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Part 1

  • Cover everything well; they will ask things.
  • Today is about Face and neck and sexual development

Face and ear

  • Read the first page of the Larsen's chapter (for each topic)
    • Cover the face and know that the ear has different origins and that the eye forms from an evagination of the brain and the lens forms from a vesicle. (?)

Pharyngeal arches

  • Arches are formed by extensions of the structures around the foregut (3-4th week onwards, foregut is folding ventrally)
  • Form on either side of the foregut (1-4, 6)
    • Craniocaudal development sequence
    • 4th and 6th cannot be seen externally
    • Focus on 1,2,3
  • Contents
    • Cartilage (neural crest)
    • Mesoderm (head mesoderm)
    • Nerve (cranial 5,7,9,10)
    • Artery (aortic arch artery)

Focus on the first 3.

  • in diagram, a,b,c refer to tuberculum impalm (?) - for the tongue
  • Membrane between arches has three layers
    • Ectoderm (laterally)
    • Endoderm (medially)
    • Mesoderm (between these)
  • Pharyngeal cleft = lateral sulcus formed between arches (ectoderm)
  • Pharyngeal pouch = medial sulcus (formed between arches)

First arch derivatives

  • Nerve: Trigeminal (CN V)
  • Maxillary portion: Nerve --> maxillary branch; cartilage --> incus
  • Mandibular portion: nerve --> mandibular branch; cartilage --> Meckel's cartilage - only to mandibular part (malleus - U shaped); muscles of mastication
    • Meckel's forms a template for the jaw (but jaw doesn't form from ossification)

Second arch

  • Nerve: Facial nerve (7)
  • Cartilage: Rechart's
    • Stapes
    • Styloid process
    • Stylohyoid ligament
    • Upper part of hyoid
      • Lesser cornura
      • Upper part of body
  • Muscles:
    • Muscles of facial expression

Third arch derivatives

  • Cranial nerve: glossopharyngeal nerve (IX)
    • Mainly sensory
  • Cartialge:
    • Lower part of hyoid
      • Greater cornura
      • Lower part of body
  • Muscle: stylopharyngeus muscle

Fourth/sixth arch derivatives

  • Cranial nerve: Vagus (X)
  • Cartilage:
    • Thyroid cartilage
    • Cricoid cartilage
    • Arytenoid cartilages
  • Muscles
    • Pharyngeal constrictors
    • Levator veli palatini
    • Intrinsic muscles of larynx

Face development

  • Established between weeks 5-10 by fusion of five prominences
    • Frontonasal
    • Maxillaryx2
    • Mandibularx2
  • Nasal placodes develop upon the frontonasal prominences
    • Medial and lateral nasal processes surround these (proliferation of tissue around the nasal placodes)
    • Medial nasal processes fuse in midline as intermaxillary processes

Palate development

  • Nasal and oral cavity separated by the rearward growth of the intermaxillary process
    • This is the primary palate
  • Contains upper four incisors
  • Incisive foramen is the limit between the primary and secondary palate
  • Secondary palate forms from medial growth of maxillary prominence
    • =palatal shelves
  • Posterior gap behind the secondary palate is the definitive choana (gap behind the hard palate)
  • First: it grows down and medially, then it elevates above the tongue and grows medially upwards.
  • Intramembranous ossification
  • Clefting occurs when palate stuff fails to fuse (either because of failure of primary palate to form from maxillary to frontonasal, or as secondary palates to fuse in the midline)

Tongue

3-4 weeks

  • Formed from the ventral aspect of pharyngeal arch (floor of pharynx)
    • (Where the prominences fuse ventrally in the midline)
    • The floor is the endoderm of that region
  • Tub. impar, copula and thyroid diverticulum are all important
  • Midline: from first pharyngeal arch you have median tongue bud (tub. impar; mandibular part of first arch)
  • Second arch = copula
  • 3rd and 4th arch = hypopharyngeal eminence (mainly the third arch)
  • Anterior 2/3 of tongue = first arch (trigeminal n)
  • Posteiror 1/3 of tongue = mainly 3rd arch (glossopharyngeal)
  • 2nd arch explains why chorda tympani supplies taste sensation to anterior 2/3
  • Muscles of the tongue are supplied by somitic mesoderm
    • Intrinsic/extrinsic muscles formed by somitic mesoderm; supplied by hypoglossal nerve
  • Medial swellings:
    • Tuberculum impar (1st arch) --> lingual nerve (br of mandibular = trigeminal branch 3)
    • Copula (2nd arch) --> chorda tympani (facial nerve)
    • Hypopharyngeal eminence (3rd arch) --> glossopharyngeal n

Fourth arch = epiglottis (vagus nerve)

Other derivatives

  • Thyroid gland - originates from apex of foramen caecum and descends to final position in front of trachea (thyroglossal duct) - descends ant. to trachea
  • Clefts
    • 1st = external acoustic meatus + tympanic membrane (membrane)
    • Others regress (if they persist and they have fluid, then they're called cervical cysts)
  • Pouches
    • 1st = pharyngotympanic tube + mastoid antrum etc
    • 2nd = palatine tonsils
    • 3rd = thymus + inferior parathyroids
    • 4th = superior parathyroids
    • 5th (transient) = ultimobranchial body (parafollicular "C" cells of thyroid - calcitonin)

Thymus descends from its position in the third pouch down to on top of the heart

Ear

  • Outer ear: auricular hillocks (1st/2nd arch) --> pinna
    • 1st cleft = EAM, 1st membrane = tympanic membrane
  • Middle ear: Ossicles: malleus - mandibular prominence cartilage (Meckel's Cartilage); incus - maxillary prominence cartilage, stapes - Reichart's cartilage
  • Inner ear: otic placode --> otic vesicle --> inner ear
    • Bony labyrinth (just a space within the temporal bone - lined by periosteum and inside that is perilymph like CSF)
    • Membranous labyrinth
  • Vestibulocochlear nerve comes from the otic placode

Sexual differentiation

  • Read the first page of the Larsen's chapter
  • Outline kidneys and lower urinary tract
  • Sexual differentiation:
    • Initial common pathway (week 6-7)
    • Internal genitalia differentiation (SRY etc)
    • External genitalia

Within each of those, look at male versus female

Kidneys

  • Originate from intermediate mesoderm (same of all the genitourinary system except primordial germ cells and the external genitalia)
    • Pronephros (cervical region)
      • Regresses, helps cause differentiation of:
    • Mesonephros (thoracolumbar region)
      • Regresses; important for sexual differentiation
    • Metanephros (sacral regions)
      • Forms the kidney; metanephric blastema, important for renal development
  • Mesonephric ducts originate medial to the mesonephros
  • Connect to the urogenital sinus (forms when the caudal region of the developing GIT/endoderm has a septum forming between the rectal and urogenital region) caudally
    • Sprout the ureteric buds just proximal to that connection (forms the ureter).
    • Invested by metanephric blastema which forms definitive kidney
  • Kidneys ascend during 6th-9th weeks to final lumbar positions
    • Failure of ascent --> pelvic kidneys; or horseshoe kidneys, where it loops around down the bottom

Lower urinary tract

  • Originates from the urogenital sinus
    • Urachus (from allantois) - covered by peritoneum and called the median umbilical fold in the adult
    • Bladder - expansion of the urogential sinus
    • Pelvic urethra (prostatic membranous urethra in male, membranous in female)
    • Phallic segment of the sinus (important for external genitalia) - ureter connects posteriorly later
  • Flared region of the ureteric duct forms the trigone, and the ductus deferens connects into this
    • Trigone = ureters and the urethra in bladder
  • Initial common pathway --> internal genitalia --> external genitalia

Initial common pathway

  • Ferilisation determines genotype
  • Key embryonic events
    • PGCs migrate from yolk sac to dorsal body wall (T10 - which is where innervation from testes/ovaries is)
    • Coelomic epithelium
      • Proliferates --> genital ridges
      • Differentiates --> somatic support cells (sustentacular or granulosa)
    • Paramesonephric (Mullerian) ducts form

End of week 6.

Internal genitalia (XY)

  • Driven by 4 key factors
    • SRY
    • AMH
    • Testosterone
    • Dihydrotestosterone
  • SRY drives
    • Somatic support cell differentiation to Sertoli cells
      • Surrounds PGCs forming sex cords
      • Inhibits meiosis 1 --> no differentiation of PGCs
      • Release AMH --> regression of Mullerian (paramesonephric ducts)
    • NB Sertoli + Leydig cells form the testis cords; which at puberty become seminiferous tubules (medulla - at puberty, we call them ST; in contrast to females where everything happens in the cortex)
  • Interstitial cells differentiate into Leydig cells
    • Produce testosterone
      • Mesonephric duct persists and differentiates (due to T)
    • Expresses 5alpha reductase to produce dihydrotestosterone
      • External genitalia develop
        • Prostate/BU glands/Penis/Scrotum
      • Testicular descent
  • Without 5alpha reductase --> a form of androgen insensitivity
  • Mesonephric ducts develop
    • Cranially
      • Above testis --> degenerates (appendix epididymis)
      • Next to testis --> epididymis
      • Below testis --> ductus deferens
    • Caudally
      • Mesonephric duct --> seminal vesicles
      • Urogenital sinus endoderm invaginates to form
        • Prostate gland
        • Bulbourethral glands

Female

  • Driven by absence of key factors: SRY, AMH, relative lack of testosterone (NB: not a completely passive process)
  • Non-expression of SRY drives
    • Somatic support cell differentiation (indirectly)
      • Surround the PGCs, forming sex cords
      • Permit PGC progression into meiosis 1
      • Stimulates SSC differentiation to follicular cells
      • No release of AMH --> Mullerian (paramesonephric) ducts persist and differentiate
  • NB: follicular cells + invest PGCs to become primary ovarian follicles (cortex of ovary).
  • Sex cords are equivalent to testis cords, but slightly better differentiated
  • Interstitial cells differentiate into thecal cells
    • Do not produce testosterone
      • Mesonephric duct degenerates
    • Do not produce DHT (no external male genitalia)
  • Paramesonephric ducts develop
    • Cranially
      • Above ovary --> fimbriae
      • Next to ovary --> infundibulum
      • Below ovary --> uterine tube
    • Caudally
      • Fused ends canalise
        • Uterus
        • Upper part of vagina
      • Sinusal tubercle/sinovaginal bulb (UG sinus)
        • Canalises to form lower vagina
  • Region where they fuse --> remnant = hymen
  • Gubernaculum in female also shortens a little, but to lesser extent. Forms the round ligament of the uterus (in male it shortens and regresses)

External genitalia

  • Common origin
    • Urorectal septum divides urogenital sinus from anorectal canal
    • Endoderm lining genital tubercle = urethral plate
    • Mesodermal proliferation forms
      • Genital tubercle
      • Urogenital fold
      • Anal fold

Male

  • In presence of DHT:
  • Genital tubercle (urethral groove)
    • Fuses in ventral midline --> penile urethra
    • Distally terminate as urethral plate
    • Needs to canalise to form lumen

Hypospadia --> no canalisation, and you get opening down on the ventral part of penis

  • Urethral folds
    • Fuse in ventral midline --> enclose penile urethra
  • Labioscrotal swellings
    • Fuse in ventral midline --> scrotum

Female

  • In absence of DHT:
  • Genital tubercle (urethral groove)
    • Bends inferiorly --> clitoris
  • Urethral folds
    • Do not fuse --> labia minora
  • Labioscrotal swellings
    • Do not fuse --> labia majora

Inserts as round ligament

Testes descent

(Ovaries also descend to smaller extent)

  • Suspensory ligaments
    • Females: suspensory ligament of ovary
    • Male:regresses
  • Gubernaculum
    • Female: round ligament of uterus
    • Male: facilitates descent of the testes

Layers dragged:

  • Transversalis fascia
  • Internal oblique
  • External oblique

Part 2

  • Read the question
  • Define key concepts
  • Structure (logical flow)
  • Tables/diagrams - anatomy/histo
  • Dot points
  • Completely lost? Write what you know
  • Start from the beginning and define the main points

Gastroenteritis

  • 5 yo child, diarrhea, vomiting, nausea
  • What is gastroenteritis
    • Inflammation of the GIT, involving stomach/SI, diarrhea, vomiting, malaise, nausea, abdominal discomfort
  • What are the common causes?
    • Viruses: Norovirus (adults), rotavirus (children; vaccine); adenovirus; astrovirus/picornavirus/parvovirus/sapovirus
    • Bacteria (blood in stools): Campylobacter jejuni (most common; zoonotic potential); Salmonella non-typhoid (second most): food poisoning; Salmonella (typhoid): s. typhi, s.paratyphi. Longer lasting, systemic; Shigella: very low infectious dose (hence antibiotics), fecal/orall, sexual; Vibrio cholera: 'rice water stools' (no blood - no epithelial damage)
    • Parasites: Giardia lamblia: protozoan (flatulence, foul smelling stools, weight loss, diarrhea, constipation) - metronidazole
  • Diagnosis
    • Exclude other possibilities (medications)
    • Blood tests - FBC, inflammatory markers (CRP, ESR)
    • Stool sample: microscopy and culture
    • If bacterial/parasite microscopy and culture will help detect (viral doesn't come up)
  • Management
    • Diet/nutrition
    • Rehydration
    • Adsorbents e.g. activated charcoal (bind to wall of gut or toxin itself and eliminate it)
    • Antimotility drugs e.g. loperamide, atropine (anticholinergic)
    • Bismuth subsalicylate: anti-inflammatory; inhibits prostaglandin synthesis and coats the GIT mucosa/protective
    • Intestinal flora modifiers
    • Anti-microbials indicated for: shigella, severe cholera, typhoid salmonella

For both diagnosis and management, they don't do much (just told to go back home, but don't even test) - just send you back home

Absorption from GIT

  • Sample question: Antony has just eaten a sugar-heavy meal. Describe the mechanism by which sugars are broken down and absorbed
  • Digestion: Mouth (salivary amylase), pancreas (pancreatic amylase), small intestine (disaccharides: lactase/maltase/sucrase)
  • Absorption: transport across the enterocyte into the bloodstream)

Salivary amylase breaks down complex sugars (e.g. starch) into simple sugars. Pancreatic amylase further breaks down complex sugars. Disaccharidases break down disaccharides into monosaccharides. Lactase: Lactose --> glucose+galactose. Maltase: maltose-->2glucose. Lactase: lactose --> glucose+galactose

  • Absorption: apical (SGLT1 for glucose/galactose; GLUT5 for fructose). Basal: GLUT2. Gradients maintained by the Na/K ATPase
  • Draw the diagrams
  • Do the same for protein and fat and calcium and iron

Thyroid physiology

  • Hypothalamus releases TRH to AP, that releases TSH to stimulate thyroid to produce T3 (10%) and T4(90%)
  • Effects of thyroid hormone:
    • Increase basal metabolic rate: glycogenolysis, gluconeogenesis, lipolysis, protein synthesis. Heat generation, increased energy usage, oxygen consumption
    • Growth effects with GH
    • Cardiac effects: increase contractility (upregulates beta adrenergic receptors, increases myosin production)
    • Developmental effects: neonatal CNS
  • A 20year old patient presents with fatigue, muscle weakness, cold intolerance, bradycardia, hypoglycaemia, constipation
    • Hypothyroidism
    • Describe two causes of hypothyroidism
    • etc

Answer:

  • explain what TH does
  • relate back to symptoms
      • muscle weakness = less protein synthesis
      • bradycardia = cardiac effects
      • cold intolerance = lowered RMR
      • hypoglycemia = sugar effects
      • constipation = slowing down body systems
  • causes of hypothyroidism:
    • definition - abnormally low level of TH
    • 3-5% of population: women,a age
    • hashimotos thyroiditis: inherited autoimmune
    • pituitary or hypothalamic disease
    • thyroid destruction
    • medications (e.g. overzealous treatment of hyperthyroidism)
    • severe iodine deficiency (common in developing countries)
  • managing hyperthyroidism
    • surgery
    • radioactive iodine (selective for thyroid gland
    • antithyroid drugs, requires knowledge of how TH is produced

TH production

  • colloid in a follicle with follicular cells surrounding, then C cells (calcitonin) around that
  • know the production of thyroid hormone
    • sodium iodide symporter (secondary active transport with Na/K atpase)
    • pendrin (anion exchanger) to get iodide into the follicle
    • inside follicle, thyroid peroxidase does iodination and conjugation of tyrosine residues. Then T3 and T4 bound to TG are stored in the colloid. TSH acts via receptor and cAMP signalling to cause release of T3 and T4 from the follicular cell. (endocytosis of TG, lysosome fuse and cause cleavage of T3 and T4 .... etc)
    • deiodinase 1 in periphery converts T4 to T3, deiodinase 2 converts T4 to T3 in hypothalamus

Antithyroid drugs

  • Carbimazole - inhibits thyroid peroxidase
  • Propyl thiouracil (PTU) - inhibits thyroid peroxidase and blocks deiodination of T4 and T3
  • More T4 produced by T3 more potent at target

Depression

Symptoms

  • Anhedonia
  • Sleep changes
  • Appetite/weight changes
  • Dysphoria (low mood)
  • Fatigue
  • Agitation (psychomotor) -- restlessness
  • Concentration loss
  • Esteem loss
  • Suicidal ideations

Questions to ask someone you suspect is depressed

  • Define depression
  • Work with ASADFACES
  • Establish chronicity
  • Discuss risk factors if relevant
  • Has this impacted on your:
    • Work
    • Relationships
    • Hobbies etc
  • Risk factors: women, 55 years old peak, etc

Management

  • Non pharm (e.g. CBT - describe what it is)
  • Pharmacological agents (name, class, mechanism of action, side effects)
    • SSRIs
      • Fluoxetine
      • erectile dysfunction/sexual dysfunction, fatigue, malaise, weight gain, nausea
    • SNRIs
      • Venlafaxine
    • MAOIs
      • Moclobemide
      • Cheese effect (can't break down tyramine in cheese, builds up - hypertensive crisis and headaches)
    • Other (venlafaxine, buproprion)
  • Electroconvulsive therapy
  • Deep brain stimulation

Developmental milestones

  • Michael brings in a 2 year old son - Down syndrome. Said his first word last week, but can crawl and cruise, has not started to walk
    • Is this normal? Why
    • What is D delay? Causes?
    • How would you assess this case?

Answer:

  • Define developmental milestones and what normal is
    • Domains: gross motor, fine motor, cognitive (Piaget's theory), personal/social, speech/language
    • 6 weeks: primitive reflexes
    • 9 months: sit alone, object permanence
    • 12 months: pull to stand, precise pincer grip, first word
    • 2 years: run, two words at two (two word sentences; vocab=50-200 words)
    • 3 years: tricycle, upstairs, mature pencil grip, use scissors, tower of 9 blocks, cooperative play, know gender, draw circle, understand 3 keyword instruction
    • 6 years: skip, bounce and catch ball, write first name, know address

Michael:

  • Clearly he doesn't fit in with what's normal
  • Down syndrome; define it and say how it delays development
  • Michael is reaching milestones later; perhaps his development isn't normal
  • Need to assess cases individually, and realise some range of normal

Causes

  • The failure to meet developmental milestones at expected periods. Global or domain specific
  • Mental retardation, CNS problems (meningitis)
  • In Utero: infection in womb, FAS (fetal alcohol syndrome), trauma
  • Chronic infection: deafness/glue ear (gentamicin can cause deafness)
  • Hormone problems -e.g. thyroid
  • Genetic/family history: e.g. DS, turner
  • Idiopathic
  • Nutritional problems

Assessing developmental delay

  • observe child
  • detailed history
  • check milestones
  • physical neurological exam
  • developmental screening e.g. parents evaluation of developmental status (PEDS)

GIT embryology

  • Ways to learn: Time points/organs
  • Pay attention to abnormalities mentioned in the lecture
  • Week 3 -gastrulation (formation of the three germ cell layers) and folding (around the notochord; how it folds; where things end up)
  • Week 4 - segmentation of mesoderm (paraxial, intermediate, lateral plate - splanchnic and somatic), formation of foregut, midgut and hindgut
  • Week 5-8: recanalisation
  • Weeks 8-10: intestinal rotation

GIT by organ:

  • Liver - hepatic diverticulum invading the septum transversum (ventral mesentery - falciform ligament)
  • Stomach (including rotation: left arm - bend forward, then right)
  • Pancreas
  • Spleen
  • Learn about which germ cell layers and key phrases (e.g. dorsal mesogastrium for spleen, septum transversum for liver)

Abnormalities

  • Oesophageal atresia/stenosis/duplication (recanalisation)
  • Meckel's diverticulum (improper closure of the vitelline duct) 2% of people, 2 feet from the caecum, 2 inches long, 2 something else