** INTRO **

Imaging Modalities
- Radiology
- CT Scan
- Magnetic Resonance Imaging (MRI)
- Contrast Studies
Radiology
- x-ray / plain lm
- attenuation >> absorption >> image production
- absorption - in uenced by atomic number of the structure
- attenuation - process of x-ray removed from a beam through absorption
-
- radio-dense/radiopaque : less photon can pass through >> appear white on x-ray (metal, bone)
- radiolucent : photons easily pass through >> appear black (soft tissue, fat, gas)
CT scan
- Computed Tomography
- digital computer + rotating x-ray >> slices of di erent organs
- detailed images ( internal organs, blood vessels, bones )
- contrast dye >> enhance structures ( blood vessels)
MRI
- magnetic property of spinning hydrogen atoms
- depend on properties of tissue and structures
- # of hydrogen atoms (proton density)
- chemical environment of H ( free water / fat bound )
- ow : blood vessel / CSF
- magnetic susceptibility : T1 relaxation time (fat) and T2 relaxation time (water)
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- Axial : inferior to superior
- sagittal : right to left
- coronal : anterior to posterior
Contrast Studies
- when NO di erence from surrounding tissue >> contrast agent ( Radiopaque / white )
- ex) Rarium Enema - gastrointestinal tract
- ex) subtraction angiography - circulatory system

** Anatomy **

Regional : upper limb, Thorax

systemic : cardiovascular, digestive
sectional anatomy : relates to imaging
surface anatomy : localize deeper organ ( use easily identi ed landmarks )
mapping : segmental nerve supply to skin & muscle ( related to development )

supine : lying on back

fowler’s : lying on back 30 degree
prone : lying down
left decubitus : lying on left side
lithotomy position : hips and knees fully exed, thighs separated

Apex of Heart : 5 th intercostal space , midclavicular line

Description of movement : movement occurring + joint where movement occurs

exion : angle reduced
extension : angle increase
adduction : toward central axis
abduction : away from central axis
medial rotation : inward rotation
lateral rotation : outward rotation
circumduction : combination of all
pronation : palm turned backward
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supination : palm turned forwards

Eponyms : terms based on names of person

- fallopian tube
- eustachian tube
- pouch of Douglas
- pouch of Morrison
Acronyms : used to remember things
NAVEL : Femoral Nerve, artery, vein, canal - empty space , lacunar ligament ( lateral to medial )

basic element : word root + combining form + su x + pre x

Cardi - heart
Gastr - stomach
Cyst - lled sac or pouch

cyan - blue
erythr - red
leuk - white
melan - black
poli - gray

abdomino - abdomen
adeno - gland
angio - vessel
arterio - artery
appendo - appendix
arthro - joint
audio - hearing
auro - ear
axillo - armpit
brachio - arm
cardio - heart
cephalo - head
cerebro - brain (cerebrum)
cervico - neck
colo - colon ( large intestine )
coccyo, coccygo - coccyx ( tail bone )
costo - rib
cranio - skull
crino - secrete
cutaneo - skin
cysto - urinary bladder
cyto - cell
dermo, dermato - skin
cholecysto - gallbladder
denti - tooth
duodeno - duodenum
encephalo - brain
entero - intestine
epiglotto - epiglottis
epithelio - skin
erythro - red
esophago - esophagus
esthesio - feeling
geno - producing
gingivo - gum
glosso, glotto - tongue
glyco - sugar
gnoso - knowledge
gyneco - woman, female
hemato, hemo - blood
hepato - liver
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** Bones **

bone : provide framework, store minerals, rely on hormone, react to stress - muscle, no stress - loss teeth

long bone : humerus

short bone : carpals
at bone : skull bone
peumatic bone : mastoid (contain air space)
irregular bone : vertebrae
sesamoid : patella (in tendon)

+ neck + tubercle + tuberosity + sulcus/groove + epicondyle + condyle

( head ) epiphysis + metaphysis + diaphysis + metaphysis + epiphysis >> long bone

skeleton : Axial skeleton + Appendicular skeleton

7 cervical - larger, thinner, straight processes, foramen for arteries

12 thoracic - small, heart shaped, process curves downwards
5 lumbar - largest, small foramen, hatchet-shaped, straight process
5 sacral
4 rudimentary fused coccygeal

rib - at bone,
- posterior : articulate with body and transverse process of vertebrae
- anterior : articulate with sternum ( via costal cartilage )
- ture rib - 1-7 directly attached to sternum
- false rib - 8-10 indirectly attached to sternum
- oating rib - 11&12 not attached to sternum
- costal groove : contain neuromuscular bundle
- angle : where easily fractures
Sternum : 3 part ( manubrium, body, xiphoid )
- at bone
- sternomanubrial : plane of reference (produce angle)
- attach to clavicle + costal cartilages
Clavicle : long bone, medial and lateral extremity, horizontal
- curved : attach to sternum ( attened larger end) - (medial 2/3 convex, lateral 1/3 concave)
- articulate with scapula + sternum
- only connection btw upper limb and trunk
Scapula : at (blade) , irregular bone + ( spine )

Joints
brous : bones departed by connective tissue, sutures ( initially mobile but fuse completely in old age )
cartilage : primary (synchondrosis), secondary (symphysis, mobile, hyaline covered + brocartilage disc in btw)
synovial : very speci c, mobile >> 6 criteria
- hyaline cartilage, synovial uid, joint capsule, synovial membrane, ligaments, varying degree of movement

axial skeleton joint

atlantooccipital
atlantoaxial
intervertebral disc
zygapophyseal
inter laminar
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** ateries veins lymphatics **

Atery & Vein

tunica intima - inner endothelial lining + basement membrane + internal elastic lamina
tunica media - Smooth muscle + external elastic lamina
tunica externa - outer connective tissue layer

Arteriovenous shunt : artery directly ows into vein

- ngers, toes, ears,
- decrease heat loss, allow blood to bypass exposed areas
Anstomosis : union of branches of two or more vessels
- venous : allow for alternative drainage of organs
- arterial : collateral circulation - alternative routes for blood to reach tissue or organ
Lymphatic system
Axillary + Groin (inguinal ) node > right lymphatic duct + thoracic duct >> cardiovascular system
- right lymphatic duct covers right trunk, right upper limb, right face
- thoracic duct covers everything else.

** Nervous system, Spinal Nerve, Somatic Plexus **

CNS - brain ( cerebrum, cerebellum, diencephalon ) , spinal cord

PNS - spinal nerve (spinal cord) , cranial nerve (brain and brainstem) , ganglia, somatic visceral enteric plexus, sensory
ANS - sympathetic & parasympathetic

Somatic Plexuses : from ventral rami, combination of somatic sensory, motor, sympathetic
Cervical plexus : C1-5
Brachial plexus : C5-T1
Lumbar plexus : L1-4
Sacral plexus : L5-S4

Visceral Plexuses : combination of sympathetic, parasympathetic, visceral a erent bers

Sympathetic Chain : sweat glands, vascular smooth muscle, arrector pilli muscle (hair)
- synapse immediately > same paravertebral ganglia
- ascend, descend > higher or lower paravertebral ganglia (sacral splanchinic)
- pass through > pre-aortic ganglia
Parasympathetic :
- CN3 : Ciliary ganglion
- CN7 : Pterygopalatine ganglion
- CN9 : Otic ganglion, submandibular ganglion
- cranial nerve 10 : heart, 2/3 abdominal viscera
- S2-4 : 1/3 descending gut and pelvic organs (pelvic splanchnic nerve)
- from lateral-horn-like are
- pelvic splanchnic nerve enter pelvic plexus
ANS a erent
- unconscious sensation
- para: atrial & GI stretch, temperature, chemical and pressure changes (peristalsis, V heart rate, blood pressure)
- conscious sensation
- sys: painful sensation - ischemia, distention (abnormal stretch), in ammation, spasmodic contraction of SM
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** early Embryology **

Week 2
1) Formation of bilaminar disc & amnion

amniotic cavity : inside embryobalst

epiblast : thicker layer, columnar cells lining amniotic cavity
hypoblast : small cuboidal cells lining exocoelomic cavity (
Amnion : amnioblast seperate from epiblast >> form amnion (roof of amniotic cavity)

2) Formation of primary umbilical vesicle and extraembryonic mesoderm

Hypoblast >> exocoelomic cavity >> endodermal cells form exocoelomic (Heuser’s) membrane
>> form primary umbilical vesicle (primitive yolk sac)

Extraembryonic mesoderm : surrounds amnion and umbilical vesicle

3) formation of extra embryonic coelom & primordial uteroplacental circulation

Extra embryonic coelom : space btw extraembryonic mesoderm >> grows to surround amnion & primitive u. Vesicle
Primordial uteroplacental circulation : maternal blood in lacunae >> oxygen and nutrition pass into embryo

4) division of extra embryonic mesoderm

Extra embryonic coelom >> divide into 2 layers >> extraembryonic somatic & splanchnic mesoderm
Somatic mesoderm : lines trophoblast , cover amnion
Splanchnic mesoderm : surrounds primitive umbilical vesicle

Chorionic sac : somatic mesoderm + 2 layers of trophoblast

Extraembryonic coelom >> chorionic cavity

5) secondary umbilical vesicle formation

Primitive umbilical vesicle >> remnant small size

Secondary umbilical vesicle forms
Bilaminar disc > cranial end > hypoblastic cells develop >> thicken columnar cell - prechordal plate ( future mouth )

Week 3
1) gastrulation (3 germ layer)
Bilaminar disc > trilaminar
Primitive streak : linear band of epiblast appears (middle plane, dorsal aspect)
Left/right caudal/cranial dorsal/ventral could be identi ed

Primitive node : cranial end of streak

Primitive groove >> primitive pit ( small depression in primitive node)

Epiblast cell displace hypoblast to form > endoderm

Epiblast cell migrate laterally > between new endoderm > intraembryonic mesoderm
Remaining epiblast > ectoderm >> neuroectoderm & surface ectoderm

Tumors
Sacrococcygeal teratoma : most common, more in female, remnant of primitive streak (caudal region),
- derivatives from all 3 layers could be found (teeth, hair, muscle, glands)
2) notochord formation
Ectoderm adhere rmly to 2 points : prechordal plate (oropharyngeal membrane) + cloacal membrane
Notochordal process : mesodermal cells at primitive node migrate to form median cellular cord
>> become notochord canal : grown btw ectoderm & endoderm ( until it reach prechordal plate )

Notochordal plate : notochordal process oor fused with endoderm >> form ring
>> detach from endoderm >> notochord (solid rod) >> imitate development of Nervous System

Intraembryonic mesoderm >> di erentiate to 3 parts > paraxial , intermediate , lateral mesoderm
Notochord induce > ectoderm >> form neural plate >> CNS
Notochord regress >> nucleus pulposus // apical ligaments
>> remants >> chordoma ( malignant tumor invading bone - skull, lumbosacral region )
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Fate of the intraembryonic Mesoderm
1. Notochord
2. Migrate cranially >> prechordal plate>> cardiogenic mesoderm
3. Paraxial , intermediate , lateral mesoderm

Paraxial : (head) loose mesenchyme > skeletal muscle of face, jaw, throat
- (trunk & neck) somites >> either side of the notochord , paired segmented bodies >> approximate embryonic age
- 21days: 1~3 somites
- 23days: 10~12 somites
- 24days: dermomyotome + sclerotome
- 26days: dermatome + myotome + sclerotome
- Somites >> form axial skeleton , dermis, voluntary muscle of head, limbs , body wall
- Dermatome > dermis ( broblasts)
- Sclerotome > vertebrae and ribs
- Myotome > primordial muscle cells
- Dorsal epitaxial : extensor of neck, vertebral column, lumbar region
- Ventral hypaxial : limbs, abdominal wall mm, intercostal mm, scalene mm, prevertebral mm,
- infrahyoid & geniohyoid mm, respiratory & pelvic diaphragm
Intermediate & lateral plate mesoderm
Intermediate : form gonads and urinary system lateral plate mesoderm
Lateral & cardiogenic : clefts appear > intraembryonic coelom > split LPM to 2 layers : parietal layer & Visceral layer
Parietal (somatopleure) : form body wall
Visceral (splanchnopleure) : form remainder organs

2nd month of development :

intraembryonic coelom > divide to 3 body cavities : pericardial (heart) , pleural (lung) , peritoneal cavity (abdominals)

3rd week Neurulation

Ectoderm
Surface ectoderm : anterior pituitary, lens, cornea
Neural tube : posterior pituitary, retina, optic nerve, brain, spinal cord > develops > neural plate & groove >> CNS
Neural crest : adrenal medulla, Autonomic & sensory nerves > migrates > PNS & ANS

Endoderm: epithelial lining GI tract, liver, lungs

Mesoderm : urogenital system, CV system, muscles, bone

Neural plate : wide cranial portion + narrow caudal portion

- somites added at the trunk region & spinal cord region
- >> Lengthen >> form neural fold >> neural tube >> neuro ectoderm
- Narrow canal > smaller
- Neural tube remain open > cranial rostral & caudal neuropores ( close at day 25 & 27 )
- Cranial neuropore : form primary brain vesicles >> secondary brain vesicles
- Primary : Prosencephalon, Mesencephalon, Rhombencephalon
- Sedondary : Telencephalon & Diencephalon, Mesencephalon, Metencephalon & Myelencephalon
- 2 cerebral hemisphere. - thalamus .. - pons, cerebellum - medulla oblongata

Caudal neuropore >> Spinal Cord Development

Neural tube >> lined by neuroepithelium >> form ventricular zone >> neurons and macroglia cells
Inner Ventricular zone >> on top >> has outer marginal zone (white matter)
Btw marginal & ventricular area >> form mantle area (intermediate zone) >> gray matter in spinal cord, brainstem
- 2 alar plate (dorsal) > receive axons > sensory
- 2 Basal plate (ventral) > send out axons > motor
- Sulcus limitans devide in the middle . ( 1 alar 1 basal )
- Neural tube > central cavity >> Ventricular zone >> ependymal lining of central canal
Neural tube derivatives > brain, brainstem, spinal cord, somatic motor, preganglionic visceral motor
1. Mesenchyme : mesenchymal cell > microglial cell, dura mater (Primordial Meninges = dura mater + leptomeninges)
- annulus brosis
2. Neuroepithelium :
- apolar neuroblast > bipolar neuroblast > unipolar > dendrite + axon + neuron
- glioblast > astroblast , oligodendroblast
- ependyma > epithelium of choroid plexus
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Neural Crest derivatives
- spinal ganglion (DRG), para & sympathetic ganglion cells, sensory ganglia of cranial nerves
- Schwann cell, melanocyte, odontoblast (teeth) ,
- chroma n (suprarenal medulla)
- Meninges (leptomeninges - pia mater & arachnoid mater )

Sclerotome
1. Caudally > densely packed cell > intervertebral disc & part of vertebral body >> form annulus brosus of the disc
- ( center is nucleus pulpous )
** hemi-vertebra occur if sclerotome fail to develop

2. Cranially > loosely packed cell > form vertebral body

3. Remnant of sclerotome > form mesenchymal primordial vertebra

- 5th week convert to cartilage
- 7th week primary ossi cation center appear ( 3 ossi cation center )
- 1. Centrum > body
- 2. Two neural arch center ( forms rst )
Neural Tube Defect (NTD) - because neuropores not closed
- genetic & environmental factors
- Folic acid can prevent neural tube defect
- Caudal neuropore x close >> spinal bi da
- Occulta : no bulge, no de cits, tuft of hair or skin dimple (lumbosacral area) - hyperkeratosis
- Cystic with meningocele : bulge seen, contain CSF in subarachnoid space, nervous tissue x herniate
- Meningomyelocele : Nervous tissue herniate too. Bulge seen. - sensory loss of lower limb, bladder dysfunction
- Myeloschisis : skin and bony defect with open spinal cord , mass of neural tissue seen

- cranial neuropore x close >> Meroencephaly

- Absence of large part of brain and skull
- Miscarriage or short live
- Environmental toxins or lack of folic acid

Defective neuro crest cell > defective autonomic ganglion of gut >> Hirschsprungs DX
- no peristalsis
- Food accumulation inside

** Imaging & Clinical of the Back **

Systematic Approach to imaging

1. Patient and image data
2. Positioning A>P or P>A , lateral view, oblique view , good image quality
3. Cortical outline - outer layer of bone > don’t miss any fracture
4. Joint spacing - cartilage loss or too much
5. Bone alignment - are there any dislocation
6. Bone texture - dense or not
7. Soft tissue - look around - any swelling (MRI)
8. More views (2 better than 1)
9. Compare sides (lung left and right could be di erent , and previous and current )
10. Keep clinical presentation in mind

Odontoid Fracture (40% of axis fracture)

Type I & III : stable fracture
Type II : most common , junction of dens - unstable fracture >> transverse ligament interposed btw fragments
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>> separated fragment (dens) no longer have blood supply > avascular necrosis
Type I : upper part of odontoid (rare, and potentially unstable)
Type III: through odontoid and lateral masses of C2 > best prognosis for healing
Hangman’s Fracture - superior & inferior articular processes > Pars inter-articularis
- traumatic spondylolysis of C2 > hyperextension of the head & neck
- Injury of spinal cord and brainstem
- Anterior displacement of C2 : traumatic spondylolisthesis

Je erson : burst fracture C1 (Atlas)

- compression from above , head on injury (football)
- Vertebra C1= (bony ring) + 2 wedged shaped lateral masses
- Vertical force > compress lateral masses btw occipital condyles & axis >> anterior and posterior arches fracture
- Spinal cord injury >> IF >> transverse ligament ruptured
Wedge / Compression fracture (T11-L1) - hall from height
- loss of height > Wedging of vertebrae anteriorly or laterally
- (T11-L1) only few degree of exion and extension
- Serious > IF >> fracture a ects adjacent vertebrae
- >> or anterior wedging greater than 50%
Burst Fracture - head on car crash - colliding
- Beverly compressed spine ( great deal of vertical force )
- Margin of spinal canal >> spread out in all direction
- Retropulsed fragment >> into spinal canal > spinal cord injury
Spondylolysis - fracture of column bones - pars interarticularis (scotty dog)

Spondylolisthesis - slipping anteriorly upon inferior counterpart

- appear decapitated scotty dog

Herniated Disc - lifting heavy baby

- nucleus pulposus pop out >> degenerated annulus brosus
- Anterior bone spurs
- Posterior facet joint hypertrophy
- Compress nerve > spinal stenosis
- C1/C2 > C2 exit/compressed
- T4/5 > T4 exit/compressed
- L4/L5 > L4 exit , L5 compressed
Lumbar Epidural anesthesia
- epidural space : dura & vertebral column
- Steroid injection
Sacral /Caudal epidural anesthesia
- reliable and e ective block for lower lumbar and sacral dermatomes
- Steroid injetion
- Landmark: sacral hiatus
- Decreased risk of entering subarachnoid space

** Axilla & Brachial Plexus **

Axilla : pyramid-shaped space btw upper arm & thorax

- axillary inlet , 4 walls , oor
- Anterior (pectoralis major and minor) - mid & lat pectoral nerve - exion, adduction, medial rotation
- posterior : subscapularis - up & lower subscapular nerve - medial rotation of arm
teres major - lower sub scapular - medial rotation adduction , extension of arm
lat dorsi - thoracodorsal nerve - medial rotation, adduction, extension of arm
- Lateral (intertubercular groove of humerus)
- medial (serrates anterior, ribs) - C5,6,7 long thoracic nerve > winged scapula
- Axillary artery + brachial plexus + vessels + lymph nodes + fat
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- Posterior scapular space : triangular space + quadrangular space + triangular interval
- Triangular space : circum ex scapular artery
- Quadrangular space : axillary nerve , posterior humeral circum ex artery
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- Triangular interval : radial nerve, deep brachial artery
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- Subclavian artery
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** limb development **

Limb buds : mesenchymal core (somatic layer of lateral plate mesoderm) + covered by ectoderm
- activation of mesenchymal cell >> start limb development (elongation)
Paraxial mesoderm : divides into 42-44 pairs of somites
Intermediate mesoderm : urogenital system
Lateral plate mesoderm : subdivision of intraembryonic secondary mesoderm + connective tissue of limbs
- somatopleure (skeletal) + splanchnopleure (smooth)

Somite >>> sclerotome (vertebrae & rib) + Myotome (muscle) + Dermatome (dermis, connective tissue)

Myotome
- epaxial : dorsal, intrinsic muscle of back , supplied by dorsal rami
- Hypoxia : ventral, regimental pattern in some region, supplied by ventral rami
- Migrate to long bones >> form muscle mass in each limb bud >> separate into exor & extensor compartment
Homeobox (HOX) gene >> initiate limb development process
- 1. activate mesenchyme >> induce Apical Ectodermal Ridge (AER) formation
- Molecular signal : Fibroblast growth factor ( FGF-2,4,8 )
- Ectoderm thickening at the apex of each limb
- Stimulate mesenchyme proliferation >> progress zone
- Growth and development of limbs >> proximodistal axis
- 2. Mesenchyme condense >> skeleton & connective tissue
Proximaldistal : AER > FGG - 2,4,8
Anteroposterior : zone of polarizing activity (ZPA) > Sonic hedgehog (Shh)
Dorsoventral : dorsal ectoderm > Went - 7a (dorsal)
ventral ectoderm > En - 1 (ventral)

4th week: Paired upper and lower limb buds appear

- upper : day 26~27 >> opposite caudal cervical segment (C5-T1)
- Lower : 1~2 days later >> opposite lumbar and upper sacral segment (L4-S3)
5th week: (32days) >> form hand and foot plates
- chondri cation center form
- Motor axons arise from spinal cord >> enter limb bud >> sensory axons enter limb bud >> covered by neural crest
- Dermatome >> area of skin supplied by single spinal nerve & ganglion
6th week: (42days) >> mesenchymal tissue in hand plate condense >> form digital ray ( nger buds)
- apoptosis >> form notches btw digital rays
- entire limb skeleton is cartilaginous
7th week: foot plate for digital ray (toe buds)
- upper limb bend at elbow
- ngers are short and slightly webbed
(49days) - limb extend ventrally >> hand & foot plates face each other
- osteogenesis of long bone begins - primary ossi cation centers >> form diaphysis
- some remain cartilaginous ( epiphysis of long bone, carpus, tarsus)

8th week: (56days) >> ngers & toes are distinct and separated
(51days) - upper limb bent at elbows & hands curved over thorax
(54days) - soles of feet face medially
(56days) - elbows point caudally, knees point cranially

First year after birth : ossi cation of carpal & tarsal bones begin
First 4 year : epiphysis formed by secondary ossi cation centers (9 month)
- epiphyseal plate >> adds length to bone (growth plate)

Limb rotation
Upper limb : laterally 90 degree
Lower limb : medially 90 degree
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Cutaneous syndactyly ( most common limb defect )
- webbing of digits - failure of web degeneration btw 2 or more digits
Osseous syndactyly
- fusion of bones - failure of development of notches btw digital rays
Polydactyly
- supernumerary digits - disruption of anteroposterior pattern > inherited dominant trait
Club foot (congenital talipes)
- talipes esquinovarus ( most common )
- Twice more frequently in male
- Sole of foot turned medially and foot inverted
- Multifactorial pattern of inheritance
Amelia - complete absence of limbs - suppression of limb bud development in 4th week
Meromelia - partial absence of limbs - disturbance of limb development in 5th week

Cleft hand & Cleft foot (ectrodactyly)

- absence of one or more central digits - failure to develop one or more digital rays
- Remaining digits partially or completely fused
- Lobster-claw deformities
Amniotic band syndrome
- tears in amnion >> result in amniotic bands > encircle fetal limbs & digits >> ring constrictions & amputation
- Maybe due to infection
VACTERL syndrome - multifactorial
- Vertebral defect, Anal atresia, Cardiac defects, Tracheo-esophageal stula, Renal anomalies, Limb abnormalities
- Typically have at least 3 of these characteristic features
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** MSK **

Primary curvature : thoracic & sacral

Secondary : cervicle (head) & lumbar (walk)

Lordosis, Kyphosis, Scoliosis

Segmental medullary artery - longitudinal spinal artery

Segmental radicular artery - dorsal and ventral roots
Artery of adamkiewicz - lumbar & sacral
Batson’s plexus - epidural space
Prostatic venous plexus > inferior vesicle > internal iliac > pelvic walls & bones

Denticulate ligament - pia mater > attach to dura mater

Dural sac / lumbar cistern : cauda equina, CSF, Film terminale, dorsal & ventral root

Traumatic lumbar puncture - internal vertebral venous plexus

Skin > subcutaneous > supraspinous > interspinous > ligament avor > epidural > dural > arachnoid > subarachnoid
Sacral / caudal epidural anesthesia : sacral hiatus landmark, V risk of subarachnoid space, e ective block

Fasciotomy - cut fascia to relieve increasing pressure in musculoskeletal compartment

Thoracolumbar fascia - longitudinal & transverse bers - bridge aponeuroses of internal oblique & transversalis muscle

Lymphatic drainage
Back >> paravertebral & retroperitoneal group of lymph nodes
Medial & deep upper limb > lateral node (humereal) - basilic vein
Lateral upper limb > apical node - cephalic vein
Breast >> 75% Anterior node ( pectoral ) , 25% parasternal
Above umbilicus >> axilla or parasternal
Below umbilicus >> super cial inguinal
Posterior abdominal >> lumbar > cisterna chyli (L1, L2) - retroperitoneal structure
Super cial Lateral foot, posterolateral leg > popliteal
Super cial antero-medial foot, antero-meidal leg, thigh > vertical super cial inguinal lymph
Deep leg & feet > popliteal > deep inguinal
Deep thing > deep inguinal > external iliac

Subclavian Artery :
Vertebral, Internal Thoracic, Thyrocervicle (Transverse cervicle, suprascapular, Interior thyroid),
Costocervicle, Dorsal Scapula
Axillary Artery :
1Proximal - Superior Thoracic, 2posterior - Thoracoacromial (acromial, pectoral, deltoid, calvcular), Lateral Thoracic
3Distal - Subscapular (thoracodorsal, circum ex scapular), Anterior & Posterior Circum ex Humeral
Radial - deep palmar arch
Ulnar - super cial palmar arch
Anterior Abdominal : thoraco-epigastric > axillary > subclavian
Superior : Internal thoracic, musculophrenic. Inferior : super cial epigastric, super cial circum ex iliac
Deep S : superior epigastric. Deep L : intercostal, subcostal. Deep In : Inferior epigastric, deep circum ex iliac
Internal iliac : umbilical, sup vesicle, medial rectal, sup inf gluteal, internal pudendal, lateral sacral, obturator, Iliolumbar
External iliac : deep circum ex iliac, inferior epigastric
Trochanteric anastomosis : medial & lateral circum ex artery + superior & inferior gluteal artery
Cruciate anastomosis : medial & lateral circum ex artery + inferior gluteal + 1st perforator branch of femoris
Ratinacular branch : medial & lateral circum ex artery + femoral artery
Obturator artery : decrease or absent when get older
Knee : super medial genicular, super lateral genicular, infer medial genicular, inferior lateral genicular, middle genicular
2 descending genicular : femoral , lateral circum ex
Feet : Anterior & Posterior tibial, (A) Dorsalis pedis, (P) Lateral planter ( deep plantar arch) + medial plantar

Triangle of auscultation : Medial trapezius, Lateral scapula, Inferior latissimus dorsi.

Triangle of petit : Anterior external abdominal oblique, Posterior latissimus dorsi, Inferior iliac crest, Floor Internal AO
Traingular space : circum ex scapular artery
Quadrangular space : axillary nerve, posterior humeral circum ex artery
Triangular space : radial nerve, deep brachial artery
Shoulder : anterior & posterior circum ex humeral artery, supra scapular artery
Cupital fossa : medial pronator teres, lateral brachioradialis, epicondyle line, (median N, brachial A, Bicep Tendon)
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Hesselbach’s triangle : medial rectus sheath, Inferior inguinal lig, lateral inferior epigastric artery
Inguinal Hernia : medial direct - super cial ring - acquired , lateral indirect - deep & super cial ring - congenital
Hydrocele - uid in tunica vaginalis , transillumination
Femoral sheath : lateral femoral artery (X lateral nerve) , inter femoral vein, medial femoral lymph (femoral canal - ring)
Femoral triangle : superior inguinal lig, medial adductor longus, lateral sartorius, oor pectineus iliopsoas, roof fascia
Femoral Hernia : under lingual ligament
Popliteal fossa : sup med semitendinosus & semimembranosus, sup lat bicep femoris, infer gastrocnemius
Medial tarsal tunnel : Tibialis posterior, exor Digitorum longus, P tibial Artery, Vein, Vein, Nerve, exor Hallucis longus

Fracture
hangman’s fracture : C2, traumatic spondylolysis, pars inter-articularis, spondylolisthesis
Je erson burst fracture : C1 Atlas, anterior & posterior arch fracture
Wedge/compression fracture : anteriorly or laterally, T11-L1
Chance / burst : vertebral body spread out in all direction
Midshaft clavicle fracture : Last Dorsi pull down + Sternocladomastoid pull up + Pec M pull medially
Step deformity ( shoulder separation ) : AC lig + CC lig tearing
Shoulder dislocation : axillary nerve & posterior humeral circum ex artery damage
Rotator cu injury : supraspinatus injury, CC lig calci ed, subacromial spurs > in amed
Nursemaid’s elbow (pulled elbow) : annular lig slip out
Supracondylar fracture : median nerve & brachial artery damage
Volkmann’s ischemic contracture : brachial artery injury > ischemic exor contracture
Posterior dislocation : ulnar nerve & median nerve & brachial artery
Radial head fracture : lifting of fat pad - sail sign, subtle & easy to miss
Tennis elbow : common extensor origin (lateral epicondyle)
Golfer’s elbow : common exor origin (medial epicondyle)
Colle’s fracture : displaced posteriorly - median, ulnar nerve injury & radial, ulnar artery >acute carpal tunnel syndrome
Smith’s fracture : displaced anteriorly - median, ulnar nerve injury, acute carpal tunnel syndrome
Carpel tunnel : median nerve
Guyon’s canal : ulnar nerve
Dupuytren’s contracture : thickening & contraction of palmar aponeurosis > unable to extend > needle aponeurotomy
Radial bursa : FPL > connect to carpal tunnel
Ulnar bursa : FDS, FDP > connect to carpal tunnel (2,3,4 digit only to phalanges)
Erb’s Palsy : upper roots of Brachial plexus, both motor & sensory loss
Klumpke’s palsy : sensory loss along medial border (C8 T1)
Saturday night : radial nerve > wrist drop, can’t extend, impaired grip, arm forearm hand sensory loss
Carpel tunnel syndrome : median nerve > Tinel sign & Phalen maneuver (test)
Cubital tunnel syndrome : medial epicondyle fracture > ulnar nerve
Flail chest : multiple rib fracture > move opposite direction when breathing
Pleuisy / Pleuritis : in ammation in pleura > sharp pain > phrenic nerve
Right phrenic nerve palsy : right dome diaphragm higher, apical lung mass causing damage to phrenic N.
Meralgia Paresthetica : lateral femoral cutaneous nerve

Cervicoaxillary canal : axillary inlet

Axillary sheath : used to block brachial plexus

Acromioclavicular joint : acromioclavicular lig. + Coracoclavicular lig

Elbow joint : radiocapitellar line & anterior humeral line interesect at capitulum

Herpes zoster (Shingles) : dorsal root ganglia, trigeminal ganglion, geniculate ganglion (facial) - unilateral
Milk line (ridges) : two vertical thickening of ectoderm from axilla to inguinal region
Polymastia : ectopic mammary gland (extra) - fully functional
Polythelia : exert nipple (male)
Gynecomastia : male with enlarged breast

Peau d’ orange : blockage of lymphatic channels

Inversion of nipples : cancerous cells invade suspensory ligament > retract nipple (dimpled, blood, discolored)
Lymphedema : side-e ect of mastectomy or radiation > decreased drainage, accumulate interstitial uid

Mid-clavicular line : 6&8

Mid-axillary line : 8&10
Paravertebral line : 10&12

Rt hypochondriac: liver, gallbladder

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Epigastric : pancreas, stomach, celiac trunk
Lt hypochondriac : spleen, left colic exure, splenic vessel
Rt lumbar : cecum
Umbilical : small intestine, SMA, renal artery
Lt lumbar : decsending colon
Rt iliac : appendix, Rt ovary
Hypogastric : bladder, IMA
Lt iliac : Lt ovary, sigmoid colon

Camper’s fascia - external

Scarpa’s fascia - deeper >> Colle’s fascia
Rectus sheath : above arcuate line (2:1) , below arcuate line (3:0)

External spematic fascia - external abdominal oblique aponeurosis

Cremaster muscle - internal abdominal oblique muscle & aponeurosis
Internal spermatic fascia - trasversali fascia
Tunica vaginalis - parietal peritoneum
Dartos muscle - puckering of skin

Inferior vena cava T8 - caval hiatus, Esophagus T10, Aorta T12 - median arcuate ligament

Cremasteric re ex : a erent - ilioinguinal N, e erent - genital branch of genitofemoral N

Sacrospinous lig (sacrum to ischial spine) + sacrotuberous lig (from sacrum to instill tuberosity)

Episiotomy : cut external anal sphincter obliquely

Pudendal nerve black : palpate vaginal canal to ischial spine
Pudendal canal (alcock’s canal) : pudendal nerve & internal pudendal artery pass out great & lesser sciatic notch

Center of gravity : anterior edge of SV 2 , anterior to knee and ankle, directly over feet

Three main ligament of capsule

Iliofemoral (X hyper-extension) , pubofemoral (X hyper-abduction), ischia-femoral (X posterior dislocation)

Gluteal Region Cutaneous Innervation

dorsal Rami : Superior Clunial N.(L1~3) & medial Clunial N. (S1~3)
ventral rami : Inferior clunial N. (S1~3)
Iliohypogastric N : suprapubic region

Deep fascia : fascia lata , iliotibial fascia, fascia cruris > increase Blood Pressure

Knee bursae : Suprapatellar , prepatellar, infra patellar, deep infrapatellar

Tibiotalar : hinge joint - dorsi exion & plantar exion (tibia + talsa)
Subtalar : inversion and eversion ( bula + calcaneus)

Lateral : posterior & anterior talo bular, calcaneo bular

Meidal : posterior & anterior tibiotalar, tibiocalcaneal, tibionavicular

Varicose vein : insu cient vein valve > chronic venous insu ciency
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** Cartilage **
Cartilage : connective tissue (unique cell)
- 95% ECM
- 5% chondrocytes chondrobalst chondroclast
- Major GS = GAG >> chondroitin-4-sulphate, chondroitin-6-sulphate, proteoglycans (aggrecan)
Function
- confer shape, exibility, elasticity
- Shock absorber
- Tensile strength
- Model for long bone formation
5% cartilage cell
Chondrogenic >> Chondroblasts
- just below perichondrium
- Chondroblasts are Ovoid and longitudinal > parallel to carriage surface
- Spaced in lacuna
- Synthesize cartilage matrix
- Responsible for external growth of cartilage >> appositional growth
Chondrobalst >> Chondrocytes
- matured in lacunae surrounded by matrix
- More deeper & spherical
- Divided by mitosis >> form 4-8 chondrocytes >> isogenous groups = Cell Nest (CN)
- Internal growth suggested
- Later mature >> move apart
Chondroclast
- from monocytes
- Help to remodel cartilage through phagocytosis
- irregular chondrocytes surfaces
- Extensive Golgi apparatus , Abundant rER , Euchromatic nucleus
- Lipid droplets and glycogen deposits
95% of cartilage volume = ECM
- composed of amorphous ground substance & collagen brils
- 15 % of total mass & TYPE II most abundant
- Same refractive index as ground substance >> glassy appearance
1. Capsular matrix : adjacent to chondrocyte / paracellular matrix > most basophilic (Less collagen, sulfated PG)
2. Territorial matrix : around isogenous groups > type II collagen bers
3. Interterritorial matrix : in btw isogenous groups

Composition: GAG
- GAG > sulphate > hydrophilic > enable di usion
- provide resilience
- PG > provide immense strength > cartilage function as a model for bone formation
Perichondrium - connective tissue covering entire cartilage
1. Outer brous layer ( broblasts) : synthesize collagen type 1 and matrix, have blood vessels
2. Inner cellular layer (chondrogenic layer) : chondrogenic cells - source of chondroblasts
** since cartilage is avascular >> nutrients from perichondrium or synovial uid articular surfaces

Hyaline cartilage : collagen type II , mesenchymal cells >> chondroblasts & chondrocytes
- appositional growth : chondrogenic > chondroblast (in peri) > from new layers
- interstitial growth : only in young cartilage, increase length , cell division within the cartilage
- Growth hormonal in uence: ^^ GH, Thyroxine, Testosterone // vv Hydrocortisone, Estradiol
- X degenerate , Very poorly regenerate, calci es in old age >> bone formation & aging
- Supportive, cushioning, shock absorber, growth plate, model for bone formation
- Glassy, ECM collagen & sulfated groups - same refractory index
- In nose, tracheal bronchial rings, fetal skeleton, epiphyseal, costal cartilages, articular surfaces of long bone
Articular Cartilage - type of hyaline cartilage >> X perichondrium
- press throughout adult life
- Remnant of original cartilage template of developing bone
- 1. Super cial Tangential layer. 2. Intermediate Transitional layer. 3. Deep Radial layer. 4. Calci ed cartilage
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Osteoarthritis
- degenerative joint dx > a ects weight bearing joints (hips, knee, lower vertebrae)
- Related to aging & injury
- Decrease proteoglycan content >> reduction of water content in matrix
- Progressive reduction of mobility >> increased pain

Elastic cartilage : collagen type II + elastic bers (yellow) , GAG & glycoproteins, multi-adhesive glycoproteins
- Mesenchymal cells > chondroblasts, chondrocytes
- Appositional & interstitial growth
- X degernate , X calci es
- Support with exibility
- Pinna of ear, external acoustic meatus, Eustachian tube, epiglottis
- Found with hyaline cartilage, perichondrium present
Fibrocartilage : collagen type I + II , no perichondrium , GAG (predominantly Chondroitin & Dermatan sulphate)
- Mesenchymal cells > broblasts transform to chondrocytes under stress
- Only interstitial growth ( absence of Peri)
- Resist deformation under stress (support and tensile strength)
- Intervertebral disc (annulus brosis), pubic symphysis, M&L menisci, attach Lig to bone, articular disc, tendon
- H&E & Trichome staining
- Fibers arranged perpendicular to the direction of stress ,, isogenous groups in linear fashion (compression)
- Calci cation
- Not found alone, found with Hyaline cartilage in conjunction
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** Bone **
Bone
- Cells and calci ed ECM form a rigid organ
- ECM
- Organic portion : 90% collagenous protein ( Type I collagen ) , 10% Ground Substance
- Inorganic portion : 50% calcium matrix ( hydroxyapatite crystals ) - bicarbonate, citrate, Mg, K, Na
- Cells - (Indian ink for bone grinding)
- Osteoprogenitor : primitive mesenchymal cells >> stem cells of bone >> osteoblast >> secrete osteoid (GAG)
- Osteoblast : synthesize osteoid >> become calci ed >> bone
- Cuboidal ( high secretion ), on periphery, euchromatic nuclei, basophilic cytoplasm
- Well developed rER & Golgi, PAS positive
- Secretion >> entrap in lacunae >> secrete osteoclast stimulating factor > osteocyte
- spindle shaped >> mature >> attened spindle shape >> inactive osteoblast
- Osteocytes : osteoblast >> mature >> osteocytes (btw lamellae in lacunae) >> regulate bone mass
- Entrapped in boney matrix , ovoid-biconvex, fat droplets
- Maintain communication & exchange nutrients >> gap junction ( lopodia)
- Heterochromatic, reduced rER & Golgi
- Osteoclasts : (multinucleate) monocyte progenitor cells >> resorbs & remodel bone (only inside - endosteum)
- release H+ ions & lysosomal enzyme & Cl ions
- Osteoblast vs Osteoclast balance >> essential for osteoporosis
- Large, multinucleated (50) - fusion of progenitor cells, macrophages located along endosteum
- Howship’s lacunae : osteolytic activity > resorption bay > depression on bone surface
- 1. Ru ed border : nger like evagination (active bone resorption)
- 2. Clear zone : surround ru ed border, micro lament anchor to boney surface
- > secrete H&Cl & lysosomal enzymes (from Golgi complex) > dissolution of calcium phosphate
- > decalci ed bone > acid hydrolases > collagenase & proteolytic enzyme absorbs
- 3. Basal region : organelles & numerous nuclei
- Bone-lining cells : inner & outer surface of bone >> endosteum & periosteum (non-remodeling bone)
- Osteoblast derived at cells - little cytoplasm & organelles
- Maintain & nutritional support
- Regulate movement of phosphate & calcium (in & out)
- Non-calci ed connective tissue layers covering external & internal surface of bones
- Periosteum : attached to outer surface ( by sharpey’s bers - type I collagen )
- >> outer brous layer : dense irregular CT > contain blood vessels & nociceptors
- >> inner cellular/osteogenic layer : contain osteoprogenitor cells & periosteal cell
- >> actively secrete matrix > increase width of bone (appositional growth)
- Endosteum : lines any space or cavity (marrow, Haversian canal, Volkmann’s canal)
- >> contain mesenchymal stem cells > osteogenic progenitor cell > osteoblast, broblast, BV, N
- >> contain osteoclast ( bone remodeling occur from within ) sympathetic
- Hematopoiesis : bone marrow > hematopoietic steam cells > form blood cells
- Lipid and Mineral storage : store adipose tissue & calcium (hydroxyapatite crystals)
- Support : form sca olding for skeletal muscle & soft tissue, framework for body
- Protection : axial skeleton surrounds major organs
Classi cation
1. Immature (primary / woven) bone (embryo, newborn, fracture callus, growth plate)
- rst compact bone elaborated
- low mineral / high water
- contain numerous osteocytes & irregularly arranged collagen
- Replaced by mature bone except (tooth sockets, suture lines of skull, insertion site of tendons)
2. Mature (secondary / lamellar) bone (develop form 1month post natal)
- replace primary bone (made by Haversian system or osteons)
- Regularly arranged concentric lamellae (3~7nm thick) >> surround BV, N, loose CT
- Osteocytes in lacunae (btw lamellae or within lamellae) (less osteocytes than immature bone)
- High mineral / low water
a. Compact bone - (corticle bone) - very dense & Heavy
- Haversian system or Osteon : cylindrical ( 4~20 concentric lamellae ) - Not all uniform/parallel
- numerous canaliculi - communicate btw lacunae & Haversian canal
- each lamella : multiple parallel collagen bers
- adjacent lamella - alternating direction > great strength
- outer & inner circumferential lamellae : deep to periosteum & next to endosteum
- Volkmann’s canal : connect adjacent Haversian canal & endoseum & periosteum (neurovasculature passage)

b. Spongy (cancellous bone) - (trabeculae) - lled with interconnected space

- long bone space > Hemopoietic(red) & primary Fat(yellow) bone marrow
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Histogenesis
1. Intramembranous bone formation - condensed mesenchyme
- mesenchyme > primary ossi cation center > di erentiate > secrete osteoid > osteoblast entrapped
- Bone ossi cation > expand into spicule > osteoblast aggregate > trabeculae form >> spongy bone develop
- BV invade undi erentiated mesenchymal cells >> bone marrow cells
- Surrounding mesenchymal cells >> outer periosteum & inner endosteum
- Numerous ossi cation center fuse >> woven bone (ex: at bone of skull)
2. Endochondral bone formation - cartilage model >> long bone
- bone outline in hyaline cartilage > perichondrium > (intramembranous process) osteogenic cells > bony matrix
- >> Formation of periosteum & subperiosteal bone color >> support diaphyseal region
- Cartilage matrix calci ed >> BV erode
- Periosteal bud form > primary ossi cation center
- subperiosteal collar > thicker > calci ed cartilage complexes
- Secondary ossi cation center (epiphyses) > epiphyseal cartilage (epiphyseal growth plate)
- Epiphyseal plate disappear > diaphyseal & epiphyseal marrow cavity fuse (~age 20)
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- Zone of reserve cartilage : small, randomly arranged, inactive chondroctytes (stem cell line)
- Zone of cell proliferation : rapid mitotic division >> rows of cartilage cells
- Zone of hypertrophy : chondrocytes enlarged > cartilage matrix become thin
- Zone of calci ed cartilage : lacunae coalesce > calci ed > apoptosis of chondrocytes
- Zone of resorption : bone begin elaborated > osteolytic activity > absorb calci ed bone-cartilage complex
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- Remnant of calci ed cartilage > covered by dark blue stained
- Newly formed bone surrounded by osteoblasts >> captured in osseous matrix >> osteocytes
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- Longitudinal ridges > osteogenic cells in periosteum >> osteoblasts >> form ridges > close o periosteal capillaries
- Periosteum lining newly formed canal > endosteum > form concentric lamellae > form osteon

Bone repair
Fracture hematoma > damage bone matrix & BV > hemorrhaging > blood clotting
>>> macrophage (osteoclast) remove debris (phagocytosis) - day 1~5
Fibroblasts proliferate in periosteum & endosteum > surround internally & externally > isolation
>>> brocatilaginous callus formed - day 5~11
Osteogenic layer > Osteoblasts >> Intramembranous bone formation > bone elaborated
Connective Tissue > di erentiate > chondrocytes > elaborate cartilage > bone (endochondral bone formation)
>>> callus (day11~28) - primary bone >> resorbed & replaced (day18~1year) > secondary bone (repair process)

Histophysiology
1. Bone
- Support body & provide attachment site for muscles
- Protect CNS & vital organs
- dynamic tissue >> change under stress >> growth directed toward applied stress
2. Calcium Reserve
- bone contain 99% of body calcium > contraction, enzyme activity, nerve impulse, adhesion, blood coagulation
- Diet inadequate >> Decalci cation of bone
- (Remodeling) Calcium transferred >> from bone >> to blood stream
3. Nutrients
- a ect bone development : low protein > low amino acid > low osteoblast synthesis
- Lack calcium ( low Vit D > low absorption in small intestine ) > poorly calci ed bone > rickets (K) / osteomalacia (A)
- 1. delayed mineralization > wide osteoid (Rickets & Osteomalacia)
- 2. delayed hypertrophic (apoptosis) chondrocytes > growth plate irregular , widened (Rickets)
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- Vit D > for proper ossi cation ( excess >>> bone resorption )
- Low Vit A > inhibit bone formation & growth ( excess >>> osteoclast & fragile )
- Vit C > for collagen formation ( low Vit C >> scurvy, poor wound healing & bone repair after fracture )
4. Hormones
- stimulate matrix producing cells // bone resorbing cells
- Parathyroid Hormone (PTH)
- Indirectly stimulate osteoclast > resorb & release Ca> elevate blood Ca level
- Activate osteocyte > osteolysis > elevate blood Ca level (from lacunae)
- Susceptible to fracture , Ca deposit in arterial walls & kidney
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- Calcitonin (peptide Hormone)
- Produced by Parafollicular cells (thyroid gland)
- Inhibit matrix resorption of osteoclast >> prevent Ca release >> low blood Ca level
- Pituitary Growth Hormone (GH)
- Stimulate epiphyseal cartilage growth >> ( excess >> giant ) // ( lack > dwarf )
- (Adult) excess > acromegaly ( enlargement of forehead, jaw, nose )
Osteoporosis - loss bone density in trabeculae >> increased risk of fracture
Primary Type I - 1/3 post menopause women ( low estrogen > low osteoclast )
- selective estrogen receptor modulators therapy
Primary Type II - elderly (70~80s)
Secondary O - drug therapy (corticosteroids)
- DX process (malnutrition, weightlessness, metastatic cancer, radiation)

** VITAMIN D **

Vit D - group of sterols - hormone like function

- Ergocalciferol (Vit D2) : found in plants
- Cholecalciferol (Vit D3) : found in animal
- (Skin) 7-dehydrocholesterol (intermediate in cholesterol synthesis) >> cholecalciferol (Vit D3)
- exposure to sunlight > prevent Vit D de ciency
- Increase Serum Ca & P absorption (Intestine) >> Form bone mineral
- Low Vit D > reduce serum Ca,P >> Stimualte PTH secretion >> demineralize bone & excrete PO4
Calcitriol formation (1,25 dihydroxy cholecalciferol) - active Vit D
1. 7-dehydrocholesterol + sunlight >> Cholecalciferol (Skin) >> 2. (liver) + 25 hydroxylase >> 25 DHCC
Diet > Cholecalciferol >>
3. 25-DHCC + 1-hydroxylase (Kidney) + Parathormone + low plasma calcium >> 1,25 DHCC (Calcitriol)
4. 1,25DHCC binds Intestinal mucosal cell (intracellular receptor protein)
- 1,25DHCC + DNA (HRE) in nucleus of intestine >> gene expression or repression >> synthesize Calbindins
(steroid, thyroid, retinoid acid)
- Increased Calbindin synthesis >> stimulation of Ca & PO4 absorption (intestine)
- Stimulate ATP-dependent Ca pump >> transport Ca to blood stream
5. (Bone) when low Serum Ca + PTH >> stimulate mobilization of Ca & PO4 from bone
(Kidney) stimulate PTH > increase Ca reabsorption > inhibit Ca excretion
PTH > increase PO4 excretion

Factors a ecting Vit D formation :

1. Increased melanin pigment >> reduces Vit D formation
2. Time of exposure & latitude
3. Exposed skin / sunscreen >> reduces formation
4. Winter months & latitude

Vit D inactivation = action of 24-hydroxylase

1,25 -DHCC + 24-hydroxylase >> 1,24,25 - DHCC (inactive)

Risk Factor : (Vit D de ciency)

1. Inadequate exposure to sunlight (sunscreen, winter, elderly) >> inadequate skin synthesis
2. Nutritional de ciency (decreased intake / fat malabsorption / exclusively breast fed infants)
- Cystic brosis , celiac DX, Whipple’s DX, Crohn’s DX
3. Chronic renal DX ( V 1-hydroxylase) , chronic liver DX ( V 25-hydroxylase) >> decreased hydroxylation of Vit D

Rickets : (Vit D de ciency in Children)

- decreased Ca absorption in diet > decreased Serum Ca > Increased PTH > Increased demineralization
- Bow-leg deformity >> soft pliable bones
- Overgrowth at costochondral junction - rachitic rosary
- Pigeon chest deformity , frontal bossing
- delayed closure of fontanelle & delayed teething (infants)
- Elevated Serum ALP (alkaline Phosphatase) , Low Ca & PO4 & 1,25 DHCC
Osteomalacia : (Vit D de ciency in adult)
- demineralized bone > susceptible to fracture > non-speci c bone pain
- Reduced exposure to sunlight , dietary de ciency, renal dx, liver dx
- Elevated Serum ALP (alkaline Phosphatase) , Low Ca & PO4 & 1,25 DHCC
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Vit D Resistant Rickets = Mutation in Calcitriol receptor
- classical rickets + Alopecia (hair loss)
- Mutation in gene encoding Vit D receptor
- unable to bind to receptor in intestinal mucosal cell >> reduced binding of calcitriol
- >> loss of feedback inhibition >> HIGH level of serum calcitriol (1,25-DHCC) + but LOW Ca absorption
- >> LOW Ca & PO4
Hypervitaminosis D >> Hypercalcemia ( high absorption )
- Vit D stored in Body > slow metabolism > increase Ca & PO4 absorption
- >> Increase Serum Ca & PO4 >> ectopic mineralization
- Prolonged Hypervitaminosis D (prescription) >> calci cation of soft tissue (Kidney)
- High dose Vit D >> appetite loss, nausea, thirst, stupor (100,000 IU for weeks or months)
** Function of Bone **
Mechanical : e ective muscle contraction & movement
Protection : brain, heart, lungs, livers, stomach, spleen
Transduce sound waves : ear drum to inner ear
Marrow : produce red & white blood cell, growth factors, store fatty acid (yellow marrow)
Storage : calcium, phosphorus, zinc copper sodium
Temporarily absorb & store toxic metals : reduce e ect on body

Inorganic
- 70% of Bone - Hydroxyapatite = calcium apatite
- calcium apatite Ca5(PO4)3(OH) // crystal form Ca10(PO4)6(OH)2
- Intrinsic factor : genetics, gender, family history
- Extrinsic factor : diet, body mass / habits, hormonal (PTH, VitD, Estrogen) , Illness, Exercise, lifestyle choices
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- 3 forms of calcium
- 1. Combined with plasma proteins - non di usible >> Ca in ECF (Plasma) = 0.2mmol/L (9%)
- 2. Combined with anionic substances in plasma - di usible but X ionized >> Ca in ECF (Plasma) = 1mmol/L (41%)
- 3. Ionized form - di usible (most important form) >> Ca in ECF (Plasma) = 1.2mmol/L (50%) >> for remodeling

98%-99% of Ca in Bone
- release Ca when low serum Ca
- Store excess Ca
- Free ionized Ca++ > Osteoblast > Ca++ + Bone matrix (Mineralization)
- Free ionized Ca++ < Osteoclast < Ca++ + Bone matrix (Resorption)
Function of Ca
- essential mineral, More than Ca than other mineral
- Mechanical stability & reservoir for ECF
- Bone formation & remodeling
- Cofactor for enzymes & signal for signaling pathway (DAG/IP3) >> blood clot, muscle contraction, heartbeat
- Neurotransmitter & resting membrane potential maintenance
Source of Ca
- milk, cheese, dairy food
- Green leafy vegetables ( X spinach )
- Soya beans, tofu, soya drinks w/ added Ca
- Fish with edible bones - Sardines
- Nuts
- Recommended Daily allowance 25-30mmol (1000-1200mg) for most adults
- Long term low Ca intake >> impair Peak Bone Mass (PBM)
- Low Ca >> ricket (without Vit D de ciency)
Absorption & Excretion ( Ca++)
Intestine : absorption (Vit D dependent)
Bone : deposition & resorption (Vit D & PTH dependent)
Kidney : excretion (PTH dependent)

Absorption & Excretion ( P )

- 85% = 600g body P >> In Bone mineral
- Intracellular = ECF = 1~2 mmol/L
- H2PO4- , NaHPO4- , HPO4 - - >>> phosphate (anions)
- Absorbed in Small Intestine >> enhanced by 1,25DHCC (Vit D)
- Excreted through Urine >> Overridden by PTH
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PTH e ect

Low plasma Ca > ^ PTH > ^ Ca mobilization > restore Plasma Ca (bone, kidney, intestine)
Bone: PTH >> Osteoblast >> ^ cytokines (M-CSF, IL-6) > ^ osteoclast > ^ bone resorption > ^ plasma Ca & PO4
Kidney: ^ free ionized Ca >> CaPO4 >> PTH excrete PO4 from Kidney > V PO4 , ^ serum Ca
- ^ Vit D synthesis >> ^ Ca absorption in GIT

Hypocalcemia
Causes
- 1. Low PTH level
- 2. High secondary hyperparathyroidism : Vit D de ciency, PTH resistance syndrome, drugs
- 3. Hungry bone syndrome after parathyroidectomy
Lab nding :
- Low 25-hydroxyvitamin > if low Vit D nutritional
- Low 1,25-hydroxyvitamin > if renal insu ciency
- Low PTH > parathyroidectomy
Features :
- tetany : ^ peripheral nerve excitability
- Carpopedal spams, stridor, convulsion
- Laryngeal spasm > breathing di culty
- Severe hypocalcemia > cardiac arrhythmias
Treatment : Ca & Vit D supplement , Calcium gluconate IV (emergency)

Hypercalcemia
Causes
1. Excessive PTH
2. hypervitaminosis
3. Excessive 1,25DHCC production
4. Excessive Ca intake
Diagnosis
1. PTH immunometric assay + blood Ca measurement
2. Elevated PTH level + asymptomatic
3. Serum PO4 low (normal if renal failure)
Lab nding :
- hypervitaminosis D : ^ Ca, ^PO4, ^VitD
- Excessive PTH : ^PTH, ^Ca, V PO4
Symptoms
- polyuria, polydipsia, renal culculo (colic), lethargy, anorexia, nausea, peptic ulceration, depression, drowsy, cognition
- If primary hyperparathyroidism >> chronic & non-speci c
- “Bones, moans, stones, abdominal groans”
Hypophosphatemia
- inadequate intestinal absorption (Vit D de ciency) , Excessive Renal excretion (PTH excess)
- Nerve, bone, red & white blood cells, membrane, muscle functional problem
- NEED close monitor of Serum PO4 & Ca (every 6~12 hour)
Hyperphosphatemia
- Decreased renal excretion (impaired Kidney) , Hypoparathyroidism, Excess PO4 release to ECF (gut, bone, therapy)
- Calci cation of soft tissue & organs (kidney, lungs, heart)
- Tetany & seizures
- Fasting Serum PO4 concentration > 1.8mmol/L
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** Muscle Physiology **

Motor Neuron Action Potential > NMJ > EPP & muscle AP (excitation)
> excitation conctraction coupling > muscle contraction

1. Action potential arrive at terminal bouton

2. Voltage gated Ca channel open
3. Ca enter >> ACh released
4. ACh di use > binds to nicotinic receptors on motor end plate
5. ACh open channels > Na & K >> Na net entry
6. Depolarization ( EPP > EPSP ) EPP = end plate potential , EPSP = excitatory post synaptic potential
7. EPP >> action potential >> alter DHP (dihydropyridien L-type Ca channel) receptor conformation
8. DHP open RrR (Ryanodine receptor channel) >> release Ca (SR) >> Ca enter cytoplasm
9. Ca bind to troponin >> actin - myosin binding >> Myosin head power stroke
10. Actin lament slide toward center of Sarcomere
11. Sarcoplasmic Ca-ATPase pump Ca back into SR ( determine the rate of myosin head resetting crossbridge cycle)
12. Decrease free cytosolic Ca >> Ca unbind from troponin
13. Tropomyosin recover binding site >> myosin head release >> muscle relaxed
** latent time = delay btw muscle action potential & beginning of muscle tension (Ca release and troponin binding time)

Weakness & fatigue : antibodies of autoimmune system >> damage nicotinic cholinergic receptors
Treatment : acetylcholinesterase inhibitors (Tensilon Test > for testing myasthenia gravis )

Lambert - Eaton Myasthenic Syndrome (LEMS)

- muscle weakness > autoimmune attack > Ca channel (NMJ)
- V Ca in ux >> V ACh release
- Proximal lower extremities a ected >> waddling gait, di culty raising arms
- Latrotoxin (venom of black widow spider) >> opens Ca Channel (presynaptic) >> release ACh > muscle contraction
- Antibody >> destroys / inhibits Ca channel
Myasthenia Gavis - ACh receptor a ected

Botulinum Toxin / Botulism / Botox

- from clostridium botulinum > food poisoning > botulism
- Protease > prevent ACh release > weakness of muscle, blurred vision, accid paralysis
- Cosmetic : botox
NMJ : Tubocurarine / Curareis : Nm blocker >> block Na/K ow
- Tubocurarine : Nm receptor antagonist, skeleton muscle relaxant
- Curareis : Nm competitive inhibitor, arrows / blow dart poison
Sarcoplasmic Reticulum (SR)
Resting membrane : intracellular Ca very low (< 10nm) , Ca bound to Calsequestrin (SR)
Contracting muscle : depolarization > SR release Ca > intracellular Ca increase ( > 10uM )

Malignant Hyperthermia
- mutation or dysregulation of Ca release from RyR
- Normal under normal conditions
- High heat or strenuous exercise >> abnormal release of Ca >> sustained muscle contraction & Heart production
- Treatment : dantrolene >> binds to RyR receptors >> stop Ca release
1. Relaxed State
- myosin head cocked
- Tropomyosin partially blocks binding site on actin
- Myosin weakly bound to actin
2. Initiation of contraction
- Ca level increase in cytosol
- Ca bind to troponin
- Troponin-Ca complex pull tropomyosin away
- Myosin binds strongly to actin >> power stroke
- Actin lament moves
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3. Contraction / Crossbridge cycle = single action potential ( all or nothing )
- ATP binds to myosin > release actin
- Myosin hydrolyzes ATP > energy rotate Myosin to cocked position
- Myosin binds weakly to actin >> ADP + p
** Rigor mortis >> if NO ATP >> no detachment > cycle stop

Length - Tension Relationship

- too much or too little overlap in resting muscle >> decreased tension
- Optimal resting length = 2.0um ~ 2.3um
Preload = stretching & resting (passive tension) - 1PL= 1X
Afterload = muscle works against during contraction ( isometric & isotonic twitches ) - active tension
Force contracting muscle = tension
Force opposing contraction = load (weight)
Isometric Contraction : length constant, load > tension, muscle X shorten, load X lifted, only generate tension
Isotonic Contraction : constant tension, load < tension, load is lifted, muscle shortens

- Phase 1: isometric contraction - elastic element stretch > sarcomere shortens

- Phase 2: isotonic contraction - elastic element already stretched > muscle shortens > sarcomere shortens
- Phase 3: isotonic relaxation
- Phase 4: isometric relaxation

Increase preload = increase Fmax (shift curve to right, increase crossbridge overlap, increase maximum weight-Fmax )
Increase velocity = same weight / after load can be moved faster
No Vmax change = ATPase activity not altered

Red: Type 1 slow oxidative, endurance postural muscle, aerobic, slow twitch, fatigue-resistant, slow ATPase
White: Type 2 fast glycolytic, powerful ocular muscle, leg muscles, low myoglobin, anaerobic, fast twitch, fast ATPase

Graded muscle contraction (2 types)

1. Temporal summation : tension produced by each ber (high frequency stimulation)
- more crossbridge > more force
- higher frequency stimulation, ber diameter, changes in ber length >> higher contraction/tension
- amount of Ca bound to troponin = amount of tension developed
- high frequency > more release than uptake > Ca increase in cytosol >> maximum titanic contraction

Tetanus : neurologic disorder caused by bacterium Clostridium Tetani

- blocks GABA release (inhibitory neurotransmitter)
- Diminished inhibition > increase in resting ring rate (motor neurons)
- Increased repetitive stimulation >> Ca released (SR) > bound to troponin > muscle do not Relax
- “Lockjay” , neck shoulder back upper lower extremities spasm
- >> could Jeopardize breathing
- Treatment : Antitoxin - neutralize circulating unbound toxin
Diazepam (GABA agonist) - control spasm

2. Spatial summation : Number of bers contracting (recruitment)

- more muscle bers contracting >> greater force >> greater tension (proportional to size)

Skeletal Muscle Source of metabolism

1. PCr > ADP > ATP
2. Glycolysis (absence of oxygen) - 2.5times faster than food
3. Oxidative metabolism : carbohydrates, fats, protein - long term contraction (95% energy)
4. Cr supplement enhance short term muscle ability

Fatigue - decrease in force & velocity

1. Proportional to glycogen depletion
2. Increase in H+ & decrease in pH
3. High ADP/ATP ratio
4. Increase P (from PCr breakdown) - reduce Ca release & decrease force production
5. Ammonia accumulation in brain
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** Cardiac Muscle **

cardiac muscle
- cylindric, branched cells, 1-3 nuclei, centrally located
- diameter 25um, length 100um
- Automaticity (ANS) - pacemaker
- intercalated disc : transverse (Fascia Adherens, Desmosome), lateral (Gap Junction)
- long Action Potential & long Refractory Period (no temporal summation & tetanic contraction)
- Heart regulate force of contraction : titrating Ca++ level
- Gap Junction : all cells are interconnected > so no spatial summation > atrial & ventricular syncytium
- myo brils - branched, interlocked (intercalated disc) - sti collagen skeleton > increase preload (starling law)
Action Potential
motor neuron : 2msec
skeletal muscle : 5msec
cardiac muscle : 200msec

Contraction : ^ Ca++ > Ca++ entry (DHP receptor) > Ca++ release (RyR2)
t-tubules : extension of cell membrane into the cell containing Ca++
CICR: Action potential > Voltage gated L-type 1,4-DHP receptor open > Ca enter > RyR-2 release Ca from SR (died)
>> Ca binds Troponin C > tropomyosin moves away > myosin-actin crossbridge > muscle contraction

Relaxation : V Ca++ > 80% by SR (SERCA pump + PLB) > 20% ECF > 3Na/1Ca exchanger & Ca-ATPase pump
- V Ca > tropomyosin unbinds Ca > blocks myosin-binding site
- Na gradient maintained by Na/K ATPase pump
Regulatory proteins
Smooth Muscle: calmodulin, No Sarcomere
Striated Muscle: troponin, Sarcomere

Thin to Thick ratio: Striated 1:2, Smooth 1:15

Think laments: myosin II (striated - bipolar, high amount // smooth - side polar, low amount)
Thin laments: Actin, Tropomyosin, Troponin (only in striated) Caldesmon & Calponin (only in smooth)

Inotropism : changed preload/afterload >> change force/strength of contraction >> shift left (Frank-Starling Curve)
- ^ Ca in ux during AP (DHP)
- ^ Ca release by SR
- sensitizing Troponin C to Ca
- Anrep e ect (abrupt ^ after load >> ^ inotropy)
- Bowditch e ect (^ heart rate >> small + inotropic e ect)
- Parasympathetic (Vagal) inhibition
- Sympathetic Activation
- Circulating catecholamines
Gs-Protein & Gi-Protein Coupled Signal Transduction
Gs: stimulate contractility > B1 receptor > AC > cAMP > PKA > open Ca channel > ^ Ca release (SR) >> contraction
Gi: M2 receptor (dominate in SA & AV node)
Gq & IP3 : NE, AII, ET1 >> R >> AT1, ET(A), PLC >> PIP2 > IP3 + DAG >> ^ Ca release >> contraction

Inotropic Drugs
- digoxin : cardiac glycoside, inhibit 3Na/2K ATPase & indirectly inhibit 3Na/Ca exchanger > for systolic heart failure
- beta agoinst : Gs-Protein linked receptors
- dopamine, dobutamine, epinephrine
- phosphodiesterase inhibitors : increase cAMP
- Milrinone
Milrinone - selective PDE-3 inhibitor (inhibit cAMP >> AMP ) in Cardiac & Smooth Muscle
- in cardiac: ^ cAMP, ^ Ca in ux >> increase inotropy & Chronotropy
- in Smooth Muscle : ^ cAMP, inhibit MLCK >> General Vasodilation

Smooth Muscle location

Gastrointestinal Tract : Propulsion of food bolus
Cardiovascular : Regulation of blood ow & pressure via vascular resistance
Renal : regulation of urine ow
Genital : contractions during pregnancy, propulsion of sperm
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Respiratory Tract : Regulation of bronchiole diameter
Integument : Raises hair with erector pili muscle
Sensory : Dilation and constriction of pupils, changing of lens shape

Smooth Muscle Cell

- fusiform, diameter 5-10um, length (bv 20um, intestine 200um, uterus 500um)
- no striated pattern, no sarcomere
- caveola : analogue to T-tubule, extracellular Ca++
- SR : poor developed intracellular Ca++
- dense bodies : a-actinin (z-lines), membrane-associated dense bodies, intermediate laments (desmin & vimentin)
- Thin lament : actin + caldesmon + calponis + tropomyosin ( lack troponin )
- Thick lament : Myosin II (side polar)
- Connective Tissue (Stroma) : Elastin & collagen bers, reticular CT >> connects cell integrity
Multi-Unit Smooth Muscle
- each bers innervated by single nerve ending & controlled independently
- ciliary muscle of eye
- sphincter pupillae muscle
- dilator pupillae muscle
- piloerector muscle
- multiunit: electrical isolation allows ner motor control
Single-Unit Smooth Muscle
- electrically coupled (syncytium)
- Thousands of bers contracting together : GAP junction
- Most viscera of body wall : GIT, Bile ducts, Ureters, Uterus, BV
- unitary: gap junction permit coordinated contraction
Smooth Muscle Cell contraction
^ Ca >> Ca - Calmodulin complex > myosin light chain kinase activated > MLC - Phosphorylated >> CONTRACTION
Total Relaxation : Ca++ < 10^-7
Graded Contraction : 10^-7< Ca++ < 10^-5
Maximum Contraction : 10^-5 < Ca++

Myosin Light Chain Kinase (MLCK) <> Myosin Light Chain Phosphatase (MLCP)
Myosin II : 2 myosin heavy chain + 2 myosin light chain (MLC) (essential MLC + regulator MLC)
- smooth vs striated >> biochemically quite di erent
- Actomyosin ATPase activity >> much slower in Smooth
- Smooth total contraction 1-3s >>> striated 30 times faster
- Calcium Channels:
- voltage-gated 1.4DHP Ca channel : Electromechanical coupling - AP, CICR (RyR)
- Ligand-gated Ca channel : Pharmacomechanical coupling - no AP, only hormone & Neurotransmitter > single unit
- Stretch-activated Ca Channel : Myogenic regulation in Arterioles (microvascular resistance)
- Leak Ca Channel : Unregulated, Mechanical stretch promotes inward movement of Ca++

Ca Channel Blockers : inhibit voltage-dependent L-type Ca channels >> V muscle contractility

- vascular smooth muscle : DHP CCB
- Amlodipine, clevidipine, nicardipine, nifedipine, nimodipine
- treat hypertension, prevent cerebral vasospasm (nimodipine)
- Heart : Non-DHP CCB
- diltiazem, verapamil
- treat atrial brillation
Via Second Messenger
- Gq-protein >> activate PLC >> PIP2 >> DAG + IP3 >> IP3R >> Ca release (SR) >> Contraction (a1)
- Gq-protein >> Rho-kinase >> inhibit MLCP >> Contraction
- Gs/Gi-protein >> activate AC >> ATP >> cAMP >> PDE >> AMP
>> (inhibit MLCK + Ca reuptake ) >> Relaxation (b2)

- NO >> activate GC >> GTP >> cGMP >> Open K channel (hyperpolarization) + inhibit Ca entry + MLCP >> Relax
B2 agonist - Gs-protein coupled
- bronchial smooth muscle relaxation (bronchodilation)
- uterine smooth muscle relaxation (pregnancy)
- blood vessel relaxation (vasodilation) - skeletal muscle
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ex) Albuterol, Levalbuterol, Salmeterol, Salbutamol (inhalation)
- for bronchodilation >> treat Bronchial Asthma
ex) Terbutaline
- for uterine smooth muscle relaxation (pregnancy) - tocolysis - prolong gestation >> treat premature labor
Milrinone - selective PDE-3 inhibitor (inhibit cAMP >> AMP ) in Cardiac & Smooth Muscle
- in cardiac: ^ cAMP, ^ Ca in ux >> increase inotropy & Chronotropy
- in Smooth Muscle : ^ cAMP, inhibit MLCK >> General Vasodilation
- treat : short term acute decompensated Heart Failure
Nitrate
- increase NO in vascular smooth muscle > dilate veins >arteries > decrease PRELOAD
ex) Nitroglycerine, isosorbide denigrate, isosorbide mononitrate
- treat angina, acute coronary syndrome
Hydralazine
- ^ cGMP - vascular smooth muscle relaxation
- dilate arterioles > veins > decrease AFTERLOADS
- treat sever hypertension (acute treatment) >> safe during pregnancy
Nitroprusside : ^ cGMP - vascular smooth muscle relaxation

CICR
SR >> Ca signal >> RyR open >> release Ca (Calcium Spark)
Gq-protein >> PIP2 >> DAG + IP3 >> IP3R >> SR release Ca

Relaxation Mechanism : V Ca, V MLCK, ^ MLCP

- cell repolarization : V Ca in ux
- reuptake Ca to SR : SERCA pump
- plasma membrane Ca-ATPase pump : ^ Ca e ux
- Na/Ca exchange mechanism : ^ Ca e ux (less important)
Latch state : no excitation & less energy >> muscle maintain full strength (Prolonged tonic contraction in Smooth M.)
- not rigor state, Low ATP utilization, Low Ca concentration requirement
- myosin dephosphorylation >> actin still attached >> crossbridge cycle
Ca sensitivity
V MLCP >> ^ MLCK + (Ca + CaM) >> Ca sensitization >> shift graph left
^ MLCP >> V MLCK >> Ca desensitization >> shift graph right
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** Pharmacogenetics **

Malignant Hyperthermia - AD
- cause death b/c anesthesia >> Halothane & Succinylcholine (muscle relaxant - intubation)
- tachycardia, ^ BP, ^ HR, muscle rigidity, acidosis, hyperthermia, hypertension, ^ consume ATP
- massive Ca release >> ATP depletion and sever muscular contraction
- 70% mutation in RyR1 gene (Ca channel) & 1% Ca Channel
- RyR1 gene very large & complex
- Halothane (directly) / Succinylcholine (depolarization) >> unregulated RYR1 release of Ca >> malignant
- if no symptom >> reduce penetrance
- if symptom > heat > deplete O2 & ATP > anaerobic > produce lactate > Energy deplete > hyperkalemia, ^ CPK
Ca eine / Halothane test : who is susceptible to MH
- need large muscle sample
- only a few testing centers worldwide
- knowledge of the gene is not need for this test
- analyze RyR1 gene from patient >> test at-risk family members >> nd out mutation

CYP2D6 - member fo cytrochorm P450

- mixed function oxidase
- add oxygen to xenobiotic molecules to aid excretion
- metabolize drugs >> add oxygen >> soluble >> enhance excretion in urine
CYP2D6 polymorphism
- poor metabolizer > slow metabolism of CYP2D6 substrates (Homozygous Recessive alleles) (1~5%)
- 5-10 % : ultra-rapid metabolizers >> multiple copies of CYP2D6 gene >> process substrate very quickly
Codeine (analgesic - opioid pain killer)
- poor CYP2D6 metabolizer >> less e ective
- Ultra-rapid CYP2D6 metabolizer >> convert to active morphine >> su er respiratory depression / arrest (need less)
Codeine >> CYP2D6 + debrisoquine hydroxylase >> Morphine

Metoprolol (b-blocker) >> decrease BP

- poor CYP2D6 metabolizer >> too little deactivated >> has too much >> adverse e ects (need lower dose)
- Ultra-rapid CYP2D6 metabolizer >> deactivates metoprolol >> need very high dose of Metoprolol

** Triplet Repeat Mutation **

Triplet Repeat
- some stable, some grow, some shrink
- ex) CAG - Gln
- Under threshold - normal, Close to threshold - permeation, Over - Disease
- 1. Slippage mechanism : daughter stand separates & Slips backward >> produce long strand
- 2. Unequal crossing over : two sister chromatids line up > not line up exactly >> one longer, one shorter
- more severe as passed down
- more younger (early onset) as passed down
Fragile X syndrome : CGG expand in 5UTR >> DNA cytosine methylation >> gene silencing ( X - linked > male)
- normally FMR1 gene has 10-50 copies of CGG
- in FX syndrome > 200 repeat CGG >> improper development of Neuronal synapses
- PCR of southern blot diagnosis (direct measure)
- Fragile site form when cultured >> folate limiting condition
- intellectual disability, autistic, learning di culties, elongated face, reduced muscle tone, macroorchidism (males)
- female less severe, male more severe
- anticipation is successive generations - expansion in oogenesis (more severe when female transmit muatation)
- Fragile X-associated Tremor and Ataxia syndrome (FXTAS)
- premutation : massive over expression of FMRP (FXTAS) - still close to normal
- rCGG binding protein used too much >> deplete protein pool >> abnormal regulation of others >> neurological dx
Friedreich Ataxia : expansion in intron >> heterochromatin >> reduced gene expression (AR)
- lack muscle coordination (voluntary movements) , ataxia, muscle weakness, progressive neurodegenerative dx
- vision & hearing impairment, scoliosis, diabetes, heart muscle degeneration, dysphagia (swallow), dysarthria (speak)
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- frataxin gene > alter chromatin > heterochromatin formed > loss of expression (autosome)
- frataxin > a ect mitochondrial iron metabolism > iron overload > oxidative damage > mitochondrial destruction
- No anticipation - AR
Huntington DX : CAG expansion >> polyglutamine AA protein >> spinocerebellar ataxia (Gain of Fx, AD)
- Chorea, memory loss, sleep disturbances, paranoia, neurodegenerative (cerebral cortex)
- anticipation, decreased age of onset, increased severity, could have sex bias - paternal lineage
- sinuses enlarged, brain is complex, loss of neurons in basal ganglia & cortex
- “attainment of Novel function” “ployglutamine tract expansion” disorder in exon > protein
- HD lowering - Antisense DNA Oligonucleotide (ASO) > target mRNA > translation reduced (cytoplasm)
Spinocerebellar ataxia (Gain of Fx, AD)
- CAG expansion >> polyglutamine AA protein
- many gene >> SCA
- progressive, neurodegenerative disorder, ataxia, dysphagia, dysarthria, muscle weakness
- atrophy of cerebellum & pons
Myotonic Dystrophy : expansion in 3UTR >> mRNA soak up RNA binding protein > change Gene expressed (AD)
- inability to relax after muscle contraction > muscle wasting
- cataracts, cardiomyopathy, endocrine changes (insulin resistance)
- developmental delay, learning problems, speech & language
- DMPK gene - protein kinase gene
- weakness in distal muscles, face, jaw, drooping eyelids
- intermediate numbers of repeats in premutation range
- “RNA toxicity” - maternal lineage
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** Integumentary **

Hyperkeratosis - thickening of stratum corneum

Parakeratosis - retention of nuclei - keratinocytes of stratum corneum
acanthosis - increase thickness of stratum spinosum
acantholysis - broken bonds >> epidermis separation from each other

Basal cell carcinoma

- UV light, basal stem cell proliferation, dark nuclei & poorly de ned cytoplasm
- palisaded periphery, randomly arranged central cell, invade dermis & deeper layer, X metastasize
- may under go ulceration - tumor cell in ltrating into dermis
Squamous cell carcinoma
- malignant tumor of keratinocytes, elderly, Fair-skinned > Dark-skinned
- UV exposure > DNA damage (inactivation of P53 gene) > loss of orderly maturation
- hyperkeratosis & parakeratosis
- common in head & neck region (UV exposure)
- Predisposing Factors: UV, industrial carcinogens, chronic ulcers, tobacco, burns, ion radiation, betel nut, arsenic
- islands show squamous pearls or swirls
Malignant Melanoma
- malignant transformation of melanocytes
- highest cause of skin canner death - Australia / S. Africa
- UV exposure (acute, intermittent, blistering)
- large atypical morphology > dermal-epidermal region
- may invade dermis (metastases - fatal)
- Asymmetry, Border irregularity, Color, Diameter 1/4 inch or 6mm, Evolving
- Melan A : immunohistochemistry marker >> stains MM cells
Albinism : a ecting pigmentation - AR
- Loss of pigmentation of skin, hair, eyes
- lack tyrosinase
- ocular / oculocutaneous
- skin cancer, reduced visual acuity / photophobia, macular hypolasia, social stigma
Vitiligo - Auto-immune dx
- depigmentation disorder, destruction of melanocytes > focal, segmental, generalized
- treatment : topical steroid therapy, psolaren photochemotherapy, depigmentation
- surgical : autologous skin graft, micropigmentation, melanocyte transplants
Proriasis
- chronic in ammation & hyperproliferative disorder of skin
- well circumscribed, erythematous, itchy plaques, silvery scale (knee, elbow, lower back, scalp)
- epidermal turnover 8-10 days
- hyperkeratosis & parakeratosis
- predisposing factors : genetic background, inciting factors (stress)
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- pathogenesis :
- exogenous/endogenous antigens : predisposing factor
- antigen presentation by APC’s : Langerhans cells
- T-lymphocyte-mediated immune response
- Cytokine secretion
- In ammation & cellular hyper proliferation >> whitish patches
- Clinical lesions of psoriasis

Bullous Pemphigoid
- damage to hemidesmosome - separation of epidermis from dermis
- chronic autoimmune blistering dx : skin & mucous membranes (bulla large uid lled vesicles)
- antibodies (IgG) speci c to hemidesmosomes > binds to basement membrane > stimulate leukocytic in ltration
- eosinophils release proteases > degrade hemidesmosomes
- uid accumulation - blister formation
- large blisters X easily rupture
- linear disposition of Ig & complement in basement membrane
Pemphigus Vulgaris
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- pemphix (blister/buble)
- rare autoimmune disorder > a ect epidermis & mucosal epithelium
- desmosomes : separation of stratum spinous keratinocytes
- antibodies target Cadherins, desmoplakins, desmogleins
- atrophy of prickle cell layer
- blister formation >> easy to rupture > Nikolsky’s sign > skin shear o easily
- sh net like Ig

Acne - in ammation of sebaceous gland

- a ect 85 -100 % people at some point in life
- genetic predisposition, common in adolescents (prior to puberty - adrenal androgens)
- a ects face, back, chest, upper arm >> increased sebaceous glands
Wound healing
- skin damage > repair to normal structure & function
- 2 type
- epidermal would healing : only epidermis a ected > cells migrate (sheet like formation) > stem cells replace lost
- deep wound healing : penetrated the dermis (4 phases)
- in ammatory (3days) : blood clot, vasodilation > neutrophil & monocyte enter, mesenchymal cell > broblast
- migratory : clot > scab, epithelial cell migrate > bridge wound, broblast form scar (collagen & glycoprotein)
damaged vessels regrow, become granulation tissue
- proliferative (3d-weeks) type 3 collagen : epithelial tissue grow randomly, vessels grow
- Maturation (6month) type1 collagen : scab sloughs o , epidermis restored, callagen organized, V broblast
blood vessels stabilize, scar = brosis

Hypertrophic scar = raised more than normal, within original wound boundary (type 3 collagen) - in organized rows
Keloid scar = excess of the boundary, extending into surrounding tissue (type 1&3 collagen)
- common in dark skinned , ear, neck, sternum, upper extremities

Burns (rule of nine - describe burn coverage over the body)

- rst degree : partial thickness, epidermis only, heals spontaneously
- second degree : partial thickness, epidermis & dermis, epithelial water, barrier disrupted, heals spontaneously
- third degree : full thickness epidermis dermis & subcutaneous tissue, water barrier disrupted,
nerves & blood vessels destroyed, does not heal spontaneously, uid loss is extensive

Integumetnary system : Epidermis & Dermis

epidermis : keratinized strati ed squamous epithelium ( from ectoderm )
dermis : dense connective tissue ( from mesoderm )
Function :
- barrier
- immunological : present antigen to lymphatic tissue
- homeostasis : regulate Body Temperature & water loss
- Sensory : external environment > information > nervous system
- Endocrine : secrete hormone, cytokines, growth factors, covert Vit D > active D3
- Excrete : secrete sweat & other products
Hypodermis : beneath the dermis = subcutaneous fascia
- contain adipose tissue (panniculus adiposis) > arranged in lobules, seperated by CT septa
- very thick in cold countries
- have hair follicles, glands, mechanoreceptors
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** Epidermal cells **
keratinocytes - largest cell population (85%)
- di erentiate from basal layer > continue throughout all layer
- produce keratin (cytokeratin) for stratum basale, keratohyalin for spinosum & granulosum
- form water barrier

langerhans - antigen presenting cell (APC’s) - immunological function (2~5%)

- originates from common lymphoid progenitor (CLP), in all epidermal layers (mostly spinosum)
- delayed type hypersensitivity reaction, express both MHC I&II, IgG receptor
- Hematoxylin blue - cytoplasm clear
- nuclear indented >> nuclear pro le uneven
- Birbeck granules : tennis racquet shaped granules (rod-like + vesicle), regular cross striation

melanocytes - pigment producing (5%)

- basal layer (stratum basale)
- from neural crest cell, large clear elongated nuclei
- multiple cytoplasmic processes >> 1 melanocyte communicate with 40 keratinocytes (1:4~1:10)
- no desmosomes, via hemidesmosome to basal lamina
- lack keratin lament, oval dark staining
- produce melanin (cytocrine secretion) to keratinocytes >> UV protection (melanin degrade in light skin)
- premelanosomes (tyrosin & melanin) > 3,4DOPA > mature melanosome (melanin)

merkel - mechanoreceptor - sensory nerve ending (6~10%)

- least numerous, abundant where sensory perception is acute ( ngertips), close with merkel’s corpuscle
- detect touch sensation, have desmosomes & keratin laments
- nucleus is lobed, cytoplasm contain neurosecretory granules
- antigen marker for epidermal & neural type

Epidermis - strati ed squamous keratinized epithelium

stratum corneum - dead keratinized cells - variable number of layers, lack organelles
- thick plasma membrane covered with lipid forming barrier > water barrier (impermeable to water)
- keratinocytes - lled with keratin protein
- abrupt transition from granulosum
- (Pemphigus Vulgaris)
stratum lucidum - Thick skin only, appear as subdivision of stratum corneum
- light microscope : light highly refractive eosinophilic band - glossy
- keratinization process well advanced
stratum granulosum - cells about to die, most super cial, nonkeratinized cells 1-3 layers thick
- conspicuous granules > granulated appearance (keratohyaline granules) > cyctine & histidine rich
- atter appearance, ill de ned nucleus, keratin laments keratohyaline granules
- ovoid bodies >> hydrophobic, glycolipid property >> water barrier - lamellar bodies (start)
- keratinization (soft keratin) > loss of organelles, thickened cell membrane, decreased pH
stratum spinosum - larger keratinocytes, langerhans cell (move freely) - several cell layers
- maturing & slowly dying cells
- make cytokeratin/tono birl/keratin laments
- prickle layer, extensive cytoplasmic processes, ovoid nucleus, abundant keratin lament
- desmosomes attached to neighboring cells (Pemphigus Vulgaris) >> node of bizzozero
- closer to surface > increase in size, attened > parallel to surface > nuclear elongated
- keratinocytes produce keratohyalin granules, lamellar bodies
stratum basale - melanocyte, merkel cell
- can di erentiate, mitotically active (keratinocyte stem cells)
- on basal lamina, hemidesmosome linked (bullous pemphigoid)
- single cuboidal to columnar, basophilic, large nucleus, perinuclear zone, small golgi, keratin lament on periphery
- keratinocytes to BM, desmosome linked, keratinocytes to spinous layer
basement membrane
Dermis

Skin Pigmentation
UV radiation - melanin production a ected by Keratinocytes
Melanin distribution - dispersed di erently in light vs dark skinned person
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- light skin (basale), dark skin (basale & spinosum)
Type of melanin
eumelanin : protect from UVR, scatter & absorb UV rays >> eliminate UV generated free radicals, degrade faster
peomelanin : greater amount of light pass through >> increase Vit D production, increase oxidative damage

Thick Skin : only in palms & soles, hairless, thicker epidermis, have stratum lucidum & thick corneum
Thin Skin : Everywhere else, thinner epidermis, hair follicle widespread except few locations

Water Barrier formation - in all layer super cial to stratum granulosum

cell envelope : insoluble proteins on inside of cell membrane - mechanical part of barrier
lipid envelope : lipid layer on outer surface - lamellar bodies - formed by golgi, lipid rich, secreted by granulosum

Keratinization
- cells accumulate keratin (cytoplasm) > lose organelles, nuclei, cytoplasm > tono laments formed >
- >> stratum corneum >> desmosome broken apart >> cells sloughed o
- total epidermal turnover (+/- 47 days)
- day1~2: keratinocytes in basale mitotically divide & migrate to spinosum
- day3~31: keratinocytes in spinosum >> granulosum
- day32~46: keratinocytes keratinized >> enter corneum

** Dermis **
Gives strength & elasticity to skin
contain epidermal appendages, nerve corpuscles, glands, smooth muscle cells (hair)

reticular layer : dense irregular connective tissue (less cells)

- smooth muscle form loose plexus around ( areolae, penis, scrotum, perineum ) > puckering of skin ( erectile organs )
- Thick & deep to papillary layer, type I collagen & courser elastic bers

papillary layer : loose connective tissue (more cells)

- super cial layer, contain blood vessels, type I & III collagen bers, elastic bers > threadlike & irregular network
- relatively thin, include dermal papillae & dermal ridges, contain Meissner corpuscles
- deeper epidermal ridges & longer closer dermal ridges form > mechanical stress >> ngerprinting

Appendages : Hair follicles, hair, sweat glands (erring & apocrine), sebaceous glands, nails, mammary glands
- grown from epidermis > dermis (embryological development)

Nail - hard plates (keratinized) - dorsal surface of phalanx

- help grip and give protection
- nail plate : visible part, on nail bed (hyponychium)
- nail root : proximal to nail plate, covered with fold of skin (eponychium)
- nail matrix : under nail root >> cell proliferate >> form nails ( 1mm/week - deposition of hard keratin )
Hair Follicle - cylindrical shaft, extend to hypodermis, produced in follicles, in thin skin only
- associated with sebaceous gland & smooth muscle (erector pili) = pilosebaceous organ/unit
- consists of infundibulum, isthmus, inferior segment
- bulb contain matrix cells for hair formation ( melanocyte stem cells in bulb )
- keratogenous zone : undergo keratinization
- Hard Keratin > not followed by internal root sheath > separated from underlying dermis - thick basal laminal (Glassy)
- cyclical process: 3 phase
- long phase of active growth (anagen) , short phase of involution (catagen) , short inactive phase (telogen)
- growth cycle vary from site to site
- hair follicle ( 2year anagen & few month telogen), others (short anagen, long telogen)
Sebaceous Glands - simple branched acinar gland pale staining
- secretory portion, located deeper dermis > open into hair follicle > holocrine secretion (Sebum - prevent dry & brittle)
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Sweat Glands (Eccrine)
- thick & thin skin
- simple coiled tubular glands, cholinergic
- secretory portion in deep dermis > merocrine : clear cell (glycogen -PAS), dark cell (rER & secretory granules),
myoepithelial cells (basal aspect of secretory segment)
- duct pass through epidermis > open to surface (gentle spiral course to epidermis, tighter toward surface)
- strati ed cuboidal epithelium ( basal layer + luminal layer)
Apocrine Glands
- only in armpit & perineum, coiled tubular glands
- secretory portion in dermis or hypodermis
- lumen larger than eccrine sweat glands > merocrine > open into hair follicle > secrete pheromones
- ducts are straight, strati ed cuboidal epithelium, narrow lumen

Free nerve Endings

- occupy papillary dermis >> twigs into epidermis (terminate in granulosum)
- no myelin or CT
- subserve multiple sensory modalities : Pain, touch, itching, temperature (hot & cold)
- free dermal endings surround hair follicles - outer root sheath - sensitive to hair movement (mechanoreceptor)
- ex) whiskers of animals
Pacinian Corpuscle (pressure change & vibration) -(onion shaped)
- large, ovoid, in deep dermis & hypodermis, 1mm macroscopic dimension along long axis
- myelinated nerve ending, surrounded by capsule structure
- no myelin after entering capsule >> covered by attened schwann cell >> concentric lamella
Meissner’s Corpuscle (tough receptor)
- tapered cylinders, 150 microns along long axis, perpendicular to skin surface, twisted skein of wools
- dermal papillae just beneath epidermal basal lamina
- 1~2 unmyelinated nerve endings, cell consists schwann cells >> form irregular lamellae > to pole of corpuscle
Ru ni’s Corpuscle (stretch & torque) - tree like
- simplest, elongated fusiform shape, 1~2 microns, thin connective tissue capsule surrounding uid lled space
- collagen bers from surrounding connective tissue
- single myelinated ber > enter capsule > loose myeline sheath > form dense axonal ending > small knoblike bulb
- axonal ending > respond to displacement of collagen bers / mechanical stress
Merkel’s Corpuscle
- Merkel’s cell in communication with a erent myelinated nerve bers
- detect acute touch sensation - pinpoint, sharp identi able precise input
- most abundant in skin ( ngertips)
- cytoplasm contain neurosecretory granules
- express antigenic markers of both epidermal and neural type
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