Anatomy, Physiology, Biochemistry Flashcards
SXMaxillary artery first part branches
MAAID
Middle meningeal (foramen spinosum) Accessory meningeal (foramen ovale) Anterior tympanic (petrotympanic fissure) Inferior alveolar (mandibular foramen) Deep auricular (external auditory meatus)
Maxillary artery second part branches
Buccal
Pterygoid
Masseteric
Deep temporal
Maxillary artery third part branches
DIPS
Descending palatine
Infraorbital
Posterior superior alveolar
Sphenopalatine
Infratemporal fossa contents
SPLMMM
Sphenomandibular ligament Pterygoid venous plexus Lateral Pterygoid muscle Medial Pterygoid muscle Maxillary artery Mandibular nerve
TMJ ligaments
1) Capsular ligament
2) extracapsular ligaments:
- Sphenomandibular
- stylomandibular
- lateral ligament
Muscles of mastication
Medial pterygoid
Lateral pterygoid
Temporalis
Masseter
Roof of infratemporal fossa
Infratemporal surface of greater wing of sphenoid bone and temporal bone
- foramen spinosum
- foramen ovale
- petrotympanic fissure
- opens to temporal fossa lateral to infratemporal crest
Infratemporal fossa anterior wall
Posterior surface of maxilla, maxillary tuberosuty
- alveolar foramina
- inferior orbital fissure (upper part)
Infratemporal fossa medial wall
Lateral pterygoid plate, lateral wall of pharynx, tensor and Lebanon veli palatini
- pterygomaxillary fissure
Infratemporal fossa lateral wall
Medial surface of mandibular ramus
- mandibular foramen
Level of bifurcation of common carotid artery
Superior border of thyroid cartilage (C4)
External carotid artery branches
Medial:
- ascending pharyngeal
Anterior:
- superior thyroid
- lingual
- facial
Posterior:
- occipital
- posterior auricular
Terminal:
- maxillary
- superficial temporal
Subclavian artery first branch
1) vertebral artery
2) thyrocervical trunk
- inferior thyroid
- ascending cervical
- transverse cervical
- suprascapular
Subclavian artery second part branches
1) Costocervical trunk
- deep cervical
- highest intercostal
Subclavian artery terminal branches
Axillary artery
Circle of Willis encircles what structure?
1) optic chiasma
2) infundibulum
3) mammillary body
Ophthalmic artery branches
Ocular:
1) central artery of the retina
2) anterior ciliary artery
3) posterior ciliary artery
Orbital:
4) Lacrimal artery
5) zygomaticofacial artery
6) zygomaticotemporal artery
7) supraorbital artery
8) supratrochlear artery
9) lacrimal artery
10) dorsal nasal artery
11) anterior ethmoidal artery
12) posterior ethmoidal artery
Lingual artery branches
Deep lingual
Dorsal lingual
Sublingual
Primary sensory cortex
Brodmann area 1,2,3a, 3b
Post central gyrus
Preliminary processing of contralateral somatosensory information
6 layers of neurons
Modality-specific columnar arrangements
Different cortical zones for propioception and mechanoception
Secondary somatosensory cortex
Upper band of lateral sulcus
Brodmann area 40
Process somatosensory information from both sides of body
Association somatosensory cortex
Posterior parietal lobe
Brodmann area 5,7
Relates sensory and motor processing
To construct abstract map of extra personal space essential for movement -> relate to PMA and SMA for grasping and reaching and tracking
Integrates somatic sensory modalities for perception
Trigrminal nerve divisions
V1 ophthalmic
V2 maxillary
V3 mandibular
V2 maxillary branches
Zygomatic nerve (-> zygomaticofacial and zygomaticotemporal)
Infraorbital nerve
Superior alveolar nerve
Palatine nerve
V1 ophthalmic branch divisions
Supratrochlear nerve Supraorbital nerve Infratrochlear nerve External nasal nerve Lacrimal nerve (SOF) Frontal nerve (SOF) Nasociliary nerve (SOF)
V3 Mandibular nerve divisions
1) Trunk branches
2) Anterior branches
3) Posterior branches
V3 trunk branches
Meningeal nerve
Nerve to medial pterygoid
V3 anterior branches
Masseteric
Deep temporal
Buccal
Nerve to lateral pterygoid
V3 posterior branches
Auriculotemporal
Inferior alveolar
Lingual
Facial nerve motor branches
Temporal Zygomatic Buccal Mandibular Cervical
End of spinal cord (level and name)
Conus medullaris (around vertebrae L1 and L2)
End of dural sac - level
S2
Arterial supply of spinal cord
Anterior spinal artery
Posterior spinal arteries *2
Radicular artery
Segmental medullary artery
Where can one find lateral horn of spinal cord
Spinal cord level T1 to L2
Major function of brain stem
1) allow passage of all ascending and descending pathways
2) contains many cranial nerve nuclei
3) contains reticular formation, which control essential life functions e.g heart beat, breathing, BP
Medulla oblongata structure
Fiber tracts
nuclei of CN V, IX-XII
Pyramid: anterior surface, descending nerve tract, decussation inferiorly
Olives: protrude from anterior surface; olivary nuclei help regulate balance, modulation of inner ear sound
Reticular formation (reticular nuclei - flexor)
Vestibular nuclei
Pons structure
Fiber tracts
Pontine nuclei: anterior portion, relay between cerebrum and cerebellum
Nuclei for CN V - IX; posterior portion
Reticular formation (reticular nucleus - extensor)
Sleep centre
Respiratory centre
Reticular formation function
1) autonomic regulation of vital organ system e.g heart beat, breathing
2) behaviour control
3) somatic motor activities
4) sleep cycle and alertness (ARAS)
6) pain modulation
Midbrain structure
Tracts:
- tegmentum
- corticospinal tract via cerebral peduncle
Nuclei:
- tectum aka corpora quadrigemina: 4 nuclei on dorsal surface; superior and inferior colliculi
- superior colliculi: visual reflex
- inferior colliculi: hearing
- red nucleus: rubrospinal tract (UL flexor)
- substantial nigra: connect with basal nuclei of cerebrum
- CN III - V
Ascending reticular activating system
1) locus ceruleus-norepinephrine system
2) raphe nucleus-serotonin system
3) pontine-acetylcholine system
4) substantia nigra-dopamine system
Function of thalamus
Major relay for all ascending sensory information except olfaction
Controls touch, temperature, pressure perception
Movement control
Diencephalon subunits
Epithalamion
Thalamus
Subthalamus
Hypothalamus
Epithalamus function
Pineal gland secretes melatonin
Subthalamus function
Connects subthalamic nuclei and basal ganglia
–> control movement and emotion
Hypothalamus function
TAN HATS thirst and osmoregulation Adenohypophysis Neurohypophysis (ADH, oxytocin) Hunger Autonomic regulation Thermoregulation Sex
Major Thalamic nuclei
VA (GP -> prefrontal)
VL (motor; BG -> sup MCor)
VPM (face sensation & taste; trigeminal and gustatory -> S1)
VPL (pain, temp, touch, pressure, proprio; spinothalamic trc & DC/ML -> S1)
LGN (vision; CN II -> visual cortex)
MGN (hearing; superior olive and inferior colliculi -> auditory cortex)
Broca’s area
Inferior frontal gyrus, dominant lobe
Assembles motor programs of speech and writing
Non-fluent aphasia
Intact comprehension
Area 44
Fibres of cerebral white matter
1) arcuate fasciculi (gyri within a lobe)
2) longitudinal fasciculi (frontal lobe with other lobes)
Wernicke’s area
Superior temporal gyrus
analysis and formulation of language content
Fluent aphasia
Non-comprehensible
Area 22
Meninges classes
Pachymeninx
- Dura mater (periosteal, meningeal)
Leptomeninx
- arachnoid mater
- pia mater
Molecular Layers of cerebral cortex
1) molecular layer
2) external granular layer
3) external pyramidal layer
4) internal granular layer
5) internal pyramidal layer
6) multiform layer
Choroid plexus component
1) pia mater invagination in ventricles
2) ependymal cells
3) blood capillaries
Composition of CSF
More Na Cl and H ions than plasma
Less Ca K ions, glucose and protein than plasma
CSF function
Nourish the brain
Fluid cushion to protect
Reduce brain weight by 97%
Cerebral artery-cortical distribution
Anterior cerebral - anteromedial surface
Middle cerebral - lateral surface
Posterior cerebral - posterior and inferior surface
Five cell types of cerebellar cortex
Purkinje cells (GABA; dual input; direct from cf; indirect from mf; only cortical output neuron) Granule cells (excitatory neurotransmitter; receive mf) Golgi cells (GABA) Basket cells (GABA) Stellate cells (GABA)
Limbic system components
Cingulate gyrus Mammillary body Amygdala Fornix Hippocampus
Major ascending tracts
Spinothalamic (anterolateral) pathway
Dorsal column-medial lemniscus pathway
Spinocerebellar pathway
Modality of spinothalamic pathway
Touch, pressure (anterior tract)
Pain, temperature (posterior tract)
DC/ML pathway modality
Discriminative touch and proprioceptive information
Spinothalamic pathway neurons
A delta fibre, C fibre
1) ipsilateral dorsal root ganglion
2) ipsilateral substantia gelatinosa; travels through central commisure to contralateral anterior or lateral spinal cord white, where they ascend to thalamus
3) VPL nucleus of contralateral thalamus
DC/LM pathway neurons
A alpha, A beta, A delta fibres
1) ipsilateral posterior root ganglion, do not synapse in spinal cord but pass into dorsal column white (fasiculus cuneatus or gracilis)
2) ipsilateral nuclei gracialis or cuneatus on posterior medulla, leave medulla and cross to contralateral side before reaching thalamus
3) VPL nucleus of thalamus
Foramen ovale contents
OVALE
Otic ganglion V3 mandibular nerve Accessory meningeal artery Lesser petrosal nerve Emissary veins
Foramen spinosum
MMM
Middle meningeal artery
Middle meningeal vein
Meningeal branch of mandibular nerve
Oral cavity boundaries
Roof: Hard palate
Floor: mylohyoid muscle
Side wall: buccinator muscle
Inferior orbital fissure contents
ZIP
Zygomatic branch of maxillary nerve
Infraorbital vessels (inferior ophthalmic vein)
Pterygopalatine ganglion’s ascending branches
Precise origin of buccinator muscle
1) from maxilla
2) from pterygomaxillary ligament (from maxillary tuberosity to hamulus of medial pterygoid plate)
3) pterygomandibular raphe (interdigitates with superior constrictor of pharynx; ends just superior end of mylohyoid line
4) external oblique line of mandible up to first molar
Separation of oral cavity and orophaynx
Palatoglossal arch - aka anterior pillar of fauces
Nasopharynx level
Below the skull and extends down to the level of soft palate (C1)
Oropharynx level
C1 (soft palate) to C3 (epiglottis)
Laryngopharynx level
C3 (epiglottis) to C6 (cricoid cartilage)
Nasopharyngeal epithelium
Respiratory epithelium
Oropharynx epithelium
Stratified squamous epithelium
Laryngopharynx epithelium
Stratified squamous epithelium
Soft palatine muscles and inner cation
Tensor veli palatini (V3 nerve to medial pterygoid)
Levator veli palatini (pharyngeal plexus)
Palatopharyngeus (pharyngeal plexus)
Palatoglosus (pharyngeal plexus)
Musculus uvulae (pharyngeal plexus)
Pharyngeal plexus
Source: CN IX, CN X, CN XI, sympathetic branches from superior cervical ganglion
Sensory: CN IX
Motor: CN XI via CN X
Cartilaginous components of larynx
1 Cricoid cartilage (hyaline)
1 thyroid cartilage (hyaline)
1 epiglottic cartilage (yellow)
2 arytenoid cartilages (hyaline)
Pharyngeal muscles
Circular:
1) superior constrictor [ph plx]
2) middle constrictor (thyropharyngeus [ph plx] and cricopharyngeus [CN X])
3) inferior constrictor [ph plx]
Longitudinal:
1) salpingopharyngeus [ph plx]
2) palatopharyngeus [ph plx]
3) stylopharyngeus [CN IX]
Fibrous components of larynx
Thyrohyoid membrane
Cricothyroid membrane
Quandrangular membrane
Extrinsic vestibular muscles
Elevation: Digastric Stylohyoid Mylohyoid Geniohyoid Stylopharyngeus Salpingopharyngeus Palatopharyngeus
Depression:
Sternothyroid
Sternohyoid
Omohyoid
Intrinsic laryngeal muscles
1) aryepiglottic
2) oblique arytenoids
3) thyroepiglottic
4) posterior cricoarytenoid
5) lateral cricoarytenoid
6) transverse arytenoids
7) cricothyroid
8) thyroarytenoid
9) Vocalis
Sensory nerve of oral cavity
V2, V3
Roof: greater palatine; nasopalatine
Floor: lingual
Cheek: buccal
Hard palate bony component
Palatine process of maxilla
Horizontal plate of palatine bone
Premaxilla
Greater palatine foramen
Greater palatine artery
Anterior palatine nerve
(Between maxilla and palatine bone)
Lesser palatine foramen
Perforated palatine bone
Middle and posterior palatine nerves
Incisive foramen
Greater palatine artery pass up to nasal cavity
Anterior palatine nerve pass up
Nasopalatine nerve pass down
Intrinsic tongue muscle
Superior longitudinal fibres
Inferior longitudinal fibres (along genioglossus, medial to hyoglossus)
Transverse fibres
Vertical fibres
ACTION: change tongue shape:
- transverse: narrow and heap up dorsal into convexity
- transverse + vertical: narrow but dorsum convexity flattened, thus smaller cross section and elongate
- trans+vert+ genioglossus: protrusion
Extrinsic tongue muscles (+innervation)
Change tongue position:
Genioglossus XII -> protrusion
Hyoglossus XII -> draw sides down
Palatoglossus (phary plx) -> raise for swallowing
Styloglossus XII -> retract for swallowing
Tongue venous drainage
Ranine vein -> underside to common facial vein
Lingual vein -> internal jugular vein
Tongue nerve supply
Anterior 2/3
- sense: lingual - taste: chorda tympani - secretonotor: C T
Posterior 1/3
- sense: IX
- taste: IX
- secretomotor: IX
Motor
XII except palatoglossus (pharyngeal plexus)
Functions of saliva
1) fluid lubricant
2) ion reservoir/ remineralisation
3) buffer
4) cleansing
5) anti microbial
6) agglutination
7) pellicle formation
8) digestion
9) taste
10) excretion
11) water balance
Saliva stimulators factors
Chewing
Vomiting
Taste (esp sour)
Food
Levels of Control of salivary secretion
1) vascular
- sympathetic vasoconstriction -> decrease filtration pressure thus scanty secretion
- parasympathetic vasodilation -> increase filtration pressure thus copious secretion
2) myoepithelial cell
- Sympathetic constriction (alpha adrenoceptor -> expulsion of saliva)
- Parasympathetic constriction (muscarinic Ach receptor -> expulsion of saliva)
3) Secretory cell
- sympathetic (beta adrenoceptor) -> protein release and scanty viscous secretion
- parasympathetic (muscarinic Ach receptor -> electrolyte transport and copious watery secretion
Factors affecting saliva composition
1) Gland of secretion (at rest 65% submandibular 20% parotid; high flow rate 50% parotid)
2) Duration
3) Circadian rhythm (Na Cl peak in morning, K peak 12 hrs out of phase, Protein peak in late afternoon)
4) Flow rate (high flow rate -> more Na Cl HCO3, pH)
5) Nature of stimuli -> affects flow rate
Levels of Control of salivary secretion
1) vascular
- sympathetic vasoconstriction (alpha adrenoceptor) -> decrease filtration pressure thus scanty secretion
- parasympathetic vasodilation (Ach muscarinic receptor or VIP receptor) -> increase filtration pressure thus copious secretion
[NOTE: 1) Increase capillary blood flow, increase capillary hydrostatic pressure, increase fluid supply to acinar cells; 2) Increase Arteriovenous anastomotic blood flow, increase venous hydrostatic pressure, increase filtration pressure via back transmission on high venous pressure, increase fluid supply to acinar cells]
2) myoepithelial cell
- Sympathetic constriction (alpha adrenoceptor -> increase intraductal pressure -> expulsion of saliva)
- Parasympathetic constriction (muscarinic Ach receptor -> increase intraductal pressure -> expulsion of saliva)
3) Secretory cell
- sympathetic (beta adrenoceptor) -> protein release and scanty viscous secretion
- parasympathetic (muscarinic Ach receptor -> electrolyte transport and copious watery secretion
Roof of nasal cavity
Frontonasal, ethmoidal and sphenoidal bones
Nose components
Nasal bones
Nasal part of frontal bone
Frontal process of maxilla
Floor of nasal cavity
Palatine process of maxilla
Horizontal plate of palatine bone
How self tolerance is achieved
Clonal deletion Clinal anergy Activation induced self death Sequestration antigen Treg cells (CD4 cd25 foxp3) release TGFbeta IL10
Treg cells antigen and cytokines and function
CD3 CD4 CD25 foxp3
Releases TGF beta and IL 10
- Inhibit potentially harmful immune responses
- prevent autoimmune responses and allograft rejection
Th0 cell cytokines
Precursor of Th1 and Th2
Releases IL2,4,5,6,10,13 IFN gamma and TNF
T helper cells subsets
Th0, Th1, Th2
All expresses CD3 and CD4
Th1 cells nature
CD3 CD4
Induced by IL12 (produced by APC) by induction of IFN gamma
Inhibited by IL4 IL10 IL13
Secretes IL2 (autocrine), IFN gamma, TNF alpha
Activates macrophages
CMI
Lymphatic system components
Lymphatic capillaries
Lymphatic vessels
Lymphatic nodes
Lymphatic trunks
Lymphatic ducts
Lymphatic tissues
Th2 nature
CD3 CD4
Induced by IL4
Inhibited by IFN gamma
Secretes IL4, IL5 IL6 IL10 IL13
Recruits eosinophil
Promote B cells IgE production
Humoral immunity
Lymphatic trunks
Jugular
Subclavian
Bronchomediastinal
Intestinal
Lumbar
Lymphatic ducts
Right lymphatic duct (drains right side of head, right upper limb, right thorax)
Thoracic duct
Lymphatic cells
NK cell B cell -> plasma cell T cell Macrophage Dendritic cell Reticular cell
Diffuse lymphatic tissue location
Throughout the body under moist epithelial membrane ie gastrointestinal, respiratory, genitourinary tracts (eg Peyer’s patches in ileum)
MALT
GALT
BALT
Location of thymus
Superior mediastinum; posterior to sternum and anterior to heart great vessels
Tonsil subtypes and histology
Pharyngeal (roof of pharynx; respiratory epithelium))
Palatine (between palatoglossus and palatopharyngeus arches; stratified squamous)
Lingual (base of tongue, stratified squamous; not as deep tonsillar crypts)
T cell regulating factors released by thymus
Thymulin
Thymopoietin
Thymosin alpha 1 and beta 4
Thymus function
Development of immunocompetent T lymphocytes to produce Th and Tc
Proliferation of clones of mature naive T cell to supply circulating lymphocyte pool and peripheral tissues
Development of immunological self tolerance
Secretion of hormones and factors to regulate T cell maturation proliferation and function
Epithelioreticular cell types
Located in thymus - 6 types
I - boundary of cortex and capsule; serve to separate thymus parenchyma from connective tissue
II - within cortex; stellate with processes and desmosomes that join long cytoplasmic processes on adjacent cells; serve to compartmentise areas for developing T cell, and T cell education
III - between cortex and medulla; functional barrier
IV - in cortex and medulla; close to type III as barrier at corticomedullary junction
V - in medulla; stellate with processes joined by desmosomes
VI - thymic/ Hasall’s corpuscles; flattened nuclei; produces IL4 and 7
Tonsil lymphatics supply
No afferent lymphatic vessels bring lymph into tonsils: supply of tonsillar lymphoid cell is exclusively by blood
Hassall’s corpuscle
Aka thymic corpuscle, found in thymic medulla
Flattened epithelioreticular cell (type VI) wrapped around each other in lamellar fashion and vary in diameter; keratinised, and joined by desmosomes and contain keratohyalin granules
Blood-Thymus Barrier
Found in the thymic cortex:
Epithelial cells form a sheath around capillaries to prevent entry of antigenic materials into spaces between epithelial cells
Blood capillary endothelial cell are not fenestrated
Endothelial cell basal lamina
Thin perivascular connective tissue with pericytes and macrophages
Type I ERCs with basement membrane
–> prevent lymphocytes from premature differentiation
How is thymus different from other lymphoid tissues
1) immature lymphocyte predominates
2) no afferent lymphatics, few efferent lymphatics
3) mature lymphocytes leave and enter blood via postcapillary venules in medulla, never recirculate here
4) blood thymus barrier
5) ERCs with few fibres in medulla
6) Hassall’s corpuscle
7) no germinal centres
What is the largest lymphoid organ
Spleen
Spleen general organisation
Covered by perineum
Encapsulated by dense connective tissue - collagen elastic fibres and smooth muscle fibres
Branching trabeculae derived from the capsule enter the spleen parenchyma
Reticular fibres form spleen stroma
White pulp (splenic nodules) and red pulp (splenic sinusoids) and marginal zone between white and red
No cortex no medulla no afferent lymphatic vessels
Vascularisation of spleen
1) splenic artery in hilum -> trabecular arteries -> central arteries (follicular arterioles) -> continues and displaces eccentrically
2a) central arteries -> periarterial lymphatic sheath PALS and penetrates lymphatic nodule/ white pulp
2b) Central arteries -> displaces eccentrically to penicillar artery, and ends as macrophage sheathed capillaries (phagocytose RBCs)
3) terminal capillary drains to splenic sinusoids (close circulation) or terminates as open-end vessels with the red pulp (red pulp)
4) splenic sinusoids -> drained by pulp veins to trabecular vein -> splenic vein
Primary lymphoid organs
Thymus and bone marrow
-> provide microenvironment for development and maturation of lymphocyte
Location of spleen
Left superior corner of abdominal cavity
Secondary lymphoid organs
Spleen, lymph nodes and nodules, GALT, MALT, BALT, Peyer’s patches of ileum
-> provide environment for lymphocyte interaction with antigens and accessory cells
Splenic White pulp anatomy physiology
I.e. Splenic nodules for immune component
1) central artery leads to periarterial lymphatic sheath PALS (T cells), which follows along secondary lymphatic nodules (B cells)
2) randomly distributed among red pulp cords and sinuses
3) corona with B cells and APCs
4) Activated B cells migrate to germinal centres near central artery
5) Plasma cells migrate to red pulp and release antibody to sinuses
Splenic marginal zone anatomy physiology
Found between red and white pulp, peripheral to periarterial lymphatic sheath PALS around central artery
Receive radial arterioles from central artery
Consist of loose lymphatic tissue with phagocytic macrophage and APCs
Dendritic cells trap and present antigens to plasma cells
This is where blood contacts the splenic parenchyma (macrophage and APCs)
Splenic red pulp anatomy physiology
Supported by reticular fibres - reticular cells and macrophage
Splenic cords = plasma cells and Mac and blood cells supported by reticular stroma
Splenic sinusoids = discontinuous vascular spaces lined by rib shaped endothelial cells oriented parallel along sinusoid long axis
Ring like strands of basal lamina and reticular fibres, as well as macrophages, surround splenic sinusoids
Open circulation (blood vessels opening to red pulp spaces) and closed circulation (blood vessels leading to splenic sinusoids) ---------
Filter to remove ages and damaged RBCs and microorganisms from blood
Storage site for RBCs
Spleen function
Blood——
1) filters blood
2) remove and destroy old and abnormal RBCs; breakdown products, bilirubin and iron are transported to liver via splenic and portal veins
3) blood passes through red pulp before leaving spleen - macrophage remove foreign substances and worn out RBCs via phagocytosis
Immune——–
4) supply effector T and B cells in white pulp, which activated during infection or inflammation
5) immune response to blood borne antigen presented via APCs
6) produce antibodies via plasma cells
7) phagocytosis
Three superficial aggregation of lymph nodes
Inguinal - from lower limb
Axillary - from upper limb and chest
Cervical - from head and neck
Lymph node basic anatomy
1) capsule of dense connective tissue
2) cortex
- trabeculae
- lymphatic nodules with dark corona of B cell; and germinal centre with lymphoblasts and plasmablasts
- mantle zone for memory cell migration
3) paracortex (deep cortex)
- T cells
- HEV (for B and T cell entry)
4) medulla
- mature B cells in medullary cords
- cords separated by medullary sinus
- plasma cells secrete Ab into efferent LVs
- follicular DCs - APC
5) subcapsular sinus
Lymphatics and vasculature of lymph nodes
Afferent lymphatic vessels enter cortex, the postcapillary high endothelial venules HEV enters paracortex and allow lymphocyte entry
Medulla with medullary cords and sinusoids
Efferent vessels at hilum
—- unidirectional flow of lymph:
1) afferent lymphatic vessels and HEV
2) subscapulr sinus
3) Trabecular sinus
4) medullary sinus
5) efferent lymphatics
Functions of lymph nodes
1) defence against foreign substances and toxins
2) filter of lymphs via reticular processes that spans sinuses -> disturb and retard lymph flow to allow time for macrophage phagocytosis of antigens and debris, and allow dendritic cells or B cells to detect for antibody production
3) maintenance and production of immune effector cells
Primary and secondary lymphatic nodules
Primary; mostly small B cells
Secondary: formed in response to antigenic challenge
- follicular dendritic cells and macrophage stimulate B cells to enlarge and prepare for mitosis
- proliferate and for plasma cell formation, producing antibody
Cutaneous mechanoceptors classifications
1) structure
- Encapsulated (meissner’s corpuscle, pacinian corpuscle, ruffini corpuscle)
- Unencapsulated (free nerve endings, hair follicle receptor, Merkel disc)
2) rate of adaptation
- slowly adapting (merkel disc, ruffini corpuscle; skin indentation depth, intensity, form and texture)
- moderately rapid adapting (meissner’s, hair follicle; velocity, motion and flutter)
- rapidly adapting (pacinian; acceleration, vibration, rapid repetitive displacement of skin)
3) modality
Meissner’s - touch, motion and flutter
Pacinian - vibration
Ruffini - skin stretch
Merkel - touch, pressure and form
Hair follicle - direction and velocity of movement
Free nerve - temperature, pain, itch and tickle
Proprioception qualities
1) body position (static limb position and trunk orientation)
2) movement (velocity and direction of joint movement)
3) forces generated by muscle contractions
Proprioceptors
1) muscle spindle (annulospiral and flower spray endings, gamma motor neuron control; sense extension - static ie muscle length and stretch - and dynamic is velocity of stretch)
2) Golgi tendon organ (sense muscle tension ie contraction)
3) joint receptor (free nerve endings and corpuscular receptors; for dynamic response; group II II IV fibres, found in connective tissues capsule and ligament of joints)
4) cutaneous mechanoceptors help
How to test for propioception
Romberg test
Patient maintain balance while standing with feet together and eyes closed
Spatial perception source
Proprioceptors
Labyrinth receptor in inner ear
Visual input
Temperature sensation
I) Static temperature detection
- detection constant skin temperature
- cold and warmth receptors
- localisation only accurate when accompanied by tactile activation
- at temperature extremes adaptation won’t occur
II) dynamic temperature sensation
- detect change in skin temperature
- depends on:
i) initial skin temperature (threshold for warmth and cold)
ii) rate of temperature change (more rapid more easily sensed)
iii) area of activated skin (spatial facilitation)
Thermoreceptors
Central Thermoreceptors
- hypothalamus and spinal cord
- thermoregulation
Cutaneous Thermoreceptors
- cold and warmth receptors
- conscious sensation of temperature
- thermoregulation
Somatosensory information, after somatosensory cortices, will be conveyed to where?
1) motor system - as continuous sensory feedback
2) limbic system eg hippocampus - for emotion and memory
3) polysensory association cortex in temporal lobe - for creation of abstract sensory map of external world
Pain definition
the subjective perception of aversion or unpleasant sensory and emotional experience associated with actual or potential tissue damage
Stimulus characteristics encoding
1) modalities
2) intensity coding
- stimulus converted to electrochemical energy
- amplitude of receptor potential and frequency of afferent fibres modulation
- population coding of recruitment
3) temporal coding
- duration of stimuli measured by discharge of receptors of different adapting speed (rapidly - onset and termination; slowly - duration)
4) spatial localisation
- receptive field
- dermatomes and sensory homunculus
- somatotopic projection
5) spatial acuity -> 2 point acuity
- size of receptive field
- innervation density
- lateral inhibition
- convergence
Nociception definition
the reception of signals in the CNS evoked by activation of nociceptors that provide information about tissue damage
Types of pain
A) Somatic pain
i) Superficial pain (skin; initial pain vs delayed pain)
ii) Deep pain (bones, joints, muscles)
B) Visceral Pain (viscera eg liver, kidney stones)
nociceptors
- Non-specialised free nerve endings
- high threshold
- non-adapting
- majority multimodal
- brain lacks nociceptor
- A-delta fibres or C fibres as afferent nerve fibres
Nociceptive afferent fibres
1) A-delta fibres
- finely myelinated
- larger diameter than C
- intense mechanical stimuli
- sharp, pricking sensation
- fast and first pain
2) C fibres
- unmyelinated
- smallest diameter
- multimodal stimuli
- burning sensation
- slow and second pain
Double Pain Physiology
A brief painful stimuli may give rise to two separate pain sensation to certain body surface as A-delta and C fibres produce different pain sensations
Pain stimuli
Associated with actual or potential tissue damage:
1) Mechanical
2) Thermal
3) Electrical
4) Chemical
Peripheral pain transduction
1) Direct from stimuli to nociceptors
2) Indirect via mediator release e.g. tissue damage releases damage byproducts and inflammatory cytokines that stimulate nociceptors; prostaglandin will sensitise nociception
Pain sensitization
A physiological process after an injury that helps healing by ensuring that contact with the injured tissue is minimised until repair is complete
tissue damage -> inflammation -> prostaglandins and bradykinin sensitise nociceptors, causing primary (at stimulation site) or secondary (site remote from original injury) hyperalgesia
Allodynia -> normally innocuous stimuli perceived as pain
Ascending pain pathways
Body and limbs -> A delta and C -> dorsal root ganglion -> substantia gelatinosa -> crosses ventral commissure -> ascent along Anterolateral system -> VPL of thalamus
Face and head -> A delta and C -> trigeminal nerve -> trigeminal nucleus -> cross midline via trigeminothalamic system through trigeminal lemniscus -> VPM of thalamus
At thalamus -> specific thalamocortical system (topographically represented) or non-specific thalamocortical system (emotional and affective aspects of pain)
Cortical projection to SI (discrimination, localisation and meaningful interpretation of pain), SII somatosensory cortex , anterior cingulate gyrus, and insula (affective components of pain)
Anterolateral system of ascending pain pathway
From body and limbs to VPL
1) Lateral spinothalamic tract
- specific thalamocortical system
- Specific thalamic nucleus to S1
- For localisation, and discrimination of pain
2) Spinoreticular tract
- to reticular formation (ARAS)
- non-specific thalamocortical system
- Intralaminar thalamic nuclei, diffuse projection to cerebral cortex in relation with limbic and hypothalamus
- for arousal, autonomic reflexes and emotional aspects of pain
3) Spinomesencephalic tract & spinotectal tract
- to midbrain and periaqueductal gray
- for affective and aversve behaviours associated with pain, initiates orienting responses, and descending pain modulation
Descending pain modulatory pathways
1) Frontal cortex and Periventricular area -> midbrain periaqueductal gray -> nucleus raphe magnus in medulla -> superficial layers of dorsal horn
2) parallel descending system from noradrenergic locus ceruleus in upper pons -> medulla -> dorsal horn
Neurotransmitters in pain pathway
Peraqueductal gray: serotonin, glutamate, opioid neuropeptides
Nucleus raphe magnus: serotonergic
Locus ceruleus: noradrenergic
Spinal cord dorsal horn: Enkephalin
Nociception characteristics
1) Modalities -> A delta and C afferent contribute to different nociceptive modalities (e.g. pricking vs burning)
2) Intensity Coding
- stimulus converted to electrochemical energy
- amplitude of receptor potential and frequency of afferent fibres modulation
- population coding of recruitment
- psychological factors
3) Temporal Coding
- little adaptation; protective
4) spatial localisation; poor because:
- low innervation density
- wide receptive field
- branching and convergent ascending fibres
- coarse topographical representation
- -> localisation aided by contribution from non-nociceptive modalities
Errors in localisation
Projected pain and referred pain
Projected pain (and examples)
Pain is incorrectly localised when ascending pathway is stimulated unnaturally
Pain sensation projected to receptive field of stimulated nerve
e.g. Spinal root compression
Ascending tract compression
Phantom Limb
Referred pain (presentation and examples)
Excitation of visceral nociceptors sensed as originating from superficial sites
Visceral pain referred to cutaneous dermatomes that share the same dorsal root (dermatomal rule)
Viscerotomes arranged according to original embryonic locations
e. g. myocardial infarction, angina; acute appendictitis, gall stone colic, renal colic, ureteric colic
Referred Pain mechanism theories
1) Axon reflex -> visceral nociception branch cause antidromic activation of cutaneous branch
2) Convergence-Projection: convergence of nociceptive cutaneous and visceral receptors onto same pool of second or higher order neutrons
3) Convergence-Facilitation: excitation of visceral afferent facilitates pain stimulus transmission from superficial pathways
4) Psychological
Body reaction to pain
1) Local reaction (triple response -> redness, swelling, warmth)
2) Reflex action
- Somatic reflex (cutaneous - flexion withdrawal; visceral - overlying muscle contraction eg peritonitis guarding)
- Autonomic reflexes (Sharp - increased sympathetic activities; Dull - decrease sympathetic activities, nausea)
3) Behavioural and emotional response
Two basic modes of muscle contraction
1) Phasic contraction
- discrete movements
- transient contraction
- rhythmic repetitive contraction e.g. walking
2) Tonic contraction
- stabilise joints eg postural maintenance
Types of movement
1) Reflex
2) voluntary movement
3) Autonomic/Rhythmic motor patterns
Motor Unit
motor neuron + muscle fibres that it innervates
Control of muscle contraction force
1) Frequency coding -> increase in frequency of firing of motor neurone allow summation of successive muscle twitches
2) population coding -> motor units recruited in fixed order from weakest to strongest
Features of reflex movement
Simple Rapid Stereotyped Involuntary Protective Controlled and elicited by stimulus
Features of automatic rhythmic movement
Repetitive movements e.g. walking running swallowing
Only the initiation and termination is voluntary; once initiated, sequence of movement is stereotyped, repetitive and automatic
Voluntary movement features
1) Complex, goal-directed (purposeful)
2) Learned (performance improve with practice -> greater practice will reduce needed conscious direction)
Nature of organization of motor control and its benefits
1) Hierarchical organization (3 level of cerebral cortex, brainstem and spinal cord)
- allow lower level to generate stereotyped movements, leaving higher centres free to generate motor commands without specifying details
2) Parallel organization
- permits higher centres to adjust spinal circuitry operation
- allows independent control of function
Motor cortex inputs
1) Sensory input:
- Somatosensory (e.g. joints, muscle spindle)
- Vestibular
- Visual
2) Corticocortical inputs
3) Subcortical inputs (via thalamus)
- Basal ganglion
- Cerebellum
Spinal cord level of motor control
Ventral horn contains lower motor neurons (final pathway for motor execution)
Somatotopically arranged with medial innervating axial muscles and lateral innervating distal muscles
Provides:
i) stereotyped response e.g. stretch reflex
ii) stereotyped motor coordination e.g. flexion reflex
iii) Rhythmic locomotor pattern e.g. walking swimming (can function with brain disconnection)
Classes of brainstem motor neurons
1) Somatic motor neurons (extraocular muscles and tongue intrinsic muscles via CN III, IV, VI, XII)
2) Special visceral motor neurons (striated muscle that control chewing, facial expression, larynx and pharynx; via CN V, VII, IX, X, XI)
3) General visceral motor neurons (parasympathetic preganglionic neurons innervating glands, blood vessels and smooth muscles)
Descending motor system for brainstem modulation
1) Lateral descending system
- rubrospinal tract
- terminates on dorsolateral spinal grey
- control of goal-directed movements, especially arms and hands (distal body parts)
2) Medial descending system
- vestibulospinal, reticulospinal and tectospinal tracts
- terminate on ventromedial spinal grey
- control of posture by axial and proximal muscles
Brainstem motor functions
1) provide motor innervation to head and neck
2) modulate spinal motor neuron and interneuron activities
3) controls posture by intergrating visual, vestibular with somatosensory information
4) Movement coordination and head and eyes
Sensory information’s importance to motor function
1) Highest level
- generate a mental image of body and its relationship with environment
2) Middle level
- tactile decisions based on memory of sensory information from past movements
3) Lowest level
- sensory feedback used to maintain posture, muscle length, tension before and after each voluntary movement
Primary motor cortex
Location: Brodmann area 4;
Precentral gyrus of frontal lobe from midsaggital sulcus to lateral sulcus
Input: receives input from PMA and SMA, direct projection from sensory area in parietal lobe and thalamus, indirect projection from cerebellum and basal ganglion
Output: terminate directly (corticospinal tract or corticobulbar tract) or indirectly (via thalamus) on spinal cord
To striatum, thalamus and pons; form elaborate neural loops through basal ganglia and cerebellum
Function: main generator/initiator of projecting signal to spinal cord; discharge frequency encodes the force of movement; direction-encoding by different populations
(note: fine digit control vai corticospinal tract)
~lowest stimulation threshold
Premotor cortex
Location: Brodmann area 6; immediately anterior to M1
Input: posterior parietal cortex (SA? for visual and somatosensory cues)
Output: medial descending system to brainstem and spinal cord to control proximal and axial muscles;
corticocortical projection to M1 for distal muscle control
Function: Sensory guidance
- proximal and axial muscles for initial phases of body and arm target orientation
- distal muscle control
~ highest stimulation threshold
Supplementary motor area
Location: Medial part of brodmann area 6; buried within the longitudinal fissure
Function: planning of movement (not directly with execution), sequence of movement, programming complex movement, coordinating bilateral movement
Efferent output from motor cortex
1) Corticospinal tract (pyramidal tract) - from middle and medial precentral gyrus
2) Corticobulbar tract - from lateral precentral gyrus
Corticobulbar tract
Origin: Motor cortex (lateral precentral gyrus - face areas)
Terminal: cranial motor nuclei (III-XII except VIII) in brainstem (all bilateral; except hypoglossal XII and lower half of facial nuclei VII which are contralateral)
Cerebellum peduncles
Superior peduncle
- output to midbrain
- ascending thalamocortical projection
Middle peduncle
- input from pons
- cortico-pontine-cerebellar circuit (pontine mossy fibres)
Inferior peduncle
- Mainly input from medulla
- spinocerebellar tract (mossy fibres)
- olivocerebellar tract (inferior olive - climbing fibres)
Cerebellum lobules
10 lobules
I to VIII lobule divided to 3 sagittal zones
IX and X are nodulus and flocculus
Cerebellum functional zones
Spinocerebellum (medial)
- vermal cortex (fastigial nucleus)
- intermediate cortex (emboliform, globose nuclei)
Cerebrocerebellum (lateral)
- hemispheric cortex (dentate nucleus)
Vestibulocerebellum (flocculonodulus)
Cerebellum input fibres
1) Mossy fibres (major afferent, e.g. spinocerebellar tract, cortico-pontine-cerebellum circuit)
- terminates at granule cells -> parallel fibres that terminates on the dendritic tree of parking cells
2) Climbing fibres (olivocerebellar tract)
- from inferior olive in medulla (with source from ruber)
- terminates <10 purkinje cells
Spinocerebellum function
Error-detector by comparing command signals (from cerebral cortex via cortico-pontine-cerebellar circuit) with the updated feedback of executed motor action via spinocerebellar tract –> moment to moment mistake correction
1) Medial corticonuclear zone (fastigial nucleus):
control postural and voluntary movement of axial and proximal muscles via
i) ventromedial descending system - vestibulospinal tract (deiters) and reticulospinal tract (ret form)
ii) ascending thalamocortical projection -> act on corticospinal component of ventromedial descending system (i.e. ventral corticospinal tract)
2) Intermediate corticonuclear zone (emboliform and globose):
coordinate voluntary movement of distal body parts via:
i) lateral descending system - rubrospinal trdact
ii) ascending thalamcortical projection -> act on corticospinal component of lateral descending system (i.e. lateral corticospinal tract)
Cerebrocerebellum function
1) Movement design (from association cortex) via cerebro-pontine-cerebellar tract reach dentate, are converted to movement programs and sent to premotor cortex via thalamocortical projection for subsequent execution of goal-directed voluntary movement (esp oculomotor control)
2) Cognitive processes
Vestibulocerebellum
1) Control of vestibulospinal reflex (postural movement via axial motor system)
- via lateral vestibulospinal tract and reticulospinal tract (ventromedial descending system)
2) Coordination of vestibule-ocular reflex
- controlled by flocculus
Vestibular nuclei
in medulla oblongata
Input: vestibular apparatus
Output: limb and trunk muscles -> extensor
Function: equilibrium and balance e.g. vestibulospinal reflexes
Red nucleus
in midbraine
Input: cerebral cortex and cerebellum
Output: rubrospinal tract -> UL flexor
Reticular nuclei
Medullary - flexor
Pontine - extensor
Central sulcus
division between frontal and parietal lobe
Sylvian fissure
divides temporal lobe from frontal and parietal lobe
Cerebral cortex input and output at molecular level
thalamus and other cortical region –> layer 4 (thickest in S1) –> spread to superficial and deep layers –> Layer 3 and 5 (thickest in M1) send output to other regions
Cerebral cortex pyramidal cell
conical cell body
apical and basal dendrites
Axon leaves base of cell to white matter
Cerebral cortex granule cells
small round cell body
interneurons that receive input from cortical afferent fibres
synapsing in output neuron
Frontal lobe function
- speaking and muscle movements
- making plans and judgements
Higher:
- problem-solving
- self-motivation
- planning
- mental tracking
- abstract thinking
- general motor control
Parietal Lobe function
- Somatoesthetic interpretation
- understanding speech
- formulate words for expression
- interpretation of shape and textures
Higher:
- space orientation
- complex movement
- recognition of self and world
- perception and integration of sensory data
Occipital lobe function
- opposite visual field’s visual information
- correlate visual image with previous experience
- integrate eye accommodation
Higher: visual and related info
Temporal lobe
- Contralateral auditory information
- Memory of auditory and visual experiences
Primary cortices
S1 and M1
Secondary cortices
PMA and SMA
S2
Tertiary cortices
Association cortex
Multimodal association
- from all sensory modalities
- handle complex function
Prefrontal association area
Works closely with motor cortices
- spatial coordinates of body
- effective motor planning
- circuitry for word formation (Broca’s)
- problem solving, self motivation, planning, abstract thinking, mental tracking
Parieto-occipito-temporal association area
Polymodal sensory high level analysis and interpretation of signals (visual, auditory and somatosensory inputs)
- memory
- spatial coordinates
- Language comprehension (Wernicke’s)
- Written words’ visual processing
- Naming of objects
Dominant hemisphere
Function: language, fine motor control
In 99% right handed, 50% left-handed -> dominant is left hemisphere
How to map brain activation
CT fMRI PET EEG MEG
Intelligence tests
IQ -> standardised test adjusted to a ge
Wechsler Adult intelligence Scale III
Folstein Mini Mental Status Examination (MMSE)
MMSE
Folstein Mini Mental Status Examination
Scale of 0-30: - Copying - Attention - Registration - Recall - Orientation - Language CARROL
Normal ageing neurological changes
- Decline in speed of central processing
- Decline on timed task performance
- Decline in recent memory retrieval
- Decline in new learning
- Decline in performance IQ
- presbyopia
- Decline in muscle bulk and strength
- Gait becomes wider based, smaller steps
- Poor balance
- Loss of ankle jerk
Motivation and its source
Definition: Needs or desire that direct behaviour
Sources (+/–):
1) Drives - internal states that pushes behaviour
2) Incentives - external stimuli that pulls behaviour
Reward stimuli
Triggers release of dopamine in striatum –> feeling “high”
Ventral striatum
i.e. Nucleus Accumbens
- responsible for incentive motivation processes
- Dopamine received from Ventral Tegmental Area (VTA)
Dorsal striatum
Caudate and Putamen
- concerned with regulation of movement and cognition
- Dopamine received from substantial nigra
Associative learning
PALOVIAN CONDITIONING
- Learning predictive relationships
- neutral cue precedes reliably a reinforcer - an unconditioned stimulus (e.g. food)
- the neutral cue acquires motivational value per se - conditioned stimulus
- Anticipatory response –> Consummatory response
INSTRUMENTAL CONDITIONING
- learning that an action leads to delivery of reward ->reinforcing an instrumental response
- Basolateral amygdala has extensive sensory cortical input that forms CS-US association
- Central nucleus of amygdala critical for CS-response outcome learning
- Amygdala connected to striatum and prefrontal cortex (palovian information linked with decision making system)
- Ventral striatum (Nuc Ac) gives motivational drive amplified via dopamine -> promote rewarding actions
- Prefrontal cortex provide info on choices and inhibitory control
Descending pathways
1) Lateral pathway
i) Lateral corticospinal tract
ii) rubrospinal tract
2) Ventromedial pathway
i) Ventral corticospinal tract
ii) Reticulospinal tract
iii) Vestibulospinal tract
iv) Tectospinal tract
Lateral descending pathway
i) Lateral corticospinal tract
ii) rubrospinal tract
Motor cortex and red nucleus -> posterior limb of internal capsule -> decussate at lower medulla (pyramid) -> lateral funiculus of spinal cord -> terminates contralaterally at interneurons (small number), or lateral ventral horn’s motor neurons
- Innervates limbs, especially distal muscles
- All terminations are unilateral and contralateral
- Terminal branch gives off few collaterals
Ventromedial descending pathway
i) Ventral corticospinal tract
ii) Reticulospinal tract
iii) Vestibulospinal tract
iv) Tectospinal tract
Origin -> posterior limb of internal capsule -> does not decussate -> ventral funiculus of spinal cord -> terminates ipsilaterally at interneurons (many), or medial ventral horn’s motor neurons -> many collaterals leading to bilateral terminations
- innervates axial and proximal muscles
- Many bilateral terminations
- terminal branch gives off many collaterals
Lateral pathway vs ventromedial pathway
1) Component tract difference
2) Lateral funiculus vs ventral funiculus
3) Terminal branch few collaterals vs many collaterals
4) Small number interneuron termination vs many
5) Lateral ventral horn vs medial ventral horn
6) All unilateral vs many bilateral
7) Innervates distal muscles vs axial and proximal
Thyroid gland embryology
midline caudal to the median tongue bud, an endodermal thickening at foramen caecum.
forms a bilobed structure and migrates ventral to the laryngotracheal tube to reach its definitive position (7th week)
During migration, thyroid remains connected to the tongue by the thyroglossal duct. This duct later disappears
Ultimobranchial body forms the C cells/ parafollicular cells of thyroid
Parathyroid gland embryology
Dorsal recess of the 3rd pharyngeal pouch becomes solid by proliferation, forming the inferior parathyroid glands
Dorsal recess of the 4th pharyngeal pouch becomes solid by proliferation, forming the superior parathyroid glands
Migrate caudally with the thymus and and become intimately associated with the dorsal aspect of the thyroid gland
Parathyroid gland location
embedded between the posterior border and the capsule of the thyroid
usually 4, but may vary from 2 to 6
Vasculature of the thyroid gland
Superior thyroid artery (from external carotid artery)
Inferior thyroid artery (from thyrocervical trunk of 1st part of subclavian artery)
Superior and middle thyroid vein (to internal jugular veins)
Inferior thyroid vein (to brachiocephalic vein or internal jugular vein)
Thyroid anatomy
Bilobed lying on either side of the trachea and the larynx
Lobes connected by isthmus at level of 2nd - 4th tracheal cartilage
50% has appendix from isthmus towards hyoid cartilage
Encapsulated by a tough fibrous capsule
pretracheal fascia binds the gland in front and at the back of the trachea
Between the gland capsule and the fibrous capsule posteriorly are the parathyroid glands
sternothyroid, sternohyoid muscles and cervical fascia lie in front
Nerves closely associated with the thyroid glands
1) External laryngeal nerve (branch of the superior laryngeal nerve; supply the cricothyroid muscle)
2) Recurrent laryngeal nerve (in the tracheo-oesophageal groove posterior to the inferior thyroid artery, 50% in pretracheal fascia; supply all laryngeal muscle except cricothyroid
Histology of the thyroid gland
Vesicular follicles formed by follicular cells (T3 T4), which are lined with simple cuboidal to squamous epithelium (will become columnar when active)
Follicular lumen filled with homogenous colloid, thyroglobulin, with many tyrosine residues (colloid will shrink when active)
Light staining parafollicular cells or C cells (Calcitonin) lies between follicles or embedded within the follicle
Histology of the parathyroid
two kinds of epithelial cells:
1) Principal cells - parathyroid hormone (PTH)
2) Oxyphil cells - eosinophilic cells; function unknown.
Thyroid innervations
Adrenergic innervation from there cervical ganglia
Cholinergic innervation from the vagus nerves.
Hormones that increase cAMP
FLAT CHAMP GG
FSH
LH
ACTH
TSH
CRH hCG ADH (V2) MSH PTH
Glucagon
GHRH
Hormones that increase IP3
GOAT HAG
GnRH
Oxytocin
ADH (v1)
TRH
H2
Gastrin
Hormones that act via steroid receptor
VETTT CAP
Vit D Estrogen Testosterone T4 T3
Cortisol
Aldosterone
Progesterone
Hormones that act via JAK/STAT pathway
PIG
Prolactin
GH
Immunomodulin
Hormones that act via tyrosine kinase pathway
inslun, IGF-1
TSH effect
Binds to thyroid follicular cells, increase cAMP level, which will stimulate:
1) thyroglobulin production
2) NI symporter
3) TH exocytosis
Thyroid hormone form
Tetraiodothyronine (T4; usually called thyroxine) Triiodothyronine (T3)
Derived from the modification of tyrosine
Difference between T3 and T4
Less T3 (~10%) released by thyroid gland than T4 (~90%)
T3 has greater biological activity (faster onset) than T4 (slower onset)
99.5% bound to plasma proteins vs 99.95%
Small pool vs large pool
Mainly intracellular vs mainly circulating
Short half life (fast turnover) vs long half life (slow turnover)
Thyroglobulin biosynthesis
Thyroglobulin (TG) is a large polypeptide which is synthesized in ribosomes of thyroid follicle cells in response to TSH/cAMP
The TG colloid is incorporated into exocytotic vesicles and extruded into follicular antrum.
Biosynthesis of TH
1) Iodide trapping
2) Oxidation
3) Iodination/Organification
4) Coupling
- ——
1) iodide is taken up actively by Na-I symporter (activated by TSH/cAMP)
2) iodide is oxidized by thyroidal peroxidase to iodine in thyroglobulin
3) tyrosine residue in thyroglobulin is iodinated and forms MIT (monoiodotyrosine) & DIT (diiodotyrosine).
4) iodotyrosines (MIT & DIT) are coupled together to form T3 & T4 [MIT+DIT=T3; DIT+DIT=T4]
Secretion of TH
When thyroid gland is stimulated (e.g. TSH/cAMP), vigorous endocytosis of colloid occurs.
Endocytotic vesicles fuse with lysosomes inside the follicular cell. T3 & T4 are hydrolyzed from the thyroglobulin and released into the circulation via exocytosis.
Transport form of TH
TH is lipid-soluble but insoluble in water, therefore usually associated with binding proteins in plasma:
1) Thyroid Hormone-Binding Globulin (~70%)
2) Pre-albumin (transthyretin) (~15%)
3) Albumin (~15%)
4) Free (<1%)
Biological active form of TH
Free or albumin bound
Activation & inactivation of TH
Deiodination reactions in the peripheral tissues activate and inactivate TH
25% of T4 is deiodinated (outer ring, by D1 or D2) to T3 in peripheral tissues. Deiodination (inner ring, by D1 and D3) may form an equal amount of reverse T3 which has no biological activity.
T3 (and rT3) may then be inactivated by further deiodination (inner ring and outer ring respectively) to form T2
Enzymes for deiodination of thyroid hormones
Deiodinase type 1 (D1) located in the liver, kidney and thyroid gland.
Deiodinase type 2 (D2) located in skeleton muscle, CNS, pituitary gland and placenta. Can only deiodinate outer ring.
Deiodinase type 3 (D3) found in fetal tissue and placenta; also present throughout brain, except in the pituitary. Can only deiodinate inner ring.
Mechanism of TH action
- Cells take up free TH from blood.
- Once inside the cell, T4 is deiodinated to T3
which enters the nucleus and binds to TH receptor (TR). - TR with bound T3 forms a complex with another nuclear receptor called retinoid X receptor (RxR) to initiate transcription of thyroid hormone response elements (TRE)
- TR can also complex with other coactivators or corepressors to regulation protein production.
Physiological effects of TH
BBBB
1) Bone growth and growth
2) Brain maturation and CNS effect
3) Basal metabolic rate and thermogenesis
4) Beta-adrenergic effects and enhance heart contraction
5) Biphasic Metabolism modulation
6) Permissive effect on other hormones
1) Stimulates endochondral ossification for skeletal maturation (more cartilage to bone)
1) Biphasic effect on protein by increase proteolysis increase protein production
1) Increase growth hormone secretion and its effects
1) Stimulation of cell growth directly
1) Normal response to parathormone and calcitonin
2) Critical for brain development (deficiency → permanent mental retardation)
2) Behaviour control through expression of beta-adernoceptors to potentiate response to catecholamine (increased excitability)
3) Increase N+/K+-ATPase, which increases oxidative phosphorylation and ATP production from ADP and the basal metabolic rate; heat is generated as a result
4) Direct effect by increasing the expression of contractile proteins
4) Expression of beta-adernoceptors enhances response to adrenaline/noradrenaline (sympathetic nervous system)
4) Metabolic effect of enhanced thermogenesis and oxidative phosphorylation leads to vasodilation, ↑blood vol. → ↑ venous return → ↑ cardiac output
5) Biphasic control on glucose (increase glycolysis, increase gluconeogenesis, increase glycogenesis, increase glycogenolysis, increase GI glucose absorption [hyperglycaemia]
5) Biphasic effect on protein by increase proteolysis increase protein synthesis; [increase protein; too high -> skeletal muscle proteolysis]
5) Biphasic effect on lipid, increase lipolysis and lipid synthesis; [decrease in serum cholesterol]
Permissive action of thyroid hormone
1) By inhibiting phosphodiesterase (prevents cAMP breakdown)
2) By increasing the synthesis of adenyl cyclase
3) By increasing receptors for another hormone e.g. T4 on beta-adrenoceptor.
TH secretion regulation
- Hypothalamic-pituitary thyroid axis: TRH -> TSH -> T3/T4 (somatostatin released by hypothalamus inhibits TSH secretion)
- Negative feedback: circulation T3/T4 inhibit TRH & TSH secretion
- Environmental factors: Cold, trauma, stress
- Excessive iodide (anti-TSH): ↓ synthesis & release of TH
Neck lymph node levels
6 levels
Level Ia submental
Level Ib submandibular
Level II upper jugular
Level III mid jugular
Level IV lower jugular
Level V posterior triangle
Level VI pretracheal
Supraclavicular fossa - lower nodes of IV and V
Structure of Neck lymph node level Ia
Submental
- lower lip
- anterior oral floor
- tongue tip
- mandibular incisors
Structure of Neck lymph node level Ib
Submandibular
- oral cavity
- tongue
- anterior nasal cavity
- submandibular gland
Structure of Neck lymph node level II
Upper jugular
- nasal cavity and sinuses
- oral cavity
- orophaynx
- nasopharynx
- supraglottic larynx
- hypopharynx
- parotid and submandibular glands
Structure of Neck lymph node level III
Mid jugular
- oral cavity
- oropharynx
- larynx
- hypopharynx
Structure of Neck lymph node level IV
Lower jugular
- hypopharynx
- larynx
- thyroid
- cervical oesophagus
Structure of Neck lymph node level V
Posterior triangle
- nasopharynx
- oropharynx
- posterior neck and scalp
Structure of supraclavicular fossa LN
Drainage from neck above or below clavicle
Right side - infra-clavicle lesion
Left side - infra-clavicle lesion of infra-diaphragmatic lesion (via thoracic duct) aka Virchow’s node
Electrical synaptic transmission
1) An action potential reaches the presynaptic terminal
2) ions flow through gap junction changes formed by connexons and depolarise post-synaptic membrane
3) Generation of action potential
Chemical synaptic transmission
1) Neurotransmitter synthesised in presynaptic terminal and stored in vesicle
2) Action potential reaches presynaptic terminal
3) Presynaptic voltage gated calcium channels open to allow calcium influx
4) Calcium influx causes fusion of vesicle and membrane that allows exocytosis of neurotransmitter vesicles
5) Neurotransmitters diffuse through synaptic cleft to reach postsynaptic membrane and bind with receptor
6) Ligand-gated postsynaptic ion channel open/close
7) Generation of EPSP or IPSP
8) Retrieval of vesicular membrane from plasma membrane
Electrical synapse vs chemical synapse
Faster response in electrical synapse (no lag phase between presynaptic and postsynaptic)
Miniature End Plate Potential (MEPP)
- Fixed size of 0.5mV
- Spontaneous in absence of stimulation
- Increased frequency with depolarisation
- Neurotransmitter release
Quantal nature of neurotransmitter release
- Higher extracellular calcium level and calcium influx will increase the probability of fusion of synaptic neurotransmitter vesicles with plasma membrane and the release of neurotransmitters (0.5mV = one unit MEPP = one vesicle)
- summation of MEPP
SNARE definition
SNAP receptor
Form complexes to pull membranes closer together for future fusion
synaptic vesicle SNARE
synaptobrevin
plasma membrane SNARE
syntaxin and SNAP-25
Synaptic vesicle fusion with plasma membrane biochemistry
1) Vesicle docking
2) Formation of SNARE complexes between synaptic vesicle synaptobrevin and plasma membrane SNAP-25 and syntaxin -> pull membranes closer together
3) Influxed calcium binds to synaptotagmin -> catalyse membrane fusion
Proteins required for endocytotic budding of plasma membrane to form vesicles
Clathrin
Dynamin (pinching off)
Protein that helps to maintain synaptic vesicle in reserve pool
synapsin
synapsin function
Reversibly bind to synaptic vesicles for cross-linking -> tether them to stay in reserve pool for future neurotransmitter release
NSF function
NEM-sensitive fusion protein
Vesicle and golgi membrane fusion
Priming synaptic vesicles for fusion
Regulate SNARE assembly
SNAP function
soluble NSF attachment protein
Vesicle and golgi membrane fusion
Priming synaptic vesicles for fusion
Regulate SNARE assembly
Monoamine neurotransmitters
Norepinephrine
Dopamine
Histamine
Serotonin
Purine neurotransmitter
ATP
Adenosine
Amino acid neurotransmitter
Glutamate
Glycine
GABA
Peptide neurotransmitters
Endorphin
Enkaphalin
Substance P
Small molecule neurotransmitter vs peptide neurotransmitter synthesis and release
Small molecule vs peptide
1) Cell body synthesise enzyme VS synthesise pre-propeptide and enzyme
2) Slow axonal transport of enzymes to axon terminal VS fast axonal transport of nascent peptide and enzyme in vesicles along microtubule tract
3) at axonal terminal, synthesis and packaging of neurotransmitter with enzyme and precursor VS enzymatic processing of nascent peptide into mature peptide
4) Release and diffusion (identical)
Acetylcholine receptor
1) Nicotinic receptor
- ligand-gated Na and K channel
2) Muscarinic receptor
- GPCR
Glutamate receptor
AMPA, NMDA, Kainate
Ionotropic glutamate receptor
AMPA - ligand-gated NA channel (Na influx)
NMDA - Mg blocks NMDA; Na influx will displace Mg, activate channel; ligand-gated Na and Ca channel -> Ca as secondary messenger
EPSP definition
A reverse potential that is more positive than action potential threshold
IPSP definition
A reverse potential that is more negative than action potential threshold
Ionotropic GABA receptor
Pentamer, ligand-gated Cl- channel
Spatial summation of post-synaptic potential
Occurs when several excitatory postsynaptic potential arrives at axon hillock simultaneously
Temporal summation of post-synaptic potential
Postsynaptic potentials created at the same synapse in rapid succession are summed
Ionotropic GABA receptor is activated by:
GABA
Benzodiazepine
Barbiturates
Neurosteroids
Ethanol
Synaptic memory
High frequency stimulation (e.g. via electrodes) of synapse can cause a long-lasting increased sensitivity to the stimulation
aka long term potentiation
Heme structure
macrocyclic compound made up of four pyrrole subunits; carries Fe2+
Metabolic functions of Heme
1) Electron carrier and ATP synthesis (cytochrome)
2) Detoxification (cytochrome P450)
3) Carrier of oxygen (haemoglobin, myoglobin)
4) Decomposition of oxidative species (catalase)
First reaction in heme synthesis pathway
Glycine + succinyl Co-A –> delta-aminolevulinic acid (ALA)
Enzyme: ALA synthase
In mitochondria
ALA synthase isoforms
ALA-S1
- chromosome 3
- ubiquitously expressed
- regulated by heme
- low abundance, high rate of protein turnover
ALA-S2
- chromosome X
- expressed in erythroid cells
- regulated by iron-dependent mRNA translation
Bone marrow-produced heme fate
Haemoglobin formation
Liver-produced heme fate
60% - microsomal cytochrome P450
15% - catalase
some for mitochondrial cytochromes
Regulation of liver heme metabolism
ALA-S1 which is regulated by heme pool
Increased heme will inhibit:
1) DNA transcription to ALA-S1 mRNA
2) mRNA translation to ALA-S1
3) translocation of ALA-S1 to mitochondria
4) directly ALA-S1
Regulation of erythroid cell heme metabolism
ALA-S1 and ALA-S2
ALA-S2 mRNA translation is inhibited when Fe-transferrin level is low (e.g. when heme is high)
Increased heme may also inhibit:
1) DNA transcription to ALA-S1 mRNA
2) mRNA translation to ALA-S1
3) translocation of ALA-S1 to mitochondria
4) Directly ALA-S1
Heme degradation
Reticuloendothelial system of spleen:
1) Haemoglobin -> verdoglobin; Oxidation of methane bridge in porphyrin ring (heme oxygenase)
2) Cleavage of methane bridge to tetrapyrrole –> biliverdin
3) Globin is degraded by proteases while Iron returns to iron pool
4) Reduction of methane bridge –> bilirubin (biliverdin reductase)
Blood:
5) Bilirubin carried by albumin from spleen to liver
Liver:
6) Bilirubin conjugated with UDP-glucuronide (udp glucuronosyltransferase) -> bilirubin diglucuronide
7) Removed from liver via bile
Intestine:
8) Urobilinogen -> stercobilin
Kidney:
9) Urobilinogen from intestine -> urobilin
Heme synthesis sites
Synthesis in almost all cells, especially liver and erythroid tissue (RBM in adults)
(not haematopoiesis site, which is erythroid tissue only)
Metabolic roles for irons
1) Involved in redox reaction
- oxygen uptake (haemoglobin)
- redox reaction for electron transport or detoxification or oxidative species (cytochrome, CYP, catalase)
- activation of oxygen (oxidase, oxygenate)
- activation of nitrogen in plants (nitrogenase)
2) Essential for cell proliferation
2) Cell proliferation
Iron uptake in diet
- Bioavailability of food iron is more important than amount of iron in diet
- Heme iron more easily absorbed than non-heme
- mostly in form of ferric iron Fe3+
Inhibitors of non-heme iron absorption
Calcium salts Phosphoprotein in egg yolk Phytates in Bran Tannates in Tea Polyphenols in vegetables
Iron uptake biochemistry
Gastroferrin (stomach glyocprotein) forms complex with ingested Ferric iron (3+)
Iron crosses brush border of intestinal mucosal cells as Ferrous iron (2+)
Carrier protein in mucosal cells binds to ferrous and distribute it to rest of the body
Proteins for transport of iron
Transferrin (less blood iron -> increase in transferrin)
Protein for storage of iron
Ferritin: storage as mobile fraction (more blood iron -> increase in ferritin)
Hemosiderin: storage as aggregate
Ferritin structure
- Apoferritin made up of 24 subunits forming a sphere
- A core of polynuclear hydrated ferric oxide phosphate
- Hold 4500 ferric ions
- 8 hydrophilic channels for communication with exterior
Ferritin function
- Store iron as mobile fraction
- detoxification
Ferritin level regulation
When chelatable iron level rises, IRP-1 (IRE repressor protein-1) or IRP-2? will dissociate will dissociate from ferritin mRNA at IRE (iron-response element) -> increase translation of ferritin
Transferrin function
- iron transport (binds iron from donor cells and delivers it via plasma to specific receptors on recipient cells)
- distribution of iron
Transferrin structure
Single polypeptide chain that binds two ferric ions tightly but reversibly
Examples of transferrin
Serotransferrin
Ovotransferrin
Lactotransferrin
Transferrin receptor structure
a glycoprotein
Transferrin receptor synthesis regulation
- transferrin receptor mRNA contains 5 IREs
- Low iron concentration, IRP-1 will bind to IRE, which increases the ability of mRNA and protects it from degradation -> increased translation
Transferrin synthesis regulation
- Iron deficiency stimulates liver transferrin gene
- increased storage iron gives negative feedback on transferrin synthesis
Iron transport biochemistry
1) Iron is stored as ferric (3+) in ferritin and will be converted to ferrous (2+) for transfer in blood
2) Ferritin reductase will transfer iron to transferrin (ferric -> ferrous) in presence of FAD and NADH2
3) ferrous -> ferric by a ferroxidase, ceruloplasmin, in transferrin before transport
4) Ferric-transferin may bind to reticulocytes for transport
Haber-Weiss reaction
Ferrous + H2O2 => Ferric + OH* + OH-
O2-* (superoxide) + Ferric => O2 + OH- + OH*
Pentose phosphate pathway features
1) Anaerobic
2) Primary source of reduced NADP - for fatty acid and cholesterol synthesis
3) Supply source of pentose (ribose) - for nucleotide and nucleus acid synthesis
4) 1 G6P produce 12 NADPH and 6 CO2
Pentose phosphate pathway Phases
Phase I (oxidation)
- G6P to 6 phosphogluconate 6PG via G6PD
- 6PG to D-ribulose 5-phosphate via 6PGD
Phase II (decarboxylation-isomerization) - forms D-ribose 5P and D-xylulose 5P
Phase III
- 5,5 -> 7,3 (2 carbon shift)
- 7,3 -> 6,4 (3 carbon shift)
- 5,4 -> 6,3 (2 carbon shift)
- forming D-fructose 6P, D-glyceraldehyde 3P
G6PD gene
- Xq28 (long arm)
G6PD deficiency not caused by single mutation, large insertion or deletion; heterogenous in nature
G6PD function
- rate limiting step in pentose phosphate pathway (G6P -> 6PG)
- Generate NADPH that protects RBC membrane from reactive oxidative species (NADPH reduce glutathione via glutathione reductase to form reduced glutathione, that reacts with reactive oxidative species via glutathione peroxidase)
Glutathione structure
A tripeptide made up of glutamate, cysteine, glycine
Glutathione reductase function
Oxidised glutathione to reduced glutathione (NADPH -> NADP); disulphide form to sulfhydryl form
Glutathione peroxidase
reduce oxidative species such as peroxides by covering reduced glutathione to disulphide oxidised form
SOD1 gene function
(mutation leads to ALS)
- binds to Cu++ and Zn++
- regulate disputation of superoxide ion into hydrogen peroxide
Anterograde transport
From cell body to neuronal end; kinesin
Retrograde transport
From neuronal end back to cell body; dynein, dynactin
PARK2 gene
Parkin (E3 ubiquitin ligase)
mutation leads to parkinson’s
attachment of polyubiquitin chains to protein targeted for proteasome proteolysis
Cleavage site for coagulation factor activation
Arginine indicates peptide bond position that require cleaving for activation
Two ends of coagulation factor
COOH end: serine protease
NH2 end: Gamma-carboxy glutamic acid (for localising coagulation
Tissue factor nature
Extrinsic pathway
- localised in tissue adventitia
- expressed in most cells except resting endothelial cells
- transmembrane protein
- exposed to intravascular space after vascular damage
- does not require proteolytic activation
Factor VII
Extrinsic pathway
- single chain zymogen
- low intrinsic enzymic activity
- highly active when bound to tissue factor
GpIb
platelet-VWF adhesion (VWF binds to subendothelial surface)
GpIIb/IIIa
platelet-platelet aggregation (binds to fibrinogen)
Role of platelet in coagulation cascade
1) Adhesion -> binds VWF via GpIb at site of injury
2) Release reaction -> release Ca and ADP (for coagulation cascade; ADP also helps platelet to adhere on endothelial surface and GpIIb/IIIa expression on platelet surface)
3) Prostaglandin relase (TXA2 -> pro-aggregation)
4) membrane vesiculation
Phospholipid in coagulation cascade
Phospholipid in plasma membrane catalysed by floppase to express greater on outer cell surface -> localised coagulation by binding to gamma-carboxy glutamic acid of coagulation factors in the presence of Ca++
Thrombomodulin
Complex with thrombin to Activate protein C for anticoagulation
Protein C function
Activated by thrombomodulin (with thrombin)
direcrly cleaves, with protein S, membrane bound factor Va and VIIIa
mediate cleavage of factor Va to Vac, which then forms complex with Protein C and Protein S, to inactivate factor VIIIa
Inhibitors of platelet response
PGI2 and NO released by normal endothelial cells
Fetal haemoglobin
HbF (α2γ2)
Adult haemoglobin
HbA (α2β2)
HbA2 (α2δ2)
α-globin gene location
Chromosome 16; total of 4 genes on 2 chromosomes
β-globin gene location
Chromsome 11; total of 2 genes on 2 chromosomes
Phases of specific immune responses
1) Recognition phase (lymphocyte recognise and bind to antigen)
2) Activation phase (proliferation and differentiation -> effector cell and memory cell)
3) Reaction phase (effector cell eliminate antigen; memory cell for immunological memory)
Innate vs acquired immunity
Rapid response VS slow response (esp first exposure)
Invariant VS variant
limited specificities VS highly selective specificity
constant during response VS improve
Features of specific immune response
1) Specificity - lymphocytes express distinct membrane receptor that distinguish different antigens
2) Diversity - gene rearrangement produce many clones that can discriminate 10^9 different antigens
3) Memory - first exposure will lead to memory cell that potentiate the secondary immune response
4) Self-regulation - immune response will wane with time after antigenic stimulation
5) Discrimination of self from non-self - self tolerance
Clonal selection theory
1) lymphocyte express surface receptors unique for one antigen
2) Antigen will bind to cells with corresponding receptor
3) specific binding to antigen will induce proliferation/ clonal expansion
4) B cell will mature into plasma cell that produce antibodies with same specificity as surface receptor
5) Some will differentiate to memory cell with as antigenic specificity
6) Contact of lymphocyte and specific antigen during embryonic development will lead to elimination of that clone
7) Removal of antigen-soecific clones result in tolerance or non-responsiveness
Stem cell definition
Cells that have the capacity to self-renew and generate different progeny
B cell development can be defined by:
1) Expression of CD antigen
2) Status of immunoglobin gene
What is CD
Cluster of differentiation (CD) refers to surface antigen expressed on membrane of leukocytes
B cell development stages
1) Lymphoid stem cell (CLP)
2) Early Pro-B cell
3) Late Pro-B cell
4) Large pre-B cell
5) small pre-B cell
6) Immature B cell
7) Mature B cell
B cell development by CD
Change in CD (e.g. CD34 in pro-B cells)
CD19, CD20, CD40 commonly used be recognise B cell lineage
B cell development by immunoglobin gene
1) Lymphoid stem cell (CLP):
2) Early Pro-B cell:
=> D-J rearranged (μ H chain)
3) Late Pro-B cell:
=> V-DJ rearranged (μ H chain)
4) Large pre-B cell:
=> VDJ rearranged (μ H chain)
=> μ H chain at cell surface as pre-B receptor
5) small pre-B cell:
=> VDJ rearranged (μ H chain)
=> V-J rearrangement (κ, λ L chain)
=> μ H chain at cell surface and cytoplasm
6) Immature B cell
=> VDJ rearranged (μ H chain)
=> VJ rearranged (κ, λ L chain)
=> IgM expressed on cell surface
7) Mature B cell
=> VDJ rearranged (μ H chain)
=> VJ rearranged (κ, λ L chain)
=> IgM and IgD expressed on cell surface
Ig gene rearrangement process
Productive Ig gene rearrangement only occur on one chromosome carrying the μ H chain locus and one of the chromosome carrying the κ or λ L chain locus.
μ H chain’s DJ rearrangement occur on both chromosome, but V-DJ rearrangement only on one chromosome; if H chain rearrangement is successful, then κ gene will be rearranged first -> if this fails, then λ gene will be rearranged
–> ALLELIC EXCLUSION (to ensure the cell expresses Ig of a single H and L chain isotype and V region specificity
Bone marrow microenvironment and B cell development
CD44 and c-kit on pro-B cell helps binding to hyaluronic acid and SCF on stromal cells
The binding will activate tyrosine kinase and stimulate proliferation
Stromal releases IL-7 (enhance survival of pre-B cells by suppressing apoptosis)
B cell selection and elimination
Unsuccessful rearrangement of Ig genes -> cell loss; only when IgM expressed on cell surface (not IgD yet) will the immature B cell undergo selection in BM
Self antigen (MHC) molecules are encountered, and immature B cells that generate self-reactive Ig are eliminated (if cell bound MHC -> apoptosis; if soluble antigen -> anergy
Note: further L chain Ig gene rearrangement (receptor editing) can rescue some self-reactive B cell
T cell differentiation
Cortex: Double negative (CD3-, CD4-, CD8-)
Corticomedullary junction: Double positive (CD3+, CD4+, CD8+)
Medulla: Single positive (CD3+, CD4+ or CD8+)
B cell subtypes
Conventional B-2 cells
CD5+ B-1 cells (10%, capable of self-renewal, in body cavity)
Different T-cell receptors
Majority are α:β TCR
5% are γ:δ TCR
T cell selection and elimination
1) Positive selection
- Within thymic cortex
- cortical epithelial cells
- self MHC present foreign peptides to TCR of double positive T cells => survival of T cells that have TCR for self MHC
2) Negative selection
- Within thymic medulla
- macrophage and dendritic cells
- TCR that recognise self peptide-self MHC complex too well are induced to undergo apoptosis
What determines antigen-binding specificity of antibody
1) Amino acid sequences of the V regions
2) 3D shape of antigen-binding site
How is antibody diversity generated
1) Numerous Ig genes especially V region genes (a lot of V, D, J genes for H chains and V, J genes for L chains)
2) Random recombination (V-D-J gene rearrangement of H chain and V-J rearrangement of L chain)
3) Junctional diversity (Terminal deoxynucleotidyl transferase add nucleotides to single strand DNA ends)
4) Ressortment of H and L chains
5) Somatic hypermutation (nucleotide substitution)
Pre-B cell receptor
- μ H chain with surrogate L chain
- signal for survival of pre-B cell
- expressed on cytoplasm and surface of early and late pre-B cells
Allelic exclusion
Productive Ig gene rearrangement only occur on one chromosome carrying the μ H chain locus and one of the chromosome carrying the κ or λ L chain locus.
μ H chain’s DJ rearrangement occur on both chromosome, but V-DJ rearrangement only on one chromosome; if H chain rearrangement is successful, then κ gene will be rearranged first -> if this fails, then λ gene will be rearranged
–> ALLELIC EXCLUSION (to ensure the cell expresses Ig of a single H and L chain isotype and V region specificity
Antibody structure
Two heavy chains (linked by disulphide bond)
Two light chains
Fab
Fc
V region (variable) C region (constant)
Sequence variability in V region of Ig
3 hypervariable regions aka complementary determining region (CDR)
- HV1 to HV3
- forms hyper variable loops
Framework region (FR) shows less variability - beta sheets that provide the structural framework
Genetic mechanism of Ig gene rearrangement
1) RAG-1 & RAG-2
(recombination-activating gene) => initiate Ig recombination
- forms a loop
2) DNA-PK, DNA Ligase
=> DNA cutting and rejoining
Ig classes
IgG IgM IgD IgA IgE
IgE
Scarce in serum, found on surface membrane of basophils and mast cells
- mediate type I hypersentivity response
- antiparasitic
IgD
Scarce in serum, found in large quantity on surface membrane of B cells
- antigen triggered lymphocyte differentiation
IgA
20% of serum Ig, predominant in sermucous secretion like saliva, colostrum, UG secretion, milk
Mainly as monomer in serum, but sometimes dimer or trimer with J-chain peptide
Secretory IgA - dimer or tetramer, with J chain peptide and secretory component (polypeptide produced by mucosal epithelial cells)
IgM
10% of serum Ig pool
Mu 2 L 2
monomer on B cell surface membrane
Secreted by plasma cell as pentamer (joint by disulphide bonds) with J-chain peptide (does not diffuse well due to its large size => remain intravascular)
**First Ig produced in plasma cell’s primary response, and first Ig synthesised by neonates
Secretory Ig
IgG
Major serum Ig, a lot extravascular as well
Gamma 2 L2
Four subclasses: IgG1 to IgG4
major antibody for secondary response
Materal IgG crosses placenta and confer passive immunity to neonates
Difference between primary and secondary humeral response
1) Time course (secondary antibody response has a shorter lag phase and extended plateau and decline)
2) Antibody titre (secondary response has much greater plateau level of antibody)
3) Antibody class (IgM in primary response, IgG in secondary response)
4) Antibody affinity (antibody affinity if higher in secondary affinity)
B cell activation types
At periphery (secondary) lymphoid organs:
1) Thymus dependent antigen activation (usu protein)
2) Thymus independent antigen activation
- TI antigen type 1 (bacterial cell wall structure e.g. lipopolysaccharides)
- TI antigen type 2 (highly repetitive molecules e.g. polymeric protein or bacteria cell wall polysaccharides with repeating polysaccharides)
T-dependent B cell activation
- > Crosslinking of antigen to B cell membrane Ig initiate B cell activation (FIRST SIGNAL)
- > stimulate intracellular secondary messenger to drive resting B cell into cell cycle for proliferation (increased intracellular Ca++ and PK activation)
- > protein antigen is internalised and processed, then presented to antigen-specific T helper cell for activation of Th; moreover B cell will also increase expression of membrane receptor for Th cell cytokines and MHC II, to allow greater response of B cell to T cell (SECOND SIGNAL -> CD40/CD40L)
T-dependent B cell activation signals
2 signals
1) TD antigen crosslinking membrane Ig
2) CD40 on B cell interacting with CD40L on activated T helper cell
Features of T-independent antigen B cell activation
- weaker in general
- no memory cells generated
- IgM predominant
Four phases of primary antibody response
1) Lag phase (clonal selection, clonal expansion, differentiation)
2) Log phase (cell proliferation, plasma cell secretion increases antibody level)
3) Plateau phase (cell proliferation, plasma cell secretion increases antibody level)
4) Decline phase (lymphocyte apoptosis)
Why does secondary antibody response have a more rapid onset and greater magnitude?
- Memory B cell population is greater than population of corresponding naive B cell
- Memory B cells more easily activated
Germinal center B cell events
1) Affinity maturation
- higher antibody affinity in secondary response due to (IgM->IgG) switching, and SOMATIC HYPERMUTATION that recombines Ig genes
2) Class switching
- allow antibody isotypes with same V domain to associate with constant region of any isotypes for different biological effector functions
- membrane CD40/CD40L interaction induce class switching
- T cell cytokines determine which new isotype by cytokine-dependent transcription of constant region DNA
3) B cell maturation
- rapid proliferation and hypermutation of B cells after antigen stimulation
- only B cell with high affinity BCR (BCL-2 gene) can compete effectively for antigen presented by follicular DC (low affinity B cell apoptosis)
TCR structure
Heterodimer, conventionally alpha and beta chain
(5% is gamma and delta chain)
Contains a V domain with CDRs
(analogue to Vab of antibody)
TCR diversity generation
1) Variable genes (V,D,J)
2) Gene recombination
3) Junctional diversity (TdT)
4) *** D segment read in 3 frames
TCR complex structure
1) TCR: antigen receptor
2) Co-receptor (CD4 or CD8)
3) CD3 as signalling complex for intracellular signal transduction upon antigen binding
MHC structure
MHC Class I
alpha (3 loops) with beta 2 microglobin
MHC Class II
alpha (2 loops) with beta (2 loops)
Which MHC present larger peptide?
MHC Class II
MHC genetics
Chromosome 6, co-dominantly expressed (can express 6 class I, 6-8 class II)
MHC Class I:
Polymorphic gene for alpha chain e.g. HLA-A, HLA-B, HLA-C
MHC Class II:
multiple genes for alpha and beta e.g. HLA-DR, HLA-DQ, HLA-DP
MHC antigen presentation pathway
1) Cytosolic pathway (MHC class I)
2) Endocytic pathway (MHC class II)
3) Cross-presentation
MHC antigen Cytosolic pathway
In MHC Class I, presents Endogenous antigens e.g. intracellular bacteria, virus, self-protein
1) Protein digested by proteasome -> peptides
2) Peptides transport via TAP (Transporter associated with Antigen Processing) to ER and loaded onto MHC class I
3) MHC-I/peptide complex translocated by golgi to cell surface for presentation to CD8 T cells
MHC antigen Endocytic pathway
In MHC Class II, presents exogenous antigens e.g. extracellular microbes and protein
1) antigen taken up by endocytosis or phagocytosis -> trapped in endolytic vesicles -> fuse with lysosome -> lysosomal proteolytic enzyme degrade protein -> peptides
2) Biosynthesis of MHC II, transport via golgi to MHC II vesicles
3) Fusion of MHC II vesicle and endolysosomes -> loading of peptide to MHC II -> MHC II/peptide translocated to cell surface for presentation to CD4 T cell
MHC antigen cross presentation
Exogenous antigen can be cross-presented in MHC class I, by specialised APC - dendritic cells
MHC I expression
All nucleated cells (therefore not in RBC)
MHC II expression
APCs (e.g. B cell, macrophage, dendritic cells, thymus epithelial cells)
APC function
1) Capture antigen and migrate to appropriate site for T cell interaction
2) Display antigen in form recognisable by specific T cells
3) Provide second signal in naive T cell activation
Cell mediated immunity effector mechanism
1) Cell-mediated cytotoxicity (NK cells, Tc cells)
2) Chemotaxis and phagocytosis (macrophage)
3) Cytokine-mediated direct target cell killing (TH1 cell)
Cell mediated cytotoxicity major types
1) Cytotoxic T lymphocyte-mediated killing
2) Antibody-dependent cell-mediated cytotoxicity
3) Natural Killer cell-mediated killing
Cytotoxic T lymphocyte-mediated killing
1) APC/virus infected cell/tumour cell present antigen via MHC I, which is detected by CD8 of Tc cells, CD3 of Tc cell react with MHC I
2) Co-stimulatory signal between Tc cell’s CD28 and CD80/86 of APC
(IL-2 from Th1 cells help activation)
3) Tc cell activation and degranulation, release of granular cytotoxic substance e.g. granzymes and perforins; also release IFN-gamma that activates macrophage
4) Osmotic lysis or apoptosis of target cell
Antibody-dependent cell-mediated cytotoxicity
by LGL Large granular lymphocytes
1) LGL have Fc receptor that binds to Fc of Ig for antigen specificity
2) Fc receptor on LGL recognise abnormal Ig on cell surface
3) Release of cytotoxic factors to kill target cell
Nk cell-mediated killing
No antigen specificity
1) Normal MHC I interacts with KIR (killer inhibitory receptor) while cell surface carbohydrate interacts with KAR (Killer activator receptor)
2) In tumour cells or graft cells, there is no self MHC I to interact with KIR, therefore inhibition loss and release of cytotoxic factors
3) In virus infected cells, foreign cell surface antigen activate KAR-> release of cytotoxic factors
Perforin
Release from cytoplasmic granules
Forms pores on target cell membrane -> allow granzymes to enter target cell, as well as water entry that cause osmotic lysis
Granzymes
- Enter cell via perforin
- Protein that activate apoptosis
- toxic to intracellular pathogen
Mechanism of recognition in phagocytosis
1) Fc receptor-mediated (Fc receptor on phagocyte interact with antibody bound to pathogen)
2) Complement receptor mediated (C1q, C3b receptor on macrophage interact with complement deposited on pathogens via classical, alternative, or lectin-induced pathways)
3) Mannose receptor-mediated (recognise mannose and fucose oligosaccharides on pathogens)
Chemotaxis
1) Bacterial component (e.g. fMLP)
2) Complement products (e.g. C5a)
3) Locally released chemokines and cytokines
Macrophage activation types
1) T-independent (chemotaxis, activation and phagocytosis, phagolysosome, killing and digestion, release of degradation products)
2) T dependent
- macrophage primed with inactivated pathogen
- macrophage CD40 interact with Th1 CD40L and MHC II/CD4
- Th1 release IL2 (autocrine) and IFN gamma (that activates macrophage)
- macrophage activated to increase lysosome formation, phagolysosom fusion, increase translation of inducible NO synthase (iNOS)
how does macrophage kill microbes?
1) Reactive oxygen intermediates
- superoxide ions (via myeloperoxidase)
2) Reactive nitrogen intermediates (via iNOS)
- Nitric oxide
3) Other mediators
- complements
- lysozyme
- chemokines
- cytokines
- defensins
Insulin secretion control
1) glucose enter Beta cells via GLUT2
2) glucokinase in cell perform oxidative phosphorylation -> more ATP
3) ATP blocks K channels, reducing K efflux causing depolarisation of membrane
4) depolarisation activates Ca channels -> Ca influx
5) increased intercellular calcium leads to exocytosis of insulin
Lipolysis and adrenoceptors
Alpha adrenoceptors suppress lipolysis
Beta adrenoceptors stimulates lipolysis
Papez circuit function and flow
Deep-lying structures for the neural circuit involved in the expression of emotions
Cingulate gyrus –> hippocampus –> mammillary body of hypothalamus –> via mammillothalamic tract –> anterior nucleus of thalamus –> cingulate gyrus
Allocortex vs neocortex
Phylogenetic (neocortex not available until reptile)
Cortical area increase with mammalian evolution
Neocortex got 6 histology layer while allocortex (e.g. hippocampus) got 3
entorhinal area
bridge the communication between hippocampus and neocortex
Paraventricular nucleus of hypothalamus
oxytocin release
Medial preoptic area of hypothalamus
bladder contraction, decreased heart rate
Supraoptic nucleus of hypothalamus
vasopressin, oxytocin release
anterior hypothalamic area and posterior pre optic area of hypothalamus
body temperature regulation, panting, sweating
Posterior hypothalamus area
increased blood pressure, pupillary dilation, shivering
Ventromedial nucleus of hypothalamus
Satiety center
If lesion, then eat excessively (loss of satiety) and tummy grow ventrally
lateral hypothalamus
Hunger center
lesion cause aphagia (lack of eating) and adipsia
septal region of limbic system
closely connected to the hypothalamus, hippocampal formation, and amygdala
Stimulation of this region causes a pleasant (euphoric) sensation; The rewarding behavior is related to the mesolimbic pathway connecting with the nucleus accumbens
Two components of emotional state
1) Physical response
2) Conscious feeling
Primary emotions
reflexive e.g. anger, fear, happiness, sadness, surprise, disgust
Secondary emotions
involve more cognitive processes, e.g. envy, shame etc
Facial skeleton function
1) protect the brain
2) House and protect sense organs
3) provide a frame on which soft tissues (e.g. muscles) can act to facilitate eating, expression, breathing, speech
Facial bones
14
Lacrimal bone*2 Zygomatical bone*2 Nasal bone*2 Maxilla*2 Inferior nasal concha*2 Palatine bone*2 Mandible Vomer
Embryonic origin of facial expression muscles (innervated by CN VII)
2nd branchial arch
Orbital group facial muscles
1) Obicularis oculi
- palpebral part (close eye gently)
- orbital part (close eye forcefully)
2) Corrugator supercilli
- draws eyebrow to midline
Nasal group facial muscles
1) Nasalis
- transverse (compress nostril)
- alar (opens nostril)
2) Proceus
- pulls eyebrows down
3) Depressor septi nasi
- pulls nose down
Muscle of the mouth
1) Obicularis oris
- close lip
- protrudes lips
Elevator of lip
1) Levator labii superioris
- elevates and everts upper lip
2) Levator labii superioris alaeque nasi
- raise upper lips
- opens nostrils
3) Zygomaticus and 4) levator anguli oris
- elevate mouth corners
- zygomatic minor helps to elevate upper lip
Depressor of lip
1) Depressor labii inferioris
- depress and evert lower lip
2) Depressor anguli oris
- depress mouth corner (sad)
3) Mentalis
- elevate and protrude lower lip
4) Platysma?
Retractor of lip
1) Risorius
- retract mouth corners (grin)
Cheek muscle
1) Buccinator
- mastication (press cheek against teeth)
- resist distension (when blowing)
Buccinator anatomical relationship
- parotid duct penetrates through opposite to 3rd molar and opens into oral cavity opposite maxillary 2nd molar
- share a common attachment with superior pharyngeal constrictor at pterygomandibular raphe
The 4 insertions (max, ptmax lig, ptmd rph, mnd)
Auricular muscles
Anterior
Posterior
Superior
Platysma function
1) Depressor of lip
2) Tense skin over lower face and anterior neck
3) Depress mandible (against resistance)
Frontalis muscle
- covers the forehead
- attached to skin of eyebrow
- lift eyebrow and wrinkles forehead (surprise)
Occipitalis muscle
- arise from posterior aspect of skill
- tighten the scalp
Relaxed skin tension lines
1) Runs penpendicular to underlying facial expression muscles
2) Surgical incisions should be made parallel to RSTLs for optimal wound healing and minimal scar
Facial cutaneous branches of trigeminal nerve
V1 Supratrochlear nerve Supraorbital nerve Infratrochlear nerve External nasal nerve Lacrimal nerve
V2
Zygomaticofacial
Zygomaticotemporal
Infraorbital
V3
Buccal
Auriculotemporal
Mental
Nerves of the face embryological origin
Head mesenchyme - V1
1st branchial arch - V2, V3
2nd branchial arch - CN VII
where does facial nerve exit skull?
Stylomastoid foramen -> enters and divide in parotid gland
arteries of face
Artery:
1) Mainly by external carotid artery branches
- facial artery (inferior labial, superior labial, lateral nasal, angular)
- superficial temporal artery (transverse facial)
2) Internal carotid artery branches
- ophthalmic artery (supraorbital, supratrochlear, dorsal nasal, lacrimal, zygomaticofacial, zygomaticotemporal)
3) Maxillary artery facial branches
- infraorbital
- Buccal
- mental
Veins of face
1) Facial vein
2) Retromandibular vein
Danger area of face
Area drained by facial vein, ophthalmic vein, infraorbital vein, deep facial vein
- leads directly or indirectly (via pterygoid venous plexus) into cavernous sinus
- infection enter cavernous sinus and cause thrombosis, cerebral edema and meningitis
Lymphatic drainage of face
Submental node, submandibular node, pre-auricular nodes and parotid nodes
Drains to superficial cervical lymph nodes
Drains to superior deep cervical lymph nodes
5 layers of Scalp
Skin, contains hair and sebaceous gland
Connective tissue, highly vascularised
Aponeurotic layer (unites with occipitofrontalis muscle)
Loose connective tissue (contains emissary veins)
Pericranium, the periosteum of cranial vault
Aponeurotic layer of scalp
- consists of frontal and occipital bellies of occipitofrontalis
- galea aponeurotica connects the two muscles
- cause forward-backward movement of scalp
Loose connective tissue of scalp
- contains emissary veins
- allow movements
- provide plane of separation (scalping) and access in craniofacial surgery and neurosurgery
- laceration won’t cause profound bleeding until this layer
Danger zone of scalp
Sensory cutaneous nerves of scalp
Anterior to ear and vertex by trigeminal
Posterior to ear and vertex by cervical spinal
V1 Supratrochlear nerve Supraorbital nerve Infratrochlear nerve External nasal nerve Lacrimal nerve
V2
Zygomaticotemporal nerve
V3
Auriculotemporal nerve
----- Greater auricular nv(C2,3) Lesser occipital nv(C2,3) Greater occipital nv(C2) Third occipital nv(C3)
Why does scalp laceration cause produse bleeding
1) Connective tissue fibres around cut vessel contract and open the artery
2) Extensive anastomoses
Danger zone of scalp
Loose connective layer
- infection may result in localised abscess and enter the valvless emissary veins to travel to diploë and dural venous sinus –> osteomyelitis and dural sinus thrombosis
Lymphatic drainage of scalp
Anterior to vertex:
- preauricular node
- parotid node
Posterior to vertex:
- mastoid nodes
- occipital nodes
Drains to superficial cervical lymph nodes and suprior deep cervical nodes
Blood supply of scalp
Ophthalmic artery
- supratrochlear artery
- supraorbital artery
External carotid artery
- superificial temporal artery
- posterior auricular artery
- occipital artery
Oral cavity space
1) Oral cavity proper: space medial or posterior to teeth
2) Vestibule: space between teeth and cheek
Parotid duct
parotid duct penetrates buccinator opposite to 3rd molar
runs obliquely under mucous membrane
penetrates mucous membrane and opens into oral cavity opposite maxillary 2nd molar
Blood supply of hard palate
- Greater palatine artery (from maxillary artery) -> descend via greater palatine canal, emerges from greater palatine foramen -> pass around palate -> enter incisive foramen to go up nose
Nerve supply of hard palate
1) Anterior palatine nerve (from pterygopalatine ganglion via greater palatine canal and foramen, goes up via incisive foramen)
2) Nasopalatine nerve (from pterygopalatine ganglion, crosses nasal roof, descend on nasal septum, through incisive foramen, supplies hard palate anterior to incisive foramen)
External Ear components
1) Auricle (yellow elastic cartilage except lobule)
2) external acoustic meatus
External acoustic meatus structures
- Outer 1/3 supported by cartilage
- Inner 2/3 by temporal bone
- leads to tympanic membrane
- isthmus is close to membrane
- ceruminous glands especially in cartilaginous part
- not straight
Nerve supply of external acoustic meatus
Mainly Auriculotemporal nerve (posterior branch of V3)
(vagus and facial nerve small branches)
-> may receive referred pain from lower teeth (lower tooth cavity)
Lymphatic drainage of external acoustic meatus
supericial cevical lymph nodes along external jugular vein
How to examine tympanic membrane
Pull auricle upwards and backwards , and then use otoscope
Middle ear mucosa
- mucosa continuous with auditory tube and nasopharynx anteriorly
- mucosa continuous with mastoid antrum and air cells posteriorly
Inner ear content
- Conchlea anteriorly and semicircular canals posteriorly
- between the two is vestibule, above which runs internal acoustic meatus carrying CN VII and VIII
Bony components of tympanic cavity
- Malleus, incus, stapes (lateral to medial)
- synovial joints between them
- Malleus is attached to umbo of tympanic membrane via its handle
- Stapes attached to fenestra vestibuli
Lateral wall of tympanic cavity
- Tympanic membrane
- chorda tympani passes medially to the membrane and neck of malleus
Tympanic membrane anatomy
- Lined externally by skin and medially by mucosa
- umbo is pulled towards the centre by malleus’ handle
- sloping downwards and inwards
- Cone of light when shone because light reflects antero-inferiorly
Medial wall of tympanic cavity
- Promontory (a bulge based by basal turn of cochlea)
- Tympanic plexus on promontory (CN IX’s tympanic branch)
- Fenestra cochleae (for pressure release)
- Fenestra vestibuli (stapes attaches here)
- facial nerve lies at end of internal acoustic meatus with geniculate ganglion
- bony bulge to accommodate facial nerve and lateral semilunar canal
Floor of tympanic cavity
- Thin
- carotid canal (internal carotid artery) lies anteriorly
- jugular foramen (internal jugular vein) lies posterio-inferiorly
- superior bulb of IJV lies inferiorly
(Ear surgery should be careful because of two great vessels)
Roof of tympanic cavity
aka tegmen tympani
- thin
- middle cranial fossa with mininges and temporal lobe lies above it
Posterior wall of tympanic cavity
- opens to mastoid antrum with air cells
- Pyramid, a bony spike projecting into middle ear which contains stapedius fibres
Mastoid antrum
- an air space in petrous part of temporal bone
- below posterior cranial fossa (cerebellum)
- enlarged by growth of mastoid process after birth
- air cells to regulate pressure and temperature
Facial nerve leaving skull and infants
- Facial nerve leaves skull via stylomastoid foramen
- stylomastoid foramen is superficial in birth due to no mastoid process
- facial nerve easily damaged by assisted forceps delivery
Anterior wall of tympanic cavity
- opens to auditory tube
- tensor tympani (turns laterally around processes cochleariformis to attach to malleus neck)
Auditory tube anatomy
- Runs downloads and medially (more horizontally in
children) from middle ear anterior wall to nasopharynx - Posterolateral 1/3 is bony (petrous temporal bone)
- Anteromedial 2/3 is cartilage
- Junction between bone and cartilage is narrowest (isthmus)
- cartilage opens wide (raised mucosa - tubal eminence) to the nasopharynx (just behind base of medial pterygoid plate)
- respiratory mucosa with copious mucous gland in cartilage part; thin and landless mucosa on bone
Nerve supply of middle ear
Tympanic plexus (supplied by tympanic branches of glosopharyngeal nerve)
Arterial supply of tympanic cavity
external carotid artery branches
Venous drainage of middle ear
Pterygoid venous plexus
Lymphatic drainage of middle ear
Parotid/preauricular or upper deep cervical lymph nodes
Auditory tube muscles
- auditory tube opens when soft palate is lifed
- levator veli palatini (phgl plx), tensor veli palatini (nv to md ptgd) => pull cartilage and open tube to introduce air into middle ear
Arterial supply of auditory tube
- Ascending pharyngeal artery
- middle meningeal artery (foramen spinosum lies lateral to auditory tube)
Venous drainage of auditory tube
Pterygoid venous plexus
Medial wall of nasal cavity
nasal septum which is partly boney and partly cartilaginous
i.e. penpendicular plate of ethmoid bone, Vomer, septal cartilage
Lateral wall of nasal cavity
- Superior, middle and inferior nasal conchae/ turbinates
- and the superior, middle and inferior nasal meatus below the turbinates
Nasal meatus function
Drainage of paranasal sinuses and nasolacrimal glands
Nasal cavity epithelium
Pseudostratified ciliated epithelium for most part (including paranasal sinus)
- roof is different as it is lined by olfactory epithelium
Nerve supply of nasal cavity
trigeminal nerve (mostly V2, a little V1)
Roof -> Olfactory nerve
Arterial supply of nasal cavity
1) maxillary artery => sphenopalatine/ nasopalatine artery
2) facial artery => alar and nasal branches
3) ophthalmic artery => anterior and posterior ethmoidal artery
Venous drainage of nasal cavity
Pterygoid venous plexus
facial vein
infraorbital vein
ophthalmic vein
Paranasal sinus structure
Air filled extension of nasal cavity in frontal, ethmoid, sphenoid, and maxilla
Paranasal sinuses function and drainage site
For resonance of voice and drainage
Frontal: Middle meatus via infundibulum
Maxillary: Middle meatus via hiatus semilunaris
Sphenoid: Sphenoethmoidal recess
Ethmoid: Middle meatus via infundibulum (anterior); middle meatus on bulla ethmoidalis (middle); superior meatus (posterior)
Pterygopalatine fossa content
1) Maxillary branch of trigeminal nerve (V2)
2) Maxillary artery
3) Pterygopalatine ganglion
Pterygopalatine ganglion branches
Parasympathetic in nature for secretomotor to lacrimal and nasal glands:
1) Orbital branches (inferior orbital fissure)
2) Greater and lesser palatine nerves (palate, tonsil and nasal cavity)
3) Nasal branches
4) Pharyngeal branches - roof of nasopharynx
5) Nasopalatine branch - incisive foramen
Pterygopalatine fossa locations and relationships
- roof: orbit
- Medial wall: palatine bone and nasal cavity
- lateral wall: infratemporal fossa
- Anterior: maxilla and orbit
- Posterior wall: pterygoid process of sphenoid bone, middle cranial fossa via foramen rotundum
Arterial supply of lynx (and trachea)
1) Superior laryngeal artery (for superior aspect)
- branch of superior thyroid artery
- passes through thyrohyoid membrane
2) Inferior laryngeal artery (for inferior aspect)
- branch of inferior thyroid artery
Arterial supply of pharynx
1) External carotid artery branches
- MAINLY ascending pharyngeal artery
- Superior thyroid a rtery
- Lingual artery
- Facial artery
- maxillary artery
2) Subclavian artery
- inferior thyroid artery
Diploic veins
Lie in diploe (middle spongy bone containing RBM) of skull
Emissary veins
Small veins connecting dural sinuses with diploic veins and veins of scalp
Valve-less
Lymphatic drainage of brain
No lymphatic vessels or nodes in CNS!!
Lymphatics of head and neck in general
Superficial lymph nodes drains to superficial cervical nodes along EJV and drains to deep cervical nodes along IJV
Superficial H&N lymph nodes
Forms a ring at base of head:
- occipital
- preauricular (parotid)
- postauricular (mastoid)
- Subamndibular
- Submental
Superficial cervical nodes
Along EJV, on superficial surface of SCM
- receive from posterior and posterolateral scalp
- drains to deep cervical nodes
Deep cervical nodes
Along IJV, divided by intermediate tendon of omohyoid into upper and lower groups
Upper: Jugulo-digastric node
Lower: Jugulo-omohyoid node
Orbit bones
7
Lacrimal Frontal Zygomatic Maxilla Palatine Ethmoid Sphenoid (greater and lesser wing)
Optic canal
Houses optic nerve
Located in lesser wing of sphenoid bone
Some spaces in orbit (draw them out)
Intraconal space Extraconal space Pre-septal space Medial anterior orbit Lateral anterior orbit Deep orbital space
Origin of extra ocular muscles
All extraocular muscles insert posteriorly to annulus of Zinn (Spiral of Tillaux ie progressively distal to iris: medial rectus, inferior rectus, lateral rectus, superior rectus, superior oblique)
EXCEPT inferior oblique muscle that does not insert posteriorly
Superior orbital Fissure contents
LFT SOV NASO2
Extraconal:
- Lacrimal nerve (V1)
- Frontal nerve (V1)
- Trochlear nerve (IV)
- Superior ophthalmic vein
Intraconal:
- Nasociliary nerve (V1)
- Abducens nerve (VI)
- Sympathetic nerve plexus
- Occulomotor (superior and inferior) III
What extra ocular muscle still function after retrobulbar anaesthetic block?
In retrobulbar anaesthesia, intraconal structures are blocked, i.e. NASO2
So occulomotor nerve blocked (superior rectus, medial rectus, inferior rectus, inferior oblique) and abducens nerve (lateral rectus)
Trochlear nerve lies outside muscle cone, therefore superior oblique muscle is spared
Venours channels of orbit
TWO VEINS:
1) Superior ophthalmic vein
2) Inferior ophthalmic vein
Superior ophthalmic vein
- forms from supraorbital vein and angular vein
- passes across superior orbit
- pass through superior orbital fissure to enter cavernous sinus
Inferior ophthalmic vein
- from muscles and posterior part of eye
- passes inferiorly in orbit
= joins with superior orbital fissure or
= pass through superior orbital fissure to join cavernous sinus or
= pass through inferior orbital fissure to join pterygoid venous plexus
What is most common location of orbital blowout fractures?
Posteromedial aspect of orbital floor, usually medial to infraorbital nerve which may be damaged
Surgical repair of orbital floor
Implant is placed as bridge along orbital floor
Lacrimal gland opens to where?
Inferior nasal meatus
Lacrimal gland secretion
When blinking, closure of eye closes puncta and squeezes lacrimal sac which form partial vacuum
when eye reopens, there will be release of pressure and entry of tear fluid to eye
Eye lid function
1) Protect globe (blink relfex)
2) Maintain ocular surface via lacrimal gland and sebaceus glands
3) Assist in focus by squinting
4) Control lighting
5) Convey emotion
6) Sexual dimorphism
Eyelid structural layers
1) Skin and sebaceous tissue
2) obicularis muscles
3) Orbital septum
4) preaponeurotic fat
5) Refeactor muscles
6) Tarsus
7) Conjunctiva
Eyelid lymphatic drainage
Preauricular node (upper) and submandibular nodes (lower)
Ethnic differences of eyelid
Asian VS Caucasian
Fuller VS less full
Lower fusion of orbital septum VS higher
Lower eyelid crease VS higher
lower tarsal height VS higher
lower levator function VS higher
Phayngeal recess
Nasopharyngeal space behind the tubal elevation of auditory tube (common NPC place)
Tensor veli palatini
(nerve to medial pterygoid muscle)
- tense soft palate
Levator veli palatini
(pharyngeal plexus)
- raise soft palate
Palatoglossus
(pharyngeal plexus)
- Pulls tongue upwards
Palatophayngeus
(pharyngeal plexus)
- elevates wall of pharynx
Musculus uvulae
(pharyngeal plexus)
- elevates uvulae
Superior pharyngeal constrictor insertion
- Interdigitates with buccinator at pterygomandibular raphe
- sides of the oral floor
Middle pharyngeal constrictor insertion
- hyoid bone from angle between greater and lesser horns
Inferior pharyngeal constrictor insertion
Thyropharyngeus: thyroid cartilage
Cricopharyngeus: cricoid arch
Circular pharyngeal muscles functions
Push food into oesophagus except cricopharyngeus, which acts as a sphincter that normally contracted to prevent food from going down, and relaxes during swallowing
Pharyngeal muscle lining
Pharyngeal fascia:
1) External thin layer - bucopharyngeal fascia
2) Internal thick layer - pharyngobasilar fascia
Origins of longitudinal pharyngeal muscles
(All run down to attach to thyroid cartilage)
Salpingopharyngeus - auditory tube cartilage
Palatopharyngeus - soft palate
Stylopharyngeus - deep styloid process between superior and middle constrictor
longitudinal pharyngeal muscles functions
Lift up the larynx during swallowing
Pharyngeal muscles not supplied by pharyngeal plexus
1) Cricopharyngeus (CN X)
2) Stylopharyngeus (CN IX)
Palatine tonsils (location)
Two on each side of oropharynx between palatoglossus (front) and palatopharyngeus (back)
- separated laterally from carotid sheath of capsule of fibrous tissue
Palatine tonsils arterial supply
Tonsillar branch of Facial and ascending pharyngeal arteries
Lymphatics of palatine tonsils
Jugulodigastric lymph node
Sensory nerve supply of laynx
Above vocal folds:internal laryngeal nerve (branch of superior laryngeal nerve)
Below vocal folds: recurrent laryngeal nerve
Venous drainage of pharynx
Phayngeal venous plexus, drains to internal jugular vein (may communicate with pterygoid venous plexus)
Lymphatics of pharynx
Mostly goes directly to superior deep cervical nodes (some go to retropharyngeal nodes)
Swallowing action (with muscles)
Oral phase (Voluntary):
- chewing
- styloglossus push bolus upward and backward to oropharynx
- levator veli palatini elevates soft palate to close nasopharynx
- starts swallowing reflex
Pharyngeal phase (involuntary):
- palatoglossus constrict the opening of oropharynx to push food further backward
- stylopharyngeus, salphingopharyngeus, palatopharyngeus and thyrohyoid muscles elevates larynx so that epiglottis covers the glottis
- vocal folds close
- pharyngeal constrictors contracts to help with peristalsis
- cricopharyngeus and upper oesophageal sphincter relaxes to allow food to enter esophagus
Esophageal phase (involuntary)
- esophageal peristalsis
- lower oesophageal sphincter relax
- airway reopens
- larynx down
thyrohyoid membrane
- Connects upper margin of thyroid cartilage to hyoid bone
- pieced by the laryngeal vessels and internal laryngeal nerve
Cricothyroid membrane
- attach medial surface of thyroid cartilage to cricoid cartilage
- Upper margins form vocal ligaments (interior of vocal folds)
Vocal folds attachment
Anteriorly to thyroid cartilage
Posteriorly to vocal process of arytenoid cartilage
Space between vocal folds
Rima glottidis
-> entrance of lower respiratory tract
Quadrangular membrane of larynx
- Superior to cricothyroid membrane
- from epiglottis to apical process of arytenoid cartilage and thyroid cartilage
- lower border is free and thickened
- lower border forms vestibular folds (false vocal cords)
Aryepiglottic muscle function
Narrowing of laryngeal inlet (recurrent laryngeal nerve)
Oblique arytenoid function
Narrowing of laryngeal inlet (recurrent laryngeal nerve)
thyroepiglottic muscle function
pulls epiglottis down (recurrent laryngeal nerve)
Posterior cricoarytenoid function
Abduction of vocal folds (recurrent laryngeal nerve)
The only muscle that opens vocal folds to breathe –> work constantly to keep airway open (recurrent laryngeal nerve)
Lateral cricoarytenoid function
Adduction of vocal folds (recurrent laryngeal nerve)
Transverse arytenoids muscle function
Approximates the arytenoid cartilage (recurrent laryngeal nerve)
Cricothyroid muscle function
Tense the vocal fold -> higher notes (external laryngeal nerve from superior laryngeal nerve of CNX)
Thyroarytenoid muscle function
Shortens vocal folds
Vocalis muscle function
Tenses the cord and brings the edge of vocal folds upward during abduction
Structure between vocal and vestibular ligaments
Herniation of mucosa (sinus leading to saccule)
Saccule contains mucous glands that moistens vocal folds and prevent damage
Communications of infra temporal fossa
To cranial cavity - foramen ovale, foramen spinosum
To orbit: Inferior orbital fissure
To pterygopalatine fossa: pterygomaxillary fissure
Temporomandibular joint
Between mandibular condyle and gleaned fossa of temporal bone
- synovial joint, lax capsule anteriorly
- biconcave intra-articular disc
Medial pterygoid muscle action
elevates mandible, assist the protrusion of lower jaw, move the mandible medially
Lateral pterygoid muscle action
Major protrude of lower jaw, assist medial movement
Jaw protrusion muscle
Mainly lateral pterygoid assisted by medial pterygoid
Jaw retraction muscles
posterior fibres of temporalis, deep head of masseter
digastric, geniohyoid
jaw elevation muscles
anterior fibres of Temporalis, masseter, medial pterygoid
Jaw depression muscles
Gravity
- digastric, geniohyoid, mylohyoid
Temporalis muscle action
anterior fibre elevates jaw; posterior fibre retracts mandible, assist side-to-side action
Masseter muscle action
elevation and retraction of mandible
Meningeal nerve’s supply
(V3 trunk branch)
- enters foramen spinosum
- sensory input to dura mater in middle cranial fossa
Nerve to medial pterygoid’s supply
(V3 trunk branch) Motor and sensory to:
- medial pterygoid muscle
- tensor veli palatini
- tensor tympani
Nerve to lateral pterygoid’s supply
(V3 anterior branch) motor:
- lateral pterygoid
Buccal nerve’s supply
(V3 anterior branch) Sensory:
- to cheek (skin, mucosa, buccal gingivae)
Auriculotemporal nerve’s supply
(V3 posterior branch)
- sensory to skin over temple, external ear, external acoustic meatus, tympanic membrane, TMJ
- carries parasympathetic secretomotor fibres of CN IX from otic ganglion to parotid gland
Inferior alveolar nerve’s supply
(V3 posterior branch)
- sensory to lower teeth and associated gingivae, mucosa and skin
- motor branch to mylohyoid
(branch to form incisive and mental nerve)
Lingual nerve’s supply
(V3 posterior branch)
- sensory to anterior 2/3 tongue, mucosa of oral cavity floor, lingual gingivae
- joined by chords tympani to provide special sensation to anterior 2/3 of tongue and parasympathetic fibres to all salivary glands below level of oral fissure
Chorda tympani
Branch of facial nerve (VII)
- passes through petrotympanic fissure
- joins lingual nerve medial to lateral pterygoid muscle
- special sensation of taste to anterior 2/3 of tongue
- presynaptic parasympathetic fibres to submandibular ganglion, which supplies sublingual and submandibular glands and tongue blood vessels
Submandibular ganglion
Hangs from lingual nerve at lateral surface of hyoglossus
- carries secondary cell bodies for chords tympani
- postsynaptic fibres travel along lingual nerve to sublingual and submandibular glands
Lesser petrosal nerve
From tympanic plexus (CN IX), descend at foramen ovale
- Otic ganglion
- > postsynaptic fibres join auriculotemporal nerve
How does maxillary artery separate to three parts
1st: Between neck of mandible and sphenomandibular ligament
2nd: related to lateral pterygoid muscle
3rd: In pterygopalatine fossa
Pterygoid venous plexus
- network of veins between medial and lateral pterygoid muscles, and lateral pterygoid and temporals
- drains nasal cavity, roof and lateral wall of oral cavity, all teeth, infra temporal fossa, paranasal sinus and nasopharynx
- Anterior: Deep facial vein
- Posterior: Short maxillary vein -> retromandibular vein
- Inferior ophthalmic vein from orbit
- communicates with cavernous sinus through infraorbital vein, inferior ophthalmic vein and emissary vein
Where does internal carotid artery enter skull?
Carotid canal
Vertebral artery ascension route
Through transverse foramina of upper six cervical vertebrae
Enters cranial cavity through foramen magnum
What does ciliary artery supply?
Choroid and sclera of eyes
Anastomoses of face and scalp artery
Between different arteries:
1) Superficial temporal and posterior auricular
2) superficial temporal and supraorbital
3) Dorsal nasal and angular artery
Between same artery from different sides:
4) Right and Left superficial temporal arteries
Facial vein anatomy
Facial vein (continuation of angular vein by joining of supratrochlear and supraorbital veins)
- drains into internal jugular vein directly or indirectly via common facial vein
- communicates with cavernous sinus via superior and inferior ophthalmic veins
- communicates with pterygoid venous plexus via infraoribital and deep facial veins
Retromandibular vein anatomy
Formed by joining of superficial temporal vein and maxillary vein
- anterior branch: joins facial vein to form common facial vein
- posterior branch: joins posterior auricular vein to form external jugular vein
External jugular vein
- formed by posterior auricular vein and posterior branch of retromandibular vein
- crosses Sterncleidomastoid
Receives:
- suprascapular
- transverse cervical
- anterior jugular vein
- ends in subclavian vein
Anterior jugular vein
Descend on either side of neck midline
- drains anterior aspect of neck and enters EJV or subclavian vein
Internal jugular vein
- begins in jugular foramen as continuation of sigmoid sinus
- descend in carotid sheath, joins subclavian veins to form brachiocephalic vein
- superior bulb at beginning and inferior bulb at termination
- receives blood from brain, H&N
Vertebral vein
- do not cross foramen magnum
- formed by small veins around skull base
- enters transverse foramen of axis (C1)
- descend with vertebral artery, ends in brachiocephalic or subclavian veins
Cavernous sinus
Location: each side of the sella turcica and sphenoid bone body
Lateral wall: CN III, IV, V1, V2
Internal carotid artery and CN VI pass through it
Communicates with pterygoid venous plexus by emissary veins and receive blood from superior and inferior ophthalmic veins
Internal vertebral venous plexus
Collect blood from vertebral column and drain into portal and systemic veins
Communicate with intracranial dural venous sinuses i.e. occipital and basilar
** (important conduit for retrograde metastases from pelvis or abdomen to cranial cavity)
External vertebral venous plexus
Collect blood from vertebral column and drain into portal and systemic veins
Eye movements
A) GAZE STABILIZATION
1) Vestibulo-ocular system (pre-rotatory and post-rotatory nystagmus, transitional VOR, ocular counter-rolling)
2) Optokinetic system (Visually evoked optokinetic nystagmus)
B) GAZE SHIFTING
1) Smooth pursuit system
2) Saccadic system
3) Vergence system
Vestibulo-ocular system function
Stabilization of retinal image during body movements (e.g. head rotation, linear motion, or head tilts)
Vestibulo-ocular system neurological circuitry
1) Canal mechanism i.e. fluid movement during acceleration and deceleration leads to vestibular afferent discharge
2) Magnitude modulated by vestibulocerebellum - where follicular purkinje cells inhibit vestibular nuclear neurons
3) When head stops, eyes are held in position by cerebellar flocculus, vestibular nucleus, and prepositus hypoglossal.
Vestibular nystagmus form
Slow initial phase (2s) countering the rotation
Fast late phase (0.2s) towards side of rotation
Optokinetic system function
Activated by movement of entire visual world
-> Stabilise gaze by holding image on the visual world steady on retina (especially useful during constant speed sustained head rotation as vestibule-ocular signal subsides)
Optokinetic system neurological circuitry
SUBCORTICAL:
Retina neurons -> CNII -> Pretectal nucleus -> Vestibular nucleus that integrates vestibular and visual inputs -> occulomotor nucleus in reticular formation
CORTICAL:
Striate cortex and middle temporal cortex -> pontine nuclei -> cerebellar flocculus -> occulomotor area in reticular formation
Smooth pursuit system function
Triggered by moving visual stimulus that slides across stationary visual background
Voluntary conjugate eye movement that keep moving target on fovea (foveal fixation) and reduce unwanted eye drifts
Smooth pursuit system neural circuitry
Gaze center is in paramedian reticular formation (midbrain center for vertical gaze, pontine center for horizontal gaze)
Same pathway as optokinetic system:
SUBCORTICAL:
Retina neurons -> CNII -> Pretectal nucleus -> Vestibular nucleus that integrates vestibular and visual inputs -> occulomotor nucleus in reticular formation
CORTICAL:
Striate cortex and middle temporal cortex -> pontine nuclei -> cerebellar flocculus -> occulomotor area in reticular formation
Smooth pursuit system neural circuitry
Gaze center is in paramedian reticular formation (midbrain center for vertical gaze, pontine center for horizontal gaze)
Same pathway as optokinetic system:
SUBCORTICAL:
Retina neurons -> CNII -> Pretectal nucleus -> Vestibular nucleus that integrates vestibular and visual inputs -> occulomotor nucleus in reticular formation
CORTICAL:
Striate cortex and middle temporal cortex -> pontine nuclei -> cerebellar flocculus -> occulomotor area in reticular formation
Saccadic system function
Triggered in response to sound, tactile stimulus, and memory of location in space
Rapid conjugate eye movement that move fovea rapidly from one target to another (no time for visual feedback to modify saccade course)
Saccadic system neural circuitry
Motor commands from frontal and supplementary eye fields via superior colliculus and basal ganglia, and Saccade generator:
1) Burst reticular cells (pulse discharge to drive eyes rapidly to new position; eye velocity command that overcome orbital viscous lag)
2) Tonic cells in prepositus hypoglossal nucleus or medial vestibular nucleus (step discharge to hold eye in place; eye position command against orbital elastic restoring force)
3) Inhibitory reticular cells (prevent unwanted eye movements)
–> relayed to oculomotor area in reticular formation
Vergence system function
Dysconjugate eye movement to align image on both fovea
Vergence system neural circuitry
Controlled by midbrain neutrons close to IIIrd nucleus
Retinal visual pathway
Laminar organization of photoreceptors, bipolar cells and retinal ganglion cells:
1) Photoreceptor: Cones and rod cells, different modality (red green VS blue yellow)
2) Bipolar cells: Concentric center-surround receptive fields (Centre and surround antagonistic in nature)
3) Retinal ganglion cells: Concentric center-surround receptive fields (On centre and off centre cells; M cells and P cells)
Cone cell VS rod cell
CONE VS ROD
i) daytime VS night-time vision
ii) Color VS B&W vision
iii) small receptive field VS large receptive field
iv) less convergence thus higher acuity VS high convergence thus lower acuity
v) One kind of Blue, green, red pigments VS rhodopsin
Bipolar cell Receptive field
Concentric center-surround receptive fields
1) On centre cells - depolarise to illumination (hyperpolarise to illumination of off-surround cells via GABA lateral inhibition of horizontal cells)
2) Off centre cells - depolarise to darkness (hyperpolarise to darkness of on-surround cells via GABA lateral inhibition of horizontal cells)
Retinal ganglion cells processing
Concentric center-surround receptive fields
1) On centre cells (depolarise to light on) and Off centre cells (depolarise to light off)
2) M cell vs P cell
- M: large receptive field, contrast, form, movement
- P: small receptive field, fine detail, color discrimination
Lateral geniculate body of thalamus visual coding
Concentric center-surround receptive fields; M cell VS P cells
1) Left visual field stimuli go to right LGB; right visual field go to left LGB
2) Inputs from 2 eyes are segregated by synapsing on alternate cell layers
3) Inputs from M cells and P cells are segregated by synapsing on alternate cell layers, Magnocellular pathway ventrally (movement, form, contrast) and parvocellular pathway dorsally (fine details, colour discrimination)
Primary visual cortex visual coding
1) Receptive field -> functional hierarchy transforms receptive field to rectangular receptive field:
- Directional selectivity for moving stimulus - Orientation selectivity (simple cell in orientation columns detects orientation, convergent to different complex cell for 2-level orientation detection, which then convey to hyper-complex cells in modular organization)
2) Modular organisation
Interaction between cortical modules lead to visual perception
Binocular receptive field helps with depth perception
- Orientation columns (vertical columns of simple cells with different axis of orientation)
- Ocular dominance columns (alternating columns from right or left eyes)
- Blobs (cell column responsive to different colour stimulus)
3) Parallel pathways
- Distinct M and P pathways from LGN; Ventral M pathway (form, movement, contrast), Dorsal P pathway (colour, fine details)
- Segregate pathway beyond striate cortex: Ventral stream (spatial task, form & color recognition, visual memory); Dorsal stream (motion perception)
Hydroxyapatite formula
Ca10 (PO4)6 OH2
Two-stage secretion of saliva
1) Isotinic secretion
- secretogogue (Ach) increase acinar cell intracellular Ca
- opening of basolateral Ca activated K channel and apical Cl channel
- K efflux to interstitium, Cl efflux to acinar lumen
- Na from interstitium to lumen by following Cl electrical gradient, via transcellular tight junction
- osmotic gradient by NaCl cause transepithelial water migration from interstitium to lumen
- Basolarteral Na K Cl cotransporter and Na K ATPase energize Cl replenishment
(HCO3 ions can replace Cl by carbonic anhydrase action on CO2; HCO3 efflux via apical Cl channel; H efflux by basolateral Na H exchanger)
2) Hypotonic secretion
- striated duct cell’s Na K ATPase actively extrude Na back to blood, Cl follow passively
- Na Cl diffuse from lumen to cell
- Water cannot as ductal apical membrane is water impermeable
- hypotonic saliva produced
Macromolecule secretion in saliva
- sympathetic stimulation of beta adrenoceptor leads to increase cAMP, thus activating PKA
- phosphorylation activates target protein, and lead to polypeptide and protein synthesis, storage and release
Plasma protein e.g. IgA are endocytosed by acinar cells, then transcellular translocation to apical membrane, then released by exocytosis (in pathological condition plasma protein enter saliva via paracellular route)
Function of nasal secretion
1) Allow mucociliary transport to remove materials deposited in nose
2) protection with Ig (IgA) and bacteriocidal proteins
3) Air conditioning by warming and humidifying inhaled air
4) Olfaction (modify inhaled odors)
Nasal secretion sources
1) Anterior nasal glands in vestibule - serous
2) Submucosal glands in respiratory and olfactory region - seromucous
3) Secretory cells in respiratory epithelium - mucous
4) Plasma exudate in pathological conditions
Control of nasal secretion
A) Neural:
1) Sympathetic nerve - induce protein secretion (beta adrenoceptor) and vasoconstriction that reduce fluid supply (alpha) -> SCANTY SECRETION
2) Parasympathetic nerve - electrolyte transport and vasodilation (muscarinic Ach) -> COPIOUS SECRETION
3) Sensory nerve - VIP leads to vasodilation -> more fluid supply this COPIOUS SECRETION
B) Inflammatory mediators
1) Histamine, bradykinin, prostaglandin
- induce electrolute transport on glandular receptor
- vasodilation
- increase vascular permeability
- activate sensory nerve and parasympathetic nerves
Flavor definition
Complex mixture of sensory input of: 1) Olfaction (smell) 2) Gustation (taste) 3) Tactile sensation (texture) of food as it is being chewed
Physiology of smell
- odorant molecule diffuse from air to olfactory epithelium
- dissolve in mucus and bind to different types of olfactory receptors on cilia of olfactory cells (each olfactory cell express one type of odourant receptor
- Binding activates Golf, increasing Na Ca conductance, leading to depolarise and fire neural discharge of cell
- sensory cells bearing same receptor have axons converge to same glomeruli on the olfactory bulb
- the distinct firing combination of olfactory neurons and activated glomeruli are translated by brain to diverse odour perception
Location of taste buds (draw them out)
Circumvallate papilla
Foliate papilla
Fungiform papilla
Basic smell qualities
Floral (rose) Ethereal (pear) Musky (musk) Camphor (eucalyptus) Putrid (rotten egg) Pungent (vinegar)
Basic taste quality and indications
- Sour (warn against intake of potentially poisonous chemicals)
- Sweet (identification of energy-rich nutrients)
- Bitter (warn against intake of potentially poisonous chemicals)
- Umami (glutamate, identification of L-amino acid)
- Salty (Proper dietary electrolyte)
Sweet taste receptor
T1R2 + T1R3 heterodimer
GPCR, activated G protein release G beta gamma that activate PLC that cleaves to form IP3 and DAG, secondary messengers finally depolarise the cell and stimulate connected neurons to relay nerve signal
Sour taste receptor
H+ influx via H+ ion channels (PKD2L1) to depolarize taste cells and stimulate connected neurons to relay nerve signal
Umami taste receptor
T1R1 + T1R3
GPCR, activated G protein release G beta gamma that activate PLC that cleaves to form IP3 and DAG, secondary messengers finally depolarise the cell and stimulate connected neurons to relay nerve signal
Bitter taste receptor
T2R
GPCR, activated G protein release G beta gamma that activate PLC that cleaves to form IP3 and DAG, secondary messengers finally depolarise the cell and stimulate connected neurons to relay nerve signal
Taste physiology
Taste receptor cells are assembled into taste buds, located within tongue papilla (circumvallate, foliate, fungiform)
Labelled line model (MORE LIKELY): Each taste quality is specified by non overlapping cells and fibres, i.e. each TRC respond to one taste and innervated by nerve fibres tunes to the taste
Across Fibre model: each individual TRC tuned to one/multiple taste qualities, and each afferent fibres carry information for more than one taste qualities
Salty taste receptor
ENaC (epithelial sodium channel)
Na+ influx via Na+ ion channels to depolarize taste cells and stimulate connected neurons to relay nerve signal
Taste quality in brain
Labelled-line model in periphery
Beside taste quality, neurons also record other attributes of chemical stimuli e.g. intensity of the taste and whether it is pleasant, neutral or unpleasant
Function of external ear in hearing
Collection and localisation of sound, conduct sound to tympanic membrane by air
Function of middle ear in hearing
1) Impedance matching - air borne vibration stops at ear drum, fluid vibration starts at fenestra vestibuli; matching of the 2 media achieved by:
a) Leverage of ossicles
b) Area-ratio between larger tympanic membrane and small oval window
2) Sound attenuation (during exposure to loud sound or vocalisation) via middle ear muscle (tensor tympani, staepidius) reflex to protect inner ear and improve speech discrimination in noise
Function of middle ear muscle reflex
Sound attenuation (during exposure to loud sound or vocalisation) to:
i) Protect inner ear
ii) Improve speech discrimination in noise
Generation of sound nerve impulse in inner ear
(Mainly inner hair cells, outer hair cell plays minimal role)
- oval window vibration from ossicles leads to perilymph vibration in Vestibular canal
- vibration transmit to endolymph in cochlear duct and displace basilar membrane
- Displacement of basilar membrane creates shearing force that displace hair cell’s cilia embedded in the tectorial membrane
- Opens pressure gated K+ channel on stereocilia and kinocilia, K+ influx leads to hair cell depolarisation
- depolarisation opens voltage-gated Ca++ channel, which prompt neurotransmitter exocytosis
- generator potential at auditory nerve
Inner hair cell VS outer hair cell
INNER VS OUTER
More involved in sound sensation transmission VS less involved
1:10 afferent connection/divergence VS >10:1 afferent connection/convergence
Less VS more (1:3)
supply 95% afferent VS 5% afferent
Inner ear sound frequency processing
Place coding: the cochlea is tonotopically represented based on physical property of basilar membrane:
i) Basal portion (stiff, narrow, short stereocilia) respond to high frequency
ii) Apex portion (floppy, wide, long stereocilia) respond to low frequency
Thus frequency of tone determines peak position of travelling wave along basilar membrane; wave subsides rapidly beyond optimal displacement with sharp cut off at apex
Inner ear sound intensity processing
Mechanical layout of organ of Corti amplifies very small vibrations
Descending efferent modulation –> Outer hair cells amplify mechanical vibration of basilar membrane by shortening the length of cell body (motor from descending auditory pathway) -> alter sensitivity of hair cells to improve detection of weak sound against background noise (selective filtering)
Auditory nerve receptive field
V-shaped tuning curve
- tip of curve is characteristic frequency (signifies the locus of hair cell on the basilar membrane with which auditory fibre innervates)
- sharply tuned to exclude frequency above CF
- permits discrimination of very soft tones with slightly different frequency
Central auditory pathway
- Auditory nerve (sound intensity and frequency processing)
- > Brainstem’s Cochlear nucleus & superior olivary complex
- > Midbrain’s inferior colliculus
- > Thalamus’ MGB
- > Cortical centres
Brainstem’s role in hearing
Lower brainstem centers (shows progressive sharpening of tuning curves to ENHANCE frequency discrimination):
1) Cochlear nucleus ro analyse intensity and frequency
2) Superior olivary complex for Binaural processing (compare time and intensity cue from both ears) for gross discrimination of sound direction
Midbrain’s role in hearing
Inferior colliculus:
- detect frequency modulation and amplitude modulation in speech
- reflex center for sound orientating response and startle response
- descending projection from auditory cortex to modulate ascending signals
Thalamus’s role in hearing
Medial geniculate body
- ascending relay to auditory cortex
- descending projection from auditory cortex to modulate ascending signals
Cortical center’s role in hearing
1) Functional column in area 41, 42:
- isofrequency bands (rostral low; caudal high)
- biaural bands (right vs left ear)
2) precise localisation of sound in space
3) Broca’s (44, 45) and Wernicke’s (22) to process complex sound of language
Some auditory test
1) Pure tone audiometry (measure hearing threshold in terms of intensity and frequency)
2) Brainstem auditory evoked response (click evoked neural activity to assess hearing ability of esp infants)
Functions of vestibular apparatus
1) Subjective sensation of motion and spatial orientation (vestibulo-cortical perception)
2) Stabilization of eyes in space during head movements (vestibulo-ocular reflex)
3) Adjustment of muscle activity and posture to prevent falling (vestibulo-spinal reflex)
Neuronal signal production in vestibular system
By hair cell (kinocilia and stereocilia)
Head movement introduces shearing force:
- bending of stereocilia to kinocilium depolarises the receptor cell (increase vestibular nerve firing)
- bending of kinocilium towards stereocilia hyperpolarizes the cell (decrease firing)
Semicircular canal function
Detects angular acceleration (i.e. rotation) of head in 3-D space
- canals on 2 sides work as complementary pairs (increase firing of one vestibular nerve means decrease firing of the other side’s)
- At onset of rotation, acceleration leads to lagging of endolymph in canal due to inertia, shearing force that displace hair cells, depolarize
- constant speed rotation -> no acceleration, cilia back to normal
- At end of rotation, endolymph displace in opposite direction due to inertia, shearing force that displace hair cells, hyperpolarize
Otolith organs structures
Utricle in horizontal plane
Saccule in vertical plane
Otolith organ function
Detects linear acceleration or head tilt
- multidirectional orientation of polarisation axis for utricle
- Up-down orientation of polarisation axis for saccule
- Head movement in particular direction increase the excitability of one subgroup and decrease another on the same otolith organ
Central processing of vestibular signals
1) Compensatory vestibular relfexes
- vestibulo-spinal reflexes (balance posture with antigravity muscles)
- vestibulo-ocular reflexes (otolith related and canal-related)
2) Subjective orientation: vestibulo-thalamo-cortical projection for conscious awareness of motion and body orientation
3) Disturbances associated with motion sickness -> autonomic nervous system foe nausea and dizziness
Otolith related VORs
1) Counter rolling (aka Doll’s eye reflex)
- 50º lateral tilt for 5º counter rolling
2) Translational VOR:
- Linear acceleration of 1m/s^2 -> 4º derivation of A-P parallel swing
Canal-related VORs
Vestibular Nystagmus
Pre rotatory and post rotary
Slow phase and fast phase
Prevention of aspiration during swallowing
1) Elevation of larynx and folding of epiglottis to cover laryngeal inlet
2) Closure of false cords
3) closure of glottis
4) Generation of positive subglottic pressure
Dysphagia crude classifications
Intraluminal (eg lodged food)
Intramural (esophageal tumour)
Extraluminal (large lymph nodes)
Vocal cord histology
A) Mucosal layer: pseudostratified epithelium with goblet cells superiorly and inferiorly; non-keratinising squamous epithelium at contact surface of medial cord
B) Subepithelial tissues: three layered lamina propr.:
i) Superficial Reinke’s space (allow free vibration of epithelium)
ii) Intermediate layer (part of vocal ligament)
iii) Deep layer (part of vocal ligament)
Note: vocal ligament formed by free thickened edge o quadrangular membrane
Articulation structures and innervations
Mandible - CN V Lips - CN VII Larynx - CN X Soft palate - CN XI Tongue - CN XII
Loudness depends on:
force of expiration -> Lung function strength of respiratory muscles
Pitch depends on:
Vocal folds
- Size (larger -> lower)
- Tension and length (tenser -> higher)
- Intrinsic laryngeal muscle strength
Neural control of swallowing?
Revisit if have time
Spinal nerve components
A mixed nerve formed from fusion of Ventral root (motor nerve) and Dorsal root (sensory nerve)
Spinal nerve communications
1) Only gray rami communicans in cervical spinal nerves
2) White and grey rami communicans in (T1 - L2?)
Intermediolateral horn function
Level of T1 to L2
- cell bodies of sympathetic motor fibres, which axon extend into same of different level sympathetic ganglion via white ramus communicans
Somatic motor nerve VS visceral motor nerve
Somatic VS visceral
- somite derived outer body tube VS inner body tube
- One neuron chain (CNS -> skeletal muscle) VS two-neuron chain (CNS -> autonomic ganglion -> smooth muscles)
- Supplies skin, skeletal muscles and vertebrae VS smooth and cardiac muscles, and glands
Somatic sensory nerve VS visceral sensory nerve
- somite derived outer body tube VS inner body tube
- One neuron link (both)
- Both’s cell body lie collected together in PNS as sensory ganglion (EXCEPT some proprioceptive neurons have cell body in CNS)
Cervical Plexus
Formed by ventral rami of C1-C4 cervical spinal nerves, gives rise to cutaneous sensory and motor branches:
1) Sensory:
- Lesser occipital
- Greater auricular
- transverse cervical
- supraclavicular
2) Motor:
- C1 to geniohyoid and thyrohyoid
- C1 - C3 (Ansa cervicalis) to infrahyoid muscles (Sternohyoid, sternothyroid, omohyoid)
- C4 Phrenic nerve to diaphragm
- nerve twigs to prevertebral muscles (longus capitis and cervicis)
Where does cutaneous branches of cervical plexus emerge?
Midpoint along posterior border of sternocleidomastoid
Four cranial parasympathetic ganglia
III Ciliary
VII Pterygopalatine
VII Submandibular
IX Otic
Cranial autonomic nerves components
A mixed nerve carried by somatic sensory branches of trigeminal nerve; contains sensory fibres of CN V, parasympatheic visceral motor fibers from CN, and sympathetic nerve from superior cervical ganglion (only parasympathetic synapse in ganglion)
cranial parasympathetic ganglia receives what kind of nerve fibres?
1) sensory fibres of CN V
2) parasympatheic visceral motor fibers from CN III VII IX
3) sympathetic visceral motor nerve from superior cervical ganglion
Ciliary ganglion circuitry
CN V: V1 nasociliary nerve -> sensory of cornea and iris
Sympathetic: Sup Cerv Gang -> dilator pupillae and blood vessels
Parasympathetic: Edinger Westphal Nuc -> ciliary ganglion -> sphincter pupillae and ciliary muscles
Pterygopalatine ganglion circuitry
CN V: V2 ->
Sympathetic: Sup Cerv Gang -> Deep petrosal nerve ->
Parasympathetic: Superior salivary nucleus -> Greater petrosal nerve -> pterygopalatine ganglion ->
Submandibular ganglion circuitry
{CN V: V3 Lingual nerve -> anterior 2/3 tongue sense (DOES NOT PASS THROUGH GANGLION!!)}
CN VII: Chorda tympani -> taste to anterior 2/3
Sympathetic: Sup Cerv Gang -> Submandibular and sublingual glands
Parastympathetics: Superior salivary nucleus -> joins chorda tympani -> synapse in submandibular ganglion -> joins lingual nerve -> submandibular and sublingual glands
(note: all post ganglionic fibres except sympathetics join lingual nerve)
Otic ganglion circuitry
CN V: V3 auriculotemporal nerve -> parotid fascia sensory
Sym: Sup Cerv Gang -> joins auriculotemporal nerve -> parotid arteries
Parasym: Inferior salivary nucleus -> tympanic plexus -> lesser petrosal nerve -> otic ganglion -> joins auriculotemporal nerve -> Parotid gland
Sympathetic innervation of H&N
1) Pregnaglionic sympathetic motor nerve cell bodies in interomediolateral horn of T1 - T2
2) Fibres ascend through sympathetic chain to reach superior cervical ganglion
3) Postgnalgionic fibres return to cervical spinal nerves or BVs via gray rami communicans
4) Travel along blood vessels to reach target
Cervical sympathetic ganglion
Superior (largest)
Middle
Inferior
- lies on longus capitis muscle about level of 2nd and 3rd vertebral body
- Gives off gray rami communicans
H&N cutaneous sensory supply
CRANIAL NERVE:
- Face by V1 V2 V3 (think of the face guy)
SPINAL NERVE:
- dorsal rami of cervical spinal nerve supplies back of head and neck
- cervical plexus supplies front and side of neck
Different salivary gland secretion
Parotid gland - serous or watery secretion
Submandibular & sublingual glands - a mixture of serous and mucous fluid
Small mucosal glands - mucous secretion
Structures that transverse parotid gland
(superficial to deep)
- facial nerve and branches
- retromandibular vein
- external carotid artery
Antithrombin III function
Form complex with thrombin or Factor Xa with heparin from endothelial cells to inhibit thrombin and Factor Xa, thus no activity and start anti-coagulation pathway
How thrombin activate anti-coagulation pathways
Bound to thrombomodulin -> protein C activation, Factor Vac, together with S, inactivate factor VIIIa
Bound to antithrombin III to form complex with heparin as well, inactivate thrombin
Anterior pituitary hormones
GBM LP FLAT
GH
Beta endorphin
MSH
Lipotrophin
Prolactin
FSH
LH
ACTH
TSH
Posterior Pituitary hormones
ADH
Oxytocin
Location of pituitary
Sella turcica, a cavity of sphenoid bone
Pituitary development
Neuroectoderm. The neural component – evaginates from the floor of the diencephalon and grows caudally. becomes posterior lobe
Oropharyngeal ectoderm. The oral component arises as an out-pocket from the roof of the primitive mouth, forming the Rathke’s pouch. Becomes anterior lobe
Pituitary Gland Structure
Anterior lobe (adenohypophysis): pars tuberalis, pars intermedia, pars distalis
Posterior lobe (neurohypophysis): Extension of neuroectoderm via infundibulum; neural fibres, palely stained
Blood supply of pituitary gland
From Internal carotid artery:
1) Right and left superior hypophyseal arteries -> forms primary capillary plexus (supply median eminence and infundibulum) -> form veins and secondary capillary plexus in adenohypophysis (**hypophyseal portal system)
2) Right and left inferior hypophyseal arteries -> supplies neurohypophysis and a small supply to infundibulum
=> hypophyseal veins
Three groups of hormone production in the three sites of the hypothalamo- hypophyseal system
1) Oxytocin and ADH: peptides produced by aggregates of neurons in the supraoptic and paraventricular nuclei of the hypothalamus => transported along axons, accumulated at the end of axons in the neurohypophysis => release to blood capillaries
2) Releasing hormones: peptides produced by neurons of the dorsal medial, ventral medial and infundibular nuclei of hypothalamus => carried along axons ending in median eminence where they are stored and secreted => enter the capillaries of the median eminence and transported to the adenohypophysis via the hypophyseal portal system for stimulation
3) proteins and glycoproteins secreted by endocrine cells in pars distalis. They are liberated into the secondary capillary plexus of the portal system and are distributed to the general circulation
Pituitary Median eminence
Location: wall of the infundibulum
- the neuro-haemal region where the neurohormones pass into the capillaries
- surrounded by extended perivascular connective tissue spaces where axon endings open into
Pituitary pars distalis
cords of epithelial cells interspersed with capillaries
- chromophobe
- Chromophile (acidophil, basophil)
pituitary acidophil function
GH, Prolactin secretion
pituitary basophil function
FSH
LH
ACTH
TSH
Pituitary pars tuberalis
funnel shaped region surrounding infundibulum
cells of this region secrete gonadotrophins and are arranged in cords alongside with blood vessels
Adenohypophysis – pars intermedia
made up of cords and follicles of weakly basophilic cells containing basophilic granules
developed from dorsal part of the Rathke’s pouch.
Pituitary pars nervosa
- Composed of unmyelinated neurons
- Neurosecretions accumulate at the end of the neurons to form Herring bodies
- ADH and oxytocin joined to neurophysin, a binding protein
Hypothalamic Hormones
- GnRH (=> LH FSH)
- CRG (Corticotropin-releasing hormone) => ACTH, MSH, beta endorphin
- Thyrotropin-releasing hormone (TRH) => TSH & Prolactin
- GHRH => GH
- Somatostatin => decrease GH, TSH, prolactin
- Dopamine => decrease prolactin
Types of Feedback loop in hypothalamo-hypophysio-? axis
- Long-loop: target gland hormone or metabolite on pituitary/hypothalamus
- e.g. cortisol on ACTH/CRH - Short-loop: pituitary hormone on hypothalamus
- e.g. ACTH on CRH
- GH on somatostatin, SRIF) - Ultra-short-loop: within pituitary or hypothalamus
- GHRH increases SRIF secretion
ACTH function
1) Binds to adrenal cortex membrane receptor that activates adenylate cyclase, increase cAMP, increase PKA
2) Stimulates the synthesis & secretion of mainly cortisol from the zone fasciculate of adrenal cortex (aldosterone mainly controlled by renin-angiotensin system)
Hypothalamo-hypophysio-adrenal feedback for Cortisol
Long loop: direct Cortisol on ACTH; indirect cortisol on CRH
Short loop: ACTH on CRH
LH and FSH biochemical structure
glycoprotein hormones consist of α and β subunits;
β sequence being different for LH and FSH.
FSH function
1) In female: Development of Graffian follicles -> Oestrogen production (for proliferative phase of endometrium & secondary sexual characteristics)
2) male: spermatogenesis
LH function
1) female: causes ovulation and maintains the corpus luteum, to produce Progesterone (Secretory phase of endometrium for implantation)
2) male: stimulate Leydig cell to produce testosterone (secondary sexual characteristic)
TSH biochemical structure
glycoprotein consists of α and β chains where α chain is identical to LH & FSH
Prolactin function
1) Lactation in mammary gland alveoli
2) Inhibits hypothalamus and gonads, reducing the production and activities of gonadotrophins
–> Breast-feeding women cannot get pregnant
–> Reason: breast-feeding elevates prolactin level, which mediate an anti-gonadotrophic effect, causing a lack of ovulation
Regulation of secretion of prolactin
Uniquely regulated by inhibition mainly
- Baby suckling of nipple activate mechanoreceptor, send signal to higher centre
- hypothalamic PIH release inhibited, thus stimulating prolactin production in anterior pituitary
Growth hormone effects
A) INDIRECT ACTION
1) causes liver to produce somatomedins/ insulin like growth factors (IGF), which ↑ glucose uptake and ↓ lipolysis initially
2) somatomedin stimulate bone growth at epiphysis of long bones
- increases deposition of protein by chondrocytic & osteogenic cells
- increases the proliferation of chondrocytic & osteogenic cells
- promotes conversion of chondrocytes into osteogenic cells
B) DIRECT ACTION
3) Promotes protein synthesis, decrease proteolysis
4) Enhances fat utilization for energy (enhance lipolysis and beta oxidation)
5) Decreases carbohydrate utilization; After a few hours: insulin antagonistic effect to ↓ glucose uptake and ↑ lipolysis; increased gluconeogenesis in liver
Regulation of GH secretion:
1) GHRH/somatostatin (pull-push mechanism) -> depend on ratio
2) Negative feedback:
- blood glucose
- somatomedins (IGF-1)
3) Other factors stimulate GH secretion:
- fasting or starvation
- hypoglycemia
- ↓ plasma FFA
- Exercise
- Stress, trauma, excitement
ADH effects
1) stimulates V1 receptor on vascular smooth muscle to cause vasoconstriction to ↑ blood pressure
2) stimulates V2 receptor on distal and collecting ducts to increases water reabsorption by insertion of aquaporin 2
What stimulates ADH release?
↑ Plasma osmolarity
↓ Circulating blood volume
↓ blood pressure
Oxytocin effects
Effect on milk ejection (letdown reflex)
- causes contraction of the myoepithelium of the breast
Effect on the uterus
- causes contraction in parturition (baby delivery)
Adrenal Gland anatomy and embryonic origin
Cortex (mesoderm) and Medulla (neuroectoderm)
CORTEX
- Zona glomerulosa: mineralocorticoids (Aldosterone)
- Zona fasciculata: glucocorticoids (Cortisol)
- Zona reticularis: androgens (DHEAS)
MEDULLA
- chromaffin cells that release catecholamine (epinephrine & norepinephrine) under sympathetic stimulation
- Innervated by cholinergic preganglionic sympathetic neurones. Acetylcholine released binds to nicotinic receptors on chromaffin cells
Actions of Aldosterone
1) ↓ Urinary excre
Regulation of aldosterone secretion
1) Renin‐angiotensin‐aldosterone system
- kidney JXG cells produced Renin converts liver produced angiotensinogen to angiotensin I which is converted by lungs’ ACE to angiotensin II
- Angiotensin II increases growth & vascularity of zona glomerulosa, increases aldosterone synthesis
2) Plasma [K+]
- higher plasma K increase aldosterone secretion
3) Atrial natriuretic peptide ANP
- ANP released by atria in response to high BP, inhibits aldosterone secretion & renal Na reabsorption, resulting in diuresis & ↓ BP
Renin‐angiotensin‐aldosterone system
Juxtaglomerular cells release Renin when:
1) ↓ perfusion pressure (dehydration, bleeding)
2) ↑ sympathetic stimualtion
3) decreased NaCl delivered to macula densa
Actions of Cortisol
BBIIG
1) Blood pressure maintenance (up regulation of alpha adrenoceptor on arterioles) -> INCREASE BP
2) BONE RESORPTION: Inhibits osteoblasts & protein synthesis; ↓ serum [Ca2+ ] by ↓ intestine and renal reabsorption; increase PTH for bone resorption
3) Immunosuppression and anti-inflammatory
4)
5) Glucose increase by gluconeogenesis, glycogenolysis, reduced glucose uptake
6) Mobilize protein (proteolysis) from non-hepatic tissues to liver for protein genesis
7) Fat : increase lipolysis, decreased lipogenesis
Hypokalemia -> weak muscle
Inhibits fibroblast proliferation & collagen formation -> striae
Polycaethemia
READ L21
Regulation of cortisol secretion
- Hypothalamic‐pituitary‐adrenal axis
- paraventricular nucleus releases CRF -> anterior pituitary release ACTH -> cortisol from adrenal cortex - Diurnal rhythm
- Diurnal rhythm of CRH, and thus ACTH & cortisol
- Cortisol high in the morning, low in late afternoon & at night
- Under control of suprachiasmatic nucleus SCN - Negative feedback
- Long loop: Negative feedback of plasma cortisol on hypothalamic CRF & pituitary ACTH production
- Short loop: plasma ACTH on CRF secretion - Stress increases CRH, ACTH & cortisol
Adrenal androgens and age
- Adrenal androgen begins to appear after birth at about 5 years of age
- DHEAS become detectable in the circulation at about 6 years of age (adrenarche)
- contributes to the appearance of axillary & pubic hair at about 8 years old
- Levels continue to increase, peak during mid‐twenties, and then progressively decline with age
Adrenal androgen function
In men, contribution of adrenal androgens to active androgens is negligible
In female, adrenal contributes 50% of circulating active androgens, required for growth of axillary & pubic hair and for libido
Calcium in bone and blood
1) BONE: 99% of calcium is found in the bone:
- Most of it in the form of hydroxyapatite crystal, Ca10(PO4)6(OH)2, in large stable calcium pool that is slowly exchangeable by bone remodeling
- surface of newly formed bones (amorphous calcium phosphate, CaHPO4); Readily exchangeable reservoir that is in equilibrium with ECF
2) MUSCLE: 0.3% of calcium is located in muscle
3) 0.1% of calcium is found in extracellular fluid:
- ionized calcium (Ca2+); 50%
- protein-bound (albumin & globulins); 40%; non-diffusible
- complexed with anions e.g. citrate or phosphate; 10%
*Two types of calcium in bone:
- Most of it in the form of hydroxyapatite crystal, Ca10(PO4)6(OH)2, in large stable calcium pool that is slowly exchangeable by bone remodeling
- surface of newly formed bones (amorphous calcium phosphate, CaHPO4); Readily exchangeable reservoir that is in equilibrium with ECF
Physiological roles of phosphate
1) important component of intracellular pH buffering and various metabolic intermediates.
2) Bone component
3) DNA, RNA and phosphoproteins
Phosphate in bone and blood
86% in the bone, 14% in cells, and 0.08% in extracellular fluid
- Most of the plasma phosphate is diffusible as inorganic orthophosphate (PO4)3- e.g. (HPO4)2- (80%) and (H2PO4)- (20%).
- Non-diffusible phosphate is bound with protein (13%)
Regulation of Plasma Ca and PO4
1) Nonhormonal regulation
- Protein-bound calcium (buffer)
- Exchangeable pool in bone (amorphous calcium phosphate)
2) Hormonal regulation
- PTH
- 1, 25 DOH Vit D
- calcitonin
- others like cortisol (bone resorption) TH (bone growth) GH (bone growth) Estrogen (prevent osteoporosis)
Parathyroid gland blood supply
inferior thyroid arteries from thyrocervical trunk
Synthesis of PTH
- PTH is translated as a pre-prohormone
- Cleavage of leader and pro-sequences in liver and kidneys
- The C-terminal fragment (PTH-C) is an inactive peptide
Regulation of PTH secretion
(MAJOR) Decrease serum Ca++ or Mg++ will increase PTH
Active vitamin D inhibits PTH gene expression, providing another level of feedback control of PTH.
Mechanism of PTH secretion
A unique calcium receptor (CaSR) on the plasma membrane of parathyroid cells senses changes in extracellular [Ca2+].
The receptor coupled to both phospholipase C (activate) and adenylate cyclase (inhibit). Binding of Ca2+ to the receptor results in increased intracellular [Ca2+] and decreased in cAMP which prevents exocytosis of PTH from secretory granules.
Action of PTH
increase plasma Ca2+ and decrease plasma phosphate:
1) increase distal tubule Ca reabsorption
2) increase phosphate excretion in proximal tubules
3) promotes the formation of 1,25-(OH)2 vitamin D in kidney to enhance GI Ca2+ absorption
4*) Increase bone resorption:
i) fast phase on osteoblast and osteocyte: PTH promotes Ca2+ pump activity in the osteocytic membrane system (overlying the bone matrix with a thin layer of bone fluid), osteocytes take up Ca2+ from the bone fluid and transport it to ECF through the osteoblasts
ii) indirect slow phase on osteoclasts (since no PTH receptor): activate osteosteoclastic activity, and promotes the proliferation of osteoclasts
Synthesis of vitamin D
1) In skin keratinocyte, 7-dehydrocholesterol is photo converted under UV to previtamin D, then spontaneously converts to vitamin D3.
2) Liver vitamin D 25-hydroxylase hydroxylate vitamin D3 yielding 25- (OH) vitamin D (calcidiol) - rate limiting step
3) Kidney VD3 1α-hydroxylase hydroxylate calcidiol yielding active 1,25- (OH)2 vitamin D (calcitriol) [stimulated by PTH and low Ca)
Actions of vitamin D
1) promotes the effect of PTH on bone resorption by increasing the activity of osteoclasts
2) stimulate absorption of Ca2+ from intestine epithelium by:
- induces the production of calcium binding proteins (CaBP or calbindins) which sequester Ca2+, buffer high [Ca2+] that arise during initial absorption and allow Ca2+ to be absorbed against a high Ca2+ gradient
- stimulates the production/activity of Ca2+ channel and transporter (TRPV6 & Na/ Ca exchanger) in intestinal epithelium.
3) also stimulates Ca2+ & PO43- reabsorption in kidney tubules (minor effect)
Calcitonin source
by the thyroid (parafollicular cells or “C” cells).
Vit D production regulation
High PTH and low Ca++ stimulate Kidney VD3 1α-hydroxylase to produce active Vit D
Calcitonin action
decrease plasma Ca2+ and phosphate by:
1) Decreases bone resorption by inhibiting osteoclastic activity and inhibiting the proliferation of osteoclasts
2) Decreases renal Ca2+ reabsorption & promotes phosphate excretion.
Calcitonin release regulation
Increased serum calcium leads to secretion
Hormonal action classes
Endocrine: chemical substances that are secreted by living cells, and upon delivery by the
circulation to a specific site, act to regulate reactions that elicit a typical response (e.g. insulin)
Paracrine: acting on adjacent cells (e.g. somatostatin)
Neurocrine: secreted at nerve endings (e.g. oxytocin)
Autocrine: acting on the cell (or cell of the same type) that secretes it (e.g. T4)
Neuroendocrine: neuocrine and endocrine e.g. somatostatin on GH secretion
Different chemical structure of hormones
Protein: prolactin
Peptide: Insulin, glucagon
Steroid: aldosterone, cortisol
Amines: thyroxine, adrenaline from tyrosine
Prostaglandins & cytokines (local hormones e.g. TNF alpha)
What is Metabolic clearance rate
volume of plasma completely cleared of a hormone per unit time
Rhythms of hormonal secretion
1) Episodic secretion: secreted in pulses but not continuously e.g. GnRH
2) Diurnal rhythem: e.g. cortisol secretion highest in morning and lowest in evening
3) Cyclic secretion: complicated cycles e.g. LH, FSH, estrogen
Basic classes of hormonal receptor models
1) Mobile receptor model (intracellular cytosolic or nuclear receptors)
- steroid hormones
=> response by genome activation/ inactivation
2) Fixed receptor model (extracellular on plasma membrane)
- peptides
- catecholamine
(cAMP, AC, calmodulin, DAG, IP3, JAK, TK)
=> response by protein phosphorylation
3) Multiple receptor model
- e.g. TH; receptor both intracellular and extracellular
Example of same hormone acting on different receptor
Vasopressin/ADH
V1 receptor (via IP3) on vessels -> vasoconstriction
V2 receptor (via cAMP) on distal tubule -> insertion of aquaporin 2
Sign VS Symptoms
Sign: Objectively measurable, as perceived by doctors e.g. tachycardia
Symptoms: Subjective, perceived by patient e.g. palpitation
Different endocrine cause of muscle weakness
Hypokalemia in hyperaldosteronism
Hypercalcemia in hyperparathyroidism
Proteolysis in hyperthyroidism
Proteolysis of limb muscles in Cushing’s
Decrease release of Ach at NMJ in hypocortisolaemia
Calculation of association constant in hormone-receptor interaction
Association constant = [HR complex] / ( [free H] * [free R] )
Scatchard plot
X axis: value of bound hormone [HR]
Y axis: ratio of bound to free hormone [HR]/[H]
When H -> infinity, then Y axis is 0, and [HR] will reach highest level (i.e. maximum binding Bmax)
X-intercept = Bmax Slope = - Ka (association constant)
Enzyme example with both slow and fast action
Thyroxine and insulin
Fast action: act on existing molecule e.g. enzymes or transporter
Slow action: increase number of molecule by protein synthesis
Protein synthesis control by hormones
- level of RNA synthesis (steroid, GH, insulin)
- level of ribosome (GH, insulin, thyroxine)
- cAMP -> transcription (glucagon) or ribosome (ACTH)
Permissive action of hormone
Presented to allow other hormones to work (e.g. T4 up regulate beta adernoceptors; cortisol inhibits phosphodiesterase)
Contradicting direct and permissive effect in hormone
e. g. Cortisol
direct: increase glycogenesis
Permissive: increase glycogenolytic effect by glucagon and adrenaline
(direct during feeding where high blood glucose inhibit glucagon; permissive during fasting as glucose produced in liver is released and not converted to glycogen)
Ways to change rate of biochemical reaction (hormone example insulin and T4)
1) change enzyme activity (insulin) (T4 stimulate mitochondrial enzyme for oxidative phosphrylation)
2) Change in substrate level (insulin increases glucose for glycolysis) (T4 increase ADP level by increasing transport into mitochondria and stimulating Na/K ATPase)
3) Change in product level (insulin stimulates glycolysis removing Acetyl CoA, the first step of FFA synthesis) (T4 increase transport of ATP out of mitochondria)
Principles of hormonal integration
1) Redundancy (same physiological effect of different hormones -> ensure critical process will take place)
- adrenaline and glucagon on glycogenolysis
- adrenaline and GH in lipolysis
2) Reinforcement (different way, same end)
- cortisol -> increase muscle proteolysis and increase liver enzyme for gluconeogenesis
3) Push-pull mechanism (dual control for precise regulation via negative feedback)
- GH by GHRH and SRIF
- glucose level by insulin and glucagon
4) Modulation of responding system
- receptor: e.g. T4 downregulate TRH receptor; estrogen up-regulate LH receptor
- post-receptor: inhibition of cAMP destruction? (i.e. permissive action)
Action of adrenaline and noradrenaline
Adrenaline (alpha beta); Noradrenaline (alpha):
1) CVS
- increase cardiac output (beta 1, heart rate and stroke volume)
- Blood pressure (alpha vasoconstriction, beta 2 vasodilation)
2) Metabolism (alpha and beta)
- increase glycogenolysis, lipolysis, gluconeogenesis
3) Smooth muscle contraction
- muscle contraction (alpha)
- muscle relaxation (beta 2)
(Same direction for GI tract)
Negative and positive feedback characters
close loop
Negative feedback: to keep hormonal level more or less constant
Positive feedback: to make level deviate more from norm -> amplification of level for action
Positive feedback example
LH surge for ovulation
Oxytocin for uterine contraction during labour
Haemorrhage feedback control
Loss of 1 litre of blood => decrease BP => negative feedback via baroreceptor and volume retention => increase BP to normal
Loss of 2 litres of blood => decrease BP => positive feedback from decreased venous return, decreased coronary perfusion => further vicious decrease in BP
GnRH release positive and negative feedback
Hypothalamus control Via kisspeptin
- Negative feedback at arcuate nucleus
- Positive feedback at anteroventral periventricular nucleus (puberty, preovulatory LH surge)
Change of negative feedback setpoint
e.g. glucose in stress
Higher glucose level in stress due to insulin decrease, glucagon increase, cortisol and adrenaline increase
e.g. ACTH in stress
Higher ACTH level in stress -> to further increase Cortisol
Feed-forward control of hormones
Anticipatory response to improve homeostasis
e. g. increase of glucose in GI tract => increase GI hormone => increase insulin secretion
e. g. Cephalic phase of eating => parasympathetics to increase insulin secretion
RELEASE of insulin in anticipation of blood glucose increase
Classes of factors affecting hormone control
EXTERNAL FACTOR (open loop where output does not affect input) e.g. lighting, stress, cold
INTERNAL FACTOR (close loop where output affect input) e.g. negative feedback by metabolites, BP
[external factor with feedback -> suckling on oxytocin positive feedback]
Peripheral resistance of hormone
Usually caused by decrease in receptor in target tissue or antagonistic action, will lead to hypersecretion of hormone to compensate to normal physiological state by:
1) Negative feedback & receptor control
e. g. decrease T4 receptor leads to decrease in T4 action; negative feedback increase in TRH receptor, thus increase T4 secretion for compensation
Main theme of peptide hormone signal transduction
Peptide hormone binds to transcellular cell surface receptor, cell receptor activate coupling protein, which activates an effector protein for intracellular signal production -> hormonal effect
Phospholipase C function in signal transduction
Cleaves Phosphatidylinositol 4,5- bisphosphate into DAG and IP3 (inositol 1,4,5 triphosphate);
DAG activates PKC
IP3 increases intracellular Ca++ from endoplasmic reticulum
Control of cAMP level in signal transduction
By formation: ATP to cAMP by adenylyl cyclase
By degradation: cAMP to AMP by phosphodiesterase
7TM receptor signal transduction mechanism
1) Peptide bind to receptor
2) Receptor Interacts with a G-protein
3) Dissociation of G-protein into the α and βγ-subunits
4) The α-subunit (From GDP to GTP-bound) activates effector proteins: adenylyl cyclase produces cAMP, phospholipase-C produces IP3 and DAG, and so on
5) In some cases, the βγ-subunits also activates phospholipase-C.
6) Hydrolysis of GTP to GDP by the intrinsic GTPase of the α-subunit disables the functional activity of the α-subunit
7) G protein reforms
Peptide hormone receptor with a single transmembrane region – signaling module
1) Peptide binds to receptor
2) Receptor dimerisation
3) The tyrosine kinase of the cytosolic domain will self phosphorylate each other’s cytosolic domain, as well as other proteins in the cytosol
4) Adaptor proteins connect added phosphate group with PLC, and other effector molecules like protein kinase and monomeric G-protein
5) Changes in activities of proteins in the cytosol, as well as expression of new genes in the nucleus bring about changes in cellular activities
How are Intracellular signals produced by hormone receptors are self-limiting?
1) GPCR are self limiting as internal GTPase activity of alpha subunit will dephosphorylate GTP to GDP, thus inactivating alpha subunit’s stimulatory effect
2) Secondary signalling molecules are degraded e.g. cAMP to AMP by phosphodiesterase
3) By Dephosphorylation of phosphoproteins
Peptide Receptor desensitisation
cAMP activates cAPK; βγ subunits activate βARK
cAPK and βARK phosphylate the peptide receptor to desensitise it, thus preventing further cAMP production and G protein activation
cAPK: cAMP-dependent protein kinase
βARK: a G-protein coupled receptor kinase (GRK)
Regulation of peptide receptor abundance
By:
1) Receptor desensitisation by phosphorylation by cAPK and βARK
2) Receptor down-regulation by GRK-arrestin pathway
3) Receptor endocytosis
Receptor down-regulation by GRK-arrestin pathway
G-protein coupled receptor kinase (GRK) phosphorylate the GPCR
β arrestin bind to phosphorylated GPCR
internalisation of receptor by endocytosis (clathrin coated vesicle) to form endosome
Receptors on endosome may be recycled
Ecdysone and insect salivary gland
- Ecdysone, an insect steroid hormone, leads to puffing (decondensation) of bands of large polytene chromosome in insect salivary gland
- Newly synthesized RNAs labelled by 3H-uridine localized to puffs
=> conclusion: DNA transcription is induced by steroid hormones
Hormone Responsive Element of different hormone receptors
HRE for glucocorticoid receptor, alsosterone receptor, androgen receptor and progesterone receptor are the same
HRE for Estrogen receptor is different
Steroid hormone signal transduction
Steroid hormone pass through plasma membrane into cytoplasm
some binds to cytoplasmic receptors -> conformational change to allow entry into nucleus
some enter nucleus and bind to nuclear receptor -> Conformational change
Receptor-ligand complex binds to HRE of the DNA, which controls transcription of the downstream sequence
transcription of DNA, produce new proteins and give new physiological function
General structure of steroid hormone receptor
1) Variable region (N-terminal: vary in length, have unique sequences, and may contain one or more activation domains.)
2) DNA binding domain (central part; considerable sequence homology among different receptors)
3) Ligand binding domain (C-terminal; less homology)
“nongenotropic” steroid hormone pathways
Requires only the ligand-binding domain of the receptor and its extranuclear localization
hormone bind to cytoplasmic receptor, activate protein kinase that will translocates into nucleus -> Control by direct phosphorylation (e.g. inactivating Bad) or activating transcription of some target genes via Elk-1/CREB
Cell growth and proliferation biochemical controller
Cell growth (cell mass increase) -> mTOR mammalian target of rapamycin, a conserved kinas
Cell proliferation (cell number increase) -> Cyclin-dependent kinase
mTOR function
For cell growth (cell mass increase)
- transcription
- translation
- RNA processing
- Protein stability
- autophagy
Exercise and growth
Exercise increases AMPK level via ATP depletion -> help with growth regulation
programmed cell death importance
- To counter cell production and maintain an appropriate number of cells in the tissues
- eliminates unwanted structures during the development of the male and female inner reproductive organs
- Remove interdigital mesoderm, initially formed between fingers
- form intestinal lumen and other tissues
Apoptosis induction
1) Protein synthesis regulated by the genes affected by the
activated transcription factors => alteration of the relative abundance of pro-apoptotic and anti-apoptotic proteins
2) Release of apoptosis-inducing factor to change mitochondrial activity
3) Activation of the caspase cascade to breakdown DNA
How do our bodies know when to initiate or stop growing?
- Contact inhibition
Key molecules in fetal growth
1) Human placenta prolactin
2) Peptide Growth factors:
- Insulin, ILGF-1, ILGF-2
- Fibroblast growth factor FGF
- Epidermal growth factor EGF
- Transforming growth factor b (TGF beta)
- platelet derived growth factor (PDGF)
Key molecules in postnatal growth
Infancy:
- Insulin, Insulin like GF-1, TH
Childhoof: GH
Puberty: Sex steroids
linear growth primary regulation target site
growth plate of bone
Cartilage end of long bone anatomy
Outer to downwards
- articular cartilage
- secondary ossification centre
- reserve cartilage (resting zone)
- proliferating cartilage
- hypertrophic cartilage
- calcified cartilage
Growth plate development regulation events
1) Stem cell giving rise to mesenchymal cell condensation, mesenchymal cell turning into osteochondro progenitor (sox 9), and then to chondrocyte (Sox 5, 6, 9)
2) Chondrocyte proliferation
3) Formation of pre-hypertrophic chondrocytes
4) Cessation of hypertrophic chondrocyte growth
Local regulators of growth plate
- Ihh (indian hedgehog)
- PTHrP
- Fibroblast growth factor (FGF)
- Vascular endothelial growth factor (VEGF)
- Runx2
- transforming growth factor b (TGFb)
What cell secrete PTHrP
perichondrial cells and chondrocytes at the ends of long bones
PTHrP action
acts on receptors on proliferating chondrocytes to keep the chondrocytes proliferating and, impair hypertrophic differentiation -> retard bone growth in endochondral ossification
-> less prehypertrophic chondrocyte, thus decrease IHH productioin
Ihh action
1) acts on its receptor on chondrocytes to increase the rate of proliferation
2) stimulates the production of PTHrP at the ends of bones
3) perichondrial cells to convert these cells into osteoblasts of the bone collar
PTHrP and Ihh feedback loop
PTHrP secreted by perichondrial cells and chodrocyte at ends of long bone, prevent proliferating chondrocytes from entering hypertrophic differentiation (and decrease IHH here)
As proliferating chodrocyte migrate further from bone end, PTHrP inhibition lifted, enters prehypertrophic differentiation and produce IHH; IHH increase proliferation rate, stimulate PTHrP production tan ends, and convert cells into osteoblasts
-> the feedback loop regulates the relative proportion of proliferating and hypertrophic chodrocyte in growth plate
What cell express IHH?
Prehypertrophic chondrocyte
FGF recrptor 1,2,3 expression sites
FGFR1 - prehypertrophic and hypertrophic chondrocytes and perichondrium
FGFR2 - perichondrium, periosteum and the primary spongiosa
FGFR3 - proliferating chodrocyte
FGF 18, expression site and action
expressed in the perichondrium, actions are:
FGFR3 - decrease chondrocyte proliferation
FGFR1 - delay terminal differentiation of hypertrophic chondrocyte
FGFR2 - delay osteoblast development
and Decrease IHH expression
Perichondrium FGFs
FGF 7, 8, 17, 18
bone morphogenetic proteins action
- Increase chondrocyte proliferation
- Accelerate terminal differentiation of hypertrophic chondrocyte
- accelerate osteoblast development
- Increase IHH expression
Endocrine regulators of growth plate
1) GH -> resting zone proliferation
2) IGF-1 -> resting and proliferative zone proliferation
3) Glucocorticoids -> inhibit proliferation, induce apoptosis
4) TH -> bone growth and proliferation
5) Estrogen -> inhibit proliferation
6) Androgen ->Stimulates proliferation
7) Vitamin D -> Permissive of hypertrophic zone normal physiology
8) Leptin -> proliferation
Growth hormone axis
Hypothatlamus: Push-pull between GHRH, somatostatin
Pituitary: GH
Liver: IGF/ somatomedin
Target: Growth
IGF action
1) ↑ glucose uptake and ↓ lipolysis initially
2) somatomedin stimulate bone growth at epiphysis of long bones
- increases deposition of protein by chondrocytic & osteogenic cells
- increases the proliferation of chondrocytic & osteogenic cells
- promotes conversion of chondrocytes into osteogenic cell
Type I VS II IGF Receptor
- Dimer VS monomer
- Postnatal VS Foetal
- mediates anabolic actions of both IGF-I and IGF-II VS bifunctional, serving both to target lysosomal enzymes and to enhance IGF-II turnover
IGF-I release control
GH -> transcription
Estrogen -> mRNA expression
T4
Imaging techniques of thyroid gland
** Ultrasound
** Radionuclide scans
(Plain XR)
(CT - require iodine contrast)
(MRI)
Limitations of plain radiographs in thyroid problems
- Does not give extent of compression or displacement of trachea
- Cannot evaluate other mediastinal structures
Ultrasound pros and cons in thyroid problem
PROS:
- No radiation and very convenient
- Excellent for evaluating superficial structures such as the thyroid gland
- excellent spatial resolution (Sensitive in detecting tiny nodule)
- can identify calcification
CONS: Unable to differentiate accurately between benign and malignancy; SENSITIVE BUT NOT SPECIFIC
Ultrasonography sign for different thyroid pathology
SENSITIVE BUT UNSPECIFIC, always use US guided FNAC or fine needle biopsy
1) Solid VS cystic, size, number
2) vascularity using colour doppler US (e.g. increased in Grave’s or papillary adenoma)
3) Microcalcifications (psammoma bodies) commonly in papillary carcinoma (or follicular or anaplastic)
4) Coarse calcification (medullary carcinoma)
5) Hypoechoic (darker -> more likely malignant)
6) Margin/Contour - Ill-defined/Irregular margin
Thyroid enlargement FNAC
Fine needle aspirate cytology
Major drawback: cannot distinguish follicular adenoma or carcinoma -> need biopsy for histology (Rely on capsular or venous invasion)
Radionuclide scans for thyroid comparison
FUNCTIONAL INFORMATION:
99m-Tc pertechnetate VS Iodide scan
Trapped by thyroid VS trapped by thyroid
Not organified VS Organified (incorporated into thyroglobulin)
Thyroid iodide scan
Use I-123 or I-131, both trapped and organised
Thyroid Radionuclide scan Use
Assess metabolic function
- Hot (increased intake)
- Cold (no intake)
Shows position of ectopic thyroid gland
Hot and cold nodules DDx in thyroid radionuclide scan
HOT
- excludes cancer
- primary hyperthyroidism e.g. Multinodular goitre
- iodine deficiency
COLD
- majority benign lesion (colloid nodule, thyroiditis, adenoma)
- all cancers are cold (CA thyroid, lymphoma)
=> always of needle biopsy
When use CT and MRI for thyroid problem?
- Cross-sectional anatomy, to evaluate local and distal extent of disease
- When there’s an Intrathoracic extension of goitre
- Post surgical or radioactive treatment surveillance for recurrence
Steroid hormone regulation
regulated at the level of synthesis rather than secretion
- > steroidogenic cells don’t store steroids
- > freely diffuse out of membrane due to lipophilic nature; no exocytosis
Substrate of Cytochrome P450
drugs and carcinogens or endogenous compounds like steroid hormones, bile acids, prostaglandins
Cytochrome P450 location
Cyto -> in mitochrondria and microsomes (endoplasmic reticulum)
Cytochrome P450 biochemical function
Monooxygenases or hydroxylases:
RH + O2 + NADPH + [H+] => ROH + H2O + [NADP+]
Biosynthesis of adrenalcortical steroids from cholesterol rate-limiting step
Cholesterol to pregnenolone by CYP11A (stimulated by ACTH)
CYP11A (function, location)
Mitochondrial, in all primary steroidogenic tissues (adrenal cortex, ovary, placenta, Leydig cells)
- required for aldosterone, cortisol and androgen production
RATE LIMITING and stimulated by ACTH
3-beta Hydroxysteroid dehydrogenase (function, location)
Microsomal, in all primary steroidogenic tissues (adrenal cortex, ovary, placenta, Leydig cells) and skin, liver, prostate, breast
- required for aldosterone, cortisol and androgen production
CYP17 (function, location)
Microsomal, adrenal cortex’s zona fasciculata and reticularis
- required for androgen and cortisol production (NOT aldosterone)
CYP21 (function, location)
Microsomal, in adrenal cortex
- required for aldosterone and cortisol production
CYP11B (function location)
Mitochondrial, in adrenal cortex (11B1 in fasciculata; 11B2 in glomerulosa)
- 11B1 for cortisol production; 11B2 for aldosterone production
Regulation of adrenalcortical steroidogenesis
Directly by by ACTH (increased in stress or morning)
Aldosterone:
1) Renin‐angiotensin‐aldosterone system
2) [K+] (more K increase production)
3) ANP (decrease production)
4) Minimally from ACTH
How does cerebellum guide volitional movement?
1) deliberate actions eg needle threading is guided in real time by moment to moment correction via sensory feedback
2) ballistic movements are too fast for sensory guidance and are orchestrated by cerebellum based on previous experience eg golf swing
Zygomatic arch components
Zygomatic process of maxilla
Zygomatic bone
Zygomatic process of temporal bone
Neck boundary
Superior: anterior mandible, posteriorly base of cranium
Inferior: sternum, clavicle, acromion, C7 spinous process
Neck fascia
1) Superficial fascia
- subcutaneous connecting skin to deep fascia
- contains platysma, superficial veins
DEEP FASCIA
2) deep investing layer
- covers sternocleidomastoid and trapezius
3) pretracheal layer
- visceral compartment
- larynx, pharynx, trachea, esophagus, thyroid thymus parathyroid
4) Prevertebral layer
- vertebral compartment
- cervical spine and spine muscles
5) carotid sheath
- vascular compartment
- common carotid artery, IJV, CN X
Anterior neck triangle
Upper: lower border of mandible
Lower: SCM anterior border
Medial: midline
Content: trachea, esophagus
Muscles connected to hyoid ie Omohyoid geniohyoid thyrohyoid sternohyoid sternothyroid
Thyroid and parathyroids
Posterior neck triangle
Apex: back of skull Anterior: SCM posterior border Posterior: Trapezius anterior border Base: middle of clavicle Roof: deep investing fascia Floor: flexor and extensor of cervical spine
Contents: Omohyoid Subclavian artery (suprascapular, dorsal scapular, occipital) EJV CN XI Branchial plexus
Submandibular triangle
Upper: mandible lower border
Lower: anterior and posterior belly of digastric
Floor: mylohyoid and hyoglossus
Content:
Submandibular gland
Submandibular lymph nodes
Deep cervical lymph nodes
External and internal carotid artery
IJV
CN X, XII
Submental triangle
Boundary: anterior belly of digastric, midline, hyoid bone
Floor: mylohyoid
Contents:
Submental nodes
Anterior jugular vein
Carotid triangle
Boundary: anterior border SCM, posterior belly of digastric, stylohyoid, upper belly of omohyoid
Floor: thyrohyoid, hyoglossus, pharynx
Contents: common carotid artery dividing
IJV
CN X, XI, XII
Deep cervical lymph nodes
Muscular triangle
Boundary: midline, hyoid, upper belly of Omohyoid, SCM
floor: sternothyroid, sternohyoid
Contents:
- trachea, esophagus, larynx
- thyroid gland
Submandibular gland position
Superficial part in submandibular fossa
Deep part in floor of mouth
Submandibular from anterior deep part run between genioglossus and sublingual gland to sublingual papilla
- > associated with facial artery, common facial vein and facial nerve’s mandibular branch
- > supply by chorda tympani from submandibular ganglion
Sublingual gland
Between mylohyoid and genioglossus
Supplied by chorda tympani from submandibular ganglion
Structure associated with hyoglossus muscle
Superficial: SHLS submandibular duct Hypoglossal nerve CN XII Stylohyoid muscle Lingual nerve (V3)
Deep:
Glossopharyngeal nerve CN IX
Stylohyoid ligament
Lingual artery
Location of parotid gland
Wedged between mandibular ramus and mastoid process of temporal bone
Parotid highland opens to
Parotid papilla which is opposite to upper second molar
Limbic system function
Memory
Emotion and behaviours
Amygdaloid complex function
- defence and attack, fear, rage
- influence hypothalamus’ endocrine
Memory brain structures
EXPLICIT MEMORY
- events (episodic) and facts (semantic): hippocampus, nucleus basalis, medial temporal lobe
IMPLICIT MEMORY:
- skills and habits: striatum, cerebellum, cortex motor area
- emotional: amygdala, insula
- conditioned reflex: cerebellum
WORKING MEMORY:
Spatial: dorsolateral prefrontal cortex
Non-spatial: ventrolateral prefrontal cortex
Amygdala stimulation leads to
Fear, anxiety
Stimulates affective aggression (medial hypothalamus)
Inhibits predatory aggression (lateral hypothalamus)
Amygdala emotional processes will go to:
1) hypothalamus for sympathetic activation of flight or fight
2) reticular formation for arousal
3) brain stem nuclei for emotional behaviours like facial expression
Where is memory for learned fear stored?
Amygdala
Hippocampus function
Learning, recent memory (lesion lead to anterograde amnesia)
Memory
Hormone action ways
Membrane permeability
Nuclear regulation
Protein synthesis control
Enzyme activation