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UTHSCSA / OTHER / CIRC 5007 / How does a cell regulate its progress?

How does a cell regulate its progress?

How does a cell regulate its progress?

Description

School: UTHSCSA
Department: OTHER
Course: Molecules to Medicine
Professor: Thomas king
Term: Fall 2017
Tags:
Cost: 25
Name: Week 2 Notes (8/7-8/11): M2M, LOM, CS
Description: Second weekly notes covering all objectives for Molecules to Medicine, Language of Medicine, and Clinical Skills.
Uploaded: 08/12/2017
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How a cell regulates its progress?



Week 2 Notes 8/7/2017­ 8/11/2017 

Day 1 (M2M)

9:00­9:20— Weekly Quiz 9:20­9:50—Intro to the Week

10:00­10:50—Cell Cycle, Meiosis & Fertility

Objectives

1. Describe the major stages of the cell cycle and how a cell regulates its progress into  and through each of these stages.

Interphase=G0 phase, G1 phase, S phase, G2 phase 

G0=non­dividing cell, inactive/performing normal functions 

G1=pre­DNA replication, varies in time, cell preps for S phase 

S=DNA replication (lasts 6­7 hours) We also discuss several other topics like When does shortage happen?

G2= post­DNA replication, 2­3 hrs, prepping for cell division 


What are the major differences between cell necrosis and apoptosis?



M phase (mitotic or meiotic)=Karyokinesis, Cytokinesis 

Karyokinesis= division of nucleus 

Cytokinesis= division of cytoplasm 

Stimulation of cell division can happen from growth factors (small peptides) which bind  to membrane receptors, sending an intracellular second message system and activating an early intermediate gene, which controls cyclin. 

Cyclin increases before division and turns on cyclin­dependent kinase (CDK) of  maturation promoting factor (MPF).  It is degraded after division. Don't forget about the age old question of How sigmund freud introduced the unconscious mind’s developmental theory?

Checkpoints to avoid mutation: when damage happens, p53 gene is activated, which  stops the cycle to repair or causes apoptosis. 


What is the biparental inheritance?



If you want to learn more check out What is the level of customer interaction?

Checkpoints of cell cycle: nucleus checks accuracy of DNA and fixes mistakes or apoptosis.   

S=replication (strands separated and doubled, only still touching at centromere).  4  stranded chromosome with two p arms and two q arms (chromatid) 

2. Describe the major differences between cell necrosis and apoptosis. Apoptosis: caused by p53 gene activation because of cell stress or DNA damage Energy dependent, Membranes are left intact, DNA fragments, nuclear blebbingDon't forget about the age old question of Who is vine deloria jr?

Necrosis: caused by toxic injury.  Energy independent, membrane is disrupted, DNA degrades  randomly, cell lyses Don't forget about the age old question of What are the animal characteristics?

3. List the major phases of mitosis and the structural features of the cell at each phase.

Mitotic figure: cell in any phase of mitosis.  Very dark chromosomes (but not everything that’s  dark is chromosomes).   We also discuss several other topics like What is gestalt psychology?

Prophase: nucleolus disappears, nuclear envelope becomes vesicles, centrioles duplicate and  form spindles, chromosomes become visible microscopically. 

Metaphase: chromosomes line up along cell equator randomly 

Anaphase: chromatids separate at centromere, chromatids move to opposite poles and begin to  decondense 

Telophase: nuclear envelope reforms (karyokinesis done), nucleolus reappears, cytokinesis  completes (two cells pinch off) 

4. Define “Maturation Promoting Factor”, explaining why it is important for cell division.

Maturation Promoting Factor (MPF) increases when cyclin production increases, and its CDK  component becomes active.  It functions to condense DNA, create the spindle apparatus, and  break down the nuclear envelope. 

5. Define the two divisions of meiosis in terms of changes in chromosome numbers and  DNA content.

Two divisions: reduction division (Meiosis I) and maturation division (Meiosis II) MI= Prophase I: homologous chromosomes pair (only happens in meiosis), cross over Metaphase I: homologous chromosomes line up on equator 

Anaphase I: separation of homologous chromosomes 

MII= Prophase II (debatable whether this exists) 

Metaphase II: chromosomes line up on cell equator 

Anaphase II: separation of chromatids, move to opposite poles 

After MI, each cell has a paired chromatid (either maternal or paternal) 

After M2, each cell has one strand of one of the chromatids (23 strands total) Slide 7 answers: different ways to define “n” numbers: DNA content or chromosome number After S phase: DNA=4n, Chromosome=2n 

Start of Reduction division (Meiosis I): DNA 4n, Chromosome 2n

End of reduction division (II):  DNA 2n, Chromosome 1n (haploid) 

End of maturation division (II): gametes.  DNA 1n, Chromosome 1n 

6. Explain the Lyon hypothesis of X chromosome inactivation.

Only one X chromosome ever gets activated, and it’s random which one.  The inactive X is  called a “Barr body.”  Only females have Barr bodies. 

7. Define the term pseudoautosomal region and explain its importance in X – Y synapsing  during meiosis.

Pseudoautosomal region: region on X/Y chromosomes that allow them to pair up as  “homologous” chromosomes even though they aren’t the same.  Most common genetic problems result from these not correctly lining up, leading to aneuploidy of sex cells (XXY=Klinefelter’s,  X0= Turner’s) 

8. Define the terms: diploid, haploid, polyploid and aneuploid.

Aneuploid: irregular number of chromosomes (too little or too much) 

Diploid: somatic cells, 2n, 46 chromosomes in humans 

Haploid: sex cells, 1n, 23 chromosomes in humans 

Polyploid: containing more than two homologous chromosomes (3n, 4n, etc.).  Instead of one  chromosome from each parent, have more than 2 of the same (not usually in eukaryotes)

11:00­11:50—Chromosomes and Mendel’s Laws

Objectives

1. Define the terms of genetics (gene, genotype, phenotype, linkage, mutation, allele, locus, recombination, haplotype, etc). See pages 4­10 of this handout for terms of genetics.

Gene: unit of DNA sequence that encodes for a specific function.  Typically, when we say genes, we mean they code for protein, but non­coding genes can also code for RNAs, miRNA 

Genotype: combination of alleles in diploid organisms at one location on DNA 

Phenotype: Characteristic related to genetic makeup that are variable results of genotype.   Examples: hair color, eye color, presence of disease. 

Linkage: Relationship between two locations on chromosome that violates independent  assortment (usually because genes are so close to each other) and creates gene families that  usually sort together

Mutation: Altered version of gene 

Allele: One member of pair of a gene (everyone has two alleles, one from each parent) Locus: Specific chromosomal/gene location 

Recombination: Exchange of DNA sequence between two chromosomes that are touching each  other in meiosis.  Results in slight variations on maternal/paternal DNA sequence for variability. 

Haplotype: Physical combination of alleles present on a chromosome. (recombination makes  more haplotypes) 

1. Recognize and define biparental inheritance.

We inherit one maternal and one paternal allele through fusing of sperm and ovum 

We NEED combo of sperm and egg (biparental inheritance) otherwise an embryo won’t be  viable.  Fetus comes from egg, placenta and extra stuff come from sperm.  If all genetic material  is from father, we have a complete mole (placenta, no embryo).  If all genetic material is from  mother, we have a dermoid cyst (mostly skin and hair like tumor) 

3. Recognize how Mendel’s laws apply to human genetics and their significance in clinical practice.

First Law: Law of Segregation.  Everyone has two alleles of a gene, one from each parent  randomly.  Dominance indicates phenotype. 

Second Law: Law of Independent Assortment.  “Inheritance Law.”  Separate genes are passed  independently of each other.  Alleles assort independently and combinations of genes in gametes  will be random (Over 8 million possible combinations!) 

4. Explain sexual determination.

Sex is determined by X/Y chromosome presence.  XX= female.  XY= male. **Y chromosome determines sex, specifically the SRY gene on Y chromosome. SRY activates S0X9 to form testes 

5. Explain X­inactivation in humans (Lyon hypothesis) and recognize the clinical significance of somatic mosaicism.

In females, only one X is active, the other is a Barr body.  The active one is chosen completely at random and gene expression comes from this active one. 

Lyon inactivation: one X in female becomes inactive to balance expression.   

Random inactivation in every cell at 32 cell stage into Barr body heterochromatin which  stays inactive in all daughter cells to form “patchwork” of expression.  Females are mosaics 

(more apparent in calico cats).  Mechanism: Xist transcripts start at center and methylate genes to inactivate them.  It peters out at the end, preserving PARs. 

6. Solve basic probability problems and explain how basic probability applies to clinical practice.

Probability has two important rules:  The addition rule, and the multiplication rule. Addition:  A OR B (mutually exclusive: cannot occur at same time) 

Exchance that someone in a group is either type O or type A= add those  probabilities (.42+.43= 85% chance) 

Multiplication: A AND B (independent: can occur at same time) 

Exchance that someone in a group at random is female and type O (.5*.42= 21%) 

Day 1 (LOM)

1:00­1:15—Galen Quiz 1

1:15­2:00—Session: Cranial Cavity

Objectives

1. Define skull, cranium and calvaria and list the bones composing the calvaria. Skull= cranium and mandible. 

Cranium= calvaria and facial skeleton 

Calvaria= braincase (cranial vault, keeps brain in).  Often used for the skullcap (roof).  Made of  frontal bone, two parietal bones, and occipital bone. 

 2. List the layers of the scalp and indicate which layer contains most of the nerves and  vessels to the scalp and which layer is the “danger space” of the scalp.

Skin, Connective Tissue (tela subcutanea), Aponeurotic layer (galea aponeurotica), Loose  connective tissue (“danger space”) and Pericranium (periosteum external to calvaria) 

Aponeurotic layer of scalp connects the muscles of facial expression (innervated by facial nerve)  of occipitofrontalis 

Loose connective “danger space” because if infection happens here, nothing to barrier spread to  periosteum.

 3. Give the location of the anterior and posterior fontanels and state their normal times of  closure.

Anterior/frontal fontanel: usually closes by end of second year.  Located between two frontal and two parietal bones of fetal skull (junction of coronal suture and sagittal suture) 

Posterior: usually closes about two months after birth.  Located at junction of sagittal and  lamboidal sutures. 

 4. List the three meningeal coverings of the brain and the spaces with which they are  associated.

Dura Mater: most external (two layers, periosteal=periosteum lining inside of cranial cavity and  inner meningeal layer continuous with dura of spinal cord).  Epidural space between periosteal  and bone.  Meningeal can separate from periosteal and form dural folds.  Contains endothelial lined venous sinuses. 

Arachnoid mater: contain arachnoid granulations that protrude through meningeal dura (drainage for return of CSF) 

Pia Mater (attached to brain surface) 

 5. Compare and contrast the dural coverings of the brain and spinal cord.

In brain, there are two layers (periosteal and meningeal).  The meningeal is continuous with  spinal cord.  In the brain, the epidural space is between periosteal and bone (not periosteum and  vertebral foramen).  Folds and venous sinuses present. 

 6. Name the dural folds and state the attachments of the falx cerebri and tentorium  cerebelli.

Dural folds are when meningeal dura separates from periosteal dura.  Special dural projections  include: 

Falx cerebri= large fold, sickle shaped, attaches anteriorly to crista galli of ethmoid bone,  separates cerebral hemispheres. big mohawk 

Tentorium cerebelli= more transverse, elevated at center relative to periphery (like a tent  over the cerebellum), attaches at periphery to occipital bone and petrous ridges of temporal  bones.  Free edge of tentorium attaches to anterior clinoid process of sphenoid bone. 

 7. Label diagrams of:

a. The basic structure of a dural venous sinus and an arachnoid granulation. See Handout page 3 

b. The system of dural venous sinuses associated with the cranial cavity and know the

direction of blood flow in this system.

See Handout page 4 

**Flow of sinuses is usually posterior and inferior.  Venous blood OUT. 

c. The system of arteries supplying blood to the brain.

See Handout page 7 

 8. State the two principal pairs of arteries supplying blood to the brain. Internal carotid, Vertebral arteries 

 9. State the likely sites of bleeding when hemorrhage occurs into:

a. the epidural space.

b. the subdural space.

Often old people’s brains shrink a little and if they fall on their head, they’ll tear the cerebral  vein and get a subdural hematoma. 

c. the subarachnoid space.

10. Describe or label on a diagram the position of origin of the cranial nerves on the surface of the brain.

Refer to Netter’s 

11. Discuss the circulation of the cerebrospinal fluid.

CSF produced by choroid plexuses of third, fourth, and lateral ventricles.  Passes from ventricles  to subarachnoid space by passing through median and lateral apertures of fourth ventricle.  Main  absorption of CSF is at arachnoid granulations. 

12. State the boundaries of the three cranial fossae and the major parts of the brain  occupying each fossa.

Three cranial fossae: anterior, middle, posterior. 

Boundary between anterior and middle is sphenoid ridges and anterior border of  chiasmatic sulcus. 

Boundary between middle and posterior is petrous ridges and dorsum sellae What parts of brain are in which fossae? 

Anterior fossae: frontal lobes.  Middle: temporal lobes and pituitary gland.  Posterior:  cerebellum, pons, medulla oblongata.

13. Name the major openings in each of the cranial fossae and the structures that traverse  them.

Anterior fossae: frontal emissary vein goes through foramen cecum.  Olfactory nerve filaments  go through cribriform plate of ethmoid 

Middle fossa: Optic canaloptic nerve and ophthalmic artery.  Superior Orbital  fissureOphthalmic vein, Ophthalmic Division of CN V, Oculomotor Nerve (CN III), Trochlear  (CN IV), Abducens (CN VI).  Foramen RotundumMaxillary division of CN V, Foramen  OvaleManidbular division of CN V.  Foramen spinosumMiddle meningeal artery.  Foramen  lacerum (defect in roof of carotid canal that covers anterior opening of carotid canal) 

Posterior fossa:  Internal Acoustic MeatusFacial Nerve (CN VII), Vestibulocochlear Nerve (CN VIII), Labyrinthine artery.  Jugular ForamenGlossopharyngeal nerve (CN IX), Vagus (CN X),  Accessory nerve (CN XI), Inferior Petrosal Sinus, Sigmoid Sinus.  Hypoglossal  CanalHypoglossal nerve (CN XII).  Foramen MagnumBrainstem, Vertebral Arteries, Spinal  roots of accessory nerves (CN XI), venous plexuses, meninges, CSF 

14. Label a diagram of a cross section of the cavernous sinus showing all structures within  and in direct contact with the sinus.

See Handout page 10 

15. By the end of this module, be able to list the venous connections of the cavernous sinus  and explain the symptoms and signs associated with cavernous sinus thrombosis.

See Handout page 11 

Symptoms of cavernous sinus thrombosis:  

Edema of conjunctiva and generalized orbital swelling, pain in orbit and forehead,  diplopia (double vision), Loss of pupillary light reflex, fever and disorientation 

16. Describe the trigeminal ganglion, its location and it meningeal relationships.

Trigeminal ganglion: location of cell bodies of most afferent fibers in trigeminal nerve.  It is  inside trigeminal cave (diverticulum of dura and arachnoid after petrous ridge) 

 (before it branches, it’s the trigeminal ganglion with lots of afferent for sense of head and no  synapses) 

17. Describe the composition of the trigeminal nerve and its division into three major  branches and know the site of exit of each of these branches from the cranial cavity.

Three divisions: Ophthalmic (leaves at superior orbital fissure), Maxillary (leaves at foramen  rotundum), Mandibular (leaves at foramen ovale)

Trigeminal Nerve 

Comes off pons (two fiber types: afferent—sensory for head, some efferent to skeletal) Goes into diverticulum, branches into… 

(before it branches, it’s the trigeminal ganglion with lots of afferent for sense of  head and no synapses) 

All e to skeletal go to sensory region of face 

**Slide 21 gives great visual of which branch of trigeminal is stimulated for each part of  face 

Day Two (M2M)

8:00­8:50—Cytogenetic and Mendelian Disorders

Objectives 

1. Describe the methods of chromosome analysis including karyotyping and FISH.

Karyotyping: chromosomes are exposed to proteolytic enzymes and buffers and stained with  various dyes, resulting in dark and light bands along chromosome.  Patterns of these bands are  specific to each pair of chromosomes and are dependent on base pair content of DNA. 

FISH: fluorescent in situ hybridization.  DNA probes adhere to specific regions on chromosomes to identify location and number in metaphase spreads or interphase cells.  Can identify  submicroscopic chromosome deletions or duplications, alterations in DNA sequence copy  number. 

Cytogenetics: study of chromosomes and abnormalities. 

Karyotyping: low resolution, good for chromosome number and translocations Nomenclature for gene starts at centromere and counts out (details on slide 10) 

Ex: 48, XX, +18, +21.  That means 48 total chromosomes, female, and an extra  18 and 21 

FISH: higher res, DNA probe can target any part of genome and check for  trisomies and see translocations. 

Flow Cytometry: sorts out individual chromosomes even higher res 

Sequencing: good for defined regions

Special Karyotyping (SKY): “chromosomal painting, very colorful chromosomes means lots of  translocations, a sign of cancer. 

Array CGH: cannot detect balanced translocations, can find gains and losses of DNA 

Sequencing: still very expensive, but SNP genotyping is cheaper to test inherited  conditions/ancestry/traits/wellness 

2. Chromosomal disorders:

Clinically significant chromosomal abnormalities seen in .7% live births and 5% stillbirths.  50% of fetuses that stillbirth in first trimester due to chromosomal abnormalities. About 13­15% of  birth defects are caused by chromosome changes or mutant genes. 

a. Recognize the clinical features of various chromosome disorders such as trisomy 21  (Down syndrome), trisomy 18 (Edwards syndrome), trisomy 13 (Patau syndrome),  monosomy X (Turner syndrome), XXY (Klinefelter syndrome).

Trisomy 21 (Down Syndrom) 

Problem: extra region of 21q22 gene. 

Survivable, but intellectural and physical impairments 

Edwards (trisomy 18): only live to 2mos­2yrs 

Patau (trisomy 13): usually die within first year 

Turner syndrome: X0.  Missing important genes at end of X chromosome, we need both despite  Barr bodies 

Kleinfelter’s (XXY): Triple dose of PAR regions causes feminized male 

b. Explain the most common causes of chromosomal abnormalities.

Chromosomal abnormalities usually result from non­disjunction in female meiosis (a disjunction  in M2 is less severe than M1) Mechanism: cohesins depleted and tension of spindle not even  (theorized) 

c. Explain biparental inheritance

We must get one set of alleles from mother and one from father.  Receiving all alleles from one  parent results in termination of pregnancy because egg creates fetus and sperm creates placenta  and extra features. 

d. Recognize translocations (Robertsonian)

Translocation: transfer of piece of one chromosome to nonhomologous chromosome (not  necessarily abnormal development).  Translocations: part of non­homologous chromosomes get  switched

Problems: pairing up and separation can be wrong, unpaired regions, X inactivation Robertsonian Translocations: involve acrocentric chromosomes (13, 14, 15, 21, 22) Frequent combos are 13/14, 14/21, 14/15 

Long arms fuse together to become metacentric and tiny arms lost as a fragment 

May only have 45 chromosomes, but all genes are still present, so still normal  phenotype.  Problems occurs with new generation 

Can occur between homologs (balanced or unbalanced) 

These cause 4% of Down cases because 14/21 translocation gives extra 21 genes 

**REVIEW SLIDE 39 to see different combos and figure out outcomes.  **Need to  know** 

(one normal, one balanced carrier, one Down, three lethal) 

Take home message: recognize acrocentric.  Different from translocations, know the results of  crossing 

A person with Robertsonian translocation has 17% (10% clinically) chance of passing Down.   Classical Down is usually only .1­2% 

**See slide 44 for other examples of translocation disorders (cri­du­chat) 

3. Single gene disorders:

a. Recognize Mendelian inheritance patterns of clinical diseases and describe examples of  these inheritance patterns: autosomal recessive (e.g. Cystic fibrosis), autosomal dominant  (e.g. Achondroplasia), sex­linked recessive (e.g. Hemophilia), and sex­linked dominant (e.g.  Hypophosphatemia).

Single Gene Disorders 

a. Autosomal Recessive 

i. The affected patient is homozygous recessive (even distribution for  

gender).  Earlier onsets, more severe phenotypes.   

ii. Compound heterozygote: affected because 2 different mutations in 2  different alleles 

iii. Application: Cystic Fibrosis 

1. Problem: mutation in CFTR gene on Chromosome 7 (usually a  

Phe508 deletion).   

2. Manifests with clinical heterogeneity: different severity of  

phenotypes for different mutations

b. Autosomal Dominant 

i. Every affected individual has affected parent.  We see male­male  

transmission (unlike many other disorders) and very rare homozygous  

dominants (often this is lethal) 

ii. Application: Achondroplasia (dwarfism) 

1. Problem: mutation of fibroblast 3 receptor. 

2. Mechanism: cartilage abnormality because collagen is messed  

up 

c. Loss of heterozygosity 

i. Breast cancer: inactivation in 2nd allele of BRCA means someone  

becomes a compound heterozygote and expresses the disease 

d. X linked recessive (hemophilia)=usually just in males 

e. X linked dominant= daughters of affected male always affected 

f. ***Good pedigrees for practice on Slide 61 

b. Recognize the difference between expressivity and penetrance with clinical examples  (e.g. Polydactyly).

Expressivity: same genetic mutation associated with phenotypic spectrum in different individuals (environment may have affect or other characteristics) 

Penetrance: proportion of individuals with mutant genotype that express phenotype.  If not all  carriers of mutant express a phenotype, then it is incomplete. 

Penetrance: frequency of expression of allele when it’s present (how dominant something is— will I express it if I have it?)  Population based 

Expressivity: variation of expression in individual for penetrant allele (severity) 

Application: Polydactyly: Parent may carry dominant allele but not be penetrant.  Expressivity is  also varied (6 toes vs 8) 

c. Using clinical examples, describe the genetic basis of phenotypic/clinical heterogeneity  (e.g. Cystic Fibrosis) and penetrance (e.g. Polydactyly).

Application: Cystic Fibrosis 

Problem: mutation in CFTR gene on Chromosome 7 (usually a Phe508 deletion).   

Manifests with clinical heterogeneity: different severity of phenotypes for different  mutations 

Application: Polydactyly: Parent may carry dominant allele but not be penetrant.  Expressivity is  also varied (6 toes vs 8)

9:00­9:50—Population Genetics & Hardy­Weinberg Equilibrium Objectives

1. Define gene frequencies and their significance in clinical practice.

Gene frequencies: how often a gene is present in given population.  studied through population  genetics, vital in clinical practice since principle of genetic medicine is counseling and  calculating recurrence risks. 

2. Explain the principle of Hardy­Weinberg equilibrium.

Hardy­Weinberg: principle for predicting genotype and allele frequencies in population given  following assumptions:  Population has random mating, population infinite in size, population  under no selection (all genotypes have same viability), population is stable without new  mutations, migration or genetic drift. 

Allelic frequencies will remain constant in population from generation to next  (equilibrium).  p+q=1, p^2 + 2pq + q^2 = 1  

P: frequency of dominant allele 

Q: frequency of recessive allele 

P^2: percentage of homozygous dominant 

Q^2: percentage of homozygous recessive 

2pq: percentage of heterozygous 

3. Recognize factors that disrupt this equilibrium in populations.

If the assumptions are not met, then equilibrium will be disrupted.  Equilibrium very rarely exists in nature. 

4. Test whether populations are in equilibrium using the Hardy­Weinberg equation. Slide 8: AA=20, Aa=30, aa=50 

P=[(2*20)+(1*30)]/200=.35 (p^2=.1225).  But the measured p is .2 so not equilibrium **Look at Practice Problems (8/10 TBL material)

10:00­11:50—Non­Mendelian Genetic Disorders

Objectives

1. Differentiate non­Mendelian genetic diseases from Mendelian genetic diseases with  clinical examples.

Mendelian genetic diseases have simple inheritance patterns, often from only one gene  (autosomal recessive/dominant, sex linked recessive/dominant), but non­Mendelian diseases are  more complex.  Examples: multifactorial inheritance, extranuclear inheritance (mitochondria),  genomic imprinting, mosaicism, triplet repeat disorders. 

2. Differentiate dominant inheritance patterns from mitochondrial inheritance.

Mitochondrial inheritance is uniparental: only the female parent passes down her mitochondria.   Both parents pass them down, but the parental mitochondria are tagged for ubiquitination and  degradation. 

37 genes in circular mitochondrial DNA 

Heteroplasmy: different mitochondria in cell have different DNA, you can pass on different % of each mitochondria which can change severity of disease (eggs have about 100,000 mitochondria  each with 2­10 copies of DNA).   

Males/females affected equally 

**Clinical Applications on Slide 20 

Slide 23 answer: both (any mutant mitochondria makes someone a carrier via heteroplasmy) 

3. Explain multifactorial inheritance (genetic and environmental effects) and its  significance to clinical practice.

Multifactorial inheritance: complex or polygenic inheritance where many factors cause disease,  including environment and mutations in multiple genes.  Examples: heart disease, Alzheimer’s,  diabetes, cancer.  Many non­disease traits are also multifactorial (eye/hair/skin color,  fingerprints, height).  They involve a strong genetic predisposition to push an individual beyond  “threshold risk” after which environment takes over About 25% birth defects are these.  Traits  are continuous (spectrum) or discontinuous (have it or don’t) 

Genetics pushes you to a “threshold risk” and environment determines if you pass that threshold 

Ex: cleft palate is predisposed by genetics and exacerbated by smoking/alc during  pregnancy 

Hallmarks: normal parents, risk increases if sibling with disorder, increased risk with increased  severity, increased risk with incest 

4. Explain the concept of uniparental disomy and genomic imprinting (inactivation by  methylation) using clinical diseases such as Prader­Willi and Angelman syndromes.

Uniparental inheritance: transmission of gene from one parent to all progeny.  Happens in  mitochondria (exclusively female parent)

Uniparental disomy: offspring receives two copies of chromosome from one parent and none  from other.  Can be random during fetal development or result of trisomic rescue.  

Genomic imprinting 

a. Silencing of genes via epigenetics (part of natural development, only about  1% of genes are imprinted) 

b. Inherited and maintained through mitosis 

i. BUT—during formation of gametes, imprinting is RESET and we pass on a new code depending on our gender (females pass on the maternal  

imprinting they inherited and males pass on the paternal, so we get a  

normal imprinting spectrum from mom and dad) 

c. One active copy of imprinted genes 

d. Clinical Applications 

i. Uniparental Disomy (2 copies from one parent, 0 from other) 

1. Can happen if trisomy has an early mitotic nondisjunction or  

monosomy duplicates itself 

ii. Prader­Willi 

1. Symptoms: low muscle tone, short stature, cognitive disability,  

constant hunger 

2. Problem: maternal UPD of chromosome 15 

3. Mechanism: 15q11­13 genes not expressed because that  

section of chromosome 15 is maternally imprinted 

iii. Angelman syndrome 

1. Problem: paternal UPD of chromosome 15 

2. Mechanism: genes on chromosome 15 are not expressed  

because their section is paternally imprinted 

5. Define the pathogenic mechanism of non­Mendelian genetic diseases such as triplet (tri nucleotide) repeat expansion diseases and genomic imprinting.

Trinucleotide repeat disorders: genetic disorders caused by aberrant unstable and abnormal  expansions of DNA triplets.  Number of repeats exceeds normal number and can make genes  defective.  Show genetic anticipation (Sherman paradox), where severity increases with each  successive generation.  Larger the repeat, earlier the age­at­onset, like in Huntington’s. 

6. Distinguish major phenotypic differences between coding and non­coding triplet repeat  disorders using clinical disorders such as (1) Fragile X syndrome, FXTAS, and Myotonic  dystrophy (non­coding) and (2) Huntington’s disease (coding, concept of anticipation).

Clinical Applications: 

Fragile X

Symptoms: Intellectual disability 

Problem: CGG triplet repeat on FMR1 gene (over 200 repeats) 

Non­mendelian X­linked dominant (Sherman paradox/anticipation/dynamic mutations:  more affected throughout subsequent generations because more repeats.  Severity increases,  earlier onset) 

Mechanism: repeats are targeted for methylation and silenced 

FXTAS: adults with premutation for Fragile X 

Extra mRNAs clump in neurons 

Myotonic Dystrophy 

Normal CUG repeats about 3­5X, disease is 2000+, causing long RNAs to not be spliced  correctly 

Huntington’s (coding repeat disorder) 

Problem: repeat of CAG codes for excess glutamine 

Mechanism: buildup of glutamine clogs neurons, degenerative basal ganglia destroyed.   Defective autophagosomes don’t bring cell waste to lysosome 

Normal repeats: 10­26, Disease: 40+ (Sherman paradox present) 

Day 3 (M2M)

9:30­10:30—Basic Tissues

Objectives

1. Define the primary functions of epithelium.

Functions: protective barrier, regulation of exchange of molecules between compartments,  synthesis and secretion of glandular products Covers and lines, separating inside and outside.   Lines all ports of entry into our body to serve as a barrier 

2. List the major characteristics of all epithelia in general.

All characterized by production of keratin intermediate filaments.  Development: ectoderm and  endoderm (lining of tubes)  Lots of cells adhered to each other.  To identify: look for free space  (outside), epithelium is next to it.  Very little extracellular space around the cells, little room to  

secrete.  They rest on a basement membrane that anchors epithelium to underlying tissue and  separates it from connective tissue, which is good because if something happens to it, it doesn’t  infect the connective tissue.  They are all polarized (one side faces basement membrane: basal, 

one side faces outward: apical) Avascular—has to get nutrients from loose connective tissue.   Unmyelinated nerve endings 

3. List the major types of epithelium based on cell shape and number of cell layers. **See table 5.1 in Wheater’s 

Surface epithelia—cover/line all body surfaces, cavities, and tubes.  Form interface between  different biological compartments.  They form continuous sheets of one or more cell layers 

Glandular epithelia—involved in secretion and arranged into glands (invaginations of epithelial  surfaces) 

Simple epithelia—surface epithelia of one layer of cells.  Used for diffusion, absorption, and/or  secretion.  Little protection (can range in shape of cell) 

Ex: simple flat in alveoli, simple cuboidal in kidney, simple columnar in digestion Stratified epithelia—two or more cell layers.  Protective, bad for absorption/secretion Squamous: flat (width greater that height), semi­permeable 

Cuboidal: width equals height, walls of ducts 

Columnar: height greater than width, absorbs and secretes 

Simple: one layer of cells 

Stratified: 2+ layers of cells 

If stratified, classify shape based on the majority of cells near the free (apical) surface,  not the underlying ones.  Basal cells will eventually become apical, but the apical ones are  actually functioning. 

Pseudostratified columnar: all cells are actually on basement layer but sandwiched between each  other in varying lengths, so it looks layered 

Transitional: can change shape (flatten or expand), bladder 

4. Define "endothelium" and "mesothelium", including their locations within the body and embryological derivation.

Endothelium—in blood vessels 

Mesothelium—lines body cavities 

**these both come from mesoderm and are NOT connected to outside world.  They have a  different protein, vimentin.  When cancerous, called sarcoma, not carcinoma 

5. Describe the basement membrane in terms of its structure and its relationship to an  epithelium and the underlying loose connective tissue.

Provides structural support for epithelium and is a selective barrier to passage into supporting  tissue.  The basement membrane is bound to the cell by hemidesmosomes, linking the  intermediate filaments. 

**Visual of parts on Slide 11 

Basal lamina: lamina lucida + lamina densa (type IV collagen and laminin proteins) 

Reticular lamina: produced by loose connective tissue.  Fine meshwork of collagen.   Connects to anchoring fiber (collagen VII).  Made of type III. 

6. List the four major types of cell­to­cell junctions and the primary proteins associated  with each.

Tight junction—claudins, occludins, tricellulin 

Adhering belt—classic cadherins, catenins 

Desmosome—Cadherins 

Hemidesmosome—Integrins, Laminins of basement membrane 

Gap junctions—Connexins 

7. Define the purpose of basal infoldings within which are mitochondria. Epithelia are polar in three layers: Apical, Lateral, Basal 

Apical: secretes, absorbs.  Lateral:  cell junctions, prevent stuff from entering.   Basal: transport with connective tissue 

8. Describe the structure of motile and nonmotile cilia and of microtubules and correlated  structure with the function of these structures.

Motile: project from apical surfaces of epithelial cells (respiratory and female reproductive), beat in wave­like rhythm to propel mucus or fluid.  Each bound by plasma membrane, has central  core (axoneme).  In motile, the axoneme is 20 microtubules in central doublet surrounded by 9  peripheral doublets linked by nexin and radial spokes to center. 

Non­motile: central doublet, nexin links, and radial spokes absent.  Microtubule doublets are  continuous with basal body (nine microtubule triplets) 

9. Describe the structure and function of microvilli.

Finger­like projections of plasma membrane in epithelium, especially for absorption.  About .5­1 micrometer in length (short compared to cilia).  Cytoplasmic core with parallel bundles of actin  under cell surface.  Actin is tightly packed in a hexagon and glued together by actin binding  proteins (ex: villin).  Microfilaments at ends of microvilli mediate contraction, elongation, and  stability.

10. Define exocrine versus endocrine glands. Define holocrine versus apocrine versus  merocrine secretion.

Exocrine—contain ducts, release onto epithelial surface 

Endocrine—no duct to epithelial surface, release directly into blood. 

Holocrine—discharge of whole secretory cells and disintegration of the cells releases secretory  product.  Ex: sebaceous glands 

Apocrine—discharge free, unbroken, membrane­bound vesicles containing secretory product  (unusual, ex: lipid secretion in breasts and some sweat glands) 

Merocrine—process of exocytosis, most common form of secretion.  Usually proteins secreted. Connective Tissue

1. Define "connective tissue" relative to the other basic tissues.

Connective tissue: tissue which provides general structure, mechanical strength, space filling  (sculpts body shape), and physical/metabolic support for specialized tissues. 

2. Describe extracellular matrix components of connective tissues.

Extracellular matrix has three components: 

Tensile strength: resists stretch/tear, provided by collagen family Collagen: 28 types!   Most abundant protein in body.  Type I is light pink in between fibroblasts (looks like bacon).   **KNOW the collagens on slide 23 (I=skin/bone/CT, II= cartilage, III=hematopoetic, IV and  VII= basement) 

Elasticity: bounce back after distortion, provided by elastin fibrils (rubbery) 

Volume: bulk, substance, provided by glycoproteins and complex carbohydrates that bind water to form Ground substance: amorphous transparent material like semi­solid gel.Provides  volume, compression resistance, turgor.  Control passage of molecules and cells through tissue  and exchange metabolites with circulatory system. 

3. Define the three major types of connective tissue. Describe the primary function of each  type.

 Loose connective tissue—underneath basement layer, more cells and less fibers 

Dense connective tissue—fewer cells, more fibers.  Can be regular (directional like in ligaments  and tendons that carry force in one direction) or irregular (non­directional, like in hands to  withstand stress from all directions)

4. List and describe the major morphologic features of connective tissue cells.

Fibroblast: light staining, egg shaped nucleus, very active (lots of euchromatin), produce lots of  collagen 

Fibrocyte: fibroblasts that aren’t doing stuff anymore.  If there’s a wound, they can  dedifferentiate back to blast.  Dark staining, scrunched up 

Lymphocyte: dense stain, small strong nucleus, little cytoplasm 

Eosinophil: bilobed nucleus, red granules 

Macrophage: huge nucleus, cytoplasm has chucky lysosomes 

Plasma cell: B­cellsplasmaantibodies.  Looks for eccentric nucleus with peripheral  heterochromatin, giving it a “clock­like” appearance. 

Adipocyte: filled with vacuole of fat that pushes nucleus to one side 

5. List the major types of specialized connective tissues.

Specializations: 

Keratinized: nuclei start to disappear (dead), all that’s left is keratin protein, used to protect like  in the palms and soles of feet 

Specialized CT 

Adipose: fat.  Can be unilocular (white fat, one vacuole, peripheral nuclei) or multilocular  (brown fat, more vacuoles, central nuclei) 

Reticular: spongy mesh netweork that lymphocytes go through 

Elastic: Elastin + fibrillin gives lots of stretch!  Aorta 

Cartilage: glassy appearance, dense perichondrium around chondrocytes in nests.  Hyaline is  type II, Fibrocartilage is type I and II, Elastic cartilage is elastin and type II. 

Bone: compact and cancellous (spongy).  Cancellous has trabeculae with bone marrow in  between.  The outside is the periosteum, inside is endosteum. 

6. Define "endothelium", "mesothelium" and "synovium", including their locations within  the body and embryological derivation.

**see epithelium objectives 

10:30­11:50—Tissue Adaptations

Objectives

1. Define the cell cycle and the basic principles that underlie its control

Cell cycle:  cytokinase, cytokinase inhibitors, clinical importance of proteins, cyclin, RB protein  controls cycle.  Cells can go round and round or differentiate or rest in G0. (See 8/7 M2M notes  for more details) 

2. Classify cell populations according to their capacity for cell division

Permanent cells: don’t divide, left cell cycle (terminally differentiated, cannot go back) (muscles, neurons) 

Stable cells: in G0, can be stimulated to enter G1 and undergo cell cycle, but go back to G0 if not needed. (hepatocytes) 

Labile cells: continuous cycling (skin, GI) 

Stem cells: Totipotent—totally potent, Embryonic stem cells can become anything.  Pluripotent —limited capacity to give rise to different types (ex: hematopoetic stem) 

For our purposes, there are no stem cells for heart, skeletal muscle, or neurons.  If  we lose these, they’re gone forever. 

3. Define atrophy, hypertrophy and hyperplasia.

Atrophy: decrease in cell size, causes decrease in organ size. 

Hypertrophy: increase in cell size, causes increase in organ size 

Hyperplasia: increase in cell number leads to increase in organ size 

4. Explain how atrophy, hypertrophy and hyperplasia of cells contribute to atrophy or hypertrophy of tissues and organs.

Atrophy: cell size decreases or cell death occurs by necrosis/apoptosis.  Applies to cell, tissue,  and organ level.  Cell sizes are irregular with some much smaller than others. 

Causes: low workload, low innervation, low blood supply, low nutrition, low endocrine  signals, duct obstruction 

Ex: low endocrine=less stimulation of prostate=atrophy 

Ex: Duct obstruction increases pressure behind duct, terminal acini of glands  atrophy organ (e.g. pancreas, saliva).   

Ex: aging causes sarcopenia (loss of flesh) 

Ex: Alzheimer’s atrophies frontal and parietal lobes so that sulci sink more and  gyri narrow.  Ischemia can cause a similar appearance. 

Ex: Thymus normally atrophies as we age because we need more immunity as  children than in adulthood

Hypertrophy:  cells increase in size 

Causes: increased demand (pathology or physiology), increased hormones, subcellular  hypertrophy 

Ex: Heart size will increase with increased blood pressure to pump harder Ex: uterus gets giant in pregnancy due to hormones (hypertrophy and hyperplasia) 

Ex: subcellular hypertrophy of organelles in phenobarbital liver because SER gets huge to metabolize lots of drug use 

Hyperplasia: increase cell number 

Ex: menstrual cycle, increase endometrial lining 

5. Define metaplasia.

One adult cell replaced by another adult cell type 

Ex: acid reflux kills lower esophageal squamous epithelium, so it’s replaced by gastric  epithelium 

6. Explain how metaplasia occurs.

Result of pathological stimulus that induces hyperplasia of stem cells in tissue followed by  differentiation to vicarious cell type (replacement). 

Barret’s metaplasia: squamous becomes columnar 

Squamous metaplasia: columnar becomes squamous.  Smoking will spur this as squamous from  underneath can more easily survive toxins. (Slide 40 great visual) 

This replacement can be a precursor to cancers, especially lung and cervical 

7. Use common examples to illustrate physiological and pathological causes of atrophy, hypertrophy, hyperplasia and metaplasia.

(See Question 4) 

Day 3 (Clinical Skills)

12:50­2:30—Vital Signs, HPI

Objectives

1.  Describe the general appearance of the patient using appropriate vocabulary HPI: History of Present Illness

1. Apparent state of health 

General judgement based on observations throughout encounter.  Significant supporting details. 

Skin, clothing, hair to determine length of sickness.  Well­kempt (description should let  other person pick them out from a room) 

2. Level of consciousness 

Awake, alert, responsive or not 

3. Signs of distress 

Cardiac/respiratory distress, Pain, Anxiety, depression, stress 

4. Body habitus and weight 

Remove shoes, determine BMI.  Notes changes over time.  Usually short/tall, build of body,  symmetry, proportions, where weight lies on body 

5. Skin color and obvious lesions 

Inspect for strange skin color, scars, plaques, nevi 

6. Dress, grooming, personal hygiene, odors of body or breath 

Hygiene, acetone breath for diabetes, alcohol breath, suitable clothing for weather, clean,  appropriate, shoe quality, unusual jewelry or piercings.  Hair=grooming, length of disease,  lifestyle, personality 

7. Facial expressions 

Observe at rest and in conversation.  Eye contact, natural? Sustained and unblinking? Averted?  Absent? 

8. Posture, gait, and motor activity 

Preferred posture, restless, quiet, frequency of changing position, involuntary motor activity,  immobile body parts, walk/limp, style of walking (confident, fear, hesitance) 

Comprehensive assessments: for new patients in office/hospital, fundamental knowledge, good  relationship builder, baseline, skill building for when need to do focused 

Components of history: identifying data, reliability, source of data, complaints, past,  family, personal/social, review of systems (fluid order)

Identifying: age, gender, marital, occupation (source can be them, fam, record) Reliability: dependent on mood, ambiguity 

Complaints: try to keep in patient’s own words 

Present illness: each symptom should have seven attributes—location, quality,  quantity/severity, timing (onset, duration, frequency), setting, aggravating factors, associated  manifestations (OLDCARTS).  Note current medications, allergies, toxin use 

Past history: childhood and past adult illness (medical, surgical, ob/gyn, psych),  immunizaitons 

Family history: present/absent diseases, deaths 

Personal/Social: education, personality, coping style, concerns, stress, finance,  religious, culture, lifestyle 

Review of Systems: overview with patients on whole body (uncovers what we  overlook)  **Table in Bate’s pg 12** 

Focused assessments: for established patients, urgency, focus on concerns/symptoms, specific  area/body system, relevant for target problem 

Subjective data: what patient tells you (symptoms and history) 

Objective data: what you detect (lab tests, physical examination) 

2.  Measure the vital signs – blood pressure, heart rate, respiratory rate, and temperature

Blood pressure: arm at heart level, cuff and stethoscope correctly positioned (not required to  report).  Person sitting in chair with feet flat on floor.  Width of bladder of cuff should be 40% of upper arm circumference.  Length 80% circumference.  Lower border of cuff about 2.5 cm above antecubital crease. Too small?  Blood pressure will read high.  Too large? BP reads low.  Put  over brachial artery, about 1.5 cm above medial epicondyle.  First sounds=systolic, no more  sounds=diastolic.  Sometimes sounds will go away between these, so we can actually palpate  blood pressure instead of listening to it.

Normal is less than 120/80.  Prehyp 120­139/80­89, hypertension is more than or equal to 140/90 

Heart rate: radial artery for 15 seconds (don’t have to report).  Check on both sides for  symmetry.  Normal is 50­90bpm.

Heart sounds in stethoscope: diaphragm is better for high­pitched sounds of s1 and s2,  murmurs of aortic and mitral regurgitation, and pericardial friction rubs.  Bell is more sensitive  to low pitch sounds (s3 and s4)

Respiratory rate: 15 seconds, be sneaky so the patient doesn’t become conscious of breathing  rate (don’t have to report).  Normal is 14­18 

Temperature: sublingual thermometer 

Pyrexia: elevated temp, hyperpyrexia: extreme elevation (more than 106), hypothermia:  low temp (below 95) 

3.  Correlate your knowledge of anatomy as you perform the physical exam 4.  Demonstrate the proper method for performing orthostatic blood pressures Orthostatic: supine, sitting, and standing (3 minutes between) measurements of blood pressure 

If the systolic falls by 20 mmHg or diastolic by 10mmHg in these transitions, orthostatic  hypotension. 

5.  Ask the HPI questions using the mnemonic OLD CARTS+

Onset, Location, Duration, Character, Aggravating/Alleviating, Radiation/Relieving, Timing,  Severity +Associated symptoms 

Day 4 (M2M)

8:00­9:50—Genetics Group Problem Set

Objectives

(For these, see TBL practice problem powerpoint for answers and practice) 

1. Apply the principles of population genetics with particular reference to the concept of  Hardy­Weinberg equilibrium.

2. Apply Hardy­Weinberg equilibrium to resolve genetic conditions and calculate gene  frequencies.

3. Calculate risk values based on gene/disease frequencies in a given population 10:00­11:50—Histopathology Lab: Basic Tissues 1

Objectives (11­19 not covered in Lab, must find on own or may be in subsequent  Labs)

1. Explain the difference basophilic and acidophilic staining, citing examples of each using  hematoxylin & eosin staining of tissues.

Hema: affinity for acid, stains DNA/RNA, blue

Eosin: affinity for base, stains other cell parts, pink 

 2. Classify and identify the major types of epithelia.

Shapes: squamous (flat), cuboidal, columnar. 

Simple: one layer of cells 

Stratified: 2+ layers of cells 

Simple squamous: needed for exchange (alveoli, nephron), Simple cuboidal: smaller ducts of  exocrine glands (ducts, thyroid, ovarian follicles, nephron), Stratified cuboidal: (ovarian follicles, ducts), Simple columnar: absorption (GI, kidney), Transitional: changes shape to  expand/contract (bladder), Pseudostratified columnar: single layer but bodies sandwich between  each other (respiratory, vas deferens), Stratified columnar: (ducts of large glands), Stratified  squamous: protection (skin, oral cavity, anal cavity) 

 3. Describe mucous vs. serous glands.

Glands—extensions of surface epithelium during embryogenesis.  Exocrine or endocrine. Serous: secrete watery protein­rich product.  Stain well with H&E 

Mucous: secrete thick mucous product.  Do not stain well with H&E.  Mucus is too difficult to  pass between cells so no demilunes. 

Combo of seromucous also present. 

 4. Identify major specializations of the apical surface of epithelia including cilia, stereocilia and microvilli.

Motile: project from apical surfaces of epithelial cells (respiratory and female reproductive), beat in wave­like rhythm to propel mucus or fluid.  Each bound by plasma membrane, has central  core (axoneme).  In motile, the axoneme is 20 microtubules in central doublet surrounded by 9  peripheral doublets linked by nexin and radial spokes to center. 

Non­motile: central doublet, nexin links, and radial spokes absent.  Microtubule doublets are  continuous with basal body (nine microtubule triplets).  Involved in mechanosensory function,  allowing cell to monitor environment.  Proteins polycystin 1 and 2 help them do this (form  calcium channel).  Fibrocystin protein.  Passively bent by motion of fluid 

Microvilli: Finger­like projections of plasma membrane in epithelium, especially for absorption.  About .5­1 micrometer in length (short compared to cilia).  Cytoplasmic core with parallel  bundles of actin under cell surface.  Actin is tightly packed in a hexagon and glued together by  actin binding proteins (ex: villin).  Microfilaments at ends of microvilli mediate contraction,  elongation, and stability.  Embedded in glycoprotein­rick matrix called glycocalyx, helps to trap  substances.

 5. Identify the location of the basement membrane found between all epithelia and the  underlying loose CT.

Sometimes thick and sometimes not visible, but there will always be a basement membrane in  between epithelial layers and loose CT.  Notable because no nuclei 

 6. Compare and contrast the major types of connective tissue (loose, dense regular and  dense irregular CT).

Loose: more cells (fibroblasts and fibrocytes), fewer fibers.  Different cells present depending on function (ex: leukocytes for immune function).  Highly vascular.  Supports. 

Dense irregular: fewer cells, more fibers.  Non directional, provides tensile strength in many  directions.  Dense with collagen (type I mostly).  Cells present are fibrocytes 

Dense regular: fewer cells, more fibers.  Directionality to fibers (tendons and ligaments) give  pull in certain direction.  Type I collagen, Cells present mostly fibrocytes.  No capsule of CT 

 7. Describe the major types of specialized connective tissues including reticular and elastic  tissues.

Adipose, Blood Cells, Cartilage, Bone, Lymphatic Tissue 

Reticular fibers: collagen type III, crosslink to form fine meshwork (lymph tissues, bone marrow, liver) 

Elastic tissues: comprised of elastin and fibrillin.  Stretchy, recoil.  Important for arteries, lungs,  skin, bladder.  Fibrillin secreted by fibroblasts to make scaffold for elastin.  Fibrillin 1 for  microfibril sheath 

 8. Describe the microscopic appearance of adipose tissues.

Two types: white and brown.  White stores energy in triglycerides, brown is for body heat.   Adipocytes don’t stain well, have giant vacuole for fat and nucleus pushed to side (unilocular,  white).  Brown cells stain a little better and nucleui round and centered.  Multiple small vacuoles  (multilocular) 

 9. Describe the microscopic appearance of hyaline cartilage and of bone. Hyaline: surround capsule with cell inside.  Glassy. 

Bone: osteocytes within lacunae and interact via canaliculi.  Osteoblasts make endosteum to  cover trabecula.  Osteoclasts: large multinucleated cells derived from monocytes.  Lots of  lysosomes for bone resorption.  Located in depressions called “Howship’s lacunae” along  surface of bone 

10. Identify and provide the primary function(s) of the following:

▪ Fibroblast

Synthesize collagen, elastin, and GAGs.  Elongated with body projections (kind of like a star).   Hard to see cell body in H&E staining, identified by egg shaped nuclei (light staining bc lots of  euchromatin) 

▪ Fibrocyte

Inactive structure cells.  Nucleus is thin, dense stained, heterochromatic 

▪ Lymphocyte

T and B, migratory, in loose CT, greater number during inflammation, plasma cells come from B lymphocytes.  Small cell with round dark nucleus and thin cytoplasm 

▪ Plasma cell

Homogenously basophilic cytoplasm, small cell, eccentric nucleus, abundant RER, “clock  faced”, produces antibodies, derived from B lymphocytes 

▪ Macrophage

Phagolysosomes (junky cytoplasm), large cell, large light stained nucleus, derived from  monocytes, phagocytic, larger number during inflammation, can fuse to form multinucleated  giant cells 

▪ Eosinophil

Cytoplasmic granules, bilobed nucleus, common in lung interstitium, come from circulating  eosinophils, associated with parasitic infection 

▪ Neutrophil

Cytoplasmic granules, trilobed nucleus, rare in loose CT, from circulating neutrophils, larger  number in acute inflammation 

▪ Chondroblast

Synthesize elastin present in matrix of elastic cartilage 

▪ Chondrocyte

Inactive chrondroblast 

▪ Osteoblast

Synthesize bone 

▪ Osteocyte

Osteoblasts surround themselves with matrix to become inactive osteocytes (bone cells)

▪ Osteoclast

Osteoclasts: large multinucleated cells derived from monocytes.  Lots of lysosomes for bone  resorption.  Located in depressions called “Howship’s lacunae” along surface of bone 

11. Identify each of the three types of muscle. Compare and contrast each from the other  two.

Skeletal: Striated

Cardiac: Striated

Smooth: not striated

12. Identify each of the following in a typical neuron (e.g., spinal cord multipolar neuron): ▪ ▪ ▪ ▪  Nucleus   Prominent nucleolus   Nissl substance   Dendrites

13. Identify the following in an H&E stained peripheral nerve:

▪ ▪ ▪ ▪  Axon   Myelin sheath   Endoneurium   Perineurium

14. Identify the following in an osmium­stained peripheral nerve:

▪ ▪ ▪ ▪ ▪  Axon   Myelin sheath   Node of Ranvier   Incisures of Schmidt­Lanterman    Endoneurium

15. Describe the microscopic appearance of nerve degeneration as well as skeletal muscle  denervation.

16. Describe the microscopic appearance of perineural (cancer cell) invasion and explain  the clinical significance of this pathology.

17. Identify hyperplasia using the nongravid vs. gravid mammary gland as an example.

18. Compare and contrast the microscopic appearance of hyperplasia (as seen in the gravid mammary gland) with hypertrophy (as seen in congestive heart failure).

19. Identify squamous metaplasia, contrasting this change with the normal lining of  airways in the lung (pseudostratified columnar epithelium with cilia).

Day 4 (LOM)

1:00­1:50—Session: Development of Central Nervous System

Objectives

1. Describe the formation of the neural tube and know when it occurs.

Neural plate forms at day 18 from area of ectoderm rostral to primitive streak.  This is induced  by notochord and mesoderm and will give rise to neural tube and neural crest.  End of  3rd/beginning of 4th week: groove deepens and neural folds approach each other in midline, fuse  to form neural tube.  Fuse happens in cervical region and expands outward cranially and caudally and finishes about the end of the 3rd week with open ends (two neuropores—cranial and caudal).  The lamina terminalis is remnant of cranial neuropore. 

TubeCNS.  Tubular wall is spinal cord/brain, tubular lumen is central canal and  ventricular system The neural tube in the spinal cord: wall becomes cord, lumen becomes central canal (which disappears) 

In the brain:  wall becomes brain, lumen becomes ventricles 

 2. Name the derivatives of the neural crest.

Dorsal root ganglia, cranial sensory ganglia, sympathetic chain ganglia, prevertebral sympathetic ganglia, parasympathetic autonomic ganglia, schwann cells of PNS, capsule (satellite) cells on  cell bodies of spinal ganglia, melanocytes, chromaffin cells including adrenal medulla, skeletal  structures originating from pharyngeal arches, portions of teeth, cells of pia and arachnoid 

(**Know derivatives, slide 10) 

 3. Describe the formation of the mature spinal cord:

A. List the three zones associated with differentiation of the neural tube wall.

Ventricular zone: first, neuroepithelial cells lead to all neurons and macroglial cells of spinal  cord (neuroblastsmigrate to form intermediate zonegray matter, axonsmarginal zonewhite  matter, glioblasts­­>intermediate zoneastrocytes/oligodendrocytes aka macroglia, ependymal  cells) 

Intermediate (mantle) zone: neuroblasts come here to form gray matter.  Glioblasts come here to  form astrocytes and oligodendrocytes (myelinate axons in CNS) 

Marginal zone: axons move here to form white matter 

B. List the derivatives of the neuroepithelial cells of the neural tube wall.

neuroepithelial cells lead to all neurons and macroglial cells of spinal cord (neuroblastsmigrate  to form intermediate zonegray matter, axonsmarginal zonewhite matter, glioblasts­­ >intermediate zoneastrocytes/oligodendrocytes aka macroglia, ependymal cells) 

In the ventricular layer are neural epithelial cells.  These span into the mantle layer to become  neurons and glial cells.  The glial cells further migrate to marginal layer to become 

oligodendrocytes (Schwann cell equivalent in CNS) and astrocytes (nutrition and  communication).  The neural epithelia cells that stay in the ventricular layer become ependymal  cells (these line the ventricles) 

C. List the components of the three zones after differentiation is complete.

Ventricular: neuroepithelial, ependymal.  Intermediate: neuroblasts, astrocytes, oligodendrocytes. Marginal: axons 

 4. Describe the relationship between the alar and basal plates and the sulcus limitans. Alar: sensory.  Basal: motor.  They are separated by sulcus limitans 

The mantle layer has a dorsal and ventral area.  Dorsal=alar (this becomes dorsal horn of spinal  cord and the sensory fibers).  Ventral=basal (this becomes ventral horn, motor fibers).  They  become the spinal cord at about 7­8 weeks. 

 5. Name derivatives of the alar and basal plates in the central nervous system. Alar: nuclei for sensory function, meet at midline to form cerebellum 

Basal: form nuclei for motor function 

 6. Know the caudal limit of the spinal cord of the 6­month fetus, newborn and adult. 6 month: S1, newborn: L3, adult: between L1 and L2 

 7. List the secondary brain vesicles and the primary vesicles from which they are derived. Primary: Prosencephelon (forebrain), Mesencephelon (midbrain), Rhombencephalon (hindbrain) Secondary: Telencephalon, Diencephelon, Mesencephalon, Metencephalon, Myelencephalon  8. List the major derivatives of the secondary brain vesicles.

TelCerebral hemispheres, DiThalami, Hypothalamus, Neural portion of pituitary.   Mesmidbrain, MetCerebellum, Pons.  MyeMedulla oblongata 

 9. List the various components of the ventricular system and describe their origin. Ventricular system develops from cephalic aspect of neural tube lumen. 

Fourth ventricle, Cerebral aqueduct, Third ventricle, lateral ventricles, interventricular foramina,  lateral apertures, median aperture, hydrocephalus (internal and external) 

10. Describe internal and external hydrocephalus and distinguish between them.

Internal: noncommunicating, hydrocephalus resulting from enlargement of all or part of  ventricular system because of obstruction of brain

External: communicating, hydrocephalus from obliteration of subarachnoid cisterns or  malfunction of arachnoid granulations. 

11. Describe the formation of the pituitary gland.

Derived from diencephalon.  Develops from two ectoderm sources: infundibulum  (neuroectoderm of diencephalon) and Rathke’s pouch (surface ectoderm of stomodeum: region  of oral cavity) 

12. Name the primary brain flexures and which one persists in the adult.

Midbrain (first to appear, persists in life), Pontine (second to appear, disappears), Cervical (last  to appear, disappears) 

13. List and describe the various types of spina bifida.

Spina bifida occulta: defect in vertebral arch only.  Associated with no neurological deficits.   Usually L5 or S1 vertebra in about 10% of population 

Spina bifida cystica: defect in vertebral arches and meninges or neural tissue protrudes through Spina bifida with meningocele: protruding meningeal sac only has CSF in it Spina bifida with meningomyelocele: also has spinal cord or nerve roots in sac Spina bifida with myeloschisis: spinal cord opens onto surface of body 

14. Compare and contrast the structures of the spinal cord and brain: A. Know what structures are derived from similar components of the neural tube and thus might be considered homologous.

The neural tube in the spinal cord: wall becomes cord, lumen becomes central canal (which  disappears) 

In the brain:  wall becomes brain, lumen becomes ventricles 

B. Know what features are unique to either the spinal cord or the brain. Unique to brain: vesicles of development, flexures, clinical malformations (encephalies) Unique to cord: layers, bifidas 

15. Describe meroanencephaly (anencephaly), meningoencephalocele, cranial meningocele and Arnold­Chiari malformation; be able to name the anomaly from a description.

Meroanencephaly: improper closing of rostral neuropore leads to abnormal development of  forebrain primordium.  Calvaria is defective and nervous tissue degenerates.  Rudimentary brain  stem.  Associated with excess amniotic fluid because fetus lacks control over swallowing. 

Meningoencephalocele: defect in cranium with herniation of meninges and part of brain 

Cranial meningocele: defect in cranium that meninges containing CSF protrude through 

Arnold­chiari: most common congenital anomaly involving cerebellum.  Herniation of parts of  medulla and cerebellum through foramen magnum into vertebral canal.  Causes communicating  hydrocephalus. Posterior fossa is small. 

Day 5 (M2M)

9:00­10:50—Synthesis Case: Maria Flores­Chow

1. Describe the duration of a normal pregnancy and list the common ways gestational  age is determined.

Normal gestation in humans is 40 weeks (280 days) from last menstrual period.

Gestational age determined during first prenatal visit.  Accuracy ensures management of  obstetric conditions like preterm labor, IUGR, and postdate pregnancy.  Determined by added 9  months 7 days to first day of last menstrual period.  Ultrasound can also determine gestational  age by measuring the fetal crown­rump length between 6 and 11 weeks.  At 12­20 weeks, age  determined within 10 days by average of measurements.  After 20 weeks, estimation is less  reliable. 

2. Define “advanced maternal age” and describe the general pattern of the maternal  age­related risk of having a baby with Down Syndrome or another chromosomal  abnormality.

Women older than 34 are at increased risk of giving birth to children with autosomal trisomies or sex chromosome abnormalities. 

3. Recognize and apply basic, standard reporting terminology used to describe  karyotype results.

When describing results, can characterize by number (trisomy, monosomy) or structure  (translocation, deletion).  Refer to arms as p (short) and q (long).  When reporting: total number  of chromosomes first, then sex chromosomes, then description of abnormalities.   Dup=duplication, del=deletion, t=translocation, der= balanced Robertsonian translocation, inv=  inverstion, r(X)= ring type X, i(X)= isochromosome

Ex: 48, XX, +18, +21 (48 total chromosomes, female, extra 18 and extra 21) 

46, XX, dup(5)(p14p15.3)= (Female with duplication of short arm of Chr 5 from  band p14 to p15.3) 

4. List, using standard karyotype reporting language, the different cytogenetic  abnormalities that result in what is clinically considered Down Syndrome.

95% of cases are due to meiotic non­disjunction of chromosomes that lead to 47 chromosomes  (extra copy of Chr 21).  4% of cases are due to unbalanced Robertsonian translocation between  Chr 21 and either 14, 15, or 22.  1% of cases are mosaic type (some cells have 47 chromosomes,  some have normal 46 as result of mitotic non­disjunction) 

1. List the physical characteristics of Down Syndrome.

Congenital heart disease (50%) including atrioventricular canal, ventriculoseptal, or atrioseptal  defects and valvular disease.  GI anomalies (10%) including duodenal atresia, annular pancreas,  and imperforate anus.  4­18% congenital hypothyroidism.  Polycythemia at birth, low leukemoid  reaction with elevated WBC (resolves). 

Decreased/poor muscle tone, short neck with excess skin at back, flat face and nose, small  head/ears/mouth, upward slanting eyes with skin fold from upper eyelid, white spots on iris,  wide short hands, single deep crease across palm, deep groove between first and second toes.   Slower overall development. 

Short attention span, poor judgment, impulsive behavior, slow learning, delayed language and  speech development. 

2. List the diseases and conditions for which people with Down Syndrome are at  increased lifetime risk.

Acquired hypothyroidism, increase risk of leukemia, susceptible to infection, cataracts, spinal  cord injury (from atlantoaxial instability of distance between C1 and C2).  Alzhemier­like  features.  Autism, gland/hormone problems, hearing loss, vision problems. 

Heart defects: 50% CHD, high blood pressure in lungs (cyanosis). 

Vision: 60% cataracts, near­sightedness, cross­eyed, rapid/involuntary movement of eye. Hearing loss: 70­75%.  Problems with ear structure, ear infections. 

Sleep disorders, gum disease, teeth problems, epilepsy, digestion problems, celiac, mental  health/emotional problems. 

3. List the testing methods used to identify Down Syndrome prenatally.

First tests to screen are non invasive: nuchal translucency, PPA, Quad test of mother’s blood (at  15­22 weeks)

If positive on first test, second round of diagnostic tests are more invasive:  amniocentesis, CVS 

Karyotyping will reveal if a fetus has trisomy 21 or a trisomy­like translocation of 21q22  resulting in the extra gene for Down syndrome. 

FISH (results faster than karyotyping) 

Microarray (more accurate than karyotyping, quicker) 

DNA testing: looks for specific gene mutations upon request (good for carriers) CVS: tissue taken from placenta as early as 10­13 weeks and quick results. 

“Quad” blood test done between 15­22 weeks to measure levels of four substances in blood to  screen for Down, Edward’s, and neural tube defects 

Cell­free DNA testing comes from DNA released from placenta into woman’s bloodstream.  Can test this at 10 weeks, 1 week for results.  Positive results should be followed by amniocentesis or  CVS (chorionic villus sampling) 

Screening of parent’s blood for carriers helpful before conception for genetic counseling. 

4. Define, compare, and be able to calculate sensitivity, specificity, positive predictive  value and negative predictive value given a clinical scenario.

Sensitivity: ability of a test to correctly identify patients with disease.  Sensitivity= true positives/ (true positives + false negatives).   

Specificity: ability of test to correctly identify patients without disease.  Specificity= true  negatives/ (true negatives + false positives).  Would rather test high sensitivity low specificity  (false positive), because still don’t have disease, just have to reconfirm with more testing. 

Positive predictive value: How likely is it that the patient has a disease if the result is positive?   PPV= True positives/ (true positives + false positives) 

Negative predictive value: How likely is it that patient doesn’t have disease if result is negative? NNV= True negatives/ (true negatives + false negatives) 

Sensitivity: find the truly sick people 

A sensitive test will cast a huge net where we find all the positive possible people Specificity: find the truly healthy people 

Screening tests should be highly sensitive (and low specificity if we have to) Diagnostic tests should be highly specific (and low sensitivity if we have to)

Timeline:  Screen first, get everybody who could possibly have it, then run more diagnostic  exams (get rid of the people who definitely don’t have it) 

Ex:  TB 

First test is a PPD (high sensitivity, low specificity).  Lots of false positives mean  people have to get further screening, but better than getting a false negative 

Second test is sputum or chest xray (high specificity, so we eliminate people who  don’t have it) 

Day 5 (LOM)

1:00­1:50—Session: The Face and Parotid Region

Objectives

1. Identify the regions of skin supplied by each of the three divisions of the trigeminal nerve and examples of specific nerves accomplishing this innervation.

V1 (branch one): Ophthalmic supraorbital region (middle of scalp to under nose knight’s helmet  dermatome) 

V2: maxillary infraorbital (giant mustache that goes to temples) 

V3: mandibular mental auriculotemporal (man’s beard area thru temples)  2. Name major muscles of facial expression and their innervation.

Innervation: CNVII (facial nerve) 

Groups of muscles: 

Scalp (epicranius): frontalis (wrinkles forehead and raises eyebrows), occipitalis (pulls  scalp posteriorly), galea aponeurotica (deepest layer of moveable scalp) 

Ears: auricular muscles 

Nose: Procerus (wrinkles nose), corrugator (draws eyebrows down and in).  These are the muscles people get botox in. 

Mouth: **zygomaticus major is a good landmark for facial artery elevators of upper lip  (zygomaticus major/minor, levator labii superioris), depressors of lower lips (depressor anguli  oris, depressor labii inferioris), others (orbicularis oris—closes lips/protrudes lips/compresses  against teeth, buccinator—compresses cheeks against teeth) 

Orbit: orbicularis oculi (closes eyelids, palpebral part forms part of eyelid)

Superficial neck muscle: platysma (depresses lower lip and corners of mouth, depresses  mandible) 

 3. Describe the course of the facial nerve and discuss testing for injury of this nerve.

Leaves brainstem, enters temporal bone via internal acoustic meatus.  Branches into greater  petrosal branch (goes to pterygopalatine ganglion) and chorda tympani branch (carries fibers to  tongue or submandibular).  Exits skull through stylomastoid foramen with only efferent to  skeletal. 

Clinical Application 

Bell’s Palsy (need to eliminate other reasons facial nerve could be paralyzed before  diagnosing) 

Problem: viral problem paralyzes facial nerve 

Symptoms: paralyzed face 

Tests: raise eyebrows, whistle, close eyes tightly 

 4. List the types of fibers found in the facial nerve and its major branches (and the cell  bodies of origin of these fibers) and the structures in which they terminate.

Fibers: Efferent to Skeletal Muscle (in facial motor nucleus of VII).  Terminates on facial  muscles, stylohyoid, posterior belly of digastric, stapedius 

Afferent (in geniculate ganglion).  Terminates on taste buds of anterior 2/3 of tongue via  chorda tympani nerve to linguinal nerve 

Preganglionic efferent (in superior salivatory nucleus).  Terminates on pterygopalatine  ganglion via greater petrosal nerve and submandibular ganglion via chorda tympani nerve to  linguinal nerve 

 5. List the principal nodes which receive lymph for the face and scalp and know how  lymph drains from these nodes to the bloodstream.

Submental: drains central lower gum, lip, chin, tongue to submandibular and deep cervical nodes 

Submandibular: drains anterior upper face (forehead, nose, upper lip, lateral lower lip, side of  tongue) to deep cervical nodes 

Buccal: drains cheek and suborbit to submandibular nodes 

Parotid: drains lateral face and scalp including forehead and eyelids into deep cervical nodes Retroauricular and occipital: drain posterior scalp into deep cervical nodes

BuccalSubmandibularSubmental 

Parotidretroauricular 

*Malignant cancers can spread via lymph pathways, so need to know what lymph vessels drains which part of face 

 6. Describe the arterial supply and venous drainage of the skin of the face and scalp.

Arteries: (Rounder and twistier paths) facial (comes from carotid, branches at neck/face,  terminates as angular artery), superficial temporal (terminal branch of external carotid, branches  off as transverse facial), occipital (from external carotid), ophthalmic (supraorbital and  supratrochlear), maxillary (terminal branch of external carotid, provides branches to muscles of  mastication, branches as infraorbital and mental) 

Veins: (highly variable person to person) facial, retromandibular (receives from superficial  temporal and maxillary veins, divides into anterior division to join facial vein and drain into  internal jugular and posterior division to join posterior auricular vein to form external jugular  vein), occipital (drains into internal jugular), supraorbital, infraorbital 

Anastomosis: blood can flow either direction in veins, important if there’s a blockage 

 7. Discuss the “danger area” of the face and how infections in this area can lead to  cavernous sinus thrombosis.

Triangular area of external nose and upper lip where facial vein does not have valves and  connects (as does maxillary vein) to cavernous sinus through superior ophthalmic vein through  pterygoid plexus.  If the facial vein inflames here (thrombophlebitis), it may extend through  these connects and involve the cavernous sinus, leading to cavernous sinus thrombosis. 

Cavernous sinus thrombosis: life threatening.  Pressure gets put on nerves, can’t move the eye  (double vision), pain and numbness in trigeminal branches 

 8. Describe the relationships of the parotid gland (and duct) and its innervation. Gland: develops as outgrowth of mouth 

Duct: courses horizontally from anterior edge of gland across masseter muscle to pierce  buccinator and oral mucous membrane near upper second molar. 

Relationships: Facial nerve bisects into superior and inferior halves (, retromandibular vein,  external carotid, great auricular nerve from cervical plexus, auriculotemporal nerve from V3 

Innervation: parasympathetic.  Pregang for parotid come from neurons in inferior salivatory  nucleus, leave brainstem in glossopharyngeal nerve.  Pass through middle ear cavity in tympanic  brain of CN IX and enter lesser petrosal nerve to reach otic ganglion to synapse.

Postgang enter mandibular division of V and pass through auriculotemporal branch to  reach parotid gland

Week 2 Notes 8/7/2017-8/11/2017 

Day 1 (M2M)

9:00-9:20—Weekly Quiz

9:20-9:50—Intro to the Week

10:00-10:50—Cell Cycle, Meiosis & Fertility Objectives

Key

Material from  

SoftChalk

Vocab

Material from  

Reading/Textbooks

Refer to a source for  explanation or visual

Material from  

Lecture

Professor says to  

know this material

Material from  

Handout

1. Describe the major stages of the cell cycle and how a cell regulates its progress into  and through each of these stages.

Interphase=G0 phase, G1 phase, S phase, G2 phase 

G0=non-dividing cell, inactive/performing normal functions 

G1=pre-DNA replication, varies in time, cell preps for S phase 

S=DNA replication (lasts 6-7 hours) 

G2= post-DNA replication, 2-3 hrs, prepping for cell division 

M phase (mitotic or meiotic)=Karyokinesis, Cytokinesis 

Karyokinesis= division of nucleus 

Cytokinesis= division of cytoplasm 

Stimulation of cell division can happen from growth factors (small peptides) which bind  to membrane receptors, sending an intracellular second message system and activating an  early intermediate gene, which controls cyclin. 

Cyclin increases before division and turns on cyclin-dependent kinase (CDK) of  maturation promoting factor (MPF). It is degraded after division. 

Checkpoints to avoid mutation: when damage happens, p53 gene is activated, which  stops the cycle to repair or causes apoptosis. 

Checkpoints of cell cycle: nucleus checks accuracy of DNA and fixes mistakes or apoptosis.  

S=replication (strands separated and doubled, only still touching at centromere). 4  stranded chromosome with two p arms and two q arms (chromatid) 

2. Describe the major differences between cell necrosis and apoptosis. Apoptosis: caused by p53 gene activation because of cell stress or DNA damage Energy dependent, Membranes are left intact, DNA fragments, nuclear blebbing 

Necrosis: caused by toxic injury. Energy independent, membrane is disrupted, DNA degrades  randomly, cell lyses 

3. List the major phases of mitosis and the structural features of the cell at each phase.

Mitotic figure: cell in any phase of mitosis. Very dark chromosomes (but not everything that’s  dark is chromosomes).  

Prophase: nucleolus disappears, nuclear envelope becomes vesicles, centrioles duplicate and  form spindles, chromosomes become visible microscopically. 

Metaphase: chromosomes line up along cell equator randomly 

Anaphase: chromatids separate at centromere, chromatids move to opposite poles and begin to  decondense 

Telophase: nuclear envelope reforms (karyokinesis done), nucleolus reappears, cytokinesis completes (two cells pinch off) 

4. Define “Maturation Promoting Factor”, explaining why it is important for cell division.

Maturation Promoting Factor (MPF) increases when cyclin production increases, and its CDK  component becomes active. It functions to condense DNA, create the spindle apparatus, and  break down the nuclear envelope. 

5. Define the two divisions of meiosis in terms of changes in chromosome numbers and  DNA content.

Two divisions: reduction division (Meiosis I) and maturation division (Meiosis II) MI= Prophase I: homologous chromosomes pair (only happens in meiosis), cross over Metaphase I: homologous chromosomes line up on equator 

Anaphase I: separation of homologous chromosomes 

MII= Prophase II (debatable whether this exists) 

Metaphase II: chromosomes line up on cell equator 

Anaphase II: separation of chromatids, move to opposite poles 

After MI, each cell has a paired chromatid (either maternal or paternal) 

After M2, each cell has one strand of one of the chromatids (23 strands total) Slide 7 answers: different ways to define “n” numbers: DNA content or chromosome number After S phase: DNA=4n, Chromosome=2n 

Start of Reduction division (Meiosis I): DNA 4n, Chromosome 2n 

End of reduction division (II): DNA 2n, Chromosome 1n (haploid) 

End of maturation division (II): gametes. DNA 1n, Chromosome 1n 

6. Explain the Lyon hypothesis of X chromosome inactivation.

Only one X chromosome ever gets activated, and it’s random which one. The inactive X is  called a “Barr body.” Only females have Barr bodies. 

7. Define the term pseudoautosomal region and explain its importance in X – Y synapsing  during meiosis.

Pseudoautosomal region: region on X/Y chromosomes that allow them to pair up as  “homologous” chromosomes even though they aren’t the same. Most common genetic problems  result from these not correctly lining up, leading to aneuploidy of sex cells (XXY=Klinefelter’s,  X0= Turner’s) 

8. Define the terms: diploid, haploid, polyploid and aneuploid.

Aneuploid: irregular number of chromosomes (too little or too much) 

Diploid: somatic cells, 2n, 46 chromosomes in humans 

Haploid: sex cells, 1n, 23 chromosomes in humans 

Polyploid: containing more than two homologous chromosomes (3n, 4n, etc.). Instead of one  chromosome from each parent, have more than 2 of the same (not usually in eukaryotes)

11:00-11:50—Chromosomes and Mendel’s Laws

Objectives

1. Define the terms of genetics (gene, genotype, phenotype, linkage, mutation, allele, locus, recombination, haplotype, etc). See pages 4-10 of this handout for terms of genetics.

Gene: unit of DNA sequence that encodes for a specific function. Typically, when we say genes,  we mean they code for protein, but non-coding genes can also code for RNAs, miRNA 

Genotype: combination of alleles in diploid organisms at one location on DNA 

Phenotype: Characteristic related to genetic makeup that are variable results of genotype.  Examples: hair color, eye color, presence of disease. 

Linkage: Relationship between two locations on chromosome that violates independent  assortment (usually because genes are so close to each other) and creates gene families that  usually sort together 

Mutation: Altered version of gene 

Allele: One member of pair of a gene (everyone has two alleles, one from each parent) Locus: Specific chromosomal/gene location 

Recombination: Exchange of DNA sequence between two chromosomes that are touching each  other in meiosis. Results in slight variations on maternal/paternal DNA sequence for variability.

Haplotype: Physical combination of alleles present on a chromosome. (recombination makes  more haplotypes) 

1. Recognize and define biparental inheritance.

We inherit one maternal and one paternal allele through fusing of sperm and ovum 

We NEED combo of sperm and egg (biparental inheritance) otherwise an embryo won’t be  viable. Fetus comes from egg, placenta and extra stuff come from sperm. If all genetic material  is from father, we have a complete mole (placenta, no embryo). If all genetic material is from  mother, we have a dermoid cyst (mostly skin and hair like tumor) 

3. Recognize how Mendel’s laws apply to human genetics and their significance in clinical practice.

First Law: Law of Segregation. Everyone has two alleles of a gene, one from each parent  randomly. Dominance indicates phenotype. 

Second Law: Law of Independent Assortment. “Inheritance Law.” Separate genes are passed  independently of each other. Alleles assort independently and combinations of genes in gametes  will be random (Over 8 million possible combinations!) 

4. Explain sexual determination.

Sex is determined by X/Y chromosome presence. XX= female. XY= male. **Y chromosome determines sex, specifically the SRY gene on Y chromosome. SRY activates S0X9 to form testes 

5. Explain X-inactivation in humans (Lyon hypothesis) and recognize the clinical significance of somatic mosaicism.

In females, only one X is active, the other is a Barr body. The active one is chosen completely at  random and gene expression comes from this active one. 

Lyon inactivation: one X in female becomes inactive to balance expression.  

Random inactivation in every cell at 32 cell stage into Barr body heterochromatin which  stays inactive in all daughter cells to form “patchwork” of expression. Females are mosaics  (more apparent in calico cats). Mechanism: Xist transcripts start at center and methylate genes to  inactivate them. It peters out at the end, preserving PARs. 

6. Solve basic probability problems and explain how basic probability applies to clinical practice.

Probability has two important rules: The addition rule, and the multiplication rule. Addition: A OR B (mutually exclusive: cannot occur at same time)

Ex????chance that someone in a group is either type O or type A= add those  probabilities (.42+.43= 85% chance) 

Multiplication: A AND B (independent: can occur at same time) 

Ex????chance that someone in a group at random is female and type O (.5*.42= 21%) 

Day 1 (LOM)

1:00-1:15—Galen Quiz 1

1:15-2:00—Session: Cranial Cavity

Objectives

1. Define skull, cranium and calvaria and list the bones composing the calvaria. Skull= cranium and mandible. 

Cranium= calvaria and facial skeleton 

Calvaria= braincase (cranial vault, keeps brain in). Often used for the skullcap (roof). Made of  frontal bone, two parietal bones, and occipital bone. 

2. List the layers of the scalp and indicate which layer contains most of the nerves and  vessels to the scalp and which layer is the “danger space” of the scalp.

Skin, Connective Tissue (tela subcutanea), Aponeurotic layer (galea aponeurotica), Loose  connective tissue (“danger space”) and Pericranium (periosteum external to calvaria) 

Aponeurotic layer of scalp connects the muscles of facial expression (innervated by facial nerve)  of occipitofrontalis 

Loose connective “danger space” because if infection happens here, nothing to barrier spread to  periosteum. 

3. Give the location of the anterior and posterior fontanels and state their normal times of  closure.

Anterior/frontal fontanel: usually closes by end of second year. Located between two frontal and  two parietal bones of fetal skull (junction of coronal suture and sagittal suture) 

Posterior: usually closes about two months after birth. Located at junction of sagittal and  lamboidal sutures. 

4. List the three meningeal coverings of the brain and the spaces with which they are  associated.

Dura Mater: most external (two layers, periosteal=periosteum lining inside of cranial cavity and  inner meningeal layer continuous with dura of spinal cord). Epidural space between periosteal  and bone. Meningeal can separate from periosteal and form dural folds. Contains endothelial lined venous sinuses. 

Arachnoid mater: contain arachnoid granulations that protrude through meningeal dura (drainage  for return of CSF) 

Pia Mater (attached to brain surface) 

5. Compare and contrast the dural coverings of the brain and spinal cord.

In brain, there are two layers (periosteal and meningeal). The meningeal is continuous with  spinal cord. In the brain, the epidural space is between periosteal and bone (not periosteum and  vertebral foramen). Folds and venous sinuses present. 

6. Name the dural folds and state the attachments of the falx cerebri and tentorium  cerebelli.

Dural folds are when meningeal dura separates from periosteal dura. Special dural projections  include: 

Falx cerebri= large fold, sickle shaped, attaches anteriorly to crista galli of ethmoid bone,  separates cerebral hemispheres. big mohawk 

Tentorium cerebelli= more transverse, elevated at center relative to periphery (like a tent  over the cerebellum), attaches at periphery to occipital bone and petrous ridges of temporal  bones. Free edge of tentorium attaches to anterior clinoid process of sphenoid bone. 

7. Label diagrams of:

a. The basic structure of a dural venous sinus and an arachnoid granulation. See Handout page 3 

b. The system of dural venous sinuses associated with the cranial cavity and know the direction of blood flow in this system.

See Handout page 4 

**Flow of sinuses is usually posterior and inferior. Venous blood OUT. 

c. The system of arteries supplying blood to the brain.

See Handout page 7 

8. State the two principal pairs of arteries supplying blood to the brain. Internal carotid, Vertebral arteries 

9. State the likely sites of bleeding when hemorrhage occurs into:

a. the epidural space.

b. the subdural space.

Often old people’s brains shrink a little and if they fall on their head, they’ll tear the cerebral  vein and get a subdural hematoma. 

c. the subarachnoid space.

10. Describe or label on a diagram the position of origin of the cranial nerves on the surface  of the brain.

Refer to Netter’s 

11. Discuss the circulation of the cerebrospinal fluid.

CSF produced by choroid plexuses of third, fourth, and lateral ventricles. Passes from ventricles  to subarachnoid space by passing through median and lateral apertures of fourth ventricle. Main  absorption of CSF is at arachnoid granulations. 

12. State the boundaries of the three cranial fossae and the major parts of the brain  occupying each fossa.

Three cranial fossae: anterior, middle, posterior. 

Boundary between anterior and middle is sphenoid ridges and anterior border of  chiasmatic sulcus. 

Boundary between middle and posterior is petrous ridges and dorsum sellae What parts of brain are in which fossae? 

Anterior fossae: frontal lobes. Middle: temporal lobes and pituitary gland. Posterior:  cerebellum, pons, medulla oblongata. 

13. Name the major openings in each of the cranial fossae and the structures that traverse  them.

Anterior fossae: frontal emissary vein goes through foramen cecum. Olfactory nerve filaments  go through cribriform plate of ethmoid 

Middle fossa: Optic canal????optic nerve and ophthalmic artery. Superior Orbital  fissure????Ophthalmic vein, Ophthalmic Division of CN V, Oculomotor Nerve (CN III), Trochlear  (CN IV), Abducens (CN VI). Foramen Rotundum????Maxillary division of CN V, Foramen  Ovale????Manidbular division of CN V. Foramen spinosum????Middle meningeal artery. Foramen  lacerum (defect in roof of carotid canal that covers anterior opening of carotid canal) 

Posterior fossa: Internal Acoustic Meatus????Facial Nerve (CN VII), Vestibulocochlear Nerve  (CN VIII), Labyrinthine artery. Jugular Foramen????Glossopharyngeal nerve (CN IX), Vagus  (CN X), Accessory nerve (CN XI), Inferior Petrosal Sinus, Sigmoid Sinus. Hypoglossal

Canal????Hypoglossal nerve (CN XII). Foramen Magnum????Brainstem, Vertebral Arteries, Spinal  roots of accessory nerves (CN XI), venous plexuses, meninges, CSF 

14. Label a diagram of a cross section of the cavernous sinus showing all structures within  and in direct contact with the sinus.

See Handout page 10 

15. By the end of this module, be able to list the venous connections of the cavernous sinus  and explain the symptoms and signs associated with cavernous sinus thrombosis.

See Handout page 11 

Symptoms of cavernous sinus thrombosis:  

Edema of conjunctiva and generalized orbital swelling, pain in orbit and forehead,  diplopia (double vision), Loss of pupillary light reflex, fever and disorientation 

16. Describe the trigeminal ganglion, its location and it meningeal relationships.

Trigeminal ganglion: location of cell bodies of most afferent fibers in trigeminal nerve. It is  inside trigeminal cave (diverticulum of dura and arachnoid after petrous ridge) 

(before it branches, it’s the trigeminal ganglion with lots of afferent for sense of head and no  synapses) 

17. Describe the composition of the trigeminal nerve and its division into three major  branches and know the site of exit of each of these branches from the cranial cavity.

Three divisions: Ophthalmic (leaves at superior orbital fissure), Maxillary (leaves at foramen  rotundum), Mandibular (leaves at foramen ovale) 

Trigeminal Nerve 

Comes off pons (two fiber types: afferent—sensory for head, some efferent to skeletal) Goes into diverticulum, branches into… 

(before it branches, it’s the trigeminal ganglion with lots of afferent for sense of  head and no synapses) 

All e to skeletal go to sensory region of face 

**Slide 21 gives great visual of which branch of trigeminal is stimulated for each part of  face 

Day Two (M2M)

8:00-8:50—Cytogenetic and Mendelian Disorders

Objectives  

1. Describe the methods of chromosome analysis including karyotyping and FISH.

Karyotyping: chromosomes are exposed to proteolytic enzymes and buffers and stained with  various dyes, resulting in dark and light bands along chromosome. Patterns of these bands are  specific to each pair of chromosomes and are dependent on base pair content of DNA. 

FISH: fluorescent in situ hybridization. DNA probes adhere to specific regions on chromosomes  to identify location and number in metaphase spreads or interphase cells. Can identify  submicroscopic chromosome deletions or duplications, alterations in DNA sequence copy  number. 

Cytogenetics: study of chromosomes and abnormalities. 

Karyotyping: low resolution, good for chromosome number and translocations Nomenclature for gene starts at centromere and counts out (details on slide 10) 

Ex: 48, XX, +18, +21. That means 48 total chromosomes, female, and an extra  18 and 21 

FISH: higher res, DNA probe can target any part of genome and check for  trisomies and see translocations. 

Flow Cytometry: sorts out individual chromosomes even higher res 

Sequencing: good for defined regions 

Special Karyotyping (SKY): “chromosomal painting, very colorful chromosomes means lots of  translocations, a sign of cancer. 

Array CGH: cannot detect balanced translocations, can find gains and losses of DNA 

Sequencing: still very expensive, but SNP genotyping is cheaper to test inherited  conditions/ancestry/traits/wellness 

2. Chromosomal disorders:

Clinically significant chromosomal abnormalities seen in .7% live births and 5% stillbirths. 50%  of fetuses that stillbirth in first trimester due to chromosomal abnormalities. About 13-15% of  birth defects are caused by chromosome changes or mutant genes. 

a. Recognize the clinical features of various chromosome disorders such as trisomy 21  (Down syndrome), trisomy 18 (Edwards syndrome), trisomy 13 (Patau syndrome),  monosomy X (Turner syndrome), XXY (Klinefelter syndrome).

Trisomy 21 (Down Syndrom)

Problem: extra region of 21q22 gene. 

Survivable, but intellectural and physical impairments 

Edwards (trisomy 18): only live to 2mos-2yrs 

Patau (trisomy 13): usually die within first year 

Turner syndrome: X0. Missing important genes at end of X chromosome, we need both despite  Barr bodies 

Kleinfelter’s (XXY): Triple dose of PAR regions causes feminized male 

b. Explain the most common causes of chromosomal abnormalities.

Chromosomal abnormalities usually result from non-disjunction in female meiosis (a disjunction  in M2 is less severe than M1) Mechanism: cohesins depleted and tension of spindle not even  (theorized) 

c. Explain biparental inheritance

We must get one set of alleles from mother and one from father. Receiving all alleles from one  parent results in termination of pregnancy because egg creates fetus and sperm creates placenta  and extra features. 

d. Recognize translocations (Robertsonian)

Translocation: transfer of piece of one chromosome to nonhomologous chromosome (not  necessarily abnormal development). Translocations: part of non-homologous chromosomes get  switched 

Problems: pairing up and separation can be wrong, unpaired regions, X inactivation Robertsonian Translocations: involve acrocentric chromosomes (13, 14, 15, 21, 22) Frequent combos are 13/14, 14/21, 14/15 

Long arms fuse together to become metacentric and tiny arms lost as a fragment 

May only have 45 chromosomes, but all genes are still present, so still normal  phenotype. Problems occurs with new generation 

Can occur between homologs (balanced or unbalanced) 

These cause 4% of Down cases because 14/21 translocation gives extra 21 genes 

**REVIEW SLIDE 39 to see different combos and figure out outcomes. **Need to  know** 

(one normal, one balanced carrier, one Down, three lethal) 

Take home message: recognize acrocentric. Different from translocations, know the results of  crossing

A person with Robertsonian translocation has 17% (10% clinically) chance of passing Down.  Classical Down is usually only .1-2% 

**See slide 44 for other examples of translocation disorders (cri-du-chat) 

3. Single gene disorders:

a. Recognize Mendelian inheritance patterns of clinical diseases and describe examples of  these inheritance patterns: autosomal recessive (e.g. Cystic fibrosis), autosomal dominant  (e.g. Achondroplasia), sex-linked recessive (e.g. Hemophilia), and sex-linked dominant (e.g.  Hypophosphatemia).

Single Gene Disorders 

a. Autosomal Recessive 

i. The affected patient is homozygous recessive (even distribution for  

gender). Earlier onsets, more severe phenotypes.  

ii. Compound heterozygote: affected because 2 different mutations in 2  different alleles 

iii. Application: Cystic Fibrosis 

1. Problem: mutation in CFTR gene on Chromosome 7 (usually a  

Phe508 deletion).  

2. Manifests with clinical heterogeneity: different severity of  

phenotypes for different mutations 

b. Autosomal Dominant 

i. Every affected individual has affected parent. We see male-male 

transmission (unlike many other disorders) and very rare homozygous  

dominants (often this is lethal) 

ii. Application: Achondroplasia (dwarfism) 

1. Problem: mutation of fibroblast 3 receptor. 

2. Mechanism: cartilage abnormality because collagen is messed  

up 

c. Loss of heterozygosity 

i. Breast cancer: inactivation in 2nd allele of BRCA means someone  

becomes a compound heterozygote and expresses the disease 

d. X linked recessive (hemophilia)=usually just in males 

e. X linked dominant= daughters of affected male always affected 

f. ***Good pedigrees for practice on Slide 61 

b. Recognize the difference between expressivity and penetrance with clinical examples  (e.g. Polydactyly).

Expressivity: same genetic mutation associated with phenotypic spectrum in different individuals  (environment may have affect or other characteristics) 

Penetrance: proportion of individuals with mutant genotype that express phenotype. If not all  carriers of mutant express a phenotype, then it is incomplete. 

Penetrance: frequency of expression of allele when it’s present (how dominant something is— will I express it if I have it?) Population based 

Expressivity: variation of expression in individual for penetrant allele (severity) 

Application: Polydactyly: Parent may carry dominant allele but not be penetrant. Expressivity is  also varied (6 toes vs 8) 

c. Using clinical examples, describe the genetic basis of phenotypic/clinical heterogeneity  (e.g. Cystic Fibrosis) and penetrance (e.g. Polydactyly).

Application: Cystic Fibrosis 

Problem: mutation in CFTR gene on Chromosome 7 (usually a Phe508 deletion).  

Manifests with clinical heterogeneity: different severity of phenotypes for different  mutations 

Application: Polydactyly: Parent may carry dominant allele but not be penetrant. Expressivity is  also varied (6 toes vs 8) 

9:00-9:50—Population Genetics & Hardy-Weinberg Equilibrium Objectives

1. Define gene frequencies and their significance in clinical practice.

Gene frequencies: how often a gene is present in given population. studied through population  genetics, vital in clinical practice since principle of genetic medicine is counseling and  calculating recurrence risks. 

2. Explain the principle of Hardy-Weinberg equilibrium.

Hardy-Weinberg: principle for predicting genotype and allele frequencies in population given  following assumptions: Population has random mating, population infinite in size, population  under no selection (all genotypes have same viability), population is stable without new  mutations, migration or genetic drift. 

Allelic frequencies will remain constant in population from generation to next  (equilibrium). p+q=1, p^2 + 2pq + q^2 = 1  

P: frequency of dominant allele

Q: frequency of recessive allele 

P^2: percentage of homozygous dominant 

Q^2: percentage of homozygous recessive 

2pq: percentage of heterozygous 

3. Recognize factors that disrupt this equilibrium in populations.

If the assumptions are not met, then equilibrium will be disrupted. Equilibrium very rarely exists  in nature. 

4. Test whether populations are in equilibrium using the Hardy-Weinberg equation. Slide 8: AA=20, Aa=30, aa=50 

P=[(2*20)+(1*30)]/200=.35 (p^2=.1225). But the measured p is .2 so not equilibrium **Look at Practice Problems (8/10 TBL material)

10:00-11:50—Non-Mendelian Genetic Disorders

Objectives

1. Differentiate non-Mendelian genetic diseases from Mendelian genetic diseases with  clinical examples.

Mendelian genetic diseases have simple inheritance patterns, often from only one gene  (autosomal recessive/dominant, sex linked recessive/dominant), but non-Mendelian diseases are  more complex. Examples: multifactorial inheritance, extranuclear inheritance (mitochondria),  genomic imprinting, mosaicism, triplet repeat disorders. 

2. Differentiate dominant inheritance patterns from mitochondrial inheritance.

Mitochondrial inheritance is uniparental: only the female parent passes down her mitochondria.  Both parents pass them down, but the parental mitochondria are tagged for ubiquitination and  degradation. 

37 genes in circular mitochondrial DNA 

Heteroplasmy: different mitochondria in cell have different DNA, you can pass on different % of  each mitochondria which can change severity of disease (eggs have about 100,000 mitochondria  each with 2-10 copies of DNA).  

Males/females affected equally 

**Clinical Applications on Slide 20 

Slide 23 answer: both (any mutant mitochondria makes someone a carrier via heteroplasmy)

3. Explain multifactorial inheritance (genetic and environmental effects) and its  significance to clinical practice.

Multifactorial inheritance: complex or polygenic inheritance where many factors cause disease,  including environment and mutations in multiple genes. Examples: heart disease, Alzheimer’s,  diabetes, cancer. Many non-disease traits are also multifactorial (eye/hair/skin color,  fingerprints, height). They involve a strong genetic predisposition to push an individual beyond  “threshold risk” after which environment takes over About 25% birth defects are these. Traits  are continuous (spectrum) or discontinuous (have it or don’t) 

Genetics pushes you to a “threshold risk” and environment determines if you pass that threshold 

Ex: cleft palate is predisposed by genetics and exacerbated by smoking/alc during  pregnancy 

Hallmarks: normal parents, risk increases if sibling with disorder, increased risk with increased  severity, increased risk with incest 

4. Explain the concept of uniparental disomy and genomic imprinting (inactivation by  methylation) using clinical diseases such as Prader-Willi and Angelman syndromes.

Uniparental inheritance: transmission of gene from one parent to all progeny. Happens in  mitochondria (exclusively female parent) 

Uniparental disomy: offspring receives two copies of chromosome from one parent and none  from other. Can be random during fetal development or result of trisomic rescue. 

Genomic imprinting 

a. Silencing of genes via epigenetics (part of natural development, only about  1% of genes are imprinted) 

b. Inherited and maintained through mitosis 

i. BUT—during formation of gametes, imprinting is RESET and we pass  on a new code depending on our gender (females pass on the maternal  

imprinting they inherited and males pass on the paternal, so we get a  

normal imprinting spectrum from mom and dad) 

c. One active copy of imprinted genes 

d. Clinical Applications 

i. Uniparental Disomy (2 copies from one parent, 0 from other) 

1. Can happen if trisomy has an early mitotic nondisjunction or  

monosomy duplicates itself 

ii. Prader-Willi 

1. Symptoms: low muscle tone, short stature, cognitive disability,  

constant hunger 

2. Problem: maternal UPD of chromosome 15 

3. Mechanism: 15q11-13 genes not expressed because that  

section of chromosome 15 is maternally imprinted

iii. Angelman syndrome 

1. Problem: paternal UPD of chromosome 15 

2. Mechanism: genes on chromosome 15 are not expressed  

because their section is paternally imprinted 

5. Define the pathogenic mechanism of non-Mendelian genetic diseases such as triplet (tri nucleotide) repeat expansion diseases and genomic imprinting.

Trinucleotide repeat disorders: genetic disorders caused by aberrant unstable and abnormal  expansions of DNA triplets. Number of repeats exceeds normal number and can make genes  defective. Show genetic anticipation (Sherman paradox), where severity increases with each  successive generation. Larger the repeat, earlier the age-at-onset, like in Huntington’s. 

6. Distinguish major phenotypic differences between coding and non-coding triplet repeat  disorders using clinical disorders such as (1) Fragile X syndrome, FXTAS, and Myotonic  dystrophy (non-coding) and (2) Huntington’s disease (coding, concept of anticipation).

Clinical Applications: 

Fragile X 

Symptoms: Intellectual disability 

Problem: CGG triplet repeat on FMR1 gene (over 200 repeats) 

Non-mendelian X-linked dominant (Sherman paradox/anticipation/dynamic mutations:  more affected throughout subsequent generations because more repeats. Severity increases,  earlier onset) 

Mechanism: repeats are targeted for methylation and silenced 

FXTAS: adults with premutation for Fragile X 

Extra mRNAs clump in neurons 

Myotonic Dystrophy 

Normal CUG repeats about 3-5X, disease is 2000+, causing long RNAs to not be spliced  correctly 

Huntington’s (coding repeat disorder) 

Problem: repeat of CAG codes for excess glutamine 

Mechanism: buildup of glutamine clogs neurons, degenerative basal ganglia destroyed.  Defective autophagosomes don’t bring cell waste to lysosome 

Normal repeats: 10-26, Disease: 40+ (Sherman paradox present)

Day 3 (M2M)

9:30-10:30—Basic Tissues

Objectives

1. Define the primary functions of epithelium.

Functions: protective barrier, regulation of exchange of molecules between compartments,  synthesis and secretion of glandular products Covers and lines, separating inside and outside.  Lines all ports of entry into our body to serve as a barrier 

2. List the major characteristics of all epithelia in general.

All characterized by production of keratin intermediate filaments. Development: ectoderm and  endoderm (lining of tubes) Lots of cells adhered to each other. To identify: look for free space  (outside), epithelium is next to it. Very little extracellular space around the cells, little room to  

secrete. They rest on a basement membrane that anchors epithelium to underlying tissue and  separates it from connective tissue, which is good because if something happens to it, it doesn’t  infect the connective tissue. They are all polarized (one side faces basement membrane: basal,  one side faces outward: apical) Avascular—has to get nutrients from loose connective tissue.  Unmyelinated nerve endings 

3. List the major types of epithelium based on cell shape and number of cell layers. **See table 5.1 in Wheater’s 

Surface epithelia—cover/line all body surfaces, cavities, and tubes. Form interface between  different biological compartments. They form continuous sheets of one or more cell layers 

Glandular epithelia—involved in secretion and arranged into glands (invaginations of epithelial  surfaces) 

Simple epithelia—surface epithelia of one layer of cells. Used for diffusion, absorption, and/or  secretion. Little protection (can range in shape of cell) 

Ex: simple flat in alveoli, simple cuboidal in kidney, simple columnar in digestion Stratified epithelia—two or more cell layers. Protective, bad for absorption/secretion Squamous: flat (width greater that height), semi-permeable 

Cuboidal: width equals height, walls of ducts 

Columnar: height greater than width, absorbs and secretes 

Simple: one layer of cells 

Stratified: 2+ layers of cells

If stratified, classify shape based on the majority of cells near the free (apical) surface,  not the underlying ones. Basal cells will eventually become apical, but the apical ones are  actually functioning. 

Pseudostratified columnar: all cells are actually on basement layer but sandwiched between each  other in varying lengths, so it looks layered 

Transitional: can change shape (flatten or expand), bladder 

4. Define "endothelium" and "mesothelium", including their locations within the body and  embryological derivation.

Endothelium—in blood vessels 

Mesothelium—lines body cavities 

**these both come from mesoderm and are NOT connected to outside world. They have a  different protein, vimentin. When cancerous, called sarcoma, not carcinoma 

5. Describe the basement membrane in terms of its structure and its relationship to an  epithelium and the underlying loose connective tissue.

Provides structural support for epithelium and is a selective barrier to passage into supporting  tissue. The basement membrane is bound to the cell by hemidesmosomes, linking the  intermediate filaments. 

**Visual of parts on Slide 11 

Basal lamina: lamina lucida + lamina densa (type IV collagen and laminin proteins) 

Reticular lamina: produced by loose connective tissue. Fine meshwork of collagen.  Connects to anchoring fiber (collagen VII). Made of type III. 

6. List the four major types of cell-to-cell junctions and the primary proteins associated  with each.

Tight junction—claudins, occludins, tricellulin 

Adhering belt—classic cadherins, catenins 

Desmosome—Cadherins 

Hemidesmosome—Integrins, Laminins of basement membrane 

Gap junctions—Connexins 

7. Define the purpose of basal infoldings within which are mitochondria. Epithelia are polar in three layers: Apical, Lateral, Basal 

Apical: secretes, absorbs. Lateral: cell junctions, prevent stuff from entering.  Basal: transport with connective tissue

8. Describe the structure of motile and nonmotile cilia and of microtubules and correlated  structure with the function of these structures.

Motile: project from apical surfaces of epithelial cells (respiratory and female reproductive), beat  in wave-like rhythm to propel mucus or fluid. Each bound by plasma membrane, has central  core (axoneme). In motile, the axoneme is 20 microtubules in central doublet surrounded by 9  peripheral doublets linked by nexin and radial spokes to center. 

Non-motile: central doublet, nexin links, and radial spokes absent. Microtubule doublets are  continuous with basal body (nine microtubule triplets) 

9. Describe the structure and function of microvilli.

Finger-like projections of plasma membrane in epithelium, especially for absorption. About .5-1  micrometer in length (short compared to cilia). Cytoplasmic core with parallel bundles of actin  under cell surface. Actin is tightly packed in a hexagon and glued together by actin binding  proteins (ex: villin). Microfilaments at ends of microvilli mediate contraction, elongation, and  stability. 

10. Define exocrine versus endocrine glands. Define holocrine versus apocrine versus  merocrine secretion.

Exocrine—contain ducts, release onto epithelial surface 

Endocrine—no duct to epithelial surface, release directly into blood. 

Holocrine—discharge of whole secretory cells and disintegration of the cells releases secretory  product. Ex: sebaceous glands 

Apocrine—discharge free, unbroken, membrane-bound vesicles containing secretory product  (unusual, ex: lipid secretion in breasts and some sweat glands) 

Merocrine—process of exocytosis, most common form of secretion. Usually proteins secreted. Connective Tissue

1. Define "connective tissue" relative to the other basic tissues.

Connective tissue: tissue which provides general structure, mechanical strength, space filling  (sculpts body shape), and physical/metabolic support for specialized tissues. 

2. Describe extracellular matrix components of connective tissues.

Extracellular matrix has three components: 

Tensile strength: resists stretch/tear, provided by collagen family Collagen: 28 types!  Most abundant protein in body. Type I is light pink in between fibroblasts (looks like bacon).  **KNOW the collagens on slide 23 (I=skin/bone/CT, II= cartilage, III=hematopoetic, IV and  VII= basement)

Elasticity: bounce back after distortion, provided by elastin fibrils (rubbery) 

Volume: bulk, substance, provided by glycoproteins and complex carbohydrates that bind water to form Ground substance: amorphous transparent material like semi-solid gel.Provides  volume, compression resistance, turgor. Control passage of molecules and cells through tissue  and exchange metabolites with circulatory system. 

3. Define the three major types of connective tissue. Describe the primary function of each  type.

Loose connective tissue—underneath basement layer, more cells and less fibers 

Dense connective tissue—fewer cells, more fibers. Can be regular (directional like in ligaments  and tendons that carry force in one direction) or irregular (non-directional, like in hands to  withstand stress from all directions) 

4. List and describe the major morphologic features of connective tissue cells.

Fibroblast: light staining, egg shaped nucleus, very active (lots of euchromatin), produce lots of  collagen 

Fibrocyte: fibroblasts that aren’t doing stuff anymore. If there’s a wound, they can  dedifferentiate back to blast. Dark staining, scrunched up 

Lymphocyte: dense stain, small strong nucleus, little cytoplasm 

Eosinophil: bilobed nucleus, red granules 

Macrophage: huge nucleus, cytoplasm has chucky lysosomes 

Plasma cell: B-cells????plasma????antibodies. Looks for eccentric nucleus with peripheral  heterochromatin, giving it a “clock-like” appearance. 

Adipocyte: filled with vacuole of fat that pushes nucleus to one side 

5. List the major types of specialized connective tissues.

Specializations: 

Keratinized: nuclei start to disappear (dead), all that’s left is keratin protein, used to protect like  in the palms and soles of feet 

Specialized CT 

Adipose: fat. Can be unilocular (white fat, one vacuole, peripheral nuclei) or multilocular  (brown fat, more vacuoles, central nuclei) 

Reticular: spongy mesh netweork that lymphocytes go through 

Elastic: Elastin + fibrillin gives lots of stretch! Aorta

Cartilage: glassy appearance, dense perichondrium around chondrocytes in nests. Hyaline is  type II, Fibrocartilage is type I and II, Elastic cartilage is elastin and type II. 

Bone: compact and cancellous (spongy). Cancellous has trabeculae with bone marrow in  between. The outside is the periosteum, inside is endosteum. 

6. Define "endothelium", "mesothelium" and "synovium", including their locations within  the body and embryological derivation.

**see epithelium objectives  

10:30-11:50—Tissue Adaptations

Objectives

1. Define the cell cycle and the basic principles that underlie its control

Cell cycle: cytokinase, cytokinase inhibitors, clinical importance of proteins, cyclin, RB protein  controls cycle. Cells can go round and round or differentiate or rest in G0. (See 8/7 M2M notes  for more details) 

2. Classify cell populations according to their capacity for cell division

Permanent cells: don’t divide, left cell cycle (terminally differentiated, cannot go back) (muscles,  neurons) 

Stable cells: in G0, can be stimulated to enter G1 and undergo cell cycle, but go back to G0 if not  needed. (hepatocytes) 

Labile cells: continuous cycling (skin, GI) 

Stem cells: Totipotent—totally potent, Embryonic stem cells can become anything.  Pluripotent—limited capacity to give rise to different types (ex: hematopoetic stem) 

For our purposes, there are no stem cells for heart, skeletal muscle, or neurons. If  we lose these, they’re gone forever. 

3. Define atrophy, hypertrophy and hyperplasia.

Atrophy: decrease in cell size, causes decrease in organ size. 

Hypertrophy: increase in cell size, causes increase in organ size 

Hyperplasia: increase in cell number leads to increase in organ size 

4. Explain how atrophy, hypertrophy and hyperplasia of cells contribute to atrophy or hypertrophy of tissues and organs.

Atrophy: cell size decreases or cell death occurs by necrosis/apoptosis. Applies to cell, tissue,  and organ level. Cell sizes are irregular with some much smaller than others.

Causes: low workload, low innervation, low blood supply, low nutrition, low endocrine  signals, duct obstruction 

Ex: low endocrine=less stimulation of prostate=atrophy 

Ex: Duct obstruction increases pressure behind duct, terminal acini of glands  atrophy organ (e.g. pancreas, saliva).  

Ex: aging causes sarcopenia (loss of flesh) 

Ex: Alzheimer’s atrophies frontal and parietal lobes so that sulci sink more and  gyri narrow. Ischemia can cause a similar appearance. 

Ex: Thymus normally atrophies as we age because we need more immunity as  children than in adulthood 

Hypertrophy: cells increase in size 

Causes: increased demand (pathology or physiology), increased hormones, subcellular  hypertrophy 

Ex: Heart size will increase with increased blood pressure to pump harder Ex: uterus gets giant in pregnancy due to hormones (hypertrophy and hyperplasia) 

Ex: subcellular hypertrophy of organelles in phenobarbital liver because SER gets  huge to metabolize lots of drug use 

Hyperplasia: increase cell number 

Ex: menstrual cycle, increase endometrial lining 

5. Define metaplasia.

One adult cell replaced by another adult cell type 

Ex: acid reflux kills lower esophageal squamous epithelium, so it’s replaced by gastric  epithelium 

6. Explain how metaplasia occurs.

Result of pathological stimulus that induces hyperplasia of stem cells in tissue followed by  differentiation to vicarious cell type (replacement). 

Barret’s metaplasia: squamous becomes columnar 

Squamous metaplasia: columnar becomes squamous. Smoking will spur this as squamous from  underneath can more easily survive toxins. (Slide 40 great visual) 

This replacement can be a precursor to cancers, especially lung and cervical

7. Use common examples to illustrate physiological and pathological causes of atrophy, hypertrophy, hyperplasia and metaplasia.

(See Question 4) 

Day 3 (Clinical Skills)

12:50-2:30—Vital Signs, HPI

Objectives

1. Describe the general appearance of the patient using appropriate vocabulary HPI: History of Present Illness

1. Apparent state of health 

General judgement based on observations throughout encounter. Significant supporting details. 

Skin, clothing, hair to determine length of sickness. Well-kempt (description should let  other person pick them out from a room) 

2. Level of consciousness 

Awake, alert, responsive or not 

3. Signs of distress 

Cardiac/respiratory distress, Pain, Anxiety, depression, stress 

4. Body habitus and weight 

Remove shoes, determine BMI. Notes changes over time. Usually short/tall, build of body,  symmetry, proportions, where weight lies on body 

5. Skin color and obvious lesions 

Inspect for strange skin color, scars, plaques, nevi 

6. Dress, grooming, personal hygiene, odors of body or breath 

Hygiene, acetone breath for diabetes, alcohol breath, suitable clothing for weather, clean,  appropriate, shoe quality, unusual jewelry or piercings. Hair=grooming, length of disease,  lifestyle, personality 

7. Facial expressions 

Observe at rest and in conversation. Eye contact, natural? Sustained and unblinking? Averted?  Absent?

8. Posture, gait, and motor activity 

Preferred posture, restless, quiet, frequency of changing position, involuntary motor activity,  immobile body parts, walk/limp, style of walking (confident, fear, hesitance) 

Comprehensive assessments: for new patients in office/hospital, fundamental knowledge, good  relationship builder, baseline, skill building for when need to do focused 

Components of history: identifying data, reliability, source of data, complaints, past,  family, personal/social, review of systems (fluid order) 

Identifying: age, gender, marital, occupation (source can be them, fam, record) Reliability: dependent on mood, ambiguity 

Complaints: try to keep in patient’s own words 

Present illness: each symptom should have seven attributes—location, quality,  quantity/severity, timing (onset, duration, frequency), setting, aggravating factors, associated  manifestations (OLDCARTS). Note current medications, allergies, toxin use 

Past history: childhood and past adult illness (medical, surgical, ob/gyn, psych),  immunizaitons 

Family history: present/absent diseases, deaths 

Personal/Social: education, personality, coping style, concerns, stress, finance,  religious, culture, lifestyle 

Review of Systems: overview with patients on whole body (uncovers what we  overlook) **Table in Bate’s pg 12** 

Focused assessments: for established patients, urgency, focus on concerns/symptoms, specific  area/body system, relevant for target problem 

Subjective data: what patient tells you (symptoms and history) 

Objective data: what you detect (lab tests, physical examination) 

2. Measure the vital signs – blood pressure, heart rate, respiratory rate, and temperature

Blood pressure: arm at heart level, cuff and stethoscope correctly positioned (not required to  report). Person sitting in chair with feet flat on floor. Width of bladder of cuff should be 40% of  upper arm circumference. Length 80% circumference. Lower border of cuff about 2.5 cm above  antecubital crease. Too small? Blood pressure will read high. Too large? BP reads low. Put  over brachial artery, about 1.5 cm above medial epicondyle. First sounds=systolic, no more  sounds=diastolic. Sometimes sounds will go away between these, so we can actually palpate  blood pressure instead of listening to it.

Normal is less than 120/80. Prehyp 120-139/80-89, hypertension is more than or equal to  140/90

Heart rate: radial artery for 15 seconds (don’t have to report). Check on both sides for  symmetry. Normal is 50-90bpm.

Heart sounds in stethoscope: diaphragm is better for high-pitched sounds of s1 and s2,  murmurs of aortic and mitral regurgitation, and pericardial friction rubs. Bell is more sensitive  to low pitch sounds (s3 and s4) 

Respiratory rate: 15 seconds, be sneaky so the patient doesn’t become conscious of breathing  rate (don’t have to report). Normal is 14-18 

Temperature: sublingual thermometer 

Pyrexia: elevated temp, hyperpyrexia: extreme elevation (more than 106), hypothermia:  low temp (below 95) 

3. Correlate your knowledge of anatomy as you perform the physical exam 4. Demonstrate the proper method for performing orthostatic blood pressures Orthostatic: supine, sitting, and standing (3 minutes between) measurements of blood pressure 

If the systolic falls by 20 mmHg or diastolic by 10mmHg in these transitions, orthostatic  hypotension. 

5. Ask the HPI questions using the mnemonic OLD CARTS+

Onset, Location, Duration, Character, Aggravating/Alleviating, Radiation/Relieving, Timing,  Severity +Associated symptoms 

Day 4 (M2M)

8:00-9:50—Genetics Group Problem Set

Objectives

(For these, see TBL practice problem powerpoint for answers and practice) 

1. Apply the principles of population genetics with particular reference to the concept of  Hardy-Weinberg equilibrium.

2. Apply Hardy-Weinberg equilibrium to resolve genetic conditions and calculate gene  frequencies.

3. Calculate risk values based on gene/disease frequencies in a given population 10:00-11:50—Histopathology Lab: Basic Tissues 1

Objectives (11-19 not covered in Lab, must find on own or may be in subsequent  Labs)

1. Explain the difference basophilic and acidophilic staining, citing examples of each using  hematoxylin & eosin staining of tissues.

Hema: affinity for acid, stains DNA/RNA, blue 

Eosin: affinity for base, stains other cell parts, pink 

2. Classify and identify the major types of epithelia.

Shapes: squamous (flat), cuboidal, columnar. 

Simple: one layer of cells 

Stratified: 2+ layers of cells 

Simple squamous: needed for exchange (alveoli, nephron), Simple cuboidal: smaller ducts of  exocrine glands (ducts, thyroid, ovarian follicles, nephron), Stratified cuboidal: (ovarian follicles,  ducts), Simple columnar: absorption (GI, kidney), Transitional: changes shape to  expand/contract (bladder), Pseudostratified columnar: single layer but bodies sandwich between  each other (respiratory, vas deferens), Stratified columnar: (ducts of large glands), Stratified  squamous: protection (skin, oral cavity, anal cavity) 

3. Describe mucous vs. serous glands.

Glands—extensions of surface epithelium during embryogenesis. Exocrine or endocrine. Serous: secrete watery protein-rich product. Stain well with H&E 

Mucous: secrete thick mucous product. Do not stain well with H&E. Mucus is too difficult to  pass between cells so no demilunes. 

Combo of seromucous also present. 

4. Identify major specializations of the apical surface of epithelia including cilia, stereocilia  and microvilli.

Motile: project from apical surfaces of epithelial cells (respiratory and female reproductive), beat  in wave-like rhythm to propel mucus or fluid. Each bound by plasma membrane, has central  core (axoneme). In motile, the axoneme is 20 microtubules in central doublet surrounded by 9  peripheral doublets linked by nexin and radial spokes to center. 

Non-motile: central doublet, nexin links, and radial spokes absent. Microtubule doublets are  continuous with basal body (nine microtubule triplets). Involved in mechanosensory function,  allowing cell to monitor environment. Proteins polycystin 1 and 2 help them do this (form  calcium channel). Fibrocystin protein. Passively bent by motion of fluid 

Microvilli: Finger-like projections of plasma membrane in epithelium, especially for absorption.  About .5-1 micrometer in length (short compared to cilia). Cytoplasmic core with parallel  bundles of actin under cell surface. Actin is tightly packed in a hexagon and glued together by  actin binding proteins (ex: villin). Microfilaments at ends of microvilli mediate contraction,

elongation, and stability. Embedded in glycoprotein-rick matrix called glycocalyx, helps to trap  substances. 

5. Identify the location of the basement membrane found between all epithelia and the  underlying loose CT.

Sometimes thick and sometimes not visible, but there will always be a basement membrane in  between epithelial layers and loose CT. Notable because no nuclei 

6. Compare and contrast the major types of connective tissue (loose, dense regular and  dense irregular CT).

Loose: more cells (fibroblasts and fibrocytes), fewer fibers. Different cells present depending on  function (ex: leukocytes for immune function). Highly vascular. Supports. 

Dense irregular: fewer cells, more fibers. Non directional, provides tensile strength in many  directions. Dense with collagen (type I mostly). Cells present are fibrocytes 

Dense regular: fewer cells, more fibers. Directionality to fibers (tendons and ligaments) give  pull in certain direction. Type I collagen, Cells present mostly fibrocytes. No capsule of CT 

7. Describe the major types of specialized connective tissues including reticular and elastic  tissues.

Adipose, Blood Cells, Cartilage, Bone, Lymphatic Tissue 

Reticular fibers: collagen type III, crosslink to form fine meshwork (lymph tissues, bone marrow,  liver) 

Elastic tissues: comprised of elastin and fibrillin. Stretchy, recoil. Important for arteries, lungs,  skin, bladder. Fibrillin secreted by fibroblasts to make scaffold for elastin. Fibrillin 1 for  microfibril sheath 

8. Describe the microscopic appearance of adipose tissues.

Two types: white and brown. White stores energy in triglycerides, brown is for body heat.  Adipocytes don’t stain well, have giant vacuole for fat and nucleus pushed to side (unilocular,  white). Brown cells stain a little better and nucleui round and centered. Multiple small vacuoles  (multilocular) 

9. Describe the microscopic appearance of hyaline cartilage and of bone. Hyaline: surround capsule with cell inside. Glassy. 

Bone: osteocytes within lacunae and interact via canaliculi. Osteoblasts make endosteum to  cover trabecula. Osteoclasts: large multinucleated cells derived from monocytes. Lots of  lysosomes for bone resorption. Located in depressions called “Howship’s lacunae” along  surface of bone 

10. Identify and provide the primary function(s) of the following:

▪ Fibroblast

Synthesize collagen, elastin, and GAGs. Elongated with body projections (kind of like a star).  Hard to see cell body in H&E staining, identified by egg shaped nuclei (light staining bc lots of  euchromatin) 

▪ Fibrocyte

Inactive structure cells. Nucleus is thin, dense stained, heterochromatic 

▪ Lymphocyte

T and B, migratory, in loose CT, greater number during inflammation, plasma cells come from B  lymphocytes. Small cell with round dark nucleus and thin cytoplasm 

▪ Plasma cell

Homogenously basophilic cytoplasm, small cell, eccentric nucleus, abundant RER, “clock  faced”, produces antibodies, derived from B lymphocytes 

▪ Macrophage

Phagolysosomes (junky cytoplasm), large cell, large light stained nucleus, derived from  monocytes, phagocytic, larger number during inflammation, can fuse to form multinucleated  giant cells 

▪ Eosinophil

Cytoplasmic granules, bilobed nucleus, common in lung interstitium, come from circulating  eosinophils, associated with parasitic infection 

▪ Neutrophil

Cytoplasmic granules, trilobed nucleus, rare in loose CT, from circulating neutrophils, larger  number in acute inflammation 

▪ Chondroblast

Synthesize elastin present in matrix of elastic cartilage 

▪ Chondrocyte

Inactive chrondroblast 

▪ Osteoblast

Synthesize bone 

▪ Osteocyte

Osteoblasts surround themselves with matrix to become inactive osteocytes (bone cells) ▪ Osteoclast

Osteoclasts: large multinucleated cells derived from monocytes. Lots of lysosomes for bone  resorption. Located in depressions called “Howship’s lacunae” along surface of bone 

11. Identify each of the three types of muscle. Compare and contrast each from the other  two.

Skeletal: Striated

Cardiac: Striated

Smooth: not striated

12. Identify each of the following in a typical neuron (e.g., spinal cord multipolar neuron): ▪ Nucleus ▪ Prominent nucleolus ▪ Nissl substance ▪ Dendrites

13. Identify the following in an H&E stained peripheral nerve:

▪ Axon ▪ Myelin sheath ▪ Endoneurium ▪ Perineurium

14. Identify the following in an osmium-stained peripheral nerve:

▪ Axon ▪ Myelin sheath ▪ Node of Ranvier ▪ Incisures of Schmidt-Lanterman ▪ Endoneurium

15. Describe the microscopic appearance of nerve degeneration as well as skeletal muscle  denervation.

16. Describe the microscopic appearance of perineural (cancer cell) invasion and explain  the clinical significance of this pathology.

17. Identify hyperplasia using the nongravid vs. gravid mammary gland as an example.

18. Compare and contrast the microscopic appearance of hyperplasia (as seen in the gravid  mammary gland) with hypertrophy (as seen in congestive heart failure).

19. Identify squamous metaplasia, contrasting this change with the normal lining of  airways in the lung (pseudostratified columnar epithelium with cilia).

Day 4 (LOM)

1:00-1:50—Session: Development of Central Nervous System Objectives

1. Describe the formation of the neural tube and know when it occurs.

Neural plate forms at day 18 from area of ectoderm rostral to primitive streak. This is induced  by notochord and mesoderm and will give rise to neural tube and neural crest. End of

3rd/beginning of 4th week: groove deepens and neural folds approach each other in midline, fuse  to form neural tube. Fuse happens in cervical region and expands outward cranially and caudally  and finishes about the end of the 3rd week with open ends (two neuropores—cranial and caudal).  The lamina terminalis is remnant of cranial neuropore. 

Tube????CNS. Tubular wall is spinal cord/brain, tubular lumen is central canal and  ventricular system The neural tube in the spinal cord: wall becomes cord, lumen becomes central  canal (which disappears) 

In the brain: wall becomes brain, lumen becomes ventricles 

2. Name the derivatives of the neural crest.

Dorsal root ganglia, cranial sensory ganglia, sympathetic chain ganglia, prevertebral sympathetic  ganglia, parasympathetic autonomic ganglia, schwann cells of PNS, capsule (satellite) cells on  cell bodies of spinal ganglia, melanocytes, chromaffin cells including adrenal medulla, skeletal  structures originating from pharyngeal arches, portions of teeth, cells of pia and arachnoid 

(**Know derivatives, slide 10) 

3. Describe the formation of the mature spinal cord:

A. List the three zones associated with differentiation of the neural tube wall.

Ventricular zone: first, neuroepithelial cells lead to all neurons and macroglial cells of spinal  cord (neuroblasts????migrate to form intermediate zone????gray matter, axons????marginal  zone????white matter, glioblasts-->intermediate zone????astrocytes/oligodendrocytes aka macroglia,  ependymal cells) 

Intermediate (mantle) zone: neuroblasts come here to form gray matter. Glioblasts come here to  form astrocytes and oligodendrocytes (myelinate axons in CNS) 

Marginal zone: axons move here to form white matter 

B. List the derivatives of the neuroepithelial cells of the neural tube wall.

neuroepithelial cells lead to all neurons and macroglial cells of spinal cord (neuroblasts????migrate  to form intermediate zone????gray matter, axons????marginal zone????white matter, glioblasts-- >intermediate zone????astrocytes/oligodendrocytes aka macroglia, ependymal cells) 

In the ventricular layer are neural epithelial cells. These span into the mantle layer to become  neurons and glial cells. The glial cells further migrate to marginal layer to become  oligodendrocytes (Schwann cell equivalent in CNS) and astrocytes (nutrition and  communication). The neural epithelia cells that stay in the ventricular layer become ependymal  cells (these line the ventricles) 

C. List the components of the three zones after differentiation is complete.

Ventricular: neuroepithelial, ependymal. Intermediate: neuroblasts, astrocytes, oligodendrocytes.  Marginal: axons

4. Describe the relationship between the alar and basal plates and the sulcus limitans. Alar: sensory. Basal: motor. They are separated by sulcus limitans 

The mantle layer has a dorsal and ventral area. Dorsal=alar (this becomes dorsal horn of spinal  cord and the sensory fibers). Ventral=basal (this becomes ventral horn, motor fibers). They  become the spinal cord at about 7-8 weeks. 

5. Name derivatives of the alar and basal plates in the central nervous system. Alar: nuclei for sensory function, meet at midline to form cerebellum 

Basal: form nuclei for motor function 

6. Know the caudal limit of the spinal cord of the 6-month fetus, newborn and adult. 6 month: S1, newborn: L3, adult: between L1 and L2 

7. List the secondary brain vesicles and the primary vesicles from which they are derived. Primary: Prosencephelon (forebrain), Mesencephelon (midbrain), Rhombencephalon (hindbrain) Secondary: Telencephalon, Diencephelon, Mesencephalon, Metencephalon, Myelencephalon 8. List the major derivatives of the secondary brain vesicles.

Tel????Cerebral hemispheres, Di????Thalami, Hypothalamus, Neural portion of pituitary.  Mes????midbrain, Met????Cerebellum, Pons. Mye????Medulla oblongata 

9. List the various components of the ventricular system and describe their origin. Ventricular system develops from cephalic aspect of neural tube lumen. 

Fourth ventricle, Cerebral aqueduct, Third ventricle, lateral ventricles, interventricular foramina,  lateral apertures, median aperture, hydrocephalus (internal and external) 

10. Describe internal and external hydrocephalus and distinguish between them.

Internal: noncommunicating, hydrocephalus resulting from enlargement of all or part of  ventricular system because of obstruction of brain 

External: communicating, hydrocephalus from obliteration of subarachnoid cisterns or  malfunction of arachnoid granulations. 

11. Describe the formation of the pituitary gland.

Derived from diencephalon. Develops from two ectoderm sources: infundibulum  (neuroectoderm of diencephalon) and Rathke’s pouch (surface ectoderm of stomodeum: region  of oral cavity) 

12. Name the primary brain flexures and which one persists in the adult.

Midbrain (first to appear, persists in life), Pontine (second to appear, disappears), Cervical (last  to appear, disappears) 

13. List and describe the various types of spina bifida.

Spina bifida occulta: defect in vertebral arch only. Associated with no neurological deficits.  Usually L5 or S1 vertebra in about 10% of population 

Spina bifida cystica: defect in vertebral arches and meninges or neural tissue protrudes through Spina bifida with meningocele: protruding meningeal sac only has CSF in it Spina bifida with meningomyelocele: also has spinal cord or nerve roots in sac Spina bifida with myeloschisis: spinal cord opens onto surface of body 

14. Compare and contrast the structures of the spinal cord and brain: A. Know what structures are derived from similar components of the neural tube and thus might be considered homologous.

The neural tube in the spinal cord: wall becomes cord, lumen becomes central canal (which  disappears) 

In the brain: wall becomes brain, lumen becomes ventricles 

B. Know what features are unique to either the spinal cord or the brain. Unique to brain: vesicles of development, flexures, clinical malformations (encephalies) Unique to cord: layers, bifidas 

15. Describe meroanencephaly (anencephaly), meningoencephalocele, cranial meningocele and Arnold-Chiari malformation; be able to name the anomaly from a description.

Meroanencephaly: improper closing of rostral neuropore leads to abnormal development of  forebrain primordium. Calvaria is defective and nervous tissue degenerates. Rudimentary brain  stem. Associated with excess amniotic fluid because fetus lacks control over swallowing. 

Meningoencephalocele: defect in cranium with herniation of meninges and part of brain 

Cranial meningocele: defect in cranium that meninges containing CSF protrude through 

Arnold-chiari: most common congenital anomaly involving cerebellum. Herniation of parts of  medulla and cerebellum through foramen magnum into vertebral canal. Causes communicating  hydrocephalus. Posterior fossa is small.

Day 5 (M2M)

9:00-10:50—Synthesis Case: Maria Flores-Chow

1. Describe the duration of a normal pregnancy and list the common ways gestational  age is determined.

Normal gestation in humans is 40 weeks (280 days) from last menstrual period.

Gestational age determined during first prenatal visit. Accuracy ensures management of  obstetric conditions like preterm labor, IUGR, and postdate pregnancy. Determined by added 9  months 7 days to first day of last menstrual period. Ultrasound can also determine gestational  age by measuring the fetal crown-rump length between 6 and 11 weeks. At 12-20 weeks, age  determined within 10 days by average of measurements. After 20 weeks, estimation is less  reliable. 

2. Define “advanced maternal age” and describe the general pattern of the maternal  age-related risk of having a baby with Down Syndrome or another chromosomal  abnormality.

Women older than 34 are at increased risk of giving birth to children with autosomal trisomies or  sex chromosome abnormalities. 

3. Recognize and apply basic, standard reporting terminology used to describe  karyotype results.

When describing results, can characterize by number (trisomy, monosomy) or structure  (translocation, deletion). Refer to arms as p (short) and q (long). When reporting: total number  of chromosomes first, then sex chromosomes, then description of abnormalities.  Dup=duplication, del=deletion, t=translocation, der= balanced Robertsonian translocation, inv=  inverstion, r(X)= ring type X, i(X)= isochromosome 

Ex: 48, XX, +18, +21 (48 total chromosomes, female, extra 18 and extra 21) 

46, XX, dup(5)(p14p15.3)= (Female with duplication of short arm of Chr 5 from  band p14 to p15.3) 

4. List, using standard karyotype reporting language, the different cytogenetic  abnormalities that result in what is clinically considered Down Syndrome.

95% of cases are due to meiotic non-disjunction of chromosomes that lead to 47 chromosomes  (extra copy of Chr 21). 4% of cases are due to unbalanced Robertsonian translocation between  Chr 21 and either 14, 15, or 22. 1% of cases are mosaic type (some cells have 47 chromosomes,  some have normal 46 as result of mitotic non-disjunction) 

1. List the physical characteristics of Down Syndrome.

Congenital heart disease (50%) including atrioventricular canal, ventriculoseptal, or atrioseptal  defects and valvular disease. GI anomalies (10%) including duodenal atresia, annular pancreas,

and imperforate anus. 4-18% congenital hypothyroidism. Polycythemia at birth, low leukemoid  reaction with elevated WBC (resolves). 

Decreased/poor muscle tone, short neck with excess skin at back, flat face and nose, small  head/ears/mouth, upward slanting eyes with skin fold from upper eyelid, white spots on iris,  wide short hands, single deep crease across palm, deep groove between first and second toes.  Slower overall development. 

Short attention span, poor judgment, impulsive behavior, slow learning, delayed language and  speech development. 

2. List the diseases and conditions for which people with Down Syndrome are at  increased lifetime risk.

Acquired hypothyroidism, increase risk of leukemia, susceptible to infection, cataracts, spinal  cord injury (from atlantoaxial instability of distance between C1 and C2). Alzhemier-like  features. Autism, gland/hormone problems, hearing loss, vision problems. 

Heart defects: 50% CHD, high blood pressure in lungs (cyanosis). 

Vision: 60% cataracts, near-sightedness, cross-eyed, rapid/involuntary movement of eye. Hearing loss: 70-75%. Problems with ear structure, ear infections. 

Sleep disorders, gum disease, teeth problems, epilepsy, digestion problems, celiac, mental  health/emotional problems. 

3. List the testing methods used to identify Down Syndrome prenatally.

First tests to screen are non invasive: nuchal translucency, PPA, Quad test of mother’s blood (at  15-22 weeks) 

If positive on first test, second round of diagnostic tests are more invasive:  amniocentesis, CVS 

Karyotyping will reveal if a fetus has trisomy 21 or a trisomy-like translocation of 21q22  resulting in the extra gene for Down syndrome. 

FISH (results faster than karyotyping) 

Microarray (more accurate than karyotyping, quicker) 

DNA testing: looks for specific gene mutations upon request (good for carriers) CVS: tissue taken from placenta as early as 10-13 weeks and quick results. 

“Quad” blood test done between 15-22 weeks to measure levels of four substances in blood to  screen for Down, Edward’s, and neural tube defects

Cell-free DNA testing comes from DNA released from placenta into woman’s bloodstream. Can  test this at 10 weeks, 1 week for results. Positive results should be followed by amniocentesis or  CVS (chorionic villus sampling) 

Screening of parent’s blood for carriers helpful before conception for genetic counseling. 

4. Define, compare, and be able to calculate sensitivity, specificity, positive predictive  value and negative predictive value given a clinical scenario.

Sensitivity: ability of a test to correctly identify patients with disease. Sensitivity= true positives/  (true positives + false negatives).  

Specificity: ability of test to correctly identify patients without disease. Specificity= true  negatives/ (true negatives + false positives). Would rather test high sensitivity low specificity  (false positive), because still don’t have disease, just have to reconfirm with more testing. 

Positive predictive value: How likely is it that the patient has a disease if the result is positive?  PPV= True positives/ (true positives + false positives) 

Negative predictive value: How likely is it that patient doesn’t have disease if result is negative? NNV= True negatives/ (true negatives + false negatives) 

Sensitivity: find the truly sick people 

A sensitive test will cast a huge net where we find all the positive possible people Specificity: find the truly healthy people 

Screening tests should be highly sensitive (and low specificity if we have to) Diagnostic tests should be highly specific (and low sensitivity if we have to) 

Timeline: Screen first, get everybody who could possibly have it, then run more diagnostic  exams (get rid of the people who definitely don’t have it) 

Ex: TB 

First test is a PPD (high sensitivity, low specificity). Lots of false positives mean  people have to get further screening, but better than getting a false negative 

Second test is sputum or chest xray (high specificity, so we eliminate people who  don’t have it) 

Day 5 (LOM)

1:00-1:50—Session: The Face and Parotid Region

Objectives

1. Identify the regions of skin supplied by each of the three divisions of the trigeminal nerve  and examples of specific nerves accomplishing this innervation.

V1 (branch one): Ophthalmic supraorbital region (middle of scalp to under nose knight’s helmet  dermatome) 

V2: maxillary infraorbital (giant mustache that goes to temples) 

V3: mandibular mental auriculotemporal (man’s beard area thru temples) 

2. Name major muscles of facial expression and their innervation.

Innervation: CNVII (facial nerve) 

Groups of muscles: 

Scalp (epicranius): frontalis (wrinkles forehead and raises eyebrows), occipitalis (pulls  scalp posteriorly), galea aponeurotica (deepest layer of moveable scalp) 

Ears: auricular muscles 

Nose: Procerus (wrinkles nose), corrugator (draws eyebrows down and in). These are the  muscles people get botox in. 

Mouth: **zygomaticus major is a good landmark for facial artery elevators of upper lip  (zygomaticus major/minor, levator labii superioris), depressors of lower lips (depressor anguli  oris, depressor labii inferioris), others (orbicularis oris—closes lips/protrudes lips/compresses  against teeth, buccinator—compresses cheeks against teeth) 

Orbit: orbicularis oculi (closes eyelids, palpebral part forms part of eyelid) 

Superficial neck muscle: platysma (depresses lower lip and corners of mouth, depresses  mandible) 

3. Describe the course of the facial nerve and discuss testing for injury of this nerve.

Leaves brainstem, enters temporal bone via internal acoustic meatus. Branches into greater  petrosal branch (goes to pterygopalatine ganglion) and chorda tympani branch (carries fibers to  tongue or submandibular). Exits skull through stylomastoid foramen with only efferent to  skeletal. 

Clinical Application 

Bell’s Palsy (need to eliminate other reasons facial nerve could be paralyzed before  diagnosing) 

Problem: viral problem paralyzes facial nerve 

Symptoms: paralyzed face 

Tests: raise eyebrows, whistle, close eyes tightly

4. List the types of fibers found in the facial nerve and its major branches (and the cell  bodies of origin of these fibers) and the structures in which they terminate.

Fibers: Efferent to Skeletal Muscle (in facial motor nucleus of VII). Terminates on facial  muscles, stylohyoid, posterior belly of digastric, stapedius 

Afferent (in geniculate ganglion). Terminates on taste buds of anterior 2/3 of tongue via  chorda tympani nerve to linguinal nerve 

Preganglionic efferent (in superior salivatory nucleus). Terminates on pterygopalatine  ganglion via greater petrosal nerve and submandibular ganglion via chorda tympani nerve to  linguinal nerve 

5. List the principal nodes which receive lymph for the face and scalp and know how  lymph drains from these nodes to the bloodstream.

Submental: drains central lower gum, lip, chin, tongue to submandibular and deep cervical nodes 

Submandibular: drains anterior upper face (forehead, nose, upper lip, lateral lower lip, side of  tongue) to deep cervical nodes 

Buccal: drains cheek and suborbit to submandibular nodes 

Parotid: drains lateral face and scalp including forehead and eyelids into deep cervical nodes Retroauricular and occipital: drain posterior scalp into deep cervical nodes Buccal????Submandibular????Submental 

Parotid????retroauricular 

*Malignant cancers can spread via lymph pathways, so need to know what lymph vessels  drains which part of face 

6. Describe the arterial supply and venous drainage of the skin of the face and scalp.

Arteries: (Rounder and twistier paths) facial (comes from carotid, branches at neck/face,  terminates as angular artery), superficial temporal (terminal branch of external carotid, branches  off as transverse facial), occipital (from external carotid), ophthalmic (supraorbital and  supratrochlear), maxillary (terminal branch of external carotid, provides branches to muscles of  mastication, branches as infraorbital and mental) 

Veins: (highly variable person to person) facial, retromandibular (receives from superficial  temporal and maxillary veins, divides into anterior division to join facial vein and drain into  internal jugular and posterior division to join posterior auricular vein to form external jugular  vein), occipital (drains into internal jugular), supraorbital, infraorbital 

Anastomosis: blood can flow either direction in veins, important if there’s a blockage

7. Discuss the “danger area” of the face and how infections in this area can lead to  cavernous sinus thrombosis.

Triangular area of external nose and upper lip where facial vein does not have valves and  connects (as does maxillary vein) to cavernous sinus through superior ophthalmic vein through  pterygoid plexus. If the facial vein inflames here (thrombophlebitis), it may extend through  these connects and involve the cavernous sinus, leading to cavernous sinus thrombosis. 

Cavernous sinus thrombosis: life threatening. Pressure gets put on nerves, can’t move the eye  (double vision), pain and numbness in trigeminal branches 

8. Describe the relationships of the parotid gland (and duct) and its innervation. Gland: develops as outgrowth of mouth 

Duct: courses horizontally from anterior edge of gland across masseter muscle to pierce  buccinator and oral mucous membrane near upper second molar. 

Relationships: Facial nerve bisects into superior and inferior halves (, retromandibular vein,  external carotid, great auricular nerve from cervical plexus, auriculotemporal nerve from V3 

Innervation: parasympathetic. Pregang for parotid come from neurons in inferior salivatory  nucleus, leave brainstem in glossopharyngeal nerve. Pass through middle ear cavity in tympanic  brain of CN IX and enter lesser petrosal nerve to reach otic ganglion to synapse. 

Postgang enter mandibular division of V and pass through auriculotemporal branch to  reach parotid gland

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