Introduction to the Nervous System

Learning Outcomes Understand the different cell types found within the nervous system The nervous system consists of the brain, spinal cord, and peripheral nerves Maintains central control of bodily functions and for various stimuli responses Nerve cells (neurons) Support cells (Schwann cells, glial cells) o Brain glial cells Oligodendrocytes for myelin production Astrocytes for structural support (Glial cells give rise to gliomas (brain tumours)) o Spinal cord Schwann cells Describe the structure of neurons Cell body (SOMA) nucleus Axon - Long cytoplasmic process that transmits impulses away from the cell body Dendrite - Process that transmits impulses towards the cell body Cytoplasm Myelin sheath insulation, protection, speed up nerve impulses Schwann cells produce myelin Nodes of Ranvier non-mylenated sections between myelin sheaths PSEUDOUNIPOLAR (soma on the left/side) o Divides after 1 cytoplasmic process speeds up conduction because impulse does not have to go through cytoplasm of cell body) o Cell bodies of SENSORY/AFFERENT/SOMATIC peripheral nerves are all collected in 1 site called the GANGLION BIPOLAR (soma is in the middle of axon) o 2 different cytoplasmic processes BI (one conducts nerve impulse from receptor to cell body and one conducts impulse from cell body to CNS) o some bipolar spinal/cranial nerves rearrange themselves to become pseudounipolar during development but olfactory,

vision, hearing and balance remain truly bipolar b/c the receptors are close to the brain MULTIPOLAR ( regular neuron found in CNS) o Motor neuron in spinal cords o more than 1 cytoplasmic process o multiple dendrites in the soma o somatic efferent nerves (towards effectors) Understand the structure and function of nervous synapses Chain of separate neurons = neural pathway Junctional zones/relay stations = synapses where impulse from terminal button of a neuron stimulates it to release neurotransmitters to generate electrical impulse across synaptic cleft to the succeeding neuron STRUCTURE o Synaptic cleft o Pre/post synaptic membrane o Synaptic vesicles o Synaptic knob (terminal button) o Mitochondrion for ATP

o Endoplasmic reticulum (surrounding mitochondrion) o Axon Identify the central and peripheral nervous systems CNS brain and spinal cord o Surrounded by cerebrospinal fluid provides nutrition, oxygen, support, and substance o Surrounded by meninges layers of tissue PNS cranial nerves arising from the brain (12 pairs) and spinal nerves from the spinal cord (31 pairs usually) Compare and contrast white and grey matter within the central nervous system CNS contains nerve cell bodies and glial cells (gray matter) and bundles/tracts of axons due to myelin (white matter) Gray outside, white inside for brain but gray inside and white outside for spinal cord (butterfly canals) Compare and contrast nuclei and ganglia Centrally located cell bodies = nucleus

 Peripherally located cell bodies (hanging on the side) = ganglion Identify the main parts of the cerebral hemispheres Right and left cerebral hemispheres Longitudinal fissure divides the right and left Lobes frontal, temporal, parietal, occipital, cerebellum Gyri (land) and sulci (ridges) Describe the origin of the peripheral nerves, including cranial and spinal Cranial nerves o 12 pairs arising from the brain o Roman numerals Spinal nerves o 31 pairs from the spinal cord o may form plexuses (different fibres from different levels combine to make new nerves with specific targets/destinations) o sensory/efferent enter from posterior aspect of spinal cord (ganglion) o motor/afferent enter from anterior aspect of spinal cord 8 cervical (neck +upper limb) C1-8 **7 cervical

vertebrae but 8 cervical nerves b/c C-1 comes out above the 1st vertebrate CI therefore there is enough space for C-8 under CVIIafter that each vertebrate corresponds with its nerve 12 thoracic (upper limb + thorax) T1-12 5 lumbar (abdomen +lower limb) L1-5 5 sacral (lower limb + perineum) S1-5 Understand the concepts of dermatomes and myotomes Dermatome area of skin supplied by a single spinal nerve root (central) Myotome region of skeletal muscle supplied by single spinal nerve root (double nerve root) Peripheral nerve distribution o Area of skin o Area of muscle Describe a simple reflex arc

When the safety of an organism demands a very quick response, the signals may be passed directly from a sensory neuron, via a relay neurone, to a motor neurone for instant, unthinking action. (MONOSYNAPTIC) Polysynaptic is when multiple relays are involved (a lot more complex) Compare and contrast the somatic and autonomic nervous systems SENSATION o Somatic we are acutely aware and are able to localize these sensations Generally occur in body wall structures instead of internal organs Fibres run in the cranial/spinal nerves (peripheral) o Autonomic (visceral) imperceptible, vaguely localizable, or only perceptible in disease Arise from blood vessels or internal organs (viscera) Fibres run in cranial/spinal nerves and also found in network of nerves associated with internal organs (autonomic plexuses) MOTOR o Sensory/afferent/voluntary motor impulses control skeletal muscle from various parts of the brain nerve impulses pass down in the spinal cord to connect to neurons whose axons pass out of the CNS to the peripheral nerves Upper motor neurons within CNS entirely Lower motor neurons cell bodies in CNS but axons pass into the PN (found in cranial and spinal nerves)

Ex. Striated muscle except for heart muscle o Autonomic/efferent/visceral/involuntary Impulses control muscle over what we do not have voluntary control Ex. Peristalsis (smooth muscle), and heart Compare and contrast the sympathetic and parasympathetic nervous systems SYMPATHETIC

o Prepares us for ACTION o Alert, dilated pupils (mydriasis) for good distance vision, speeds up heart, bp rises, sphincters closed (no washroom), blood vessels to the muscle dilate for movement but vasoconstriction to viscera (slow down blood flow to direct to muscle), secretion of sweat for cooling o Noradrenaline is the neurotransmitter that brings upon this action o T1 L2 spinal segments PARASYMPATHETIC

o Relaxes us for visceral activity (gastric, salivary, peristalsis etc) o Sphincter relaxation o Miosis (pupil constriction) o Relaxing of gut tube muscle o Slowing of the heart o Acetylcholine nicotinic and acetylcholine muscarinic o Brainstem cranial nerves and S2-S4 sacrum segments Understand how cerebrospinal fluid is made and reabsorbed CSF is produced mainly by a structure called the choroid plexus in the lateral, third and fourth ventricles. CSF flows from the lateral ventricle to the third ventricle through the interventricular foramen (also called the foramen of Monro). The third ventricle and fourth ventricle are connected to each other by the cerebral aqueduct (also called the Aqueduct of Sylvius). CSF then flows into the subarachnoid space through the foramina of Luschka (there are two of these) and the foramen of Magendie (only one of these). Absorption of the CSF into the blood stream takes place in the

superior sagittal sinus through structures called arachnoid villi . When the CSF pressure is greater than the venous pressure, CSF will flow into the blood stream. However, the arachnoid villi act as "one way valves"...if the CSF pressure is less than the venous pressure, the arachnoid villi will NOT let blood pass into the ventricular system. List the layers of the meninges Dura (naked eye)

Arachnoid (naked Subarachnoid space Pia

Extra Notes Direction of nerve impulse Sensory/Afferent Away from the effector organ/tissue and towards the CNS Motor/Efferent Towards the effector organ/tissue and away from the CNS

Surface Anatomy and Osteology of the Lower Limb

Learning Outcomes Become Become familiar with basic anatomical terms Face forward Hands by side, palms forward Feet together, toes forward Inferior margin of orbit level with top of external auditory meatus familiar with anatomical planes Superior/inferior up and down Lateral/medial what position is A away from B with respect to the

sagittal plane Anterior/posterior front and back Superficial/deep Identify the bones of the lower limb Describe the bony pelvis, including parts, joints, and ligaments Describe the femur, including articular surfaces, attachments, and bony features Identify the tibia and fibula and their main bony features Describe the fascia lata Deep layer of fibrous connective tissue membrane that encloses all muscle in the thigh and gluteal region **in the lower leg, it is called deep fascia but they are essentially the same thing Understand how intermuscular septae form muscular compartments within the lower limb Thigh anterior, medial, posterior (w/ femur and linea aspera) Lower leg anterior, posterior, lateral (w/ tibia and fibula) Describe the long saphenous vein, including origin, course, and tributaries Saphenous = visible in latin Tributary = A stream that flows into a larger stream or other body of water. Superficial vein directly subcutaneous The GSV originates from where the dorsal vein of the first digit (the large toe) merges with the dorsal venous arch of the foot. After passing anterior to the medial malleolus (where it often can be visualized and palpated), it runs up the medial side of the leg.

At the knee, it runs over the posterior border of the medial epicondyle of the femur bone. The great saphenous vein then courses laterally to lie on the anterior surface of the thigh before entering an opening in the fascia lata called the saphenous opening. It joins with the femoral vein in the region of the femoral triangle at the saphenofemoral junction. Describe the anatomy of the saphenopopliteal junction Lateral dorsal venous arch of foot (small pinky toe) Posterior to lateral malleolus Continuing to popliteal fossa (crevice behind knee joint) Joins at saphenopopliteal junction behind knee to the popliteal vein Understand how varicose veins may develop Occur in the superficial veins of legs High blood pressure inside your superficial leg veins causes varicose veins. Veins permanently twisted/dilated Veins contain one-way valves, which help to propel blood back to the against the forces of gravity. These valves are situated every few inches along the length of the vein. If a leak develops in any of these valves the blood falls back down the vein and causes swelling at the valve below. The veins become permanently dilated (widened) and can assume the appearance of a bunch of grapes at the back of the leg. Identify the nerves that may be damaged by surgical removal of the saphenous veins and their areas of distribution Saphenous nerve o resulting in loss of cutaneous sensation in the medial leg. This is due to the intimate path that the saphenous nerve and the great saphenous vein travel. Distribution: knee joint, subsartorial and patellar plexuses, skin on medial side of leg and foot nerve sural nerve subserves a purely sensory function distribution: kin on back of leg, and skin and joints on lateral side of heel and foot;

o Sural o o

Identify the superficial inguinal lymph nodes superficial inguinal lymph nodes form a chain immediately below the inguinal ligament. Iliotibial tract longitudinal fibrous reinforcement of fascia lata extends from iliac tubercle to lateral condyle of tibia (Gerdys tubercle) contributes to lateral knee stabilization when knee flexes, ITB moves posteriorly when knee extends, ITB moves anteriorly thigh flexion at hip, abduction, and medial rotation of hip

Membrane Potentials
Learning Outcomes **see handwritten notes**

11/19/2013 9:02:00 AM

Understand the physic-chemical properties of nerve cell membranes Be able to differentiate between active and passive transport mechanisms Describe, both qualitatively and quantitatively, the transmembrane gradients for major ions Understand and be able to describe the Na-K pump as driving force for membrane potential, transporters, and exchangers Be able to calculate membrane potentials according to Nernst Quantitatively describe a cells resting membrane potential Describe the structure and role of Ion channels (Na, K, Cl, Ca) To identify and describe the differences between voltage and ligand gated ion channels

Femoral region, anterior and medial compartments of the thigh 11/19/2013 9:02:00 AM
Discuss the muscles and innervation of the anterior and medial compartments of the thigh ANTERIOR o Sartorius o Tensor fascia lata o Iliopsoas Iliacus Psoas major o Quadriceps femoris Rectus Vastus Vastus Vastus femoris lateralis medialis intermedius

MEDIAL o Adductor group Adductor brevis Adductor longus Adductor magnus Gracilis

Pectineus Understand the structure and function of the iliotibial tract Describe the boundaries and contents of the femoral triangle Medial medial aspect of adductor longus Lateral medial aspect of Sartorius Superior inguinal ligament Floor iliopsoas, pectineus, adductor longus Roof fascia lata Understand how femoral hernias may occur and how these present clinically Demonstrate clinical landmarks on examination of the anterior and medial thigh. Interpret radiological imaging of the bones and vessels of the lower thigh Ligaments Inguinal

 Nerves

Sacrotuberous Sacrospinal Anterior sacroiliac Posterior sacroiliac Interosseus Iliolumbar Lumbosacral Pectineal Lacunar Patellar Iliofemoral Ishiofemoral pubofemoral

Saphenous o Branch of femoral nerve o Intimate path with great saphenous vein o Can result in loss of cutaneous sensation in medial leg o L2, L3, L4 Obturator Femoral Sural Sciatic o L5, S1, S2 Pudendal Gluteal o Inferior o superior Tibial Common peroneal (or fibular) Femoral Abnormal obturator Profunda femoris Popliteal

Arteries

Veins Great saphenous vein Short saphenous vein Perforating vein Femoral vein

Neurotransmission

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**see handwritten notes** Be able to differentiate between autonomic and sensory-somatic nervous system Be able to differentiate between sensory and motor neurons Define what a neurotransmitter is Understand and describe the differentiation between depolarisation (excitation) and hyperpolarisation (inhibition) Be able to describe the mechanism of action potential generation , mechanism of action potential propagation and the mechanism of action of local anaesthetics Be able to identify and describe the defects in nerve conduction in multiple sclerosis

Fertilization, blastocyst, two layered embryo, notochord

Learning Outcomes

Outline gametogenesis in the male and female

SPERMATOGENESIS i. In the basement membrane of the seminiferous tubule in the testis, there are spermatogonium (2n) ii. High rate of cell division mitosis = spermatogonia (2n) iii. S-phase (growth), spermatogonia grow to form primary spermatocytes (2n) iv. Primary spermatocyte undergoes meiosis I to become 2 secondary spermatocytes (n) v. Secondary spermatocytes undergo meiosis II to become 4 spermatids (n) vi. Sertoli cells nourish the spermatids to differentiate into spermatozoa (tail, acrosome head, etc) OOGENESIS i. Oogonia (medulla region of ovary) are arrested at prophase I (2n) before puberty found within primary follicles ii. Oogonium divide by mitosis to make many oogonia iii. FSH causes primary follicles to develop into secondary follicles (Graafian follicle) iv. Primary oocyte (2n) undergoes meiosis I = secondary oocyte (n) and polar body v. Secondary oocyte undergoes meiosis II = ovum (n) and polar body (AT FERTILIZATION) vi. Ovum progresses to the end of meiosis when fertilization takes place

Describe the process of embryonic fertilization

Mature ova goes from ovary into peritoneal cavity and into the ampulla (widest part) of the fallopian tube Ejaculation 200-500 of 200-500 million spermatozoa reach this point Capacitation (changes in sperm for fertilization - conditioning) occurs in the uterus or in a petri dish for IVF outside fallopian tube

Spermatozoa passes through corona radiata and adheres to glycoprotein layer zona pellucida In humans, ZP3 is the binding receptor Acrosome reaction head of the spermatozoa called acrosome releases digestive enzymes to make a pathway for the spermatozoa to penetrate through and to be engulfed by the oocyte Cortical reaction cortical granules fuse with the glycoprotein to seal off zona pellucida to prevent polyspermy

Outline the early embryonic stages (i.e. morula). Describe the development of the blastocyst and the two layered embryo
Mitosis occurs 24-36 hours post fertilization zygote begins to divide Cleavage cells get smaller and smaller because there is no net growth 3-4 days after MORULA (still inside ZP) approx. 32 cells space starts forming inside morula blastocyst emerges from ZP with fluid filled cavity called blastocoel trophectoderm/trophoblast extraembryonic membranes for placenta formation inner cell mass forms the embryo (small portion of the blastocyst)

Outline the passage of the early embryo from the fimbriae (finger-like projections) of the fallopian tube to the uterus
Ovum released at fimbriae of fallopian tube from ovary Fertilization occurs at ampulla of fallopian tube Zygote continues along fallopian tube towards upper part of uterus Zygote divides 23-36 hours post fertilization 3-4 days = morula w/ zona pellucida (32 cells) Full blastocyst when it reaches uterus w/ inner cell mass (top little bump), trophectoderm/trophoblast cells surrounding, and blastocyst cavity

Explain how an ectopic pregnancy occurs and what the clinical risks of this are
Development of embryo outside uterus (most often in the fallopian tube) Delay of passage of fertilized egg usually due to scarring, blockage Implantation occurs in fallopian tube wall but it is too thin to sustain growth Tube can rupture and cause hemorrhage (internal bleeding)

Describe how implantation of the embryo into the uterine wall occurs, and how the placenta then develops
Blastocyst adheres to uterine wall, inner cell mass is found near attachment site 2 types of trophoblast syncytiotrophoblast (very invasive and eats into the uterine, parasite), and cytotrophoblast (starts the placenta)

Describe the development of the epiblast and hypoblast and their associated cavities
Part of inner cell mass Epiblast development of amniotic space fluid for embryo for the next 9 months Hypoblast primary yolk sac **bilaminar disc = embryonic disk

Describe the process of gastrulation and the development of the three layered, three dimensional embryo
Embryonic ectoderm Embryonic mesoderm gastrulation where cells from epiblast move to the groove to drop off and lie between the epiblast and hypoblast layers Embryonic endoderm These three layers = trilaminar disc Primitive streak (stick), develop 13-14 days post fertilization and appear in the epiblast Midline groove develops in the streak primitive node (lollipop hole) then appears **look at UCLA link

Understand the three main tissue types found within the embryo following gastrulation
Embryonic ectoderm epidermis and nervous system Embryonic mesoderm stuffing = bone, muscle, connective tissue Embryonic endoderm inner lining of gastrointestinal tract

Gluteal Region & Posterior Compartment of the Thigh11/19/2013

Learning Outcomes Describe the bones of the pelvis and thigh Discuss the contents of the gluteal region, including muscles, nerves and vessels SUPERFICIAL o Gluteus maximus o Gluteus minimus o Gluteus medius DEEP Piriformis Obturator internus Obturator externus Gemelli brothers Superior gemellus Inferior gemellus o Quadratus femoris Explain Trendelenburg gait Discuss the greater and lesser sciatic foramina o o o o Explain the anatomy of intramuscular injections to the gluteal region Discuss the muscles and innervation of the posterior compartment of the thigh Semimembranosis Semitendinosis Biceps femoris o Long head o Short head

NM 8 - Notochord, Neural Tube, Segmentation, Myotomes, Dermatomes

Learning Outcomes

Describe the process of gastrulation and the development of the three layered, three dimensional embryo
Third week of gestation gastrulation to establish 3 germ layers in the embryo (ectoderm, mesoderm, endoderm) Source of the 3 layers epiblast These 3 layers give rise to all tissues and organs in the embryo 1. Formation of primitive streak on surface of epiblast narrow groove with slightly bulging regions on either side o Primitive streak dictates body axis, tail end o Cephalic end of the streak Primitive node 2. Cells of epiblast migrate to primitive streak o Become flask-shaped, detach from epiblast, slip beneath it INVAGINATION o Some cells displace hypoblast to create embryonic endoderm o Others lie between epiblast and endoderm to form mesoderm o The rest remaining in epiblast form ectoderm o

Understand the three main tissue types found within the embryo following gastrulation
Trilaminar disc made of 3 layers o Embryonic ectoderm epidermis and nervous system o Embryonic mesoderm stuffing = bone, muscle, connective tissue o Embryonic endoderm inner lining of gastrointestinal tract 2 areas of embryonic disc with only ectoderm and endoderm o oropharyngeal membrane which dissolves to make

stomodeum mouth o cloacal membrane proctodeum anus Describe the development of the notochord 1. Prenotochordal cells in primitive pit move forward until they reach prechordal plate 2. Form notochordal plate in midline of embryo

3. Cells of notochordal plate proliferate and detach from endoderm to form a solid cord of cells called notochord which lies under the neural tube o Notochord serves as basis for axial skeleton o Made of mesoderm/endoderm o Positioned dorsally and longitudinally o Becomes cartilaginous in structure o Over time, notochord disintegrates and the only part left is the nucleus pulposus which is the jelly-like substance in the middle of the spinal disc

Explain the development of the neural plate, groove and tube (NEURULATION)
Neural tube forms brain and spinal cord o ** fundamental, distinguishing characteristic of vertebrates Neural plate o Appearance of notochord and prechordal mesoderm induces ectoderm to thicken and form neural plate Neural groove o Lateral edges of neural plate become more elevated and fold to form neural folds o The depressed midregion is the neural groove Neural tube o Neural folds from both sides come into contact with each other and fuse (zipping occurs at about day 22) o This forms the dorsal, hollow, neural tube o Closure begins in the middle of the embryos back (cervical region) then extends cranially (towards head) and caudally (towards tail) until fusion is complete Cranial end fuses first 3-4 days later (broader region cranial end = brain) Tail end 2-3 days subsequently (narrow caudal end = spinal cord)

Outline vertebral development

Fourth week of development Somites give rise to most of axial skeleton including vertebral column o Somites segmented beads from mesoderm (responsible for myotomes and dermatomes) Ventral and medial part of each somite becomes known as sclerotome give rise to vertebrae Sclerotomes shift position to surround spinal cord and notochord o Sclerotomic segments separated by less dense intersegmental mesenchyme o Intersegmental arteries o Segmental nerves Caudal portion of each sclerotome segment proliferates extensively and condenses into the subjacent intersegmental tissue and BINDS to cephalic half of subjacent sclerotome Incorporation of intersegmental tissue precartilaginous vertebral body The intersegmental mesenchymal cells between the cephalic and caudal parts of the original sclerotome segment fill the space between 2 precartilaginous vertebral bodies and contribute to formation of intervertebral disc along with notochord Notochord persists and enlarges in the region of intervertebral disc and contributes to nucleus polposus

Explain the development of spina bifida and understand its different types and presentations
Neural tube defect = failure of proper neural tube fusion o If spina bifida occurs once it can/will happen again in the next child (congenital) o Folic acid could potentially reduce risk of spina bifida Dramatic decrease shown through studies o Does not affect brain development but interferes with drainage of cerebrospinal fluid (hydrocephalus) Spina bifida occulta defect in vertebral arches covered by skin o Marked by patch of hair on affected region o Lack of fusion of vertebral arches Meningocele fluid filled meninges protruding through defect in vertebral arches and skin to form cystlike sacs o Neurological deficits but not mental retardation Meningomyocele neural tissue (spinal cord) is included into the sac with fluid Raschisis neural folds do not elevate and remain a flattened mass of neural tissue Raschisis (folded neural tissue) **hydrocephaly (fluid accumulation in brain) develops in virtually all cases of spina bifida cystica

Explain how the embryo folds longitudinally and laterally to form an intracoelomic cavity
Up until now, the embryo is a flat disc Simultaneously with neural tube formation, folding of the embryo occurs cephalocaudally and transversely o **Tube within a tube** head fold and tail fold ectoderm wraps around mesoderm and squeezes out endoderm (yolk sac) to only keep a small portion of endoderm as gut lining the rest disintegrates embryo obtains round appearance w/ amniotic sac around ectoderm and everything else inside embryo remains attached to placenta in anterior region

o remnant of yolk sac becomes umbilical cord eventually

Describe how the mesodermal layer begins to differentiate into different parts
17th day of gestation approx. Mesodermal germ layer can be divided into 3 layers o Paraxial forms somites which form axial skeleton, muscles of body wall, neck, and limbs Cells close to midline proliferate and form a thick plate of tissue Somites form from paraxial mesoderm Paired aggregations of mesoderm cells cuboid in shape Segmental form cephalocaudally o Intermediate connects paraxial and lateral plate mesoderm o Lateral Laterally of the mesoderm layer remains thin and is known as the lateral plate Appearance and coalescence of intercellular cavities in lateral plate cause lateral tissue to divide into 2 more layers that are continuous with the mesoderm: Somatic/parietal mesoderm/somatopleural mesoderm Attached to ectoderm and surrounds amnion Helps to form body wall, contributes to dermis, bones, muscles and connective tissue to body wall Splanchnic/visceral mesoderm/splanchnopleural mesoderm Attached to endoderm and covers yolk sac Contributes to inner epithelial surface of gut & digestive organs & most of bladder, urethra, lungs

Describe the origin and derivatives of somites from the paraxial mesoderm
See above Somites push out to make dermatomes and myotomes ***First 7 somitomeres do not form somites*** o give rise to striated muscle of the face, jaw, throat (pharyngeal arches) Ventral + medial part of somite sclerotome to make vertebrate Dorsal + lateral part dermomyotome which contribute to dermis and striated skeletal muscle Arrangement of somites impose segmental pattern on other body tissues o Segmental outgrowth of nerves from spinal cord o Segmental blood vessel outgrowth from aorta o These are related to initial segmental pattern of somites

Outline the lateral mesodermal layers (somatic and splanchnic) See above

Embryology of the Limbs: Myotomes, Dermatomes, Developmental Defects 11/19/2013 9:02:00 AM

Learning Outcomes Understand the germ layers and steps involved in limb development Somatic mesoderm (or somatopleural mesoderm or parietal mesoderm) formed from lateral plate mesoderm and attached to ectoderm Gives rise to dermis, inner lining of body wall, limbs Limbs begin as outgrowths laterally from body Upper limb buds appear first, lower limbs appear 4 days later Buds elongate Distal ends become paddle shaped (digital plate) Grooves appear between sites of digit formation and eventually separate into digits through apoptosis (programmed cell death webbing breakdown) Ectoderm along apex of bud differentiates into ridge-like thickening o Raised at the tip to form AER (apical ectodermal ridge) which is the outer covering of hands and feet Tendons and blood vessels develop from lateral plate mesoderm of limb buds

Understand process of bone formation specifically limb bone formation Ossification occurs at weeks 8-12 Bone development stops at age 25 For intermembranous and endochondrial ossification, see NM histology notes. In short o Intramembranous bone forms directly from vascularized connective tissue membrane Mesenchymal stem cells from mesoderm osteoblasts produce osteoid (collagen type 1, bone specific alkaline phosphatase, other proteins) which mineralizes to form bone trabecular bone (cancellous network of strut supports) Ie clavicle, patella, skull o Endochondrial bone forms through replacement of initial hyaline cartilage model

Cartilage grows within interstitially (from within) and appositionally (add on) on surface 1. Stage 1 a. Hypertrophy chondrocytes enlarge in centre of model b. Chondrocytes enlarge lacunae and matrix forms struts which calcify, depriving cells of nutrition c. Chondrocytes die due to calcification (apoptosis) 2. Stage 2 a. Blood vessel proliferate perichondrium at mid shaft (primary ossification site) b. Inner osteoprogenitor cells differentiate to osteoblasts which lay down woven bone to make periosteum from perichondrium (osteoblasts bind to mineralized matrix and deposit bone matrices) 3. Stage 3 a) primary ossification forms due to osteoblast activity and restrict proliferating chondrocytes to epiphyses of bones 4. Stage 4 a. Osteoclasts come with blood vessel invasion to resorb calcified cartilage and cylindrize shaft b. Activity of osteoblasts and osteoclasts at metaphysis + growth of hyaline cartilage at epiphysis produce growth in length and diameter of bone i. Length epiphyseal plate proliferation towards shaft ii. Width periosteum and cylinderisation 5. Stage 5 a. Centres of epiphyses develop secondary ossification centres when blood vessels invade the epiphyses 6. Stage 6 a. Epiphyses become filled with spongy bone b. As growth ceases in bone the primary and secondary ossification centres fuse c. Cartilage remains on articular surface and epiphyseal plate

a. **blood vessels do not cross growth plates..dangerous for children to damage epiphysis b/c compromise blood supply and growth whereas adults have retinacular arteries Describe how limb muscles develop and migrate to the limb buds Limb muscles (skeletal) are derived from somites o Paraxial mesoderm Dorsolateral region of somite expresses gene to provide progenitor cells for limb and body wall Condensation of migrated mesenchyme cells near base of limb buds to form muscles (invasion to limb bud) Understand how muscles become positioned with respect to dorsal and ventral surfaces of the limbs Slight lateral rotation of upper limb Medial rotation of lower limb Ventral (anterior) = flexors, adductors, pronators Dorsal (posterior) = extensors, abductors, supinators Describe twisting spiral of the dermatomes on the limbs As lower limb bud grows, medial rotation of limb occurs Results in twisting spiral of dermatomes o Affects cutaneous and motor innervation patterns Describe some of the more common congenital limb abnormalities and how they occur Reduction defects o Meromelia part of limb missing o Amelia all of limb missing o Adactyly all digits missing Duplication defects o Polydactyly extra limb elements ie digits Dysplasia malformation of limb (improper formation due to proliferation of cells) o Syndactyly fusion of digits (ie toes stuck together) Club foot is usually seen with syndactyly Sole of foot turned medially Foot adducted and plantar flexed Mainly in males

o Gigantism excessive growth of parts o **dysplasia - the enlargement of an organ or tissue by the proliferation of cells of an abnormal type CAUSES o Aetiology (origin) of most limb defects is unknown o Ideally genetic or teratogenic (environmental) o Most limb defects multifactorial, interaction between environmental factors and genetics Describe how teratogens may affect limb development Effect of some therapeutic drugs o Thalidomide used to be a drug for morning sickness, caused many gruesome birth defects Social drugs

Hip Joint and Popliteal Fossa

Learning Outcomes

11/19/2013 9:02:00 AM

Describe the structures of the different classes of joint found within the musculoskeletal system Fibrous little to no movement o Bones joined by fibrous collagen tissue o Examples sutures between skull bones, inferior tibiofibular joint (syndesmosis - immovable) Cartilaginous some movement o Primary - synchondroses Bone and hyaline cartilage meet Very strong Ex epiphyseal growth plate growth plate between 2 ossifying ends of a bone o Secondary - symphyses 2 types of cartilage present hyaline and fibrocartilage articular surfaces of bone covered in hyaline cartilage and then united by fibrocartilage disc ex pubic symphysis (secondary tends to be midline joint) some movement possible for giving birth Synovial allows movement o Hyaline articular cartilage prevent friction o Capsule keeping it together Medially margin of acetabulum, acetabular labrum, transverse ligament (fills in acetabular notch) Laterally to femur Anteriorly intertrochanteric line Posteriorly 2cm proximal to intertrochanteric crest (halfway) Retinacular arteries capsular fibres reflected proximally from distal attachments (like a fish hook) Blood supply to head of femur Torn if neck of femur fractured avascular necrosis o Synovial membrane

Lines all intracapsular non-articular surfaces (Lig Teres (ligament to head of femur), fat pad in acetabular fossa, inner aspect of capsule) Synovial fluid allows smooth movement as a lubricant Bursae closed sacs of serous membrane Delicate connective tissue membrane capable of secreting fluid to lubricate a smooth internal surface Occurs in locations subject to friction (enables one structure to move more freely over another) Occasionally communicate with synovial cavities of joints SITS BEHIND ILIACUS AND PSOAS MAJOR Hip joint communicates with iliac bursa anteriorly in 10%

o Ligaments Extracapsular Iliofemoral (Y shaped) Ishiofemoral (spiral shaped) Pubofemoral (triangular shaped) Intracapsular Ligamentum teres ligament of head of femur Tranverse acetabular ligament Haversian fat pad o Movement ball and socket o Types of synovial Ball and socket 3 degrees of freedom flexion and extension abduction and adduction medial and lateral rotation ball spherical head of femur with articular cartilage socket acetabulum of hip bone, acetabular labrum (cartilaginous surroundings of acetabulum), and transverse ligament

 acetabular fossa filled in by fat pad Discuss the hip joint, including structure, actions and neurovascular supply Flexion has to cross hip joint o Iliopsoas o Rectus femoris o Sartoris Extension o Gluteus maximus (running or jumping) o Hamstrings (semitendinosus, semimembranosus, biceps femoris) Abduction o Gluteus medius and minimus o Piriformis Adduction o Pectineus o Adductor magnus, longus, brevis Lateral rotation o Gluteus maximus o Deep muscles short lateral rotators Obturator internus/externus Gemelli brothers Quadratus femoris Piriformis Medial rotation o Anterior fibres of gluteus medius o Gluteus minimus Innervation hiltons law: nerves that supply muscles that move a joint also send fibres to the joint itself

o Sciatic nerve hamstrings, posterior compartment + everything below knee o Femoral nerve- anterior o Obturator adductor compartment o Superior and inferior gluteal nerves Discuss hip dislocation and fracture and the complications that may arise as a result of these two injuries

Shentons line inferior margin of neck of femur should form a continuous curve with upper margin of the obturator foramen

Posterior dislocation of hip sciatic nerve at risk Fracture of femoral neck leg appears shortened (muscular pull) and externally rotated o Intracapsular fracture at risk of avascular necrosis + need for hemiarthroplasty half a hip replacement (new head) o Gardner classification Type I valgus (partial) Type 2 complete fracture

Type 3 partial displacement (tear of blood supply) Type 4 total displacement (tear of blood supply) Fracture of proximal femur extracapsular blood supply intact so no need to replace femoral head Osteoarthritis of hip joint - total hip replacement, new acetabular cup and femoral head o Appears to be no space between joint, white due to sclerosis o Signs of osteoarthritis Osteophytes new bone, calcification Subchondral sclerosis (whitening around joint line)

Bone below cartilage Space between articulating surfaces narrower wearing of cartilage Pseudocysts lake of fluid (synovial) from cracks in bone Posterior dislocation and supracondylar fracture of femur risk of injury to popliteal artery Describe the boundaries and contents of the popliteal fossa Diamond shaped intramuscular space behind knee Superiorly hamstring muscles (semitendinosus/membranous medially, biceps femoris laterally) Inferiorly gastrocnemius (medially and laterally) Roof fascia lata pierced by short saphenous vein Floor popliteal surface of femur, capsule of knee joint, popliteus muscle Contents o Popliteal artery (deepest) o Popliteal vein

o Sciatic nerve Tibial nerve Common peroneal nerve o Lymph nodes o Popliteus muscle o Fat Interpret radiological imaging of the hip and popliteal fossa

Extra Notes Blood supply to hip joint Retinacular arteries originate from trochanteric anastomosis Trochanteric anastomosis of vessels o Profunda femoris medial and lateral circumflex femoral arteries o Some vessels from internal iliac superior and inferior gluteal vessels Minor supply from artery of head femur (Lig Teres) **cruciate anastomosis is at the level of lesser trochanter and can act as secondary bypass Popliteal artery Femoral artery which travels down subsartorial canal and passes through adductor hiatus and changes name to popliteal artery Lies posterior to knee and in popliteal fossa Runs vertically down fossa Deepest structure lies on floor Exits popliteal fossa and runs between 2 heads of gastrocnemius Passes under fibrous arch of soleus muscle in posterior compartment of leg Divides into anterior and posterior tibial arteries BRANCHES of popliteal artery muscular branches to gastrocnemius, genicular arteries (5) to knee joint Popliteal vein deep veins of leg + short saphenous joining Sciatic nerve splits in proximal popliteal fossa Tibial (L4 S3) o Runs vertically along middle of popliteal fossa o Passes between heads of gastrocnemius o Supplies posterior compartment of leg Popliteus Gastrocnemius Plantaris Soleus Cutaneous sural nerve Articular to knee Common Peroneal (L4 S2)

o Runs laterally to lie on medial side of biceps tendon o Enters peroneus longus before splitting into superficial (peroneal/lateral compartment) and deep (anterior compartment) branches o Lies on neck of fibula RISK OF INJURY FOOT DROP o Branches lateral cutaneous nerve of leg o Articular to knee joint Popliteus Action unlocks knee o Pulls lateral meniscus posteriorly o Pulls lateral condyle of femur posteriorly Nerve supply tibial nerve Palpation of popliteal artery 2 hands, slight flexion of knee, compress against popliteal surface of femur to feel arterial pulsation Popliteal aneurysm

Leg, Dorsum of Foot, Flexor Retinaculum, Venous Drainage of Lower Limb 11/19/2013 9:02:00 AM
Learning Outcomes Describe the bones of the leg, ankle and foot Bones o Tibia and fibula Form skeleton of leg Connected by interosseus membrane Articulate with each other via immovable proximal tibiofibular joint and distal tibiofibular joint Articulate with femur proximally and tarsal/ankle bones distally Tibia is the weight bearing bone (over 90% of weight on ankle joint) Fibula is NOT part of the knee joint and is only for muscle attachment o Tarsus Composed of 7 tarsal bones that form posterior half of foot Medial talus, navicular, medial/intermediate/lateral cuneiforms Talus weight bearing o Trochlea superiorly (articulates with tibia) o Head, neck, and body Lateral calcaneus, cuboid Calcaneus weight bearing o Sustenaculum tali process that supports talus

o Multiple articular facets Body weight carried primarily on talus and calcaneus Talus articulates with tibia and fibula superiorly and calcaneus inferiorly o Metatarsals 5 metatarsals in mid region of the foot Base towards calcaneus

 Shaft Head towards toes o Phalanges Distal portion of foot Big toe hallux Little toes digitorum Discuss the muscles and innervation of the anterior, posterior and lateral compartments of the leg Anterior (ankle dorsiflexor and primary toe extensors) o Tibialis anterior o Extensor digitorum longus o Extensor hallucis longus o Innervation: Deep peroneal nerve (L5-S1) Posterior (ankle plantarflex and toe flexors) o Superficial Gastrocnemius Weak knee flexor Soleus Does not flex knee b/c it is below knee joint Plantaris o Deep Tibialis posterior Flexor digitorum longus Flexor hallucis longus o Innervation tibial nerve (L5-S3) Lateral (eversion of foot) o Peroneus longus o Peroneus brevis o Peroneus tertius assists in longus and brevis for eversoin o Innervation superior peroneal nerve (L5-S1) Inversion of foot tibialis anterior and tibialis posterior and extensor hallicus longus the tarsal tunnel and its contents Flexor retinaculum makes the tarsal tunnel Helps tendons turn corners Found along medial aspect of ankle joint behind medial malleolus

Identify

Contents (from medial to lateral) tibialis posterior (with sheath), flexor digitalis longus (w/ sheath), posterior tibial artery + posterior tibial vein (venae comitantes) + tibial nerve, flexor hallucis longus (w/ sheath) o Tom, Dick, and a very nervous Harry Recognise the extensor retinacula overlying the anterior compartment tendons Superior extensor retinaculum (transverse band) Inferior extensor retinaculum (y-shaped) What goes through them? o Extensor tendons from extensor hallucis, extensor digitorum, peroneus tertius (tendon that runs anterior to lateral malleolus that looks like another extensor digitorum brevis) o Deep peroneal nerve o Anterior tibial artery (which means dorsalis pedis artery as well)+ venae comitantes Describe the trifurcation of the popliteal artery and the course of the resulting branches Aorta common iliac artery external iliac artery common femoral artery superficial femoral artery popliteal artery genicular arteries anterior/posterior tibial arteries anterior becomes dorsalis pedis artery /posterior splits to peroneal/fibular artery and then into medial+lateral plantar Dorsalis pedis goes deep at first metatarsal and joins with lateral plantar artery **anterior tibial artery goes through hole in superior interosseus membrane

Review the anatomy of the long and short saphenous veins Interpret radiological imaging of the leg Extra notes Tendon sheaths provide lubrication Course of sciatic nerve L4-S3 sciatic nerve tibial nerve and common peroneal nerve

common peroneal superficial/deep peroneal nerve (bifurcation at head of fibula) Tibial nerve genicular nerves sural nerve

Venous Drainage of Lower Limb Inferior vena cava common iliac vein external/internal iliac vein External iliac femoral vein great saphenous vein Femoral vein popliteal vein anterior tibial vein posterior tibial vein and peroneal vein o Short saphenous vein joins up with popliteal vein at popliteal fossa Anterior tibial vein dorsalis pedis vein dorsal venous arch and metatarsal veins Posterior tibial vein plantar veins forming plantar arch digital veins Injury Lateral side of knee joint o Fracture of tibial condyles o Fracture of neck of fibula common peroneal nerve can be damaged Muscles of anterior + lateral compartment are paralysed Foot drop loss of sensation occurs anterolateral leg and dorsum of foot and toes Plantar flexed foot and inverted

Neuromuscular Junction
Learning Outcomes

11/19/2013 9:02:00 AM

Be able to differentiate between skeletal, smooth muscle and cardiac muscle Skeletal o Striated o Attached to skeleton o Usually voluntary control by sensory-somatic system o Rapid, strong contractions o Cell bodies of motor neurons located in ventral horn (gray matter) o Motor neurons lose thick myelinated sheath at motor end plate/NMJ Fine branches with varicosities (swellings) synaptic boutons Synaptic cleft present Boutons lie over postsynaptic junctional folds on muscle Cardiac o Striated Nuclei distributed all over tissue but still in bands

o Rhythmic contraction o Involuntary (autonomic nervous system) Smooth o Non-striated inorderly structure Nucleus distributed all over tissue o Slow and sustained contractions o Involuntary (ANS) o Found in walls of hollow organs (except heart) Describe the sequence of events occurring during neurotransmission at the neuromuscular junction Motor neurons and skeletal muscle fibres chemically linked at NMJ o NMJ motor end plate, junction between terminal of motor neuron and muscle fibretype of SYNAPSE AP travels down large, myelinated motor neurons of sensorysomatic efferent branch causes contraction of skeletal muscle fibres at which they terminate

o ALWAYS EXCITATORY - immediate, quick depolarization to coordinate movement of body 1 axon terminal of motor neuron to form 1 NMJ with 1 muscle cell (1 to 1) depolarization causes voltage-gated calcium channels to open o influx of Ca2+ causes fusion of vesicles to terminal bouton and release of neurotransmitter neurotransmitter ACh passed between nerve terminal and muscle fibre o cholinergic system (excitatory) o acetylcholine is produced in the pre-synaptic terminal of motor neuron by choline acetyltransferase which uses acetyl coenzyme A (Acetyl CoA) and choline as substrates o terminals of motor axons contain thousands of vesicles with NT ACh o AP reaches axon terminal hundreds of vesicles release ACh onto cluster of ligand-gated ion channels in postsynaptic membrane binding triggers opening of specific channels in motor end plate o ligand-gated ion channels opened by ACh (intrinsic receptor channel) o Na+ diffuse in reducing the RMP of -90 mV Creates EPP (end plate potential) by depolarization ion movements depolarize motor end plate, producing MEPP (motor end plate potential or end plate spike) local current flow between depolarized end plate and adjacent muscle cell membrane brings adjacent areas to threshold o depolarizing effect of EPP opens voltage-gated Na+ channels

AP initiated and propagated throughout muscle fibre o Contraction of muscle ACh destroyed by acetylcholinesterase Describe the role of acetylcholinesterase in neurotransmission at the neuromuscular junction On external surface of postsynaptic membrane (next to ligand binding channels) and in synaptic cleft (partly soluble)

Enzyme breaks down NT ACh in NMJ (25,000 molecules per second!!) Na+ channels close Field cleared for arrival of other nerve impulse Characterisation of nicotinic receptors at the neuromuscular junction Receptor for ACh at postsynaptic membrane of skeletal NMJ is muscle type NICOTINIC RECEPTOR o Found at NMJ of skeletal muscles o Also in ANS (ganglion) and CNS Ionotropic carry ions o Ion channel is an essential part of the receptor Mediate very rapid responses Drug nicotine activates this receptor as well Nicotinic cholinergic receptors at NMJ can be blocked by several drugs o Induce paralysis/cessation of breathing o ***respiratory muscles are skeletal muscles too o Curare contains substances that inhibit binding of ACh to nAChR (nicotinic acetylcholine receptor) Paralyzes skeletal muscles D-Turbocurarine + related agents used for neuromuscular blocking for surgical anaesthesia to relax skeletal muscle for full control o Botulinum toxin (Botox) Blocks release of ACh which prevents muscles to respond to nerve impulses Break synaptic proteins for vesicle release Vesicles inhibited to fuse so no NT is released = no contraction Very toxic! 0.0001 mg can kill adult Also treats dystonias (disorder including spasms, involuntary twitches) o Myesthenia gravis immune system attacks motor-end plate ACh receptor Most common primary disorder in NM transmission Too little ACh extreme muscle contraction weakness

Drooping eyelid, cannot hold contraction No influx of Na+ = no muscle contraction Treatment AChE inhibitor (neostigmine acetylcholine esterase inhibitor) to prolong effect of ACh and/or immunosuppressants

Extra Notes Axon hillock last part of soma before AP initiation in axon 2 types of sodium channeling proteins o membrane receptor (ligand) intrinsic o voltage gated Effect of ACh on effector organs o Stimulation only o Inhibition is possible through IPSP (inhibitory post synaptic potential) on dendrites and soma of motor neurons Higher Centres involved in control CNS, motor cortex, basal nuclei, cerebellum (balance)

Foot, Peripheral Pulses

Learning Outcomes

11/19/2013 9:02:00 AM

Describe the arches of the foot, including osteology, supporting ligaments and tendons Medial longitudinal arch o Calcaneus, talus, navicular, 3 cuneiforms, first 3 metatarsals and phalanges o Medial collateral ligaments (deltoid) Anterior tibiotalar Posterior tibiotalar Tibiocalcaneal Tibionavicular Lateral longitudinal arch o Calcaneus, cuboid, 2 metatarsals o Lateral collateral ligaments Anterior talofibular Posterior talofibular Calcaneofibular Transverse arch o Junction between metatarsals and tarsals o Includes cuboid and 3 cuneiforms Maintenance of arches o Bones o Ligaments (spring, plantar ligaments, aponeurosis) o Muscles (flexor tendons)

Explain the movements of inversion and eversion, including participating joints and muscles Inversion sole faces medially Eversion sole faces laterally Tarsal joints o Subtalar (synovial plane joint) Between talus (inferior surface of body) and calcaneus (upper surface) Ligaments medial and lateral ligaments of ankle joint o Talocalcaneonavicular (synovial plane variety TCN)

Clockwise t shaped joint between talus (rounded head), calcaneus (sustentaculum tali), and navicular (posterior concave surface) Ligaments plantar calcaneonavicular ligament spring ligament o Calcaneocuboid Type (synovial plane joint) Anterior end of calcaneus and posterior surface of cuboid Capsule encloses joint with synovial membrane Ligaments long plantar, short plantar, bifurcated plantar o The midtarsal joints are for inversion and eversion Describe the main ligaments of the foot (i.e. spring and plantar) Spring (plantar calcaneonavicular) ligament o Strong o Anterior margin of sustentaculum tali to inferior surface and tuberosity of navicular bone o Holds arches together and stabilizes TCN joint Plantar ligaments (of calcaneocuboid joint) o Long plantar Looks like paw minus 1 finger Strong ligament on undersurface of joint Undersurface of calcaneus to cuboid to bases of 2,3,4,5 metatarsal bones o Short plantar Little medial ligaments Anterior tubercle on undersurface of calcaneus to cuboid o Bifurcated (y-shaped) On top of short plantar medial Lateral limb goes to cuboid Medial limb goes to navicular See NM11

Outline the layers of the sole of the foot Skin thick, hairless w/ sweat glands o Firmly bound to underlying deep fascia by numerous fibrous bands Plantar aponeurosis (deep fascia) o Triangular in shape, occupies centre of sole o Apex attached to calcaneus and divides into 5 slips Each slip divides into 2 and diverge around flexor tendons o Function firm attachment to skin to protect neurovascular bundle o Maintains arch 4 muscle layers

Identify the long tendons in the sole of the foot and their attachments Tendons of flexor hallucis longus and of flexor digitorum longus Tendons of tibialis posterior and peroneus longus Describe the vascular supply of the sole of the foot and the plantar arch Arteries posterior tibial artery behind medial malleolus o Splits into o Medial plantar artery smaller and ends by supplying big toe medially o Lateral plantar artery larger and passes deep to flexor retinaculum to muscles of foot Forms plantar arch Joins with dorsalis pedis artery at first intermetatarsal space Supplies digit arteries to toes Veins o Medial and lateral plantar veins accompany corresponding arteries o Unite behind medial malleolus to form posterior tibial venae comitantes (plexus surrounding arteries assisting in venous return) o

Describe the termination of the tibial nerve into its plantar branches and their areas of distribution Tibial nerve medial plantar nerve and lateral plantar nerve Medial plantar nerve o Muscular branches (sole foot) o Cutaneous to medial 3 and toes Extend onto dorsum and supply nail beds and tips of toes Lateral plantar nerve o Lateral 1 cutaneous nerve + nail beds and tips of toes as well o Muscular branches for sole of foot Describe the surface anatomy of the peripheral pulses of the lower limb and identify these on examination Femoral artery o Midway between ASIS and pubic symphysis (midinguinal point) o Right below it Popliteal artery o Partially flexed knee o Put 2 thumbs on top o Press hard down Posterior tibial artery o Behind medial malleolus o Pulsation felt between medial malleolus + heel Dorsalis pedis artery o Best felt in proximal space at 1 dorsal metatarsal space between tendons of EHL medially and EDL laterally o Cant be felt lower down b/c DPA goes deep Identify some of the more common traumatic injuries to the leg, ankle and foot, such as fractures and dislocations Most injuries of ankle and foot are minor and will heal with conservative therapy (non operative) Fractures exist alone or with dislocations

Toe fractures treated with buddy taping or cast shoe Ligament sprains o Lateral collateral ligament (most commonly injured) excessive inversion of foot with plantar flexion of ankle Anterior talofibular first to be damaged, then calcaneofibular, and then posterior talofibular Rapid changes in direction, esp uneven surfaces o Medial collateral ligament (deltoid) Excessive eversion of foot associated with fracture of tip of medial malleolus b/c such a strong ligament Fractures of shaft of tibia (pilon fracture involve many fragments and enter ankle joint)) o Nutrient artery torn fracture to distal third of tibia o Common, open fractures o High energy fracture Potts fracture (just above ankle) o External rotation and overeversion of foot Lateral+medial malleolus + fragment of tibia o Due to backwards displacement of leg when foot is fixed Bone bruise talus o Fluid build up (edema) + microfractures Tibial stress fractures o Fatigue fractures Bones are constantly remodeling, rate of crack accumulation exceeds remodeling causes fatigue fractures o Insufficiency fractures Calcaneal fracture (lovers fracture) o Caused by fall from height o Bohlers angle of calcaneus is usually 30 40 degrees but for this it is nearly flat 2 lines tangent to calcaneus Extensor digitorum brevis dorsum of foot (soft ball tissue) soft mass anterior to lateral malleolus only muscle on dorsum of foot o Sinus tarsi depression on lateral side of tarsus same level as lateral malleolus

Disappears during inversion injuries of foot and swells up = can be mistaken for extensor digitorum brevis

Autonomic Nervous System I

11/19/2013 9:02:00 AM

Describe the divisions of the nervous system See handwritten notes Be able to define the role, function and regulation of the ANS Involuntary branch of efferent (towards effectors) division of PNS Homeostasis control bodys internal environment (visceral activities) in coordinated manner o Heart rate & circulation, digestion (enteric), respiration Controls o Heart o Lungs o Eye (pupil) o Stomach & GIT o Spleen o Pancreas blood glucose level o Bladder & rectum o Kidney & liver store energy, eliminate surplus, hormones Controlled by o Medulla (in brain stem) Cardiovascular, respiratory, digestive

o Hypothalamus Major role in hypothalamic-pituitary-adrenal gland axis (HPA) adrenal gland stress response Heart rate, BP respiration (via medulla) o Spinal cord Autonomic reflexes not subject to higher control (bypass) Ex urination, defecation Be able to describe in detail as well as differentiate parasympathetic (cholinergic) control of tissues and sympathetic (adrenergic) control of tissues Most visceral organs innervated by both divisions o Can hit both at the same time but responses would be questionable o dual system rapid and precise control over organ/tissues activity o rapid transitions

2 divisions exert mostly opposing effects o ex epinephrine and acetylcholine partial activation under most circumstances o tonic activity constant slight activity even at rest brought by discharges in the motor nerve to the muscle PARASYMPATHETIC (CHOLINERGIC) CONTROL o Restorative, maintenance, repair, filling up energy depleted areas o Rest and digest o Promotes normal maintenance/homeostasis of body Secretion and mobility of different parts of digestive tract (ie enzymes, juices) Also involved in urination, defecation SYMPATHETIC (ADRENERGIC) CONTROL o Activated in emergency situation sudden burst of energy required o Fight or flight o Increase in cardiac output and pulmonary ventilation Blood vessels dilate to allow blood to circulate

quicklyATPO2 o Blood glucose elevated o Digestion slowed down and kidney filtrationfunctions not needed during emergencies o Whole sympathetic system goes off together NOT THE CASE for parasympathetic Understand and be able to describe the neuroeffector junction in ANS 2 neuron chain CNS preganglionic fibre autonomic ganglion preganglionic NT postganglionic fibre varicosities (swelling) post ganglionic NT effector organ Parasympathetic o Preganglionic (long) cranial (X- vagus nerve) and sacral (spinal cord) o Post ganglionic (short) o Effector organ Sympathetic

o Preganglionic (short and myelinated) thoracic and lumbar regions of spinal cord o Sympathetic ganglia lie in a chain along either side of spinal cord SYMPATHETIC TRUNK o Postganglionic (long and unmyelinated) Understand and describe the neurotransmitters and receptors located in the ANS ALL preganglionic are cholinergic (release ACh) Postganglionic parasympathetic nerves are also cholinergic Postganglionic sympathetic nerves are adrenergic Extra Notes Enteric nervous system vast network of nerve fibres that innervate digestive tract (3rd division of ANS) Autonomic ganglia have ACh receptors for neuroeffector junction Adrenal medulla o Extension of sympathetic nervous system o 2 adrenal glands located on each of kidneys (top) o preganglionic fibre directly stimulates hormone release of chromaffin cells which secretes 20% noradrenaline and 80% adrenaline directly in blood to extend duration of their effects o hormones synthesized in medulla of adrenal glands medulla modifies sympathetic ganglion without post ganglionic fibres

Autonomic Nervous System II

Learning Outcomes

11/19/2013 9:02:00 AM

Understand and describe the neurotransmitters and receptors located in the ANS Describe the properties and mechanisms of action of neurotransmitter receptors within the ANS Autonomic NT can stimulate activity in some tissues but have lower activity in others ie noradrenaline accelerates heart rate but decreases contraction of digestive tract Response belongs to the TISSUE not the NT!! Tissue-specific response b/c tissue/organ targets possess 1 or more receptor NT receptor coupling o Ionotropic receptor o Metabotropic receptor (G-protein coupled) Secondary messenger NT receptors of ANS o Parasympathetic ALL ACh receptors but DIFFERENT at ganglion and target tissue o Sympathetic AChR at ganglion Na-R at target tissue Cholinergic receptors 2 types that bind ACh o Nicotinic Found on all postganglionic ANS cell bodies (ganglion) Activated by ACh released from preganglionic parasympathetic/sympathetic nerves Ionotropic, fast reponses (depolarization of post synaptic cell..new AP transmitted) ACh binding opens intrinsic Na+/K+ channel Also activated by tobacco derivative nicotine ** this is the N2 receptor type, N1 is found at skeletal NMJcertain compounds have different effects on each receptor o Muscarinic

Found on effector cell membranes (ie smooth muscle, glands, cardiac muscle) Binds ACh released from postganglionic parasympathetic nerves 5 types of muscarinic ACh receptor M2 inhibitory response On cardiac tissue Receptor couples to increase K+ conductance, inhibit calcium channels Ex decrease heart contraction M3 excitatory reponse Digestive system G protein couples to Ca2+ second messenger system Ex increase glandular secretions, increase GIT motility all are metabotropic receptors slower acting effects which makes sense due to parasympathy also activated by mushroom poison muscarine

Adrenergic receptors 2 major classes that bind NA and AD o Found at effector organ synapses (after postganglionic sympathetic nerves) o All metabotropic, have different sensitivity for NA vs AD Alpha (NA>>AD) Alpha 1 Excitatory Located on most sympathetic target cells G-protein couples to Ca2+ second messenger system Ex increase in contraction of arterioles for raised blood pressure Alpha 2 Inhibitory Digestive system G protein couples to inhibit cyclic AMP system

 Beta Beta Beta

Ex decreased smooth muscle contraction reduced GIT motility 1 (NA=AD) Excitatory Heart couples via G-protein to cyclic AMP/PKA 2 (AD>>NA) Inhibitory Skeletal muscle (adrenaline from blood),

smooth muscle of some vessels and organs Couples via g-protein to cyclic AMP/PKA Ex relaxation of smooth muscle, bronchiolar dilation Describe how parasympathetic (cholinergic) control of tissues relates to pathophysiology of disease Describe how sympathetic (adrenergic) control of tissues relates to pathophysiology of disease Panic attack induces sympathetic activation and activation of HPA axis Blood vessels o Arterioles and veins are innervated by sympathetic NS only **NOT ARTERIES AND CAPILLARIES liver (glycogen stores) o release of glucose (gluconeogenesis) by sympathetic NS sweat glands mainly sympathetic innervation o terminal fibre releases ACh (NOT NA!!!!) EXCEPTION muscarinic receptor o unpleasant odour from breakdown of ACh Extra Notes Higher CNS influence on ANS o Brain cortical pathways can modify autonomic function and vice versa Vagal stimulation suppresses cortical seizures, intractable epilepsy

Other NTs in ANS o Nitric oxide, ATP, vasoactive intestinal peptide o All co-transmitters released by non-neuronal cells to help control function of ANS on target tissue Termination of NT o ACh destroyed by acetylcholinerase at synapses (breakdown to acetate and choline) o Noradrenaline re-uptake by pre/post synaptic cell then metabolized/recycled Steps of neurochemical transmission targets for pharmacological intervention o Nerve terminal (neurotransmitter release) o Post-synaptic membrane (neurotransmitter-receptor interaction) o Neurotransmitter effect termination (neurotransmitter degradation) ANS DRUGS o Mimic ANS responses (agonists) at receptors o Inhibit ANS responses (antagonists) at receptors o Therapeutically useful Atropine (muscarinic antagonist) Blocks parasympathetic actions at effector tissues by blocking muscarinic R Reduces salivary/bronchial secretion (during surgery for example) Salbutamol (beta-2 adrenergic receptor agonist) Dilates bronchioles (treatment of asthma and chronic obstructive pulmonary disease) No effect on beta 1 = no effect on heart Atenolol (beta-1 adrenergic receptor antagonist) Lowers blood pressure treatment for hypertension

Knee, Ankle, and Tibiofibular joints

Learning Outcomes

11/19/2013 9:02:00 AM

Discuss the knee joint, including structure, actions and neurovascular supply Largest and most complex joint in body o However, most unstable joint of lower limb and often injured Synovial joint modified hinge joint (ginglymus) o 2 articular surfaces are molded to each other o little rotation, motion occurs in one place o Actions flexion and extension (only 2 degrees of movement) Medial and lateral rotation occur when knee is in flexion from contraction of hamstring muscles articulating surfaces are o 2 femoral condyles o 2 articular surfaces on tibial plateau o posterior surface of patella (sesamoid bone embedded within tendon) o **fibula does not articulate with knee joint Capsule femoral attachment and tibial attachment with menisci o Extracapsular Patellar ligament lower border of patella to tibial tuberosity Medial collateral ligament Wide and flat Medial femoral epicondyle to medial tibia Attached to medial meniscus Lateral collateral ligament Thin and cord-like Lateral femoral epicondyle to head of fibula

Not attached to lateral meniscus Popliteus tendon intervenes o Intracapsular Anterior cruciate ligament Anterior tibial plateau to lateral femoral condyle Prevents femur from sliding POSTERIORLY on tibia Prevents hyperextension of knee

Posterior cruciate ligament Posterior tibial plateau to medial femoral condyle Prevent femur from sliding ANTERIORLY on tibia Flexed knee Important in walking downhill Medial/lateral menisci C-shaped fibrocartilaginous discs to increase stability in joint Poles attached to intercondylar ridge Deepens articular surfaces and act as a cushion

(shock absorber) Lateral meniscus receives tendon derived from upper 1/2 popliteus muscle Medial meniscus deep fibres of medial collateral ligament attached laterally o Synovial membrane Lines interior of capsule Attached to articular ligaments except for Popliteus tendon which enters joint to attach to femoral epicondyle Runs between capsule and synovial membrane Cruciate ligaments Synovial membrane runs anterior to ligaments **these structures are intracapsular but extrasynovial o synovial bursae suprapatellar handsbreath above patella, behind quadriceps tendon continuous with joint cavity infrapatellar anterior and posterior to patellar ligament can become inflamed does not communicate much with knee joint

others prepatellar = between patella and skin can also be inflamed popliteal gastrocnemial fibular collateral anserinal Blood supply o Genicular arteries from popliteal artery Nerve supply

o Hiltons law any nerve that supplies muscles that moves a joint supplies the joint too Femoral nerve (Sartorius, quad femoris) Tibial nerve (long head of biceps femoris, semitendinosus, semimembranosus) Common peroneal nerve (short head of biceps femoris) Explain how passive rotation of the joint occurs (locking and unlocking) and how this important for stability of the joint Increased stability while standing Locking passive (less energy to stand) o Keeps knee reasonably stable in extension without muscular activity maintaining it Unlocking active o Popliteus muscle laterally rotates femur on tibia by pulling condyle of femur and meniscus back

Explain how to identify ligamentous injuries to the knee joint and their clinical significance ACL o Femur would move posteriorly from tibia Sudden change in movement, direction, o Lachman test/anterior drawer test Sit, knee flexed, pull tibia anteriorly to see if much movement or not PCL o Less common because knee is often not hyperextended

o Posterior drawer test o Harder to manage without PCL Collateral ligament injuries o Medial meniscal is 20x more common than lateral because it is attached to medial collateral ligament Unhappy triad tear in medial collateral ligament, medial meniscus, and ACL o Lateral blow Other clinical injuries in knee joint o Bursitis housemaids knee (prepatellar swelling w/ extra fluid) and clergymans knee (infrapatellar swelling) o Synovial herniation bakers cyst: fluid collection, similar symptoms to DVT o Orthopaedic Knee dislocation lining of popliteal artery may be damaged Supracondylar fracture of femur popliteal artery may be damaged Gastrocnemius pulls down lower condyle of femur Knee replacement (for osteoarthritis) Patellar dislocation and or fracture (pull from quadriceps)

Define the superior and inferior tibiofibular joints Superior tibiofibular joint o Synovial joint o Separate from knee joint o Small degree of movement Inferior tibiofibular joint o Fibrous joint (syndesmosis) immovable o Part of ankle joint Describe the bones of the ankle and foot See NM11 **plantar flexion not as stable because not full surface of talus articulates (ie high heels) Discuss the ankle joint, including structure, actions and neurovascular supply

Type: synovial hinge joint (ginglymus) Movement 1 degree of movement (dorsiflex, plantarflex) Weight bearing inferior surface of tibia, superior surface of talus Stabilization lateral and medial malleoli on either sides of talus Blood supply anterior + posterior tibial arteries, peroneal artery Innervation Deep peroneal (anterior compartment), saphenous, sural, tibial (posterior compartments) and occasionally superficial peroneal (lateral compartment) Ligaments o Lateral collateral ligament Calcaneofibular Posterior talofibular Anterior talofibular (most commonly injured from inversion of foot) o Medial collateral (deltoid) ligament stronger than lateral collateral ligament) Superficial Tibionavicular Tibiocalcaneal (to sestanaculum tali) Plantar calcaneonavicular (spring ligament) Sustenaculum tali to navicular

deep anterior tibiotalar posterior tibiotalar Name some of the traumatic injuries that may occur to the ankle joint or its related structures (i.e. lateral collateral ligament strain) Inferior tibiofibular joint o Disruption of syndesmosis o Rare Ankle joint o Ligamentous sprains lateral are more common (inversion of ankle more common) **anterior talofibular joint o fractures malleolar, bimalleolar, trimalleolar (lateral/medial + fragments of tibia = potts fracture)

o fracture of talus risk of avascular necrosis need screws to treat Interpret radiological imaging of the knee and ankle joints Extra Notes Less important ligaments in knee joint Extracapsular o Patellar retinacula o Oblique popliteal Intracapsular o Meniscofemoral o Transverse ligament

Weightbearing, Locomotion, the Back

Learning Outcomes

11/19/2013 9:02:00 AM

Understand the anatomy of the vertebral column and its curvatures Lordosis o Posteriorly concave curvatures cervical and lumbar Bend into back Kyphosis o Posteriorly convex curvatures thoracic and sacral o Kyphotic curvatures are the primary curvatures; babies start with fully convex spine and then neck and sacrum Vertebral column articulates with ribs (1 rib or a pair of ribs)

Describe a typical vertebra and list the types and numbers of vertebrae within the vertebral column Numbers of vertebrae o Cerebral vertebrae (C1-C7) o Thoracic vertebrae (T1-T12) o Lumbar vertebrae (L1-L5) o Sacrum (S1-S5) 5 fused vertebrae o Coccyx 4 little vertebrae General structure of vertebrae o Spinous process posterior projections o Transverse processes lateral projections o Superior/inferior articular processes o Pedicle connect body to transverse process (before superior articular process) o Lamina bridge between transverse process to spinous process Cauda equina = end of spinal cord o L1-L2 for adults o L3-L4 for children

Outline the ligaments which help support the vertebral column Anterior and posterior longitudinal ligaments o Anterior attached along centrum anteriorly

o Posterior posterior to centrum (anterior to vertebral foramen) Supraspinous o Posterior and longitudinal along each spinous process o Continues as nuchal ligament in neck thicker at neck This is why the transverse processes in cervical spinal segments are not there because the space has to be there for nuchal ligament Interspinous o In between each spinous process Ligamentum flavum o From middle junctions superiorly and inferiorly of spinous and transverse processes o **runs along laminae connecting vertebrae together

Describe the intervertebral joints and the tissues found here Intervertebral joints secondary cartilaginous joint (hyalinefibrocartilaginous disc-hyaline) Fibrocartilage disc annulus fibrosus o Fibres of collagen and fibrocartilage (collagen type 1) Nucleus pulposus middle of intervertebral disc o Inner gelatinous nucleus that gives disc elasticity and compressibility Remnant from notochord

Outline the muscles of the back and the layers of the thoracolumbar fascia Extrinsic limb and respiratory movements o Trapezius o lattissimus dorsi o Levator scapulae o Rhomboids Intrinsic maintain posture and control movement of vertebral column o Superficial Splenius muscles o Deep (post vertebral)

Erector spinae muscles Spinalis (medial) Longissimus (intermediate) Illiocostalis (lateral) Illiocostalis lumborum (lower back) o Transversospinal muscle group (between spinous and transverse processes) All the muscles are enclosed by thoracolumbar fascia o Anterior layer (quadratus lumborum fascia) o Middle layer o Posterior layer

Understand how the different types of movement occur in the vertebral column as a whole and at individual joints Movements o Upright standing o Spinal flexion First 50-60 degrees of motion occurs in lumbar spine o Spinal flexion and pelvic tilting Motion segment 2 vertebral bodies and associated soft tissues o Disc weightbearing o Annulus fibrosus coiled spring holding vertebrae together (collagen fibres) o Nucleus pulposus ball bearing the vertebrate rolling over during flexion, extension, and lateral bending Hydrophilic, gelatinous As we get older, nucleus pulposus becomes less hydrophilic and dries out o Tension and compression between one side of the disc and another Flexion compression in front and tension at the back o Spinal rotation creates shear stress that twist the disc fibres around its periphery Largest shear is on the outside o Facet joint superior/inferior articular surfaces

Provides 40% of spines ability to resist rotational torsion and shear Sustain 30% of vertical compressive loads 15-30% low back pain emanates from facet joints L5 and S1 sustain largest contact forces

Describe the anatomy and symptoms of a herniated intervertebral disc Slipped disc herniated disc Posterior or posterior-lateral protrusion of nucleus pulposus through annulus pulposus o C5/C6, C6/7, L4/5, L5/S1 Posterior longitudinal ligament prevents direct posterior herniation o Usually wont compress spinal cord b/c usually happens in lower lumbar region Nerves can be impacted

Describe the gait cycle, both walking and running Gait analysis assess treatment of leg injuries and in sports science o Pain, injury, imbalances, or inflexibility can cause gait deviations o In order to understand pathological conditions, it is important to understand normal conditions Bipedal walking o Each leg must be able to support body weight Balance must be maintained in single leg stance Swinging leg advances in position where it can take over supporting role Sufficient power needed for limb movements and advance trunk Functional requirements of gait o Stability Against gravitational forces Against inertial forces o Propulsion Add energy to system

o Efficiency (minimize energy expenditure) Minimize changes in kinetic energy and potential energy Shock absorption Prevention of repetitive injury Walking gait cycle o Stance phase (62%) First double support Heel strike (initial contact) Foot flat (loading response accept weight) Single limb stance Midstance heel off (other foot) Second double support Terminal stance (preparing for toe off in other foot) Preswing (and then toe-off) o Swing phase (38%) Initial swing (acceleration) Midswing Terminal swing (deceleration) heel strike o ***double support phase = both feet are in contact with ground (12% of total cycle) represent smooth transition of support from one limb to another Running gait cycle o Stance phase is shortened swing phase lengthened o No double support, instead there are phases in which neither leg is weight bearing called double float o Stance initial contact, absorption, midstance, propulsion, toe off o Swing half of initial swing = double float, midswing, terminal swing (last half is double float), initial contact again o What affects normal running gait? Speed, age, somatotype (body build endomorph, mesomorph, ectomorph) Stride length + cadence (rhythm) affect velocity o Increased speed

Joint motions increase vertical joint stress increases Center of gravity lowered Knee has greater flexion and less extension Ankle plantar flexion can reach 75 degrees Trunk forward lean increases Ground reaction forces increase (force exerted from ground to body) o Multijoint system of movement Propels body forward efficiently Minimizes center of gravity pathway Adjusts to varying surfaces and terrain Contributes to sinusoidal motion Wavelike motion where bodys center of gravity moves This conserves energy and reduces impact forces Much of mechanism is devoted to moving centre of gravity as little as possible to conserve energy o What helps this sinusoidal motion? Pelvic rotation Pelvic tilt Knee flexion at midstance Ankle motion Lateral motion of pelvis TOTAL effect = vertical displacement of c of g during gait cycle is less than 5 cm and lateral sway is less than 5 cm as well However there is much variation in pathological gait

Describe the typical abnormalities of gait that may be seen in clinical practice Aging (non-pathological) o Shorter step and stride length o Reduced cadence (dont walk as quickly) o Greater variation in step length and stride width o Wider base of support

o Result: longer periods of double support time and thus greater stability (psychological) Osteoporosis trabecular bone becomes thinner, cross bridges lost o Any shift in movement abruptly would cause rigidity fracture Antalgic gait (limping) unilateral pain (one side), attempts to shift forces from affected joint Trendelenberg gait excessive pelvic tilt on side opposite injury o Buttock on non-weight bearing side fails to rise waddling gait with excessive shoulder swing o Usually minimus + medius contract allowing leg opposite to come forward Gait Assessment o Patient walks for several minutes o Must observe anteriorly, posteriorly, and laterally o General observations stride length, stride width, cadence (# steps/min), trunk lean, arm swing o Specific observations head and shoulder positions, shoulder movement in relation to pelvic movement, foot and heel positions, knee and hip positions

Extra Notes **** center of gravity is AT S2! SACRUM 2!!!!***

Autonomic Nervous System Pharmacology11/19/2013 9:02:00 AM

Learning Outcomes Understanding of where, and how, the autonomic nervous system can be pharmacologically manipulated for clinical advantage Drugs can target o Sympathetic/parasympathetic Ganglionic synapses/postganglionic-effector organ synapses Drugs can be for.. o Promotion agonists/mimetics o Inhibition antagonists/lytics o Agonists and antagonists are DIRECT b/c they bind to receptors o Mimetics and lytics are INDIRECT b/c they modify agonist synthesis/storage/release/metabolism Can also be direct sympathomimetics and sympatholytics Describe the mechanisms of action, uses, and predictable side effects of commonly used classes of drugs which impact on the adrenergic ANS. Mechanism of noradrenaline in noradrenergic junction to adrenoreceptor o Tyrosine transported into noradrenergic ending via carrier A o Converted to dopamine o Transported into vesicle by VMAT (vesicular monoamine transporter) o Converted into noradrenaline in vesicle o Stimulus of Ca2+ influx causes release of vesicular contents onto adrenoreceptors o Fusion of vesicle back into bouton **fusion of vesicle can be blocked by drugs (ie bretylium and guanthidine) o released NA recycled by uptake via NAT (noradrenaline transporter) **NAT can be blocked by cocaine and TCAD (tricyclic antidepressants) o alpha 1 adrenoreceptor on postsynaptic neuron

high affinity for NA activation causes increase in intracellular Ca ions leading to tissue specific responses ie muscle contraction/secretion o alpha 2 adrenoreceptor on presynaptic neuron inhibits release of NA b/c activation of this receptor decreases production of cAMP negative feedback o NA synthesis L-tyrosine converted to dopa (transported to noradrenergic ending via carrier A) Dopa dopamine Dopamine transported into vesicle by VMAT Dopamine NA in synaptic vesicles NA AD in adrenal medulla Dopamine, NA, AD = catecolamines!

o Be able to classify adrenergic receptor and describe its principal functions Adrenoreceptors ligands adrenaline and noradrenaline o AD and NA are very similar, the only difference is the methyl group (CH3) on NA therefore they interact with the same receptors but with different approaches Classification of receptors into alpha and beta subtypes based on order of potency among agonists o There are selective antagonists for different receptor subtypes o Alpha noradrenaline > adrenaline > isoprenaline Alpha 1 (NA >> AD) (post-junctional) Excitatory Vasoconstriction (constriction of blood vessels to increase BP) Increases peripheral vascular resistance Mydriasis (excessive dilation of pupil) Increased closure of bladder sphincter Decreased motility in GIT Alpha 2 (prejunctional) Inhibition of NA release (negative feedback)

Beta isoprenaline >adrenaline>noradrenaline Beta 1 (NA = AD) post-junctional Stimulatory Tachycardia (increased heart rate) Increased myocardial contractility Increased release of renin (promotes angiotensin in kidney) Increases aqueous humour = Increased intraocular pressure Beta 2 (AD >> NA) post junctional Inhibitory Vasodilation o Decreased peripheral resistance (slightly) to bring blood to skeletal muscle Bronchodilation Increased muscle and liver glycogenolysis o Increased release of glucagon in pancreas (breakdown of glycogen to glucose in liver) Relaxed uterine smooth muscle Relaxed bladder delay need to go to washroom 3 Lipolysis adipose tissue Thermogenesis (skeletal muscle) shivering, tremors

Beta

Outline adrenergic receptor agonists/antagonists as well as being able to explain Indirect adrenergic receptor mimetics/lytics Noradrenaline and adrenaline are natural agonists at alpha and beta receptors (beta also isoprenaline) Always most potent to natural agonists and THEN drugs except isoprenaline Selectivity = less side effects 2 types of adrenergic drugs

o directly acting adrenoreceptor agonists (direct sympathomimetics) adrenoreceptor antagonists/blockers (direct sympatholytics) o indirectly acting sympathomimetics sympatholytics Alpha adrenoreceptor agonists Selective a1 agonists phenylephrine o Cause vasoconstriction o Used as vasopressor (raise BP), nasal decongestant, eye exam (for mydriasis) Selective a2 agonists clonidine o Fall in BP due to inhibition of NA release

Alpha adrenoreceptor antagonists A-receptors determine arteriolar and venous tone in vascular smooth muscle A1,a2 antagonists non-selective (phentolamine) = lowering of peripheral resistance (vasodilation), fall in BP o Unstatisfactory bc induce tachycardia, dysrhythmia, increased GIT activity selective a1 antagonist doxazosin, prazosin o treat hypertension o little effect on cardiac function (this is beta 1s job!) o unwanted effects postural hypotension when you get up from sitting/lying down position, sympathetic reflex causes vasoconstriction to facilitate cardiac return of blood failure of reflex (blocking a1 receptor) = postural hypotension = fainting Phaeochromocytoma neuroendocrine tumour of adrenal medulla o Excessive secretion of catecolamines (hormones from adrenal gland) ie NA AND AD!

o Clinical presentation nervousness, sweating, rapid heart rate, hypertension, GIT pain, irregularly increased breathing pattern o Alpha antagonists used in preoperative management (phenoxybenzamine equipotent on a1 and a2) o B-antagonists may be needed to reverse cardiac effects o Alpha-methyl tyrosine can be used to prevent synthesis of catecolamines = no NA/AD but it is ineffective w/ beta receptors) Other applications of alpha antagonists o Urinary obstruction (sphincter controlled by alpha receptors) o Erectile dysfunction (enhances amount of noradrenaline released) vasodilation A2 antagonist - yohimbe

Beta adrenoreceptor agonists Selective b1 agonist dobutamine o Increase cardiac contractility o All b1 agonists cause cardiac dysrhythmias o Used to treat acute heart failure, bradycardia (low heart rate below 60bpm), anaphylactic shock o Opening of calcium channel (adenylyl cyclase activity stimulated) Selective b2 agonist salbutamol, terbutaline o Smooth muscle relaxant o Treat asthma and COPD (bronchodilator) o Closing of calcium channel (AC activity stimulated) Selective b3 agonist amibegron o Lipolysis treatment for obesity Side effect- can also cause tremors due to other effect Main reason why we dont use as weight loss agents Beta adrenoreceptor antagonists (beta blockers) Selective b1 (cardioselective) atenolol/timolol o Treat hypertension, cardiac dysrhythmia, angina, myocardial infarction, anxiety

o Hazards bronchoconstriction, bradycardia, cardiac failure o Side effects cold extremities, insomnia, depression Propranolol non-selective antagonist for both beta 1,2 Cardiovascular effects o Lower BP Other applications o Respiratory effect increased airway resistance May cause increased airway resistance in B2 receptors but there is NO CLINICAL USE for b2 antagonists o Eye reduce intraocular pressure in glaucoma by reducing aqueous humour production (beta 1) o Metabolic/endocrine inhibit stimulation of lipolysis o Local anaesthetic activity/membrane stabilizing activity

Targets for pharmacological intervention with adrenergic transmission Receptor agonist/antagonists indirect o NT synthesis o Re-uptake of NT into neuron o Re-uptake of NT into post synaptic tissue o Feedback pathway INDIRECT SYMPATHOMIMETICS Amphetamine o Facilitates NA release by displacing NA from vesicles o NA escapes via NAT (norepinephrine transporter) Cocaine, tricyclic antidepressants o Inhibit catecholamine reuptake + metabolism of catecholamine o Maintain transmitter action MAO and COMT inhibitors inhibit metabolism of catecholamine (so it stays there) o Pargyline is also used to treat hypertension Should not eat tyramine-containing foods such as blue cheese and beer = hypertensive crisis

Yohimbine o Alpha 2 adrenoreceptor antagonist permits further NA release o Override autoinhibitory feedback mediated by A2 adrenoreceptors Can also be used to treat ADHD o Release of NA o Alpha 2 agonist

INDIRECT SYMPATHOLYTICS Inhibit NA synthesis o Alpha-methyl-tyrosine = neurotoxin inhibits tyrosine hydroxylase phaechromocytoma o carbidopa = inhibit DOPA decarboxylase treatment for parkinsons keep L-DOPA in the brain, stop conversion to dopamine in bloodstream parkinsons loss of dopamine in brain Inhibit NA storage o Reserpine interrupts NA transport into synaptic vesicles (where high conc of NA should be) o Disrupts synaptic vesicles (VMAT) Inhibit NA release o Bretylium inhibit NA release o Clonidine a2 agonist that inhibits further NA release

DISADVANTAGES OF INDIRECT SYMPATHOMIMETIC/LYTIC DRUGS Broad spectrum o Mimetics potentiate both alpha and beta effects o Lytics = loss in alpha/beta effects Unopposed parasympathetic tone CNS + peripheral ANS effects o Amphetamine, cocaine NA release and euphoria, alertness

Extra Notes Isoprenaline sympathomimetic beta adrenergic agonist medication

Inotrope = agent which increases or decreases force of muscular contractions

Surface Anatomy Nerve Injuries

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Sciatic nerve Spinal nerves L4 S3 Distribution o Muscular Thigh - Posterior compartment of thigh (hamstrings) + adductor magnus hamstring portion Lower leg all 3 compartments (tibial/common peroneal deep/superficial peroneal) All of foot o Sensory posterior aspect of gluteal region + thigh, most of lower leg except for medial aspect, sole of foot o Hiltons knee joint Potential injury (causing sciatica radiating pain in lower back, gluteal region, and back leg) o Intramuscular injections not in upper lateral quadrant Must avoid sciatic nerve and superior gluteal artery o Spinal disc herniation (slipped disc) Posterior or posterior-lateral protrusion of nucleus pulposus can compress or irritate sciatic nerve o Piriformis syndrome (entrapment neuropathy) Anatomical variation sciatic nerve runs through piriformis When piriforimis shortens (short lateral rotator, abductor) or spasms due to trauma or overuse, this can compress the sciatic nerve Wallet sciatica o Spinal stenosis Tumours, inflammation, herniation, etc causing narrowing of spinal canal composed of individual vertebral foramen Compresses/irritates nerve o Total hip arthroplasty o Posterior dislocation of hip Motor deficits o Post thigh + adductor magnus Hip extension

Knee flexion Medial knee rotation Hamstring portion of magnus lateral knee rotation as well o Lower leg + foot Weakness of foot movements inversion, eversion, dorsiflex, plantarflex Sensory deficits o Pain in back of thigh, all of lower leg except for medial aspect, sole of foot

Femoral nerve Spinal nerves L2 , 3, 4 Distribution o Muscular - Anterior compartment of thigh (except psoas major) o Sensory Skin over anterior thigh, knee jerk (patellar reflex) o (also everything in saphenous nerve) o Hiltons knee joint Potential injury sites o Anterior hip dislocation o Trauma o Disease Motor deficits o Anterior compartment of thigh hip flexion, knee extension (quads), lateral rotation (Sartorius) Sensory deficits o Front and medial side of thigh (anterior and medial cutaneous nerves) o Medial aspect of lower leg and foot (saphenous nerve) Patellar Reflex Tests L3, L4 spinal segments and femoral nerve (in addition to skin over anterior thigh for sensory) Patient sitting, hit patellar tendon right under patella (fleshy) Knee extension should occur

Saphenous nerve (from femoral nerve) Spinal nerves L2, 3, 4 Distribution o Sensory medial skin of lower leg, medial skin of foot Potential injury sites o Varicose vein surgery (great saphenous vein) Saphenous nerve accompanies GSV Motor deficits o None because it does not supply any muscle Sensory deficits o Medial skin of lower leg, medial skin of foot

Sural nerve Spinal nerves S1, 2 Distribution o Sensory postero-lateral lower leg, lateral foot o **because it is superficial and its absence would be trivial deficit, it is easy to locate and can be used to nerve biopsy and nerve grafts Potential injury sites o Short saphenous vein surgery Sural nerve accompanies SSV o Achilles tendon rupture surgery Motor deficits o None purely sensory, no deficit in motor aspect Sensory deficits o Postero-Lateral lower leg, lateral foot

Tibial nerve (medial branch of sciatic nerve) Spinal nerves L4-S3 (same as sciatic) Distribution o Muscular Posterior compartment of lower leg, muscles of foot o Sensory Sole of foot (medial and lateral plantar nerves), Heel

Medial plantar nerve medial 3 and toes on sole + nail beds on dorsum Lateral plantar nerve lateral 1 toes on sole o Hiltons knee joint Potential injury sites o Direct trauma (popliteal fossa trauma) o Pressure on nerve (externally or from nearby body structures entrapment neuropathy) Motor deficits o Ankle planterflexion, toe flexion Sensory deficits o Sole of foot, heel weakness

Calcaneal reflex Tests S1,2 spinal segments and tibial nerve Have person lie down in prone position with foot slightly dorsiflexed Using hammer, tap on Achilles tendon Foot should slightly planterflex as reflex (push back) Common peroneal (superficial/deep) Spinal nerves L4-S2 Distribution o Muscular Superficial Lateral compart of lower leg (L5-S1) Deep Anterior compart of lower leg (L5-S1) o Sensory Superficial lower lateral aspect of lower leg, medial aspect of foot, most dorsum of foot Deep skin between big toe and second toe Potential injury sites o Bumper car hit neck of fibula fracture/trauma o popliteal fossa trauma Motor deficits o Foot drop weakness in ankle dorsiflexion (anterior) and eversion (lateral) + toe extension (anterior)

foot is plantarflexed and inverted Sensory deficits o Skin in antero-lateral aspect of lower leg and dorsum of foot (superficial) o Skin between big toe and 2nd toe (deep)

Obturator Spinal nerves L2, 3, 4 (same as femoral) Distribution o Muscular medial compartment of thigh o Sensory medial aspect of thigh o Hiltons knee joint Potential injury sites o Entrapment neuropathy lies between adductors o Surgery on obturator artery, vein Motor deficits o Hip adduction, hip flexion, medial rotation Sensory deficits o Medial (inner) thigh

Lateral cutaneous nerve of thigh Spinal nerves L2, L3 Distribution Sensory only lateral aspect of thigh Potential injury sites o Entrapment neuropathy usually at inguinal ligament Usually passes under but can also go through inguinal ligament causing the parasthesia or pins and needles Various causes Mechanical prolonged sitting, standing, pelvic tilting Intrapelvic appendicitis, abdominal tumour, pregnancy Extrapelvic trauma to ASIS area, tight garments

Motor deficits o None Sensory deficits (meralgia parasthetica)

o Lateral aspect of thigh Superior gluteal nerve Spinal nerves L4, L5, S1 Distribution o Muscular gluteus minimus/medius, tensor fascia lata Injury trendelenburg gait o Difficulty in hip abduction as well

Pulses Femoral below midinguinal point Popliteal knee flexed slightly, 2 hands midline deep in pop fossa Posterior tibial behind medial malleolus Anterior tibial between 2 malleoli Dorsalis pedis lateral to extensor hallucis longus tendon Dermatomes L3 at knee over patella S2 pop fossa L5 under 1st toe S1 under 5th toe Straight leg raise test for disc herniation at L5 (sciatic nerve damage) Lasegues test

Muscle Structure and Contraction

Learning Outcomes

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Be able to describe the structure of the skeletal muscle cell including its distinctive substructures and their functions/properties Striated, voluntary (somatic) Made of connective tissue ability to contract and a little bit of elasticity Lets break it down o Whole muscle (organ) epimysium o Fascicles (groups of muscle cells) surrounded by perimysium o Muscle fibers (cell) surrounded by endomysium o Myofibrils (specialized intracellular structures) Thick (myosin) and thin (actin) filaments cytoskeletal elements and protein molecules Make up 40% of body weight depending on weight, sex Cells can be very large (100 microns in diameter and several cm in length) or small Multinucleate syncytial (single cell w/ multiple nuclei) structure due to myotubes in embryology Understand what myofibrils are and describe the structure and composition of the sarcomere, T-tubule system, triads, actin & myosin, accessory proteins Myofibril = overlapping myosin and actin with accessory proteins o Intracellular structures specialized for muscle contraction Band and zone structures o Z-line separates the sarcomeres (sections of myofibril consisting of actin and myosin) o I-band only actin here at extremities of sarcomere (held together by z-line) o A band where all of myosin extends (thick band) Anchored into place by Z-line Includes H-zone area where there is ONLY myosin thick bands M-line - middle of sarcomere (bisects H-zone)

Many mitochondria, nuclei Sarcolemma plasma membrane of whole muscle Sarcoplasmic reticulum o Surrounds each fascicle o Main deposit of Ca2+ for excitation/cross-bridge cycle o Terminal cisternae w/ receptors on either sides of T-tubules for excitation T-tubules (transverse tubules) o Invaginations of sarcolemma deep into muscle o Carries AP and works with sarcoplasmic reticulum Myosin o 1 thick filament surrounded by 6 thin filaments usually o look like 2 golf clubs next to each other o 2 heads (which form the cross bridges) make a V have actin binding site also myosin ATPase site (to hydrolyze ATP for movement) o 2 tails Actin o Double helix pearl-like structure o Each pearl has a binding site for attachment of myosin head o Tropomyosin filament that holds the structure together and inhibits binding sites by covering them for protection o Troponin protein to which Ca2+ binds to in order to expose binding site for myosin heads Accessory proteins o For anchoring, they maintain structure o Alpha-actinin maintains actin lattice (w/ tropomyosin and troponin) o Dystrophin anchors actin filaments to sarcolemma Muscular dystrophy (wasting away of muscle) can occur when there are mutations/problems with dystrophin

Explain what muscle contraction is and how it occurs Muscles of body shorten to generate tension Sliding filament model

Be able to describe what the sliding filament model is and apply it to muscle contraction Sliding filament mechanism causes muscle contraction brought by cross-bridge interaction between actin and myosin ATP driven enzymatic reaction Actin (thin) filaments slide inwards over STATIONARY myosin (thick) towards M line (centre) o Due to power stroke Pulls Z-lines closer together = sarcomere shortens = entire muscle fiber shortens **A band is always the same, actin does the sliding not myosin o I band shortens (less space between only actin filaments bc slide into A band) o H zone shortens (b/c area where there is only myosin is now with actin as well)

Be able to describe the interactions between actin and myosin in muscle contraction Relaxed no excitation o No cross bridge binding bc site on actin is covered by troponin-tropomyosin complex o Myosin head is in cocked position with hydrolyzed ATP (ADP + Pi) ready to go Excited Ca2+ released o Binds with troponin which pulls TT complex aside to expose cross bridge binding site o Cross bridge binding occurs o Power stroke triggered Describe in detail how a power stroke is generated during a crossbridge cycle Binding myosin cross bridge head binds to actin filament binding site

Power stroke cross bridge bends pulling actin inwards towards Mline Detachment cross bridge detaches at end of power stroke due to binding of ATP and returns to original conformation Binding binds again with distal actin Repeat as long as there is Ca2+ and ATP

Extra Notes Calcium links excitation and contraction (T tubules and sarcoplasmic reticulum) o ACh released at motor end plate and depolarizes it to stimulate skeletal muscle contraction o AP generated over entire membrane of muscle cell carried by t-tubules inside T-tubules have voltage-gated receptors called DIHYDROPYRIDINE receptor which undergo conformational change when there is AP o Causes RYANODINE receptors on terminal cisternae of SR to release Ca2+ in response

Regulation of muscle contraction and energy sources

Learning Outcomes Define and describe the steps involved in excitation-contraction coupling in muscle Somatic motor neuron releases ACh at NMJ Entry of Na+ through ACh receptor-channel = AP AP propagates along sarcolemma (surface of muscle) and T-tubule system Dihydropyridine receptor on TT and ryanodine receptor on terminal cisternae of SR communicate with each other (INTRINSIC LINK) Dihydropyridine receptor acts as voltage sensor (voltage-gated) and causes ryanodine to open Ca2+ channel in response o DHP receptor conformational change due to AP in TT Release of Ca2+ from terminal cisternae to cytoplasm causes intracellular Ca2+ concentration to increase from 10^-7 to 10^-5 molar Ca2+ binds to troponin for myosin head binding to actin Release of ADP and Pi from myosin ATPase on myosin Sliding filament model

11/19/2013 9:02:00 AM

ATP binds to myosin ATPase causing dissociation of cross bridge, hydrolysis of ATP and back to cocked position Relaxation occurs when sarcoplasmic Ca2+ concentration returns to normal by active transport (ATP NEEDED!!) back into SR where it is bound to calsequestrin

Identify and describe the specific roles of calcium, ryanodine and dihydropyridine receptors in excitation-contraction coupling See above Describe the energy sources used and their processes during muscle contraction (ATP, creatine phosphate, glycogen breakdown) Need ATP for muscle contraction (power stroke, active transport for Ca2+ back to SR) o Breakdown of ATP to ADP + Pi releases energy Sources of ATP o Creatine phosphate (fast)

Small store of ATP Creatine phosphate + ADP creatine + ATP (reversible and enzyme creatine kinase needed for ATP) ***high serum levels of creatine kinase = indicator for muscle disease ie myocardial infarction, muscular dystrophy, rhabdomyolysis (severe muscular breakdown), acute renal failure creatine kinase has not been used to generate ATP and creatine o Glucose + glycogen (min, but this is last resort usually) Breakdown of pyruvate to lactic acid (anaerobic) or undergo glycolysis for small ATP production (aerobic) or oxidative phosphorylation for max o Oxidative metabolism of carbs, fats, proteins (hours) Oxygen required, most efficient in making ATP Be able to describe what rigor mortis and malignant hyperthermia are and how/why they occur Rigor mortis o Death results in disappearance of ATP o Myosin heads cannot detach from actin causing muscle rigidity o Ca2+ rises in cytoplasm (failure of Ca2+ pump that needs ATP to go back to SR) o Subsides after several hours/days when contractile proteins destroyed Malignant hyperthermia o Rare disorder where anaesthesia causes rapid rise in body temp, muscle rigidity, rapid heart rate (tachycardia), muscle damage, and death o Caused by abnormal ryanodine receptor (left open) = excessive Ca2+ entering sarcoplasm Increased muscle contractions o Treated with DANTROLENE muscle relaxant to block ryanodine receptor, quick cooling with ice, termination of inhaled gas, IV therapy

Be able to explain the timing of electrical and mechanical events during a single muscle twitch in skeletal muscle Neuron membrane potential in resting = -70 mV o Depolarized to +30 mV and back down o Quick, AP change is fast Muscle fiber membrane potential in resting = -90mV +30mV o Not as fast!! o Latent period (during depolarization and repolarization) for 2 msec o THEN contraction and relaxation phases occur and take about 10-100 msec for full tension generation o As neuron membrane potential is repolarizing/hyperpolarizing, muscle fiber membrane potential depolarizes which is the latent period o Once muscle repolarizes, contraction occurs and relaxation which takes 10-100 msec Extra Notes Tension force exerted by contracting muscle on object o DEPENDS ON # OF MYOSIN HEADS bound to actin shorter the sarcomeres, the more tension produced Load force exerted by object on muscle o OPPOSING FORCES

Muscle Mechanics
Learning Outcomes

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Be able to describe in detail the length-tension relationship that exists in skeletal muscle Tension contracting muscle on object Load object on muscle Whether a muscle fibre will shorten during contraction or remain the same depends on relative magnitudes of tension and load forces o Different depending on muscle workload and its function Length-tension relationship relationship exists between length of muscle before onset of contraction (initial length of muscle) and tension that each contracting fibre can subsequently develop at that length o Isometric contraction tension depends on initial length of muscle before contraction (this is its optimal length for max force) o Initial length-tension relationship curve is constructed by varying muscle length at rest and measuring isometric tension when muscle is maximally stimulated at that length Range of tension Explain why resting length is important in skeletal muscle for muscle mechanics 2 micrometers in length = optimal sarcomere length (maximal tetanic tension) o shortened muscle no power stroke in the middle (not maximal tension) o resting muscle length maximal optimal overlap o stretched (longer sarcomere length) power stroke only acts on the outer edges

Describe and be able to differentiate between isometric, isotonic and eccentric contractions Isometric

o Generate force without changing length Muscle contracts, same tension, no change in length o ex. Move your mouse as arm is flexed or when you are holding a coffee cup, locked position in legs muscles generate sufficient force to prevent object from being dropped, joints of hand dont move isotonic (same tension) concentric and eccentric o causes muscle to change in length as it contracts tension increases until = weight/load to be lifted muscle tension = constant as muscle changes length o causes movement of body part o concentric muscle tension rises to meet resistance, then remains the same as muscle shortens o eccentric muscle lengthens due to resistance being greater than muscle force production

Explain the length-tension relationship in skeletal muscle using Huxleys model Can PARTLY explain the length tension relationship o Tension vs length graph (peak is optimal) Optimal length = length where tension development is maximal (optimal crossbridge overlap) Skeletal muscle is usually near optimal length Ex lung hyperinflation (COPD chronic obstructive pulmonary disease) reduces diaphragm force o Reduction/increase of length of sarcomere = reduction of diaphragm contraction Contractions of whole muscle can be of varying strength o Tension depends on number of muscle fibres contracting within muscle and the tension developed by each contracting fibre Describe what summation and tetanus are and how they occur in skeletal muscle AP of skeletal muscle 5 milliseconds o Muscle can be activated > 200 times per second

o Muscle twitch can have duration of a few hundred milliseconds, never refractory (responds to stimulus, needs it; refractory means not responding to stimulus) Muscle can thus be activated to contract many times even before it was time to relax High frequencies of activation = build up of tension (summation) When maximum tension is reached, complete tetanus Single twitches single, spaced out APs o Muscle relaxes completely between stimuli Summation AP closer together = generate knock-on effect and thus increasingly more tension o Muscle cannot relax fully due to close stimuli summation leading to unfused tetanus where stimuli are still far enough apart to allow muscle to relax slightly between stimuli (still fluctuating at plateau area) Summation leading to complete tetanus o Max steady tension reached = plateau (4-5x twitch tension) o Complete contraction o Fatigue causes muscle to lose tension despite continuing stimuli

Be able to explain what the staircase phenomenon (Treppe) is and how it occurs Muscle stimulated repetitively at a frequency below that which causes summation Progressive increase in tension developed with each twitch until maximum twitch is reached increase tension in twitches How to determine whether it is Treppe, summation, or tetanus with variable frequencies of muscle stimulation? o Low frequency (<10 stimuli/sec) Identical twitch response (there is time for muscle to completely relax) o Moderate (10-20) Treppe phenomenon

Each twitch has time to recover but develops more tension than the one before Calcium not completely back into SR Heat of tissue increase myosin ATPase efficiency o Higher (20-40) Summation and incomplete tetanus Generates gradually more strength of contraction Stimuli arrives before last one recovers Wave/temporal summation Incomplete /unfused tetanus = sustained fluttering contractions (fluctuations) o Maximum (40-50) Complete tetanus twitches fuse into smooth prolonged contraction Muscle has no time to relax at all This rarely occurs in body Extra Notes Muscle mechanics o 2 tension forces relationship between contractile component (sarcomeres) and series-elastics component (plasticity of muscle intracellular titin, connective tissue, tendon) skeletal muscle contraction internal tension myofibrils in the muscle fibers (power stroke) external tension internal tension applied to extracellular fibers to create external tension notebook, rubberband, finger analogy finger is muscle fibers (internal tension) rubber band is attached tendon (external tension) notebook bone of skeleton exert tension w/ finger (internal), rubber band starts to stretch and become stiffer (external tension rises) rubber band becomes sufficiently taut external meets internal tension notebook moves (overcomes friction)

Smooth and Heart Muscle

Learning Outcomes

11/19/2013 9:02:00 AM

Be able to define, describe and differentiate between multiunit and singleunit (visceral) cells in smooth muscle Smooth muscle smaller, unstriated, spindle shaped, single nucleus (no functional syncytium), shorter length than skeletal muscle (10 microns) No z-lines scattered dense bodies instead act to anchor actin filaments (no regular pattern of segmentation) Thin:thick filaments 10-15:1 Multiunit o Each node has a fiber, more spaced out o MYOGENIC controlled solely by local factors, stretch, and hormones (sparse innervation) originates in muscle tissue o Electrically linked by gap junctions functional syncytium Pacemaker cells initiate contraction by itself via electric links spontaneous o Slow wave potential o Ie GIT Single-unit (visceral b/c predominantly in visceral organs) o Appear more clumped together with less fibres o NEUROGENIC controlled by nerves o Rich innervation o Well developed NMJ o No spontaneous activity/AP o No electrical coupling (like multiunit) Lattice structure always around hollow tube so needs less specialized structure to make pushing out movement o Different kind of torsion due to stepping stone structure, turns and wraps o Same power stroke just zigzag shortening Describe what plasticity is and the role it plays in smooth muscle When smooth muscle stretches, it causes contraction but a sustained stretch can also allow relaxation (lattice structure) o Tension - Irregular relationship with length

o Slow and economical with ATP latch phenomenon (enables myosin heads to latch onto actin filaments for a longer period of time to maintain tension with less ATP use) Be able to define, describe and differentiate between excitation-contraction coupling in smooth muscle and heart muscle (particularly compared to skeletal muscle) Smooth muscle chemical change o Comparison to skeletal muscle no t-tubule system, no troponin, poorly developed SR Ca2+ comes from extracellular fluid Chemical change vs physical change in skeletal (repositioning of trypomyosin) Myosin ATPase activity is slow here but fast at skeletal o Calmodulin (protein) bound to Ca2+ from ECF to make calmodulin-Ca2+ complex o Activates myosin light chain kinase o Phosphorylates myosin head (cross bridge) which permits binding with actin o ADP+Pi released o Myosin ATPase activity is slow and muscle contraction is slow and sustained basal level of activity at smooth muscle o Relaxation occurs by pumping Ca2+ by active transport out of cell allowing myosin phosphatase to inactivate myosin head Cardiac muscle o Comparison to skeletal muscle SR moderately developed, 1 terminal cisterna per T tubule (diad) therefore only 1 diad per sarcomere whereas skeletal is triad, tubules occur at z line whereas in skeletal occur at A-I junction Ca2+ comes from ECF (during AP) and SR o AP generated and passes down t tubules o Entry of small amount (10%) of Ca2+ from ECF triggers release of Ca2+ from SR through ryanodine receptors (90%) o Troponin-tropomyosin complex pulled aside

o o o o

Cross bridge between actin and myosin Actin slide inside Contraction Ca2+ exits the cell mainly by ATP-dependent Na+/Ca2+ exchanger (slow removal)

Understand and be able to describe the role of Ca2+ in smooth and heart muscle Skeletal muscle not affected by ECF Ca2+ Hypocalcaemic tetany spasm of skeletal muscle due to increased motoneuron excitability o Low ca conc o More Na+ comes inside cell to correct lack of Ca2+ Smooth and cardiac muscles sensitive to ECF Ca2+ and to agents that affect its entry into cells o Ca2+ channel blocking drugs (verapamil) will reduce contractility of heart and dilate blood vessels

Describe length-tension relationship that determines muscle mechanics in heart muscle Heart cannot modulate force generation like skeletal muscle by changes in motor nerve activity Changes in cardiac contractility (inotropy) result in changes in force generation, independent of sarcomere length What causes cardiac muscle fibers to vary in length prior to contraction? o In response to Preload end diastolic volume Apply Frank Starlings law to muscle mechanics in heart muscle Heart ejects what it receives Greater the filling = larger end-diastolic volume More heart is stretched = longer initial muscle length b/c ejects what receives When exercising, total peripheral resistance in cardiac muscle is lower for higher cardiac output because more input o Opposite for vasoconstriction

Explain why it is that heart muscle cannot be tetanized Muscle fibre length depends on preload (end diastolic volume) o Preload also determines initial muscle length Tension = stroke volume (volume of blood pumped from one ventricle of heart with each beat) Length = end diastolic volume (degree of diastolic filling of heart) Capacity to respond to different EDV to eject what it receives because the initial muscle length constantly changes (FrankStarlings law) therefore.. depends on INOTROPY Heart muscle cannot tetanize, summate o Long action potential cause AP is as long as refractory period o You do not want to increase tension because you want the sys/dia to be regulatedthis is why we have inotropy

Extra Notes Cardiac muscle striated, autonomic innervation, myogenic (pacemaker), interconnected with gap junctions o Regular actin/myosin arrangement striated o Cells joined at intercalated discs w/ gap junctions of low electrical resistance o Not a structural but it is a functional syncytium pacemaker cells initiate AP to be passed down intercalated discs regulating fixed sys/dia Part of troponin complex unique to heart muscle is released into blood following myocardial infarction useful measure for heart damage

Pharmacology of Cholinergic Systems

Learning Outcomes

11/19/2013 9:02:00 AM

Be able to classify cholinergic receptors and describe its principal functions Acetylcholine (ACh) o Quaternary ammonium group Strongly basic, cationic (strong positive charge) o Ester group (COOC) Partially anionic Makes ACh susceptible to hydrolysis o Rapidly hydrolyzed by ubiquitous acetylcholinesterase (ACE) within 1 ms (cleaves ester bond) Cholinergic receptors ACh as NT o Nicotinic also located in brain o NMJ Skeletal muscle NICOTINIC RECEPTOR (N1) o Preganglionic neuron ganglion (sympathetic and parasympathic) NICOTINIC RECEPTOR (N2) Ionotropic receptors (channel-linked) Rapid depolarization Made of different proteins that guard channel 5 subunits 2 alpha, beta, delta, gamma there are variances in subunits and variances in receptor pharmacology 2 ACh molecules bind to 2 alpha subunits channel opens forming ion pore in post synaptic membrane for influx of Na+ and efflux of K+ = AP

AP causes Ca2+ release from intracellular stores and activates contractile machinery 2 types of nAChR differ in structure and pharmacology o Postganglionic neuron Effector organ/tissue (parasympathetic) MUSCARINIC RECEPTOR (M1-M5) **M1-M3 most imp 7TM Metabotropic receptors (G-protein linked)

M1,3,5 increase cellular excitability M2,4 decrease cellular excitability Second messenger cascade depends on receptor M1/M3 IP3 and DAG production from PKC formation (Gq) M2 inhibit adenylate cyclase (Gi) M1/M2 activation of K+ channels or o Inhibition of Ca2+ channels heart, smooth muscle, glands slow transmission (msecs)

Explain in detail the mechanisms of action and uses of commonly used classes of drugs which impact the cholinergic ANS and neuromuscular junction Drugs that affect muscarinic receptors only parasympathetic o Muscarinic agonists Vasodilation Bradycardia Decreased DP Contraction of gut smooth muscle Exocrine secretions Contraction of ciliary muscle for adjustment of near vision Regulation of intraocular pressure Drugs ex Carbachol, pilocarpine treatment of glaucoma (decrease intraocular pressure) Carbachol works on all muscarinic receptors

o Muscarinic antagonists Control bradycardia Dilate pupils for eye exam Treatment of asthma smooth muscle relaxant (bronchodilation) Control secretion of saliva GIT slow down gut motility for endoscopy

GIT control secretion of gastric acid (treatment for irritable bowel syndrome) Anti-nausea/motion sickness/anti-emetic (antivomit) Parkinsons euphoria in brain Drug examples Atropine competitive antagonist, potent anticholinergic, works on all muscarinic receptors Drugs that affect ganglia o Ganglion stimulating (agonist) Nicotine (low dose) Stimulates both para and sympathetic ganglia = multiplicity of effects = no therapeutic usage simply for experimental tool side effects tachycardia, increased BP, increased secretions (both para and sym), variable effects on GI motility o Ganglion blocking (antagonist) Nicotine (high doses) Prolonged depolarization = ganglionic blockade Used for hypertension Other effects inhibition of secretions, paralysis of GI tract during surgery (decrease in motility and tone) Hexamethonium ANS ganglia 6 C distance for 2 alpha receptors Drugs that block neuromuscular transmission/nicotinic receptors (antagonists) o Non-depolarizing Competitive antagonist of ACh at receptor Reversible by anti-AChE drugs (increase number of ACh) Muscle relaxants/paralysis (ie w/ anaesthesia) Drug examples Tubocurare (muscle loses all tone flaccid paralysis)

Side effects fall in arterial BP due to ganglion block (can perhaps induce effect at parasympathetic level) Loss of muscle tone to cause vasoconstriction to bring blood to heart o Depolarizing Cause initial activation of receptors but induce a block due to sustained depolarization/activation of receptors Non-competitive antagonist not reversible by antiAChE drugs blockade is potentiated by anti-AChE drugs Drug examples Decamethonium NMJ 10 C distance for the 2 alpha receptors **both decamethonium and hexomethonium have quaternary ammonium groups similar to ACh so they can bind to the receptors nicotine (high dose) Side effects no ganglionic side effects Hyperkalemia high levels of K+ dysrhythmia (due to channel being open) Prolonged paralysis genetics Good for preanaesthetic

Display knowledge of Indirect cholinergic receptor mimetics/lytics Drugs that affect cholinergic transmission o Indirectly acting cholinolytic drugs can Block choline uptake (ex hemicholimium -- obsolete) Block ACh release Botulinum Toxin (BOTOX) Very potent, irreversible Progressive parasympathetic and motor paralysis Dry mouth, slurred vision Difficulty swallowing, respiratory paralysis

Can be used to treat painful muscle spasms and for cosmetic treatment Beta-bungarotoxin snake venom (Krait) Neurotoxin at presynaptic terminal causes release of ACh until depletion of stores o Inhibitors of cholinesterase (anti-cholinesterase) Combine with AChE (similar structure quaternary ammonium to ACh) to prevent ACh hydrolysis and kill the effect of the enzyme suicide mission Uses Post-surgery reverse non-depolarizing blockage (from ie tubocurare) Glaucoma Myasthenia gravis Short acting and medium duration types They are irreversible (non-competitive) failure to remove ACh from synapse after nerve stimulation stimulatory effect muscle contractions (spasms) muscle depolarization paralysis called organophosphates due to phosphorylation of serine group at AChE active site war gas, pesticides antidote atropine and oxime to restore enzyme functionality b/c they are chemical antagonists of AChE inhibitors due to

greater affinity to organic phosphate residue than enzyme o Stimulants of ACh release Disadvantages of cholinomimetics and cholinolytics o Mimetics potentiate all nicotinic and muscarinic actions o Lytics loss of all autonomic function and impaired voluntary movement o CNS effects as well in addition to PNS

o Solution local application Describe the process of events in neuromuscular junction blockade See above Understand and describe the management of myasthenia gravis Muscle weakness Fluctuating weakness and lethargy Autoimmune disorder Weakness caused by antibodies that block ACh receptors at postsynaptic NMJ May cause resp failure due to exhaustion of resp muscles Treated with immunosuppression and cholinesterase inhibitors o Improve muscle function and reduce autoimmune process o Thymectomy surgery to remove thymus gland o Emergency Plasmapheresis (removing plasma and hence antibodies) IVIG intravenous immunoglobin at high dose Diagnosis o Edrophonium test short acting anti-AchE If muscle weakness temporarily improved, positive Be able to describe and list cholinergic receptor agonists/antagonists See above Extra Notes Cholinergic transmission o Dietary choline = water soluble essential nutrient of Vit B complex o Acetylised in vesicles with acetyl coA o Released by exocytosis M2 inhibitory response On cardiac tissue Receptor couples to increase K+ conductance, inhibit calcium channels Ex decrease heart contraction

M3 excitatory reponse Digestive system G protein couples to Ca2+ second messenger system Ex increase glandular secretions, increase GIT motility

Fast and Smooth Muscle, Disorders of Muscle Function 11/19/2013 9:02:00 AM

Learning Outcomes Define what a motor unit is and describe its properties Motor unit = motor neuron from spinal cord + all muscle fibres it innervates Can be large or small depending on what they innervate o Small = finer control (ie extraocular, hand muscles) When motor neuron is excited stimulus to all fibres (cannot be selective) Single muscle fibre can determine degree of its length and thus tension How is the force of muscle contraction increased? o Recruitment activating more motor units o increase stimulus frequency (by activating more motor units) and thus reach summation/tetanus

Describe the role and clinical application of electromyography in neuromuscular disorders Electromyography (EMG) electrical activity of skeletal muscle recorded with electrodes in or near muscle o Electrodes amplifier recorder We can tell where there are direct discrepancies (ex myasthenia gravis) o Nerve problem? Where?

Be able to characterise the different types of muscle fibres and differentiate between fast and slow muscles 3 types of muscle fibres categorized by oxidative capacities (ability to generate energy) o Type I slow oxidative Always uses oxidative phosphorylation over glycolysis Slower o Type IIa fast oxidative o Type IIb fast glycolytic

Quick generation of ATP (sprinters have a lot of this) o Muscle fibres cannot be both a and b, has to be either or Muscles are dictated by their fibres, role o Slow muscles slow, sustained, tonic (continuous), fatigueresistant Postural muscles Aerobic metabolism therefore higher number of mitochondria, myogloblin, vascularity Appears red o Fast muscles rapid, phasic, intense, fatigued quickly Gastrocnemius Appears white due to lack of mitochondria, myoglobin, and vascularity Adapted for anaerobic metabolism (IIb) o IIa is best of both worlds because its both glycolytic and oxidative Whole muscles contain both fast/slow but majority determines that kind of muscle it is o Whether the muscle fibre is slow/fast is determined by motor neuron (innervation) not its properties o Muscles can change properties if required! See cross innervation experiment below o However, type I cannot become type II fibres (training does not affect numbers..genetics) Endurance athletes will have lots of slow fibres genetically whereas sprinters will have lots of fast muscles The motor neurons in slow fibres are smaller so their cell bodies are more excitable, first to be recruited during moderate contraction Fast muscles are only recruited during intense contractions

Be able to describe the effects of cross-innervation in skeletal muscle Switch nerves of fast/slow muscle with each other o Slow soleus adopted fast muscle functional properties

o Fast flexor digitorum longus adopted properties of slow muscle can achieve same outcome by electrical stimulation of fast muscle at low frequency and vice versa

Define what denervation is and summarise its effects in skeletal muscle Lower motor lesion from spinal cord (lesion of motor nerves to skeletal muscle) flaccid paralysis Fasciculations seen at NMJ, ACh is released due to motor neuron degeneration causing twitching o When this happens for a long time = denervation o The spread of ACh receptors from NMJ to all over sarcolemma causes fibrillations (quivering movements) Denervation hypersensitivity gradually develops Nerve regeneration can reverse this and restore function Failure to regenerate (spinal injury) = type I and II atrophy

Describe what atrophy, hypertrophy and neuromuscular disorders are and be able to give examples and elaborate on common neuropathies, myopathies and junctionopathies Neuropathy - disease or dysfunction of one or more peripheral nerves, typically causing numbness or weakness Atrophy disease of muscle, lose mass o Denervation o Peripheral neuropathy (Type I and II) o Type II atrophy disuse of muscle Aging (sarcopaenia atrophy due to aging) Parkinsons (deregulation in dopenergic neurons) Hypertrophy o Type I and II occur in dystrophies (hereditary condition marked by progressive weakening and wasting of the muscles) Duchenne muscular dystrophy not getting efficient sliding due to lack of dystrophin 3-7 years old, no efficient anchoring of actin

clumsy thick lower leg muscles (hypertrophy) muscle replaced with fibrous tissue = hardened o Type II hypertrophy weight training to increase mass of muscle Motor neuron disease degeneration of upper or lower motor neuron o 3-5 years survival, no cure o no muscle contraction if at lower MN = atrophy multiple sclerosis loss of effectiveness of nerve impulse to demyelination junctionopathy myasthenia gravis (ACh receptor blocked at NMJ and therefore no ACh release into post-synaptic neuron)

Extra Notes Testosterone o Promotes synthesis and assembly of actin and myosin available for contraction o Bulk up