: https://drive.google.com/drive/folders/1le00y4yoJTEVzca3esYY6za7TUcRUVYL?usp=sharingRules & disclaimers • Please turn off camera and microphone • Ask questions in the chat, facilitator or tutor will get to it • Please give feedback to the tutors at the end – link at the end • Zoom will be recorded- by participating, you are giving permission to be recorded My rules: 1. Please send me questions – I’ll answer them when I’ve finished talking 2. Laugh at my memesLearning outcomes • Drugs – Know what the COX domain is and the drugs acting on it • Know the key features of inflammation • Understand basic principles of inflammation • Understand bone fractures and osteoporosis • Understand how wounds heal • Understand pain management and the pain ladder Drugs Inflammatio Drink milk and you’ll be strong! n One of the most important things in this case! SBA 1 Dylan, a 21 year old gentleman suffers a small cut on his foot. Two days later the cut is red and hot to the touch, there is also fluid leaking out of the wound. He also takes regular paracetamol. Which of the five cardinal signs of inflammation would you expect to present next? A – Heat B – Loss of function C – Painful D – Redness E – Swelling SBA 1 Dylan, a 21 year old gentleman suffers a small cut on his foot. Two days later the cut is red and hot to the touch, there is also fluid leaking out of the wound. He also takes regular paracetamol. Which of the five cardinal signs of inflammation would you expect to present next? A – Heat B – Loss of function C – Painful D – Redness E – Swelling Inflammation The 5 signs are: Cause 1. Redness 2. Heat Cell death or injury by external 3. Swelling stimuli by: 1. Oxygen deprivation 4. Pain 2. Physical agents 5. Loss of function 3. Infections agents 4. Immune reaction This cell death can be necrosis or apoptosis Vascular changes Occur to protect tissues: • Transient vasoconstriction followed by vasodilation (histamine, nitric oxide) • Increased permeability of vessels – protein leakage • Stasis (stoppage/slowdown in flow of blood) and concentration of RBC • Neutrophil migration Ρεδνεσσ – δυε το βλοοδ λεακινγ ουτ οφ ϖεινσ ανδ χαπιλλαριεσ Ηεατ – δυε το αν ινχρεασεδ τεµπ το κιλλ οφ βαχτερια//τηε ηιγη µεταβολισµ ρατε οφ λψµπηοχψτεσ Σωελλινγ – δυε το τισσυε φλυιδ λεακινγ ουτ οφ χελλσ + βλοοδ Παιν – δυε το ρελεασε οφ ινφλαµµατορψ µεδιατορσ Λοσσ οφ φυνχτιον – ασ αλλ τηε φλυιδ µακεσ ιτ διφφιχυλτ το µοϖε Causes of cell injury Οξψγεν δεπριϖατιον – ηψποξια (λεσσ οξψγεν ρεαχηινγ τισσυεσ) ορ ισχηαεµια (λαχκ οφ βλοοδ συππλψ) Πηψσιχαλ αγεντσ Ινφεχτιουσ αγεντσ − συχη ασ βαχτερια ανδ ϖιρυσεσ) Ιµµυνολογιχ ρεαχτιονσ – σιχκλε χελλ αναεµια Inflammation Is the cellular responses to stress and noxious stimuli Cells can withstand physiologic demands and maintain homeostasis Physiologic stresses and some pathologic stimuli causes cells to adapt: Ηψπερπλασια (ινχρεασε ιν νυµβερ) Ηψπερτροπηψ (ινχρεασε ιν σιζε οφ ινδιϖιδυαλ χελλσ Ατροπηψ (δεχρεασε ιν σιζε ανδ φυνχτιον) Μεταπλασια (χηανγε φροµ ονε χελλ τψπε το ανοτηερ) Types of cell deathThis takes on two different forms: Νεχροσισ – αλωαψσ πατηολογιχ Αποπτοσισ – σερϖεσ µανψ φυνχτιονσ, νοτ νεχεσσαριλψ ασσοχιατεδ ωιτη χελλ ινϕυρψ – α χασχαδε ωιλλ χαυσε τηε χελλ το βρεακ δοων ανδ βε πηαγοχψτοσεδ Vascular changes These occur to protect damaged tissue and include: Τρανσιεντ ϖασοχονστριχτιον φολλοωεδ βψ ϖασοδιλατιον (ηισταµινε, νιτριχ οξιδε) Ινχρεασεδ περµεαβιλιτψ οφ ϖεσσελσ – προτειν λεακαγε Στασισ (στοππαγε/σλοωδοων ιν φλοω οφ βλοοδ) ανδ χονχεντρατιον οφ ΡΒΧ Νευτροπηιλ µιγρατιον The vascular changes occur as the macrophage recognise the DAMPs (damage associated molecular proteins) on the damaged cells, these PRRs on the macrophage stimulate the secretion of cytokines (such as TNF-a (increases permeability of blood vessels) and CXCL8 (brings neutrophils to the damaged site)) which initiate the immune response Cellular changes Λευκοχψτε εξτραϖασατιον ανδ πηαγοχψτοσισ Ιν τηε λυµεν: µιγρατιον, ρολλινγ, αδηεσιον οφ νευτροπηιλσ Τρανσµιγρατιον αχροσσ τηε ενδοτηελιυµ Μιγρατιον τοωαρδσ χηεµοταχτιχ στιµυλυσ This occurs due to phagocytosis of apoptosing cells by macrophages The transmigration occurs due to Selectin being present and allowing neutrophils to attach to the endothelium of cells and enter to the tissues following the gradient of the chemokine (CXCL8) to the damaged areas Immune system and inflammation What happens after detection? Detection occurs in two forms 1. PAMPs and DAMPs 1. PAMPs (pathogens) detected by PRRs on 2. DAMPs (damaged/necrotic tissue) macrophages 2. PRRs stimulate cytokine release and signal phagocytes 3. Cytokines released inc permeability of surrounding Cytokinv sselsns 1. Cellular differentiation 2. Cellular proliferation 3. Leukocyte mobilization 4. Cellular Activation 5. Cell death 6. Cell survival What does the immune system do to detect and initiate inflammation? Μιχροβεσ συχη ασ ϖιρυσ, βαχτερια, φυνγι ανδ παρασιτεσ αρε δετεχτεδ An inflammatory response is produced when pathogen associated molecular patterns (PAMPs) on pathogens are detected This results in an inflammatory response to eliminate the infectious threat (can lead to an adaptive immune response) Δαµαγεδ/νεχροτιχ τισσυε The immune system recognises structures (DAMPs) – damage associated molecular patterns – released by necrotic cells This results in an inflammatory response to remove necrotic cells and debris (doesn’t lead to adaptive immune response) Pathogen recognition by macrophages initiates inflammatory responses The macrophage recognises the PAMP on cells by action of toll like receptors (pattern recognition receptors (PRRs) This activates phagocytosis and digestions The PRRs stimulate the secretion of cytokine, which initiate inflammatory and immune responses Cytokines from macrophages A macrophage will generally secrete TNF-a and CXCL8 in response to PAMPs Communication within cells The cytokines and chemokines released by the phagocyte increases the permeability of the surrounding blood vessels Tissue fluid, white blood cells and antibodies then enter into the tissues What are cytokines?The key molecules mediating communication across the immune system The majority are soluble, so can diffuse away from infected cells The function of cytokines Χελλυλαρ διφφερεντιατιον Differentiation of white blood cell subsets from bone marrow stem cells Χελλυλαρ Προλιφερατιον Clonal expansion of T-cells during adaptive immune responses Λευκοχψτε µοβιλισατιον Chemotaxis of white blood cells to sites of infection Χελλυλαρ Αχτιϖατιον Turning normally inactive white blood cells into ‘battle ready’ cells Χελλ δεατη Removal of clonally expanded T-cells at the end of immune responses Χελλ συρϖιϖαλ Preservation of memory T-cells at the end of immune responses The action of cytokines During inflammatory responses multiple cytokines are expressed at the same time, however the specific activity is controlled: Τηεψ βινδ το σπεχιφιχ ρεχεπτορσ Τηε εξπρεσσιον οφ εαχη χψτοκινε ρεχεπτορ ισ ρεγυλατεδ, αλτερινγ τηε ρεσπονσιϖενεσσ το χψτοκινεσ Χψτοκινε σεχρετιον ισ βριεφ ανδ σελφ−λιµιτεδ Μανψ χψτοκινεσ ηαϖε α λιµιτεδ ρανγε οφ αχτιϖιτψ; τψπιχαλλψ ιν τηε λοχαλ χελλυλαρ ενϖιρονµεντ Most cytokines signal via autocrine or paracrine fashion to local cells But some are stable and potent enough to signal in an endocrine fashion Types of cytokines TNF-alpha Cytokines and chemokines Induces the acute stage released by the phagocyte response by upregulating the increases the permeability of the complement system surrounding blood vessels Encourages clotting of small Tissue fluid, WBC and antibodies enter damaged blood vessels Increases vascular permeability CXCL8 (IL-8) 1. Tethers to surfaces and ECM 2. IL-8 acts on receptors of neutrophils to activate adhesion molecules 3. Promotes tight binding of cells to the blood vessel 4. Neutrophils follow the gradient of tethered IL-8 in the sub-endothelial space IL-8 (CXCL8) – movement chemokine (family of cytokines) IL-8 tethers to the surfaces and extracellular matrix Interaction of IL-8 with IL-8 receptors on blood neutrophils activates adhesion molecules, promoting tight binding of cells to the blood vessels ready for migration In the sub-endothelial space, neutrophils follow a gradient of IL-8 tethered to extracellular matrix towards the infected site IL-8 control Neutrophils express receptors for IL8 IL8 expression is induced by other cytokines, or following recognition of PAMPs by Toll-like receptors (TLRs) or PRRs IL-8 in depth Secreted IL-8 (CXCL8) ‘tethers’ to cell surfaces (1) and extracellular matrix (2). Interaction of IL-8 with IL-8 receptors on blood neutrophils activates adhesion molecules (3), promoting tight binding of cells to the blood vessel ready for migration. In the sub-endothelial space, neutrophils follow a gradient of IL-8 tethered to extracellular matrix (2) towards the infected site. In this diagram the blue is the extracellular matrix and the white is the lumen of the blood vessel SBA 1 Franklin has had inflammation of his left hand after a fall on an outstretched hand four months ago. Which of the following cells is indicative of this type of inflammation? A – Eosinophils B – Macrophages C – Mast Cells D – Natural Killer Cells E – Neutrophils Neutrophils Eosinophils Mast Cells Natural Killer cells SBA 1 Franklin has had inflammation of his left hand after a fall on an outstretched hand four months ago. Which of the following cells is indicative of this type of inflammation? A – Eosinophils - immune response to parasites B – Macrophages C – Mast Cells – allergic reaction D – Natural Killer Cells E – Neutrophils - acute inflammation µαχροπηαγεσ αρε φουνδ ιν αλλ τισσυεσ ανδ αρε ρεσπονσιβλε φορ δετεχτινγ πατηογενσ, πηαγοχψτοσινγ τηεµ ανδ ινιτιατινγ ινφλαµµατορψ ρεσπονσεσ Νευτροπηιλσ αρε αλσο ηιγηλψ πηαγοχψτιχ χελλσ ανδ εξιστ ιν ηιγη νυµβερσ ιν τηε βλοοδ στρεαµ βυτ νοτ ιν ηεαλτηψ τισσυεσ. Ηοωεϖερ, νευτροπηιλσ αρε ρεχρυιτεδ το τισσυεσ ιν ηιγη νυµβερσ δυρινγ ινφλαµµατορψ ρεσπονσεσ ωηερε τηεψ κιλλ ανδ χλεαρ πατηογενσ Μαστ χελλσ αρε φουνδ ιν µοστ τισσυεσ ανδ υσε συρφαχε βουνδ αντιβοδιεσ (ΙγΕ) το δετεχτ τηρεατσ ανδ ινιτιατε ινφλαµµατορψ ρεσπονσεσ βψ ρελεασινγ ηισταµινε ανδ οτηερ ινφλαµµατορψ µολεχυλεσ πηαγοχψτοσεδ ανδ σο τηε ιµµυνε σψστεµ υσεσ τηεσε χελλσ το ενχουραγε ϖοµιτινγ, διαρρηοεα, χουγηινγ, σχρατχηινγ ανδ µυχουσ/τεαρ σεχρετιον ιν τηε ηοστ τοε εϕεχτ παρασιτιχ οργανισµσ φροµ τηε βοδψ. Τηισ παρτ οφ τηε ιµµυνε σψστεµ ισ αλσο ρεσπονσιβλε φορ αλλεργιχ δισεασε Νατυραλ Κιλλερ Χελλσ αρε τηε µαιν ιννατε ιµµυνε χελλσ ρεσπονσιβλε φορ δετεχτινγ ανδ ελιµινατινγ ϖιρυσ ινφεχτεδ χελλσ ανδ σοµε χανχερουσ χελλσ Acute vs chronic Acute Chronic Cell of importance – Inflammation of prolonged neutrophil duration (weeks to months), in Any inflammation that occurs which active inflammation, tissue rapidly and stops before three destruction and attempts at repair proceed simultaneously. months Cell of importance – Termination occurs when the macrophage offending agent is eliminated Causes: Mediated by cytokines in 1. Persistent infection response to tissue damage 2. Prolonged exposure to toxic Outcomes: agents 1. Complete resolution 3. Autoimmunity 2. Healing process 3. Chronic inflammation The stimuli that cause cell injury also induce INFLAMMATION in vascularised tissues. Important thing in this sentence is the vascularised as inflammation will only occur in vascularised tissue Aim: to neutralise the offending agent- a protective responseAnd start the process of repair Cell of acute inflame – neutrophil Cell of chronic inflam – macrophages – becomes chronic as cells change What mediates acute inflammation?- chemical factors derived from plasma proteins or cells; produced in response to/ activated by the stimulus that initiates inflammation. Termination: offending agent is eliminated, mediators that have been secreted are broken down, anti-inflammatory mechanisms Outcomes of acute inflam – complete resolution, healing or chronic inflammation Vascular changes transient vasoconstriction followed by vasodilation (histamine, nitric oxide) increased permeability of vessels - protein leakage stasis and concentration of RBCs neutrophil margination Cellular changes Leukocyte extravasation and phagocytosis In the lumen: margination, rolling, adhesion Transmigration across the endothelium Migration towards chemotactic stimulus Χηρονιχ ινφλαµµατιονInflammation of prolonged duration (weeks to months), in which active inflammation, tissue destruction and attempts at repair proceed simultaneously. May follow acute inflammation, but frequently begins insidiously as a low grade, smouldering and often asymptomatic response. Causes of chronic inflammation: 1. Persistent infection 2. Prolonged exposure to potentially toxic agents- exogenous or endogenous 3.Autoimmunity Drugs Bone health Drink milk and you’ll be strong! One of the most important things in this case! SBA 1 Trevor has broken his arm but feels and looks completely fine, so much so that his mother thought that he was faking it. Upon Xray there is a fracture to the bone only without damage to the surrounding tissues or skin. Which type of fracture does Trevor have? A – Closed fracture B – Comminuted fracture C – Fragility D – Open fracture E – Simple fracture Open Closed Comminuted Fragility SBA 1 Trevor has broken his arm but feels and looks completely fine, so much so that his mother thought that he was faking it. Upon Xray there is a fracture to the bone only without damage to the surrounding tissues or skin. Which type of fracture does Trevor have? A – Closed fracture B – Comminuted fracture C – Fragility D – Open fracture E – Simple fracture Warning shot!!! Blood and guts and gore Bone fractures Causes of fractures 1. Single traumatic event 2. Repetitive stress 3. Pathological fracture Bone fractures A fracture is a break in the structural continuity of bone The possible reasons for a fracture are: 1. A single traumatic event – such as falling from a height 2. Repetitive stress (stress fractures) – such as a tumour in the bone 3. Pathological fracture//an abnormal weakness in bone – such as a tumour Οπεν – (ΑΚΑ χοµπουνδ) τηερε ισ αν οπεν ωουνδ ορ βρεακ ιν τηε σκιν νεαρ τηε σιτε οφ τηε βροκεν βονε Χλοσεδ − α βροκεν βονε τηατ δοεσ νοτ πενετρατε τηε σκιν Χοµµινυτεδ − α βρεακ ορ σπλιντερ οφ τηε βονε ιντο µορε τηαν τωο φραγµεντσ Σιµπλε − α φραχτυρε οφ τηε βονε ονλψ, ωιτηουτ δαµαγε το τηε συρρουνδινγ τισσυεσ ορ βρεακινγ οφ τηε σκιν Φραγιλιτψ φραχτυρεσ − φραχτυρεσ τηατ ρεσυλτ φροµ µεχηανιχαλ φορχεσ τηατ ωουλδ νοτ ορδιναριλψ ρεσυλτ ιν φραχτυρε Φραχτυρε δισλοχατιονσ − βοτη φραχτυρε ανδ δισλοχατιον τακε πλαχε σιµυλτανεουσλψ Remodeling Vs Formation Bone Remodeling Bone formation 1. Osteoclasts resorb dead/ 1. Osteoblast cells deposit damaged bone osteoid 2. Osteoblast cells deposit 2. Osteoid is mineralized osteoid There is about 10 says between 3. Osteoid is mineralized deposition and mineralization Basically formation with another step! Bone SBA 1 Trevor receives treatment in the ED from Dr. Charmaine, she helpfully explains the stages of bone repair. However, because she missed this session she forgets at what stage small groups of cartilage cells form. During which stage of bone healing would this occur? A – Callus B – Granulation C - Haematoma D – Inflammation E – Remodelling SBA 1 Trevor receives treatment in the ED from Dr. Charmaine, she helpfully explains the stages of bone repair. However, because she missed this session she forgets at what stage small groups of cartilage cells form. During which stage of bone healing would this occur? A – Callus B – Granulation C - Haematoma D – Inflammation E – Remodelling SBA 1 Trevor’s bone must undergo healing in order for him to function properly. As he broke his bone two weeks ago he is undergoing the repair process. What stage of bone healing is Trevor most likely undergoing? A – Callus B – Granulation C - Haematoma D – Inflammation E – Remodelling SBA 1 Trevor’s bone must undergo healing in order for him to function properly. As he broke his bone two weeks ago he is undergoing the repair process. What stage of bone healing is Trevor most likely undergoing? A – Callus B – Granulation C - Haematoma D – Inflammation E – Remodelling 5 stages of bone healing The 5 stages are: Haematoma 1. Haematoma 2. Inflammation 1. Blood vessel tearing occurs 3. Granulation 2. The fracture is filled with a 4. Callus blood clot 5. Remodeling Inflammation 1. Injury results in acute inflammation 2. Macrophages invade the clot 3. Destruction of pathogens and bone fragments 4. Vascular ingrowth occurs Ηαεµατοµα Blood vessel tearing occurs, resulting in local bleeding Defect between the fracture ends is filled with a blood clot Ινφλαµµατιον The injury results in acute inflammation Macrophages invade the clot and start the destruction Followed by vascular ingrowth 5 stages of bone healing Granulation Callus 1. Granulation capillaries occur 1. Islands of cartilage appear 2. Granulation tissue then replaces 2. Calcium is deposited in the the clot cartilage 3. Small groups of cartilage form 3. Osteoblasts produce a seam within the clot of osteoid across the fracture Remodeling 1. Woven bone is replaced by lamellar bone 2. Excess bone is slowly reabsorbed Γρανυλατιον Vascular ingrowth (granulation capillaries) By day 5 granulation tissue has replaced the clot and extended into the marrow cavity In the granulation tissue small groups of cartilage cells form Χαλλυσ Islands of cartilage appear (especially near the periosteum) The fracture ends are not united by a sleeve of vascularised granulation tissue and cartilage = provisional callus At the end of 1 week the calcium is deposited in the cartilage and osteoblasts start to produce a seam of osteoid across the fracture Ρεµοδελλινγ Woven bone (immature) replaced by lamellar bone (osteoblasts and osteoclasts) Excess bone is slowly reabsorbed Takes year and is often incomplete – why broken bones are not as good as the origional SBA 1 Louise, an 80-year-old female with no children suffers a break to her femur. Upon further inspection she has global skeletal tenderness and suffers from severe kyphosis. What is the most probable cause of her fracture? A – Primary osteoporosis B – Rheumatoid arthritis C – Secondary osteoporosis D - Osteoarthritis E – Osteopeania SBA 1 Louise, an 80-year-old female with no children suffers a break to her femur. Upon further inspection she has global skeletal tenderness and suffers from severe kyphosis. What is the most probable cause of her fracture? A – Primary osteoporosis B – Rheumatoid arthritis C – Secondary osteoporosis D - Osteoarthritis E – Osteopeania Diagnosis Completed using a Osteoporosis bone density scan Signs looking at spine and If the patient is hips shorter than they were Skeletal tenderness Kyphosis Hump Risk factors Unsteady • Female • Being over 50 • No children DEXA scan • Slim Treatment We look at the T-score • Increased T-score is greater than -2.5 then alcohol • Stopping smoking osteoporosis consumption • Increasing Calcium and T-score is between -1 and -2.5 • Smoker vitamin D intake then Osteopaenia • Reducing alcohol intake Types of Osteoporosis Osteoporosis is a medical condition in which the bones become brittle and fragile from loss of tissue Primary – post menopausal or age related Secondary – drug related or comorbidities Diagnosis of Osteoporosis A bone density scan (DEXA) is the standard in diagnosis of osteoporosis, the spine and hip are both measured On the right of the image is a loss of bone density, on the left is a normal bone DEXA scan In a DEXA scan we find the T-score which is an objective score The T-score (standard deviation) is then compared with normal healthy adult in their 20s of the same sex If the T-score is greater than -2.5 SD then osteoporosis If the T-score is between -1 and -2.5 SD then Osteopaenia Osteoporosis risk factors These include: female, being over 50yrs , no children, slim, alcohol and smoking Osteoporosis and OestrogenLow levels of Oestrogen cause an increase in the osteoclast (absorbs):osteoblast (makes) ratio This is because low oestrogen causes apoptosis of osteoblasts, thereby we can’t lay down more bone when the old bone is destroyed Signs of osteoporosis Ιφ τηε πατιεντ ισ σηορτερ τηαν τηεψ ωερε Σκελεταλ τενδερνεσσ Κψπηοσισ Ηυµπ Υνστεαδψ Tests for osteoporosis XR id there is a fracture DEXA Full blood count Bone profile Renal test Osteoporotic fracture NICE - a fragility fracture is caused by a force which would not normally break a bone. (Low energy trauma WHO - low energy trauma causing osteoporotic fracture is equivalent to falling from standing height Osteoporosis predictors Any recent fracture in anyone over 50 should prompt an osteoporosis investigation Strongest predictor of a fragility fracture is any previous factor or a new fracture soon after the 1 Treatment of Osteoporosis Stopping smoking Increasing Calcium and vitamin D intake Reducing alcohol intake Drugs Wound healing I bleed therefore I am Time heals all wounds! It has been said that time heals all wounds SBA 1 Walter cuts himself, and goes to Dr. Charmaine, she explains the process of wound healing and goes into great detail about each phase. However, Walter forgets the stages involved in the proliferative stage. Which process would be found in this stage of wound healing? A – Clotting B – Collagen realignment C – Inflammation D - Phagocytosis E – Wound contraction SBA 1 Walter cuts himself, and goes to Dr. Charmaine, she explains the process of wound healing and goes into great detail about each phase. However, Walter forgets which stage the myofibroblasts are involved in. Which process would this cell type be found in stage of wound healing? A – Clotting B – Collagen realignment C – Inflammation D - Phagocytosis E – Wound contraction Stages of wound healing Processes Scarring 1. Clotting Fibroblasts over-express 2. Inflammation collagen to form a 3. Proliferation collagen matrix 4. Maturation Collagen This cross-links making the matrix a dense scar deposition • Produced by Re-epithelialization fibroblasts Formation of granulation • Increase the Wound contraction tissue allows this to occur strength of the When fibroblasts Migration of keratinocytes wound differentiate into into the wound • Controlled by myofibroblasts These stay under the clot cytokines Myofibroblasts separating the scab from adhere to the ECM the tissue and pull edges closed Clotting Clotting begins when the soft clot has been laid down The intrinsic vs extrinsic pathways are represented on the right It is important to note that the exposed collagen is the intrinsic pathway Thrombin is activated factor II The Fibrin is then laid down over the soft clot to reinforce it Processes involved in healing 1. Clotting 2. Inflammation – dead cells are cleared along with other pathogens 3. Proliferation – during this phase angiogenesis, collagen deposition, granulation tissue formation, epithelialisation and wound contraction occur 4. Maturation – collagen is realigned and cells that are no longer needed undergo apoptosis Re-epithelialization The formation of granulation tissue in an open wound allows reepithelialisation to occur Is accomplished by the migration of epidermal cells (keratinocytes) into the wound As the keratinocytes migrate they move over the granulation tissue but stay under the clot (scab) thereby separating the scab from the tissue Collagen deposition This is produced by fibroblastsImportant as it increases the strength of the wound It is controlled by cytokines, when cytokines such as TNF and IL-1 are released by the PRRs on the macrophage they stimulate fibroblasts to undergo collagen synthesis and deposition When the cytokines are reduced deposition decreases but does not stop Wound contraction Occurs when the fibroblasts have differentiated into myofibroblasts The myofibroblasts adhere to the ECM and the actin present in the myofibroblasts contract against the collagen pulling the edges of the laceration together Scarring Fibroblasts over-expresses collagen inside the provisional matrix (laid down during cell proliferation) to form a collagen matrix The collagen then cross-links, making the matrix dense, forming a scar SBA 1 Dr. Charmaine decides to let the laceration heal via primary intention. Which of the following best describes a feature of this type of healing? A – Broad scar B – Epithelialisation C – Healing by granulation D – Risk of infection E – Wound contraction SBA 1 Dr. Charmaine decides to let the laceration heal via primary intention. Which of the following best describes a feature of this type of healing? A – Broad scar B – Epithelialisation C – Healing by granulation D – Risk of infection E – Wound contraction Primary and Secondary healing Primary – no tissue has been removed Secondary – wound separated and tissue missing Primary Secondary Wound edges brough Healing by granulation together Epithelialisation Broad scar Minimal scarring Wound contraction Risk of infection Regular cleaning required First intention – is a clean laceration where no tissue has been removed, such as a surgical cut + sutured Second intention: wounds with separated edges and often with tissue missing The diagram on the right depicts the main difference In secondary intention regeneration will take longer as new tissue has to be synthesised, as the original edges of the wound are far apart contraction occurs In primary there is very little loss of tissue, so less clotting and less granulation occurs, resulting in less angiogenesis as less granulation tissue is present Wound healing Infection Factors affecting healing Contamination – presence of organisms in wound Colonisation – replicating Local Systemic organisms in wound without Oxygenation Stress Infection Hormones inflammatory response Local infection – organism + Foreign Age tissue response body Spreading invasive infection – organisms + inflammation + Vascularity Medication spread Factors affecting wound healing Some of these can cause infection and slow down healing of the wound drastically, such as old age, which decreases the inflammatory response, so delayed angiogenesis can occur, so slower collagen synthesis which results in slower epithelialisation Classification of wound infections Wound infections are caused by the enzyme + toxin that the pathogen secretes, these allow subcutaneous spreading of infection The different types of infection are: Χονταµινατιον – πρεσενχε οφ οργανισµσ ιν ωουνδ Χολονισατιον – ρεπλιχατινγ οργανισµσ ιν ωουνδ ωιτηουτ ινφλαµµατορψ ρεσπονσε Λοχαλ ινφεχτιον – οργανισµ + τισσυε ρεσπονσε Σπρεαδινγ ινϖασιϖε ινφεχτιον – οργανισµσ + ινφλαµµατιον + σπρεαδ Inadequate formation of granulation tissue This is caused by delayed angiogenesis (formation of new blood vessels) and delayed collagen synthesis// early collagen breakdown This is because if there is not enough collagen the granulation tissue cannot protect the wound as it would not be strong enough If delayed angiogenesis occurs then little blood would get to the new tissue Fibrosis and its consequences Fibrosis is the formation of excess fibrous connective tissue This is in response to injury (scarring) Fibrosis hinders the action of the muscle, such as fibrosis of the heart, as scarring does not produce any myocytes, so heart contraction is less efficient DPain Painful… just like this lecture One of the most important things in this case! SBA 1 Mr Scott is explaining to his students the different types of pain. He explains that one type of pain is experienced when someone cuts their finger with paper. Which type of pain would be experienced? A – Chronic B – Neuropathic C – Somatic D – Sympathetic E – Visceral SBA 1 Mr Scott is explaining to his students the different types of pain. He explains that one type of pain is experienced when someone cuts their finger with paper. Which type of pain would be experienced? A – Chronic B – Neuropathic C – Somatic D – Sympathetic E – Visceral Durational pain Pain types • Acute • Recent onset and limited duration • Caused by activation of nociceptive sensory neurons • Chronic • Persistent after healing time • In absence of injury • Lasting for 3+ months Nature of pain Nociceptive – Obvious tissue injury Visceral – organs Somatic – from skin Non-nociceptive – damage to nervous system Neuropathic – nerve Sympathetic – unexplained Classification of pain Pain can be classified either by duration or by nature: If pain is classified by duration we look at: Αχυτε παιν − Pain of recent onset and probable limited duration − Caused by activation of nociceptive sensory neurones Χηρονιχ παιν − Pain that persists after expected healing time, or in absence of injury − Pain lasting for more than 3 months Then we can also classify pain by nature: Νοχιχεπτιϖε - Obvious tissue injury or illness - Also called physiological/inflammatory pain - Has a protective function Sematic pain comes from the skin, visceral pain comes from the organs Νευροπατηιχ (χαυσεδ βψ δαµαγε ορ δισεασε το τηε σοµατοσενσορψ νερϖουσ σψστεµ) - Tissue injury may not be obvious - Nervous system damage or abnormality - Does not have a protective functionMeasuring pain Either by a verbal report: − Draws on large, informal vocabulary people use to describe pain − Throbbing pain; shooting pain; a constant dull ache Or pain questionnaires: − Nature of pain − Intensity of pain − Emotional components + functional impact of pain SBA 1 Mr Pinchemain is explaining the process of nociception, and goes into specific detail about the A-delta and C fibres. In which stage would the nociceptive signal travel along these fibers? A – Facilitation B - Modulation C – Perception D – Transduction E – Transmission SBA 1 Mr Pinchemain is explaining the process of nociception, and goes into specific detail about the A-delta and C fibres. In which stage would the nociceptive signal travel along these fibers? A – Facilitation B - Modulation C – Perception D – Transduction E – Transmission Nociception Process Explanation Part of body Transduction exposure to noxious Periphery stimulus produces action potential Transmission travels along A-delta or C Spinal cord fibres from point of transduction to dorsal horn and subsequently to the brain Perception experience of discomfort, Brain pain, conscious, emotional + subjective Modulation response to pain, Spinal cord facilitation or inhibition of nociceptive output Nociception Thermal, chemical, mechanical stimuli capable of causing tissue damage, these activate specialized sensory neurones, which transmit nociceptive signals to CNS Specific response characteristics of primary afferent neurones determined by specific receptors + channels expressed by that neuron in periphery Activation of nociceptors in modulated by inflammatory influences in local extracellular environment Nociception – Physiology of pain Nociception occurs in four main phases 1. Transduction – exposure to noxious stimulus produces action potential (periphery) 2. Transmission – travels along A-delta or C fibres from point of transduction to dorsal horn and subsequently to the brain (spinal cord) 3. Perception – experience of discomfort, pain, conscious, emotional + subjective (brain) 4. Modulation – response to pain, facilitation or inhibition of nociceptive output SBA 1 Mr Pinchemain is explaining the process of nociception, and goes into specific detail about the A-delta fibers. Which of the following nociceptive signals would activate A-delta fibers? A – Chemical B – Heat C – Light touch D – Mechanical E – Vibration SBA 1 Mr Pinchemain is explaining the process of nociception, and goes into specific detail about the A-delta fibers. Which of the following nociceptive signals would activate A-delta fibers? A – Chemical B – Heat C – Light touch D – Mechanical E – Vibration In the periphery Spinal cord 1. Tissue injury 1. Nociceptive input enters CNS at 2. Release of chemicals dorsal horn 3. Stimulation of pain 2. Substantia gelatinosa receives receptors input 4. Signals travel to A- 3. Nerves synapse delta and C fibers 4. Second nerve travels up opposite Fibers Signal Myelination Speed side of spinal cord carried A-delta Heat Myelinated 3-30 m/s Pressure In the brain C Thermal Unmyelinated 0.5-2 m/s Mechanical 1. Thalamus is the second relay Chemical station 2. Connections to many parts of the A-beta Non-noxious Myelinated 33-75 m/s brain (ie cortex, limbic system Light touch (memory), brainstem) Vibrations 3. Pain perceptions occur in the cortex In periphery 1. Tissue injury (exposure to noxious stimuli) 2. Release of chemicals (ATP + ASICs) 3. Stimulation of pain receptors (nociceptors) 4. Signal travels in Aδ or C nerve to spinal cord Three primary types of afferent nerve fibres A-delta fibres – respond to heat and pressure (myelinated) C fibres – polymodal, respond to thermal, mechanical and chemical stimuli (unmyelinated) A-beta fibres – respond to non-noxious stimuli, detect light touch + vibrations (myelinated) Spinal cord 1. Nociceptive inputs enter CNS at dorsal horn 2. Substantia gelatinosa of dorsal horn receives inputs from Aδ or C nerve, which synapses with second nerve 3. Also receives input from A𝛽 fibres 4. Second nerve travels up opposite side of spinal cord (decussated as spinothalamic tract) In the brain 1. Thalamus is the second relay station 2. Connections to many parts of the brain (ie cortex, limbic system (memory), brainstem) 3. Pain perceptions occur in the cortexModulation Descending pathway from brain to dorsal horn Usually decreases pain signal Chronic noxious stimulation Sensitization may occur either peripherally or centrally Misfiring of normal nociceptive pathway can be triggered in the periphery by neutral stimulus (light touch), amplifying signal to the brain Can also occur in absence of stimulus, with neurones firing in spinal cord or brain circuits responsible of pain perception Gate theory Excitation along A-delta + C-fibres open gate Excitation along A-beta Psychological modification fibres closes gate • Pain perception involves several psychological processes: • Attentional orientating to painful sensation and its source What is substance P? • Cognitive appraisal of the meaning of When a nociceptive receptor the sensation is stimulated it releases • Subsequent emotional and behavioral substance P reactions This induces mast cells to • These in turn feedback to influence pain release histamine perception Promoting inflammation and increasing vascular permeability Blocking of pain sensation (gate control theory) Gating mechanism within tract prevents passage of nociceptive signals from periphery to brain Influenced by relative degree of excitatory activity in spinal cord transmission cells Excitation along A-delta + C-fibres open gate Excitation along A-beta fibres closes gate (‘counter-stimulation’//mechanical stimulation) Effectively rubbing of a wound will prevent the nociceptive nerve fibres from firing to the CNS, as the mechanical receptor (A-beta) prevents it Pain modulation Involves multiple complex descending modulatory pain pathways that can have excitatory or inhibitory effects on transmission of pain Endogenous (originating from within an organism) pain modulation can explain variation in how people perceive and report pain Inhibitory neurotransmitters involved in the modulation of pain include endogenous opioids (endorphins). Serotonin, GABA and noradrenaline Νοτε τηατ ενδογενουσ οπιοιδσ πρεϖεντ τηε ρελεασε οφ εξχιτατορψ νευροτρανσµιττερσ (συχη ασ συβστανχε Π) ανδ σο βλοχκ τηε τρανσµισσιον οφ νοξιουσ στιµυλι Emotions and mood Fight or flight stress response may dampen pain via release of noradrenaline + activation of PAG and endogenous opioids Chronic stress + negative emotional states increases pain intensity Expectancies about pain and the placebo effect Placebo is defined as Any medical procedure that produces an effect in a patient because of its therapeutic intent and not its specific nature, whether chemical or physical The expectation of pain relief can exert a powerful analgesic effect, even when pain is severe Mechanisms for placebo analgesia operate within the neural circuit for the descending control of pain, including the PAG and opioids (subsequently block neurotransmitter – substanceP) Pain modulation (PAG) PAG – primary control center for the descending pain modulatory system 1. Receives information from ascending pain tracts 2. Stimulation of the PAG activates enkephalin releasing neurone 3. Raphe nucleus releases serotonin 4. Interneurones in the substantia nigra release opioid neurotransmitters 5. Bind to Mu-opioid receptors 6. Inhibition of substance P binding Blocking of pain sensation (gate control theory) Gating mechanism within tract prevents passage of nociceptive signals from periphery to brain Influenced by relative degree of excitatory activity in spinal cord transmission cells Excitation along A-delta + C-fibres open gate Excitation along A-beta fibres closes gate (‘counter-stimulation’//mechanical stimulation) Effectively rubbing of a wound will prevent the nociceptive nerve fibres from firing to the CNS, as the mechanical receptor (A-beta) prevents it Pain modulation Involves multiple complex descending modulatory pain pathways that can have excitatory or inhibitory effects on transmission of pain Endogenous (originating from within an organism) pain modulation can explain variation in how people perceive and report pain Inhibitory neurotransmitters involved in the modulation of pain include endogenous opioids (endorphins). Serotonin, GABA and noradrenaline Νοτε τηατ ενδογενουσ οπιοιδσ πρεϖεντ τηε ρελεασε οφ εξχιτατορψ νευροτρανσµιττερσ (συχη ασ συβστανχε Π) ανδ σο βλοχκ τηε τρανσµισσιον οφ νοξιουσ στιµυλι Descending endogenous pain modulatory system The brain does not passively receive pain info from the body, but actively regulates sensory transmission via descending influences on the spinal dorsal horn Periaqueductal gray (PAG) forms a key part of the pain-inhibition system Contributes to environmental (flight or fight) and opiate analgesia (inability to feel pain) Some descending pathways can facilitate pain and may contribute to chronic pain Higher cortical brain systems contribute to descending pain modulatory pathway Role of the periaqueductal gray (PAG)PAG is the primary control centre for the descending pain modulatory system Integration of ascending pain stimuli and descending influences from higher cortical regions Ρεχειϖεσ ινφορµατιον φροµ ασχενδινγ παιν ανδ τεµπερατυρε φιβρεσ οφ τηε σπινοτηαλαµιχ τραχτ Στιµυλατιον οφ τηε ΠΑΓ αχτιϖατεσ ενκεπηαλιν−ρελεασινγ νευρονε τηατ προϕεχτ το τηε ραπηε νυχλευσ ιν τηε βραινστεµ Τηισ λεαδσ το α ρελεασε οφ σεροτονιν, δεσχενδινγ το δορσαλ ηορν ανδ βινδινγ το ιντερνευρονεσ ον τηε συβσταντια γελατινοσα οφ τηε δορσαλ ηορν Υπον αχτιϖατιον, ιντερνευρονεσ ρελεασε ενδογενουσ οπιοιδ νευροτρανσµιττερσ τηατ βινδ το µυ οπιοιδ ρεχεπτορσ ον τηε αξονσ οφ Α−δελτα ανδ Χ φιβρεσ Μυ−οπιοιδ ρεχεπτορσ ινηιβιτ ρελεασε οφ συβστανχε Π, ινηιβιτινγ εξπεριενχε οφ παιν A nociceptive receptor is stimulated which releases substance P, this induces mast cells to release histamine (promoting inflammation as it increases vascular permeability) Analgesia Drugs Fun stuff Welcome to adulthood, I hope you like ibuprofen and not sleeping One of the most important things in this case! Biochemistry of NSAIDs Arachidonic Acid (AA) Prostaglandin H synthase Polyunsaturated omega-6 PGHS converts AA and O2 into PGG2 fatty acid formed from a and PGH2 fatty acid being cleaved by phospholipase A2 PGH2 • Pain sensitizer + inflammatory mediator • Platelet aggregation and local vasoconstriction • Or platelet aggregation and local vasodilation The PGHS is split into two portions, the COX domain and the peroxidase domain Arachidonic acid (AA) – don’t need to know this but is helpful for understanding COX AA is a polyunsaturated omega-6 fatty acid designated as 20:4 (ω-6) It has 20 carbon atoms and 4 C=C The presence of the double carbon bonds causes the kink in the middle The number of reactive double bonds makes AA a versatile eicosanoid (signalling molecule) pre-cursor Prostaglandin H synthase (PGHS) PGHS converts AA and O in2o 2 initial endoperoxides (PGG2 and PGH2) which can then be modified into cell-specific prostaglandins As seen in the diagram to the right both AA and O en2er the Cyclo-oxygenase domain to generate PGG2, this then enters the Peroxidase domain which converts the PGG2 into PGH2 Roles of PGH2 The cell/tissue effect observed is a function of the type of G-protein that is activated when the PG activated the receptor The specific intracellular cascade then determines the effects observed in the tissue This explains why PGH2 can have 2 different effects in tissues, this is because it can bind to two different receptors which both have differing resulting effects PGH2 can be considered the progenitor for a huge range of bioactive lipid molecules Some synthase enzymes are able to convert PGH2 into specific derivatives: ΠΓ−Ε2 σψντηασε χονϖερτσ ΠΓΗ2 ιντο ΠΓΕ2 This is used in GI mucosa and renal protection, it causes uterine contraction, is a pain sensitizer and inflammatory mediator, causes vasodilation, histamine release Τηροµβοξανε σψντηασε χονϖερτσ ΠΓΗ2 ιντο ΤΞΑ2 TXA2 causes platelet aggregation (sticking together) and local vasoconstriction ΠΓ−Ι2 σψντηασε χονϖερτσ ΠΓΗ2 ιντο ΠΓΙ2 Inhibits platelet aggregation, causes local vasodilation SBA 1 Jenny hits her leg real bad, so bad in fact that you need to prescribe her ibuprofen. What is the mechanism of action of this medication? A – Inhibit the action of phospholipase A2 B – Irreversibly inhibit the cyclo-oxygenase domain C – Irreversibly inhibits the prostoglandin H synthase D – Reversibly inhibit the cyclo-oxygenase domain E – Reversibly inhibits the prostoglandin H synthase Whilst D and E are both correct, D is more correct correct, this is an example of a difficult SBA C abd E are not specific enough This explains why corti are far better at controlling inflammation as with NSAIDs some PGH2 slips thru the uninhibited COX domains, whereas with corti we have nil production of AA SBA 1 Jenny hits her leg real bad, so bad in fact that you need to prescribe her ibuprofen. What is the mechanism of action of this medication? A – Inhibit the action of phospholipase A2 - corticosteroid B – Irreversibly inhibit the cyclo-oxygenase domain - aspirin C – Irreversibly inhibits the prostoglandin H synthase D – Reversibly inhibit the cyclo-oxygenase domain - ibuprofen E – Reversibly inhibits the prostoglandin H synthase Whilst D and E are both correct, D is more correct correct, this is an example of a difficult SBA C abd E are not specific enough This explains why corti are far better at controlling inflammation as with NSAIDs some PGH2 slips thru the uninhibited COX domains, whereas with corti we have nil production of AA NSAID mechanism All have the same class of action: The general order is: • Inhibition of cyclo- • Paracetamol or Ibuprofen oxygenase domain • Paracetamol and Ibuprofen activity in the PGHS • Co-codamol No PGG2 and PGH2 is produced • Codeine • Morphine Anti-inflammatory effects • Fentanyl Reduces the extent and duration of inflammation by preventing PGH2 binding at tissues So less vasodilation and vascular permeability Inflammation is: rubor (redness), calor (increased heat), tumor (swelling), dolor (pain), and functio laesa (loss of function) NSAID mechanism NSAIDs have the same ‘class’ action: they inhibit cyclo-oxygenase domain activity in the PGHS, thus preventing generation of the precursor endoperoxides PGG2 + PGH2 for subsequent conversion NSAIDs differ individually in how they inhibit PGHS and their specificity for different PGHS isoforms Anti-inflammatory effects NSAID inhibition of PGHS-2derived prostaglandins reduces the extent and duration of local inflammation caused by vasodilation and increased vascular permeability Compared to steroid NSAIDs are not as potent at reducing inflammation as they act locally, whereas steroids inhibit the synthesis of arachidonic acid via inhibiting phospholipase A2, so no prostaglandins can be formed at all SBA 2 After prescribing Jenny ibuprofen she decides to take it without eating on multiple occasions which results in her having severe epigastric pain. Which of the following adverse drug reactions has Jenny suffered? A –Allergic reaction B - Compromised renal function C - Gastric ulceration D - Hypertension E - Pregnancy SBA 2 After prescribing Jenny ibuprofen she decides to take it without eating on multiple occasions which results in her having severe epigastric pain. Which of the following adverse drug reactions has Jenny suffered? A –Allergic reaction B - Compromised renal function C - Gastric ulceration D – Hypertension – found in corticosteroid E – Pregnancy – contraindication for NSAIDs Nonsteroidal Anti-Inflammatory Drugs Ibuprofen (NSAID) Aspirin Competes with AA for Acylates the serine COX domain residue in the COX Reversible inhibitor domain Irreversible inhibitor Paracetamol ADRs Contraindications Gastric ulceration Pregnant May be chosen before Renal impairment Sensitised to salicylates/ NSAID use NSAID allergic We don’t know how it Already on an NSAID works Under 16 years old Ibuprofen Produced as a racemate, the S-enantiomer is the active NSAID It competes with AA for the cyclo-oxygenase (COX) domain active site of PGHS 1+2 It is a reversible inhibitor Aspirin Acetyl salicylic acid is the only irreversible inhibitor of PGHS It acylates the serine residue in the COX domain active site Paracetamol May be chosen before NSAIDs as it can have better analgesic and anti-pyretic (reduce fever) effects, but it has very little anti-inflammatory activity How it works is under debate Is a weak inhibitor of PG synthesis of COX-1 and COX-2 in broken cell systems, but, by contrast, ADRs and contraindications There are 2 significant NSAID ADRs you must familiarise yourself with: Ποτεντιαλ φορ γαστριχ υλχερατιον Χοµπροµισεδ ρεναλ φυνχτιον NSAIDs are contra-indicated if:Πρεγναντ Σενσιτισεδ το σαλιχψλατεσ/ ΝΣΑΙΔ αλλεργιχ Αλρεαδψ ον αν ΝΣΑΙΔ Ψουνγερ τηαν 16 ψεαρσ ολδ (ασ υσε ισ ασσοχιατεδ ωιτη δεϖελοπµεντ οφ Ρεψε’σ σψνδροµε) SBA 3 Unfortunately, Jenny now has chronic pain. She is currently on ibuprofen (still) and paracetamol. According to the WHO pain ladder what is the most appropriate analgesia to prescribe her? A – Co-codamol B - Corticosteroids C - Fentanyl D - Morphine E - Oramorph SBA 3 Unfortunately, Jenny now has chronic pain. She is currently on ibuprofen (still) and paracetamol. According to the WHO pain ladder what is the most appropriate analgesia to prescribe her? A – Co-codamol B - Corticosteroids C - Fentanyl D - Morphine E - Oramorph Know your pain ladder people!!! WHO pain ladder The general order is: • Paracetamol or Ibuprofen • Paracetamol and Ibuprofen • Co-codamol • Codeine • Morphine • Fentanyl Know your pain ladder people!!!!! WHO guidelines for pain management are akin to a ladder that indicates the intensity of pain The prescription of drugs is dependent on the pain level Note that when we prescribe NSAIDs for inflammation we slow the healing process as inflammation is needed Final SBA • A 32-year-old mixed martial arts fighter could not continue his fight after receiving a side leg kick to the neck of his left fibula. The fighter reported paresthesia and numbness on the entire dorsum dragging on the floor during the swing phase of his gait. Asymmetry in his normal foot position was also noted by the physician (see photo) as well as weakness in eversion of the foot at the ankle joint. What nerve was damaged? (A) Tibial nerve (B) Deep fibular nerve (C) Superficial fibular nerve (D) Common fibular nerve (E) Sciatic nerve Final SBA A 32-year-old mixed martial arts fighter could not continue his fight after receiving a side leg kick • to the neck of his left fibula. The fighter reported paresthesia and numbness on the entire dorsum of his left foot. During his physical examination, the patient often stumbled with his left toes dragging on the floor during the swing phase of his gait. Asymmetry in his normal foot position was also noted by the physician (see photo) as well as weakness in eversion of the foot at the ankle joint. What nerve was damaged? (A) Tibial nerve – loss of plantarflex “tiptoe” st (B) Deep fibular nerve – foot drop only + 1 dorsal webspace sensation (C) Superficial fibular nerve - eversion + doral sensation (D) Common fibular nerve - All above (E) Sciatic nerve – thigh hamstring muscles also affected Q.46 Common fibular nerve. – footdrop Neck of fibular = division into superficial and deep fibular nerve Damage to the common fi bular nerve would lead to all of the symptoms seen in this patient, such as weakness in eversion and dorsiflexion of the foot at the ankle joint, foot drop, and loss of sensation to the dorsum of the foot Latereal leg Nerve Motor Sensory Typical mechanism of injury & notes Femoral nerve Knee extension, thigh flexion Anterior and medial aspect of the Hip and pelvic fractures (Anterior thigh compartment) thigh and lower leg Stab/gunshot wounds Obturator nerve Thigh adduction Medial thigh Anterior hip dislocation (Medial compartment) Lateral cutaneous nerve of the thigh None Lateral and posterior surfaces of the Compression of the nerve near the ASIS → thigh meralgia paraesthetica, numbness in the distribution of the lateral cutaneous nerve Tibial nerve Foot plantarflexion and inversion Sole of foot Not commonly injured as deep and well (posterior compartment of leg) protected. Popliteral lacerations, posterior knee dislocation Common peroneal nerve Foot dorsiflexion and eversion Superficial : Dorsum of the foot and Injury often occurs at the neck of the fibula Extensor hallucis longus the lower lateral part of the leg Tightly applied lower limb plaster cast • Superficial = lateral compartment of leg • Deep = Anterior compartment of leg deep peroneal : loss of 1 doral Superfical cause loss of foot eversion and dorsal webspace (between big toe) –L5 sensation Deep:causes foot drop, and loss of big toe dorsiflexion Superior gluteal nerve Hip abduction None Misplaced intramuscular injection (gluteal minimums and medius) Hip surgery ,Pelvic fracture ,Posterior hip dislocation Injury results in a positive Trendelenburg sign Inferior gluteal nerve Hip extension and lateral rotation None Generally injured in association with the sciatic (gluteal Maximus) nerve Injury results in difficulty rising from seated position. Can't jump, can't climb stairs WHO guidelines for pain management are akin to a ladder that indicates the intensity of pain The prescription of drugs is dependent on the pain level Note that when we prescribe NSAIDs for inflammation we slow the healing process as inflammation is needed DKeys If you stopped paying attention listen to me now consepts One of the most important things in this case! DAMPs and PAMPs on macrophages stimulate cytokine release. The CXCL8 then attracts neutrophils to mop up the wound TNF-alpha is a chemokine but CXCL8 is a cytokine (bc movement!) Neutrophils – acute but Macrophages – chronic stage Chronic is anything over 3 months Bone healing goes: haematoma, inflammation, granulation, callus, remodeling Osteoperosis is diagnosed using DEXA scan (greater than -2.5SD), being female and old are biggest RFs Wound healing goes: clotting, inflammation, proliferation, mutation Scarring occurs due to over-expression of collagen matrix from too much fibroblasts. Wound contraction occurs due to myofibroblasts Primary intention = nice scar as endges brought together, secondary = ugly scar and healing by granulation + wound contraction Visceral (organ pain) and somatic (Skin) are nociceptive pain, non-nociceptive is nerve pain Learn the tables on 42 and 45 (speed of transfer came up) substantia nigra secretes exodgenous opiod which binds to mu receptor. Raphe secretes serotonin COX domain is reversibly inhibited (ibuprofen) and irreversibly (aspirin). Corticos inhibit PLA2 Learn slide 58 WHO guidelines for pain management are akin to a ladder that indicates the intensity of pain The prescription of drugs is dependent on the pain level Note that when we prescribe NSAIDs for inflammation we slow the healing process as inflammation is neededI’ll stop talking now The endThank you! Cheers for listening if you have any questions that you don’t want to ask on the chat or questions about the slides after you get them, hit me up by email or Facebook: PinchemainTW@cardiff.ac.uk TJ PinchemainQR code for feedback form • Fill in the feedback form to receive the slides