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• The Ear
• The Respiratory System
• The Integumentary System
• Gastrointestinal System
• Principles of Development / Development of Eye and Ear

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EXTERNAL EAR:

• External Auditory Canal: Serve to amplify the original sound wave coming in.
• Cerumen (ear wax) is produced by modified sweat glands in the canal.

MIDDLE EAR: The middle ear is an air-filled cavity.

• TYMPANIC MEMBRANE: Barrier between external and middle ear. It attaches to the Malleus Bone.
• OSSICLES: Pathway is Tympanic Membrane ------> Malleus ------> Incus ------> Stapes ------> Oval Window. This serves to amplify and focus the sound.
• Middle Ear muscles:
• Tensor Tympani: Muscle attaches to the tympanic membrane, to dampen repeated vibrations and loud sounds, and thus to protect middle ear.
• Stapedius attaches to Stapes and serves same purpose.
• Eustachian Tube: Equilibrates air pressure in middle ear with nasopharynx.
• Otitis Media: Middle Ear Infection with fluid buildup in middle ear. Occurs readily in children due to anatomic immaturity.
• Chronic otitis media can lead to speech problems, due to lost or impaired incoming sound stimuli, which are necessary for speech development.

INNER EAR: General structure

• Compartmental Divisions: By location
• COCHLEA: Medial and inferior
• Scala Media: Contains endolymph. It divides the Scala Tympani from the Scala Vestibuli.
• Scala Vestibuli: It contains perilymph and is continuous with the vestibule.
• Scala Tympani: The lower section of cochlea, through which "spent" vibrations pass. It contains perilymph, below which exits the round window
• VESTIBULE: Central part of inner ear, containing
• UTRICLE + SACCULE: Detect linear acceleration.
• The Utricle is connected to the Semicircular Canals
• The Saccule is connected to the Cochlea
• SEMICIRCULAR CANALS: Superior part of inner ear; detect angular acceleration.
• Compartmental Divisions: By layer
• Bony Labyrinth:
• PERILYMPH: Fluid between the bony labyrinth and membranous labyrinth, it is continuous with the subarachnoid space and therefore contains Cerebrospinal Fluid.
• High Na⁺
• Low K⁺
• Membranous Labyrinth: Fits into the bony labyrinth like a sock in a shoe.
• ENDOLYMPH: The Membranous Labyrinth contains Endolymph, which is like intracellular fluid.
• High in K⁺, low in Na⁺

HAIR CELLS: Both semicircular canals and Organ of Corti contain hair cells as sensory receptors.

• There are two types of hair cells.
• TYPE I HAIR CELLS: Synapses with only one large VIIIth nerve calyx.
• TYPE II HAIR CELLS: Can synapse with multiple VIIIth nerve calices.
• STRUCTURE: Hair cells are bipolar, sort of like epithelial cells (but they aren't epithelia).
• Stereocilia are on the apex of the bipolar neuron. They are the sensory apparatus.
• VIIIth Afferents are at the base (basal end) of cell.
• FNXN: Hair cells have a resting level of activity, which is up-regulated or down-regulated according to which direction the stereocilia move.

UTRICLE + SACCULE MACULAE: The part of the Utricle and Saccule containing the sensory apparatus.

• STRUCTURE:
• Stereocilia stick up into a gelatinous area, on top of which lie Otolith Crystals (CaCO₃).
• Stereocilia lie on top of a hardened Cuticular Plate, which keeps them in place at the base.
• FNXN: Otolith crystals shift and come to rest as you move around ------> deform gelatinous layer ------> move the stereocilia ------> change in membrane potential.
• UTRICLE is adjacent to the Semicircular Canals.
• SACCULE is adjacent to the Cochlea and continuous with the Scala Vestibuli compartment.

SEMICIRCULAR CANALS CRISTA AMPULLARES: The sensory part of each semicircular canal.

• CUPULA: Stereocilia stick up into a little dome shaped structure in the Crista Ampullares.
• FNXN: The Cupula deflects according to the movement of the Endolymph Fluid inside the semicircular canals ------> move the stereocilia.
• Stereocilia move toward kinocilium ------> depolarization
• Stereocilia move away from kinocilium ------> hyperpolarization

COCHLEA:

• MODIOLUS: The central "shaft" of the Cochlea, around which it screws.
• The modiolus contains the Cochlear Nerve (VIII)
• SPIRAL GANGLION: The starting point of the VIIIth nerve, it is in the Modiolus at the base of the Spiral Lamina.
• STRUCTURE: Each turn of the Cochlea has three compartments.
• SCALA MEDIA: Endolymph. The Scala Media contains the sensory hair cells and the Organ of Corti
• TECTORIAL MEMBRANE is inside the scala media, right on top of the hair cells.
• FNXN: Shearing Force is created by movement of the Tectorial Membrane across the hair cells. Sound waves cause the tectorial membrane to move.
• The Tectorial Membrane tends to move in an opposite direction as Basilar Membrane. This aids in the shearing force.
• This shearing force transduces the mechanical sound wave into an electrical stimulus.
• Interdental Cells secrete the glycoprotein substance that makes up the Tectorial Membrane.
• STRIA VASCULARIS: Highly vascular epithelium forming one wall of the Scala Media.
• FNXN: It secretes endolymphatic fluid.
• SCALA TYMPANI: In cross section, it is the section below each Scala Media, below the Basilar Membrane.
• BASILAR MEMBRANE: It separates the Scala Media from the Scala Tympani. It forms the base of the Scala Media.
• The Organ of Corti, containing sensory hair cells, lies on the basilar membrane.
• The Basilar Membrane is kept in place by the OSSEUS SPIRAL LAMINA on one end (nearest the spiral ganglion), and by the Spiral Ligament on the other end (nearest the lateral bony wall).
• SCALA VESTIBULI: In cross section, it is the section above each Scala Media, above the Vestibular Membrane.
• VESTIBULAR (REISSNER'S) MEMBRANE: Very delicate membrane separating the Scala Media from the Scala Vestibuli.
• The Scala Vestibuli is continuous with the Oval Window. It therefore conducts sound waves, through perilymph, toward the apex of the Cochlea.
• ORGAN OF CORTI: It is located in the Scala Media, atop the Basilar Membrane.
• INNER HAIR CELLS: Nearer the middle, adjacent to Tectorial Membrane. They are closer to the Modiolus.
• There is usually only one single row of inner hair cells.
• FNXN: These cells are the primary sound receptors. They respond to shearing movements of the Tectorial Membrane.
• Inner Hair Cells send primary VIIIth Afferents into the CNS, via the Spiral Ganglion.
• OUTER HAIR CELLS: There are more of them, located laterally, away from the tectorial membrane. They are closer to the Stria Vascularis.
• They are in multiple rows.
• FNXN: These cells can move the basilar membrane and can "tune" the frequencies of the basilar membrane.
• Outer Hair Cells get input from primary VIIIth Efferents coming from the CNS. These efferents will act on the outer hair cells, causing them to modify the shape of the basilar membrane.
• SUPPORT CELLS: There are lots of support cells besides the ones listed below.
• PHALANGEAL CELLS: Cochlear support cells, both Outer and Inner, corresponding to the Outer and Inner hair cells.
• PILLAR CELLS (RODS OF CORTI): Cochlear support cells.
• DAMAGE to hair cells can occur with loud sounds. This is due to too much movement of the Basilar Membrane.
• FREQUENCY SELECTIVITY: Sound is mapped to different parts of the Cochlea according to frequency.
• Outer part (base) of Cochlea transduces high frequency waves
• Inner part (apex) of Cochlea transduces low frequency waves.

BENIGN PAROXYSMAL POSITIONAL VERTIGO (BPPV):

• PATHOPHYSIOLOGY: In the semicircular canals, otoliths become dislodged and filter down on top of the Cupula.
• This causes the Semicircular Canals to behave as though they were gravity (linear acceleration) detectors when in fact they are angular acceleration detectors.
• Misplacement of otoliths thus results in Vertigo.
• ETIOLOGY: Idiopathic, by head trauma, or by viral disease
• SYMPTOMS: Vertigo, and no associated hearing loss.
• DIAGNOSIS
• Dix-Hallpike Maneuver is a test for vertigo. Have patient rapidly place one ear down with head hanging off a table. Resultant vertigo makes for a positive test.
• Nystagmus is a sign of dizziness. It should come o, after some latency period, when patient changes head-position. Then, it should go away after a while.
• Electronystagmography (ENG) is a way to quantify Nystagmus.
• TREATMENT
• Physical Therapy do repetitive exercise to fatigue the vertigo response out and desensitize it. Fairly high success rate.
• SURGERY:
• Canal Procedures: Block off membranous portion of inner ear so that cupula cannot move.
• Nerve Section is dangerous procedure

MENIERE'S DISEASE:

• TRIAD OF SYMPTOMS: Patient will get ringing in ear, then a "fullness" in ear, then hearing loss will drop off, then vertigo.
• Tinnitus (ringing in ear)
• Fluctuating Hearing Loss
• Episodic Vertigo
• ETIOLOGY: Idiopathic, Traumatic, Post-Syphilis, Viral
• PATHOPHYSIOLOGY:
• TRAUMA: Damage to the Endolymphatic Sac; you can't absorb endolymph fluid ------> fluid overload.
• Vestibular Membrane ruptures from buildup of inner fluid and pressure.
• Hair Cell Toxicity then occurs from mixing of endolymph and perilymph fluids. Some cell death. They think the membrane can heal itself, hence resultant hearing loss is only temporary.
• TREATMENT: Most common treatment is medicine designed to decrease the amount of inner ear fluid.
• Salt balance / diuretics play a big role in treatment.
• Meclizine-Antivert, Valium, and Compazine can all be used as Vestibular suppressants.
• SURGICAL: Only if they don't respond well to medicine.
• Endolymphatic Shunt:: A surgical method that enhances the fluid-resorption of endolymphatic fluid.
• Vestibular Nerve Section (not preferred) in the case of severe Vertigo. The problem is that this treatment is only symptomatic.
• Labyrinthectomy: Removal of semicircular canals, resulting in complete destruction of all of VIII -- both Vestibular and Cochlear.
• Oscillopsia is a terrible visual side-effect where people bounce up and down.
• PROGNOSIS: Progressive, untreated Meniere's disease leads to irreversible hearing loss. Early treatment is therefore essential.

SENSORINEURAL HEARING LOSS: Congenital hearing loss.

• ETIOLOGY: Sometimes the problem is with CN VIII, but more often the problem is with the sensory hair cells.
• MICHEL HEARING LOSS: The worst congenital deafness. No development of cochlea.
• MONDINI HEARING LOSS: Cochlea develops only about 1 turns.
• The resultant hearing-level varies greatly, from nearly normal to virtually deaf.
• SCHEIBE HEARING LOSS: Normal cochlea and vestibule. Problem is strictly with the hair cells.
• NEURAL DAMAGE?: If the nerve is normal, than corrective surgery can be done of some form or another. If the nerve (including the hair cells, which are considered part of the nerve) did not develop or are abnormal, then nothing can currently be done, although some experimental things are being worked on.

INFECTIOUS HEARING LOSS: Hearing loss from infection.

• TORCH: Toxoplasmosis, Rubella, Cytomegalovirus, Herpes, can all result in hearing loss.
• Meningitis -- probably most common cause of acquired hearing less.
• Syphilis results in endolymphatic hydrops which causes a variety of problems in the inner ear.

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UPPER AIRWAY EPITHELIA: Pseudostratified Columnar Ciliated Epithelium is throughout the upper airways, with five exceptions.

• EXCEPTIONS:
• Nasal Vestibule
• Olfactory Mucosa
• Nasopharynx
• Epiglottis
• True Vocal Cords
• As we progress down the airways, epithelia gradually change shape: Pseudostratified Columnar ------> Simple Columnar ------> Cuboidal ------> Simple Squamous

OLFACTORY MUCOSA: Olfactory receptors are located on Superior Concha, adjacent Nasal Septum, and roof of nasal cavity.

• BIPOLAR CELLS: Their nuclei approximately form the middle layer of the mucosa. These are the olfactory nerves.
• Olfactory Cilia: The apical part of the Bipolar Cell. Proximal part forms typical cilia, but the distal parts are the olfactory receptors.
• BASAL POLE: Basal parts of the bipolar cells will go through cribriform plate ------> olfactory bulb
• OLFACTION PATHWAY (proposed): Odorant molecule binds to transmembrane receptor ------> GTP hooks to G-Protein and cAMP is released ------> open ligand-gated cation channels to change membrane potential.
• SUSTENTACULAR CELLS: Their nuclei approximately form the outer layer of the mucosa.
• They are supportive cells with cilia. Function is poorly understood.
• BASAL CELLS: Their nuclei approximately form the lower layer of the mucosa. Supportive cells. Some of them serve as Bipolar-Cell precursors.
• BOWMAN'S GLANDS: Serous glands secrete substance that bathes the odorant chemicals and continuously removes them from nasal mucosa.
• This secretion is necessary for olfaction. You can't smell without it.
• The olfactory mucosa contain no goblet cells and no motile cilia.

LARYNX:

• TRUE VOCAL CORDS contain Stratified Squamous Epithelium on the anterior aspect.
• FALSE VOCAL CORDS: Normally pseudostratified columnar. Metaplastic epithelia will develop with laryngeal cancer.

TRACHEA:

• TRACHEAL LAYERS
• Epithelium: Pseudostratified Columnar Ciliated.
• Goblet Cells are found in the epithelium.
• Lamina Propria forms extended, highly vascular basement membrane.
• Submucosa contains numerous mixed (sero-mucous) glands that secrete mucous into respiratory lining.
• Cartilage Rings: Hyaline cartilage forms the outer layer of the trachea, interspersed with fibro-elastic tissue between the cartilage rings.

BRONCHI: Next several generations

• LAYERS: PRIMARY BRONCHI
• Epithelia: Pseudostratified Columnar, but less tall and with fewer goblet cells than trachea.
• Lamina Propria contains lots of elastins and mast cells
• Histamine / ACh will both cause bronchoconstriction and vasodilation, leading to mucosal swelling and asthma.
• Epinephrine / Atropine will both cause bronchodilation.
• Smooth Muscle layer beneath the lamina propria
• Submucosa which also sort of intermixes with the smooth muscle
• Cartilage: flattened, interconnected plates, rather than C-Shaped rings.
• SEGMENTAL BRONCHI: Epithelia continue to shrink.
• SMALLER BRONCHI: The next few generations, I guess.

MUCOUS: Functions

• Glycoproteins trap particles in the airways, which are then cleared by epithelial cilia.
• ANTIBACTERIAL: Mucous has several antibacterial agents:
• Peroxidase
• Lysozyme
• Immunoglobulins (not sure which one)
• Lactoferrin

BRONCHIOLES: At about the 19th generation, you first begin to see small isolated alveoli attaching to the airway.

• LAYERS:
• Epithelia: Simple columnar (shorter) or cuboidal; ciliated. Few or no goblet cells.
• Lamina Propria is much smaller than before
• Smooth Muscle layer is prominent, in highest relative proportion at this level.
• No cartilages.
• CLARA CELLS: Non-ciliated bronchiole cells.
• Prominent SER, possibly related to cholesterol synthesis.
• SURFACTANT PROTEIN A synthesis has been localized to these cells. Of course, no surfactant is found at this level.
• SENSORY CELLS:
• Brush Cells: Non-Ciliated cells in the Bronchioles. They have well-defined microvilli. Sensory function is unknown but proposed.
• Granulated Cells: Contains serotonin, calcitonin, enkephalins, + other neuropeptides. Nerve terminals.
• FNXNS:
• They are proposed to have a sensory function because of nerve terminals: recognition of hypoxia (such as with high altitude) ------> bronchodilation
• They also cause (induce) the differentiation of lung epithelia, via bombesins
• ENDOCRINE CELLS: They aggregate into Neuroepithelial Bodies; they have nerve fibers terminating in the area, and again have proposed sensory features.

ALVEOLAR DUCTS, ALVEOLI:

• ALVEOLAR CELL TYPES:
• Endothelial Cells (42%): Endothelial cells of pulmonary capillaries are the most prevalent cells
• Interstitial Cells (35%)
• Type II Pneumocytes (13%): Surfactant-secreting
• Type I Pneumocytes (11%): Gas-exchange pneumocytes
• TYPE-I PNEUMOCYTES: Squamous cells that cover about 97% of surface area, because they wrap around the endothelial cells.
• The gas-exchange wall is called the Alveolar Septum
• IDENTIFY: Type-I Pneumocytes won't be typical cellular shape because they are wrapped around. If you can see a cellular shape, then it is either a Tpe-II cell or a Macrophage.
• FNXNS: Primary function is gas exchange
• Reuptake of old surfactant through constitutive pinocytosis.
• REGULATION: In the adult, surfactant secretion is stimulated by hyperventilation and beta-adrenergic agonists.
• TYPE-II PNEUMOCYTES: Surfactant factories; cuboidal epithelia
• LAMELLAR BODIES are released via exocytosis, containing surfactant. Once inside, they unravel and form surface film surfactant.
• Type II pneumocytes are progenitors of Type I Pneumocytes, developmentally.
• PULMONARY CAPILLARY ENDOTHELIAL CELLS:
• FNXNS:
• They make Angiotensin Converting Enzyme (ACE): Which converts Angiotensin I to Angiotensin II ------> potent vasoconstriction.
• ALVEOLAR MACROPHAGES: They're there. Reuptake of surfactant, debris, etc.
• They are carried up to pharynx by ciliary action and swallowed.
• FIBROBLASTS: They're there. They will cause contraction following injury or insult to lung tissue.
• ALVEOLAR PORES of KOHN: Openings in alveolar wall. They serve to equalize intra-alveolar pressure, for communication, and to provide collateral routes for ventilation.
• NERVOUS REGULATION:
• PARASYMPATHETIC STIMULATION:
• Secretomotor to all pulmonary glands except individual goblet cells (which respond to local factors)
• Bronchoconstriction
• SYMPATHETIC STIMULATION: Is bronchodilatory via inhibition of parasympathetics.
• Sympathetics have little effect on pulmonary blood vessels.

IMMOTILE CILIA SYNDROME (ICS): Congenital impaired ciliary function, not only in lungs but in other places where cilia are required.

• Pulmonary Symptoms: Productive Cough, Sinusitis, Nasal Polyps, Airway Obstruction Other Abnormal Symptoms that often appear with lung disease:
• Non-Pulmonary Symptoms that often also appear:
• Otitis Media
• Situs Inversus -- reversal of location of organs
• Digital Clubbing
• Infertility
• ETIOLOGY: Several structural defects in microtubules can occur. Many of these defects are also common to male infertility.
• STRUCTURAL DEFECTS:
• Dynein defects: Lack of dynein arms in microtubules seems to be most common problem.
• Defects in Nexin links
• Radial Spoke defects
• Microtubular Transposition defects.
• NON-SYNCHRONOUS BEATING: Defects can also occur due to mis-orientation of the direction of the cilia with respect to the basal membrane.
• Basal Foot extends away from basal body in a random fashion rather than an ordered fashion resulting in non-synchronous beating.

SURFACTANT: Yeah that sexy soapy suds -- surfactant.

• FNXN: Reduce surface tension of alveoli.
• COMPONENTS:
• Dipalmitoylphosphatidylcholine (DPPC): 40%
• Unsaturated Phosphatidylcholine: 25%
• Other phospholipids 15%
• Surfactant-Associated Proteins 10%
• SURFACTANT-ASSOCIATED PROTEINS:
• SURFACTANT-ASSOCIATED PROTEIN A (SAP-A):
• FNXNS:
• Participates in tubulomyelin formation, thus it directly helps reduce surface tension.
• Involved in Receptor-Mediated endocytosis (reuptake) of surfactant
• Activates lung macrophages
• Regulates surfactant secretion
• SAP-A helps prevent bacteria overgrowth in IRDS.
• SURFACTANT-ASSOCIATED PROTEIN B (SAP-B)
• FNXN:
• Inhibits surfactant phospholipid synthesis.
• Aids in reduction of surface tension.
• They are lipophilic and remain in lipid-soluble extracts used for IRDS drug-therapy.
• SURFACTANT-ASSOCIATED PROTEIN C (SAP-C)
• FNXN:
• Inhibits surfactant phospholipid synthesis.
• Aids in reduction of surface tension.
• They are lipophilic and remain in lipid-soluble extracts used for IRDS drug-therapy.
• TURNOVER: Surfactant turns over every few hours.
• Type-I Pneumocytes and macrophages reuptake surfactant. Type-II cells may reuptake some, too.
• REGULATION OF SURFACTANT SECRETION
• MAIN PATHWAY: Glucocorticoids cause fibroblasts to make Fibroblast Pneumocyte Factor (FPF) ------> stimulates Type II Pneumocytes to synthesize surfactant.
• INHIBITORY to pathway:
• Testosterone inhibits Type-II pneumocytes and fibroblasts in this pathway.
• Insulin inhibits the pathway through one or the other cell; thus diabetic mother's fetuses are at higher risk for IRDS.
• STIMULATORY to pathway:
• Estrogen stimulates both Type-II pneumocytes directly, and fibroblasts in this pathway.
• Thyroid Hormone stimulates Type-II cells directly but does not affect fibroblasts.

INFANT RESPIRATORY DISTRESS SYNDROME (IRDS): Also called Hyaline Membrane Disease

• ETIOLOGY: Premature birth, or delayed or absent surfactant production.
• 36-37 weeks (slight premie): surfactant is usually OK.
• 28-31 weeks: You see a lot of IRDS babies.
• PATHOPHYSIOLOGY:
• Lack of surfactant causes the lungs to collapse with each breath.
• SYMPTOMS: Look for the following symptoms in the baby
• Tachypnea
• Flaring of the nose
• Cyanosis
• Grunting (to create positive pressure)
• INFANTILE CONSEQUENCES: Cranial Hemorrhage can occur with IRDS, but I'm unsure why.
• ADULT CONSEQUENCES of IRDS: Three classic adult consequences with severe cases
• Chronic Lung Disease
• Neurologic Impairment
• Visual Impairment / Retinal Disease
• TREATMENT:
• HISTORICAL TREATMENTS:
• Continuous Positive Airway Pressure (CPAP): 1970's, increases pressure in lungs and expands them. However, continuous pressure can damage the lungs.
• AEROSOL: Early aerosol contained DPPC but no protein component.
• Bovine Surfactant was developed, containing a protein component which they found was necessary for effective treatment. PROBLEMS:
• There was a risk of contracting infectious disease using it (that's why its no longer used anymore).
• There were antigen problem in interacting with the babies lungs.
• EXOSURF: Synthetic surfactant with no protein component, but with a synthetic substitute.
• It contains DPPC as the detergent, plus Tyloxapol as an agent to replace the protein.
• This drug acts a lot more slowly than agents containing SAP proteins.
• The drug also appears to help prevent bacterial overgrowth (such as pneumonia) that comes with IRDS. SP-A will do the same thing, but Exosurf appears to be a suitable substitute for this function.
• Glucocorticoids are administered before birth, when IRDS is suspect.
• EXOSURF CLINICAL TRIALS were performed with fetal rabbits:
• Experiment Groups: Placebo was plain air.
• Prophylactic Treatment: exosurf -vs- placebo, given to at-risk infants before their first breath.
• Prophylactic Treatment: Three doses exosurf -vs- one placebo
• Rescue Treatment: Exosurf -vs- Placebo, only given once IRDS symptoms set in.
• MEASUREMENTS: If one of the below proved to be true, then prophylactic treatment was not indicated and subject was excluded.
• Lecithin/Sphingomyelin (L/S) Ratio: If it is high enough, it indicates that there is no IRDS.
• Phosphatidylglycerol presence indicates no IRDS.
• RESULTS showed decreased mortality, but residual effects from IRDS.
• Rescue Trials showed that exosurf decreased intracranial hemorrhaging.
• EXOSURF SIDE EFFECTS: 4% adverse side-effects in the trial; generally the drug was considered to be safe.

LUNG DEVELOPMENT: The lung develops as a lung bud derived from developing foregut.

• ENDODERM: Airway epithelia + alveoli derive from endoderm.
• MESODERM: Cartilages, muscle, blood vessel, pleura derive from mesoderm.
• EMBRYOLOGY STAGES:
• Pseudoglandular Stage: First 16 weeks; all major branches of conducting airways are formed.
• Epithelia are in the form of non-differentiated columnar cells.
• Canalicular Stage: Up to 24 weeks; primitive pneumocytes appear at this stage.
• (Type II) Epithelia are now cuboidal, with lamellar bodies intact.
• Terminal Sac (Saccular) Stage: 24 weeks to term.
• Fully differentiated epithelia.
• LUNG CELL LINEAGE:
• Basal Cell ------> Basal Cell
• Mucous Progenitor ------> Goblet Cell, Clara Cell, Serous Cell ------> Ciliated Epithelia
• Type II Pneumocyte ------> Type II Pneumocyte ------> Type I Pneumocyte
• Type I Pneumocytes develop from Type-II Pneumocytes!
• Endoderm ------> Endocrine Cell
• Monocyte ------> Macrophage

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EPIDERMAL LAYERS: The following layers constitute the EPIDERMIS

• STRATUS BASALE: Contains Stem Cells. Some minimal cell division occurs in this layer.
• HEMIDESMOSOMES: They hook the stratum basale cells to the underlying basal lamina.
• TONOFILAMENTS are through the cells, connected to the hemidesmosomes, forming cytoskeletons.
• Desmosomal Junctions, as well as hemidesmosomes, are prominent between cells.
• STRATUM SPINOSUM: This is the main proliferative layer. Some synthesis begins in this level too.
• Membrane-Coating Granules (MCG) begin formation in this layer, near the top.
• STRATUM GRANULOSUM: This is the mature synthetic layer, where cells are synthesizing the granular components (Keratin, MCG) of skin.
• KERATOHYALIN GRANULES are formed in this layer.
• FILAGGRIN (F) GRANULES: Filaggrin granules will ultimately be released into the stratum corneum.
• Rich in Histidine
• FNXN: Filaggrin causes tonofilaments to clump together. It serves to pack tonofilaments together in cell in the stratum corneum.
• LORICRIN (L) GRANULES: Another Keratin granule. It coats the inner surface of the cell envelope in the stratum corneum.
• Rich in Cysteine
• MEMBRANE-COATING GRANULES (MCG): MCG's are discharged into the granular layer, in the intracellular spaces.
• FNXN: They help make the skin impermeable to water.
• (STRATUM LUCIDUM): Only thick skin, a thin layer of flat cells marking the uppermost border of the Stratum Granulosum. They aren't apparent in thin skin.
• STRATUM CORNEUM: 15-20 layers of dehydrated, non-nucleated keratinocytes, packed with tonofilaments containing filaggrin.
• The cell membrane in the Stratum Corneum is thickened because it is lined with Membrane Coating Vesicles.

DERMIS: Highly vascular layer underlying the epidermis.

• Cell-Types Found in the Dermis:
• Langerhorn's Cells
• The base of hair follicles
• PAPILLARY LAYER: Immediately underlying epidermis.
• RETICULAR LAYER: Forms the extracellular bulk of the dermis, with lots of capillaries interspersed.

HYPODERMIS: Below the dermis. Pale-staining because of fat cells.

• This layer is equivalent to gross-anatomy superficial fascia.

THIN SKIN: Overlies most of the body and contains no stratum lucidum.

THICK SKIN: Has a prominent (i.e. large) stratum corneum and an identifiable stratum lucidum.

• DISTRIBUTION: Thick skin is primarily found on palms of hand and soles of feet.
• MEISSNER'S CORPUSCLE'S are found in thick skin, in the papillary layer of the dermis.
• It is surrounded by epidermal pegs on both sides.
• They are tactile receptors

MELANOCYTES:

• DEVELOPMENT:
• They are of neural crest origin.
• Early in development they migrate to the dermis.
• Later in development they migrate to the basal layer of the epidermis, where they remain.
• RACIAL DIFFERENCES:
• The number and nature of melanocytes is relatively constant across races.
• Skin color is determined by the size, number and aggregation-pattern of melanosomes (melanin pigments) present in epithelial cells.
• BLACK SKIN: Large melanosomes, greater in number, and evenly distributed.
• WHITE SKIN: Smaller melanosomes, fewer in number, and aggregated into groups.
• In white skin, many of the pigment granules will be degraded in epithelial cells.
• STRUCTURE: Melanocytes have dendritic processes.
• MELANIN PIGMENT: Multiple types all derive from Tyrosine
• Premelanosomes are assembled from Tyrosinase (from RER) and structural proteins / granules from SER.
• Tyrosinase then transforms Premelanosomes into melanosomes. In this process DOPA is oxidized by tyrosinase.
• EPIDERMAL MELANIN UNIT: Functional unit of one melanocyte, plus around 36 keratinocytes (i.e. skin cells) that it serves. The mature keratinocytes will all have endocytosed melanin from the one melanocyte in the basal layer.
• Cytocrine Secretion is the process by which melanin pigment is exocytosed through the dendritic processes of melanocytes.
• MELANOCYTES -VS- KERATINOCYTES:
• Keratinocytes have extensive desmosomes and hemidesmosomes. Melanocytes don't.
• You can see tonofilaments in keratinocyte cytoplasm. Melanocytes don't have tonofilaments.
• MELANOCYTE STIMULATING HORMONE (MSH): It stimulates (1) melanocyte synthesis and (2) melanocyte cytocrine secretion into epidermal cells.
• ADDISON'S DISEASE: Hyperpigmentation from deficient cortisol ------> increased ACTH (Adrenal Corticotropin Hormone) ------> increased MSH ------> increased melanosomes.
• Addison's Disease is a pathological deficiency of Cortisol, leading to chronically high ACTH.

LANGERHORN'S CELLS: Antigen-Presenting Cells in the Dermis and Epidermis, derived from bone-marrow.

• DISTRIBUTION:
• Stratum Spinosum of Epidermis
• Dermis
• Hair follicles
• Sweat glands: Apocrine and Sebaceous
• They contain Granules of Birbeck which look like two tennis racquets with handles facing opposite each other (yeah right??)

MERKEL CELLS: Forms Merkel's DIsk in the stratum basale of the epidermis.

• Neuroendocrine cell; it is considered to be a sensory receptor.

PACINIAN CORPUSCLE: Located in the dermal-hypodermal junction -- very deep. They are mechanoreceptors.

HAIR:

• Three hair types:
• Lanugo Hair: Prenatal hair; very fine and unpigmented.
• Vellus Hair: Pre-pubescent, non-pigmented hair; peach fuzz.
• Terminal Hair: Hair on scalp; and adult pubic and axillary hair.
• DEVELOPMENT: Pilosebaceous Apparatus grows as a downgrowth of the epidermis that pokes into the dermis.
• Apocrine Sweat Glands, Arrector Pili, and sebaceous glands grow in association with this downgrowth, surrounding the hair follicle.
• CELL-TYPES:
• Inner Root-Sheath Cells grow in the same fashion as epidermal cells.
• Cuticle Cells accumulate large granules but no tonofilaments.
• Cortical Cells have tonofilaments but no granules.
• Medullary Cells have huge granules but no tonofilaments.
• HAIR GROWTH CYCLE:
• ANAGEN PHASE: Growth period extends for 2 - 6 years.
• 80-90% of hair is in this phase at any point in time.
• CATAGEN PHASE: Regression period takes 2 - 3 weeks.
• TELOGEN PHASE: Resting period takes 3 - 4 months.
• 10-20% of hair is in this phase, and is thus shedding.
• After Telogen phase, the old hair shaft is shed and a new one appears.

SWEAT GLANDS:

• SEBACEOUS GLANDS:
• SECRETION: HOLOCRINE The entire cell is lysed and secreted as sebum.
• FNXN of sebum may be water-barrier or bacteriocidal. It is not clear.
• Sebaceous glands begin secretion at puberty.
• MEROCRINE (ECCRINE) GLANDS:
• SECRETION: Glands open into sweat ducts that carry sweat to skin.
• MUCOUS and SEROUS glands are both present in merocrine glands.
• DISTRIBUTION; Virtually everywhere on body except genitals. High concentration in thick skin of palms of hand and sole of foot.
• SWEAT composition: Hypotonic, with active ion resorption in the ducts.
• STIMULATION of eccrine sweat glands is cholinergic
• STIMULATED by heat primarily (thermoregulation) but also by anxiety (as in sweaty palms).
• APOCRINE GLANDS:
• DISTRIBUTION
• Axilla
• Anogenital Region
• Eyelid
• External Auditory Meatus
• STIMULUS is both adrenergic and cholinergic.
• STRUCTURE: The sweat ducts open into hair follicles, and myoepithelial cells help secretion.
• SECRETION: Odorless when excreted, but smells like body odor once it has undergone bacterial decomposition and fatty acids are created.

NAIL:

• Nail Bed underlies the nail.
• Nail Bed Epithelium looks like skin but has no granulosum layer.
• Hyponychium: skin underlying the tip (distal edge) of the nail.
• Paronychium: Lateral nail folds; skin around the lateral edge of the nail.

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LAYERS OF THE GI TRACT:

• MUCOSA: Composed of three layers
• EPITHELIUM
• LAMINA PROPRIA:
• MUSCULARIS MUCOSA: Smooth muscle intermixed with the lamina propria.
• FNXN: Contraction of the muscularis mucosa allows for epithelial motility; mixing, propulsion, etc.
• SUBMUCOSA: Collagenous connective tissue; vascular tissue; glands
• SUBMUCOSAL PLEXUS: Enteric nerves in the submucosa.
• MUSCULARIS EXTERNA:
• MUSCULARIS CIRCULARIS: Circular Layer
• MYENTERIC PLEXUS: Enteric nerves between the two layers of external muscle.
• MUSCULARIS LONGITUDINALIS: Longitudinal Layer
• ADVENTITIA (SEROSA): Several layers of loose connective tissue; the mesentery.

ESOPHAGUS:

• MUSCULATURE:
• Upper 1/3 SKELETAL
• Middle 1/3 is Skeletal + Smooth
• Lower 1/3 SMOOTH
• EPITHELIUM: The esophagus has stratified squamous epithelia.
• So does the oral cavity and anus. The rest of GI has simple columnar epithelium.

STOMACH:

• STRUCTURE: It has a thick muscularis layer and thin submucosa.
• CELL TYPES:
• PARIETAL (OXYNTIC) CELLS:
• RESTING: Parietal cell has TUBULOVESICLES and abundant mitochondria. Tubulovesicles are the acidic vesicles that are later exocytosed. Three ion channels create the acid:
• H⁺/K⁺-ATPase pumps H⁺ into lumen of vesicle.
• Carbonic Anhydrase provides the source of H⁺ (and HCO₃^- which exits as alkaline tide)
• Cl^--Channel ejects Cl^- into lumen (to form HCl)
• Na⁺/K⁺-ATPase maintains concentration gradient.
• ACTIVE: Tubulovesicles fuse with the apical plasma membrane to exocytose the H⁺. This forms INTRACELLULAR CANALICULI near the apical membrane.
• Tubulovesicles are no longer present in active parietal cells.
• Active parietal cells have long, secreting microvilli on the apical surface. These microvilli essentially were the former tubulovesicles.
• Tubulovesicles can be distinguished from microvilli because microvilli have actin in them and tubulovesicles don't.
• MUCOUS NECK CELLS: Are located along the villi of the stomach.
• MUCOUS is made of proteoglycan which forms a slippery film that protects stomach epithelium from acid. Functions in the stomach and intestine:
• Protection from digestive enzymes
• Provides HCO₃^- pH buffer from acidic chyme
• Provides a sticky environment for IgA to stick to
• Lubricant
• CHIEF (ZYMOGENIC) CELLS: Secrete pepsinogen. From cuboidal to pyramidal in shape.
• ENTEROENDOCRINE CELLS: Secrete a variety of hormones into GI-System.
• They have reversed polarity, as they secrete the hormones into the blood space rather than GI-Lumen.
• G-CELLS secrete gastrin.
• E-CELLS secrete somatostatin.
• HELICOBACTER PYLORI: Implicated in lots of diseases.
• Gastric Ulcers; Gastric Cancer; Duodenal Ulcers; Gastritis
• MECHANISM: Proposed is that bacteria are ingested and get into stomach epithelium ------> cause inflammation which increases permeability of gastric mucosa ------> acid invades and you get gastritis symptoms and ulcers.
• OMEPRAZOLE: H⁺/K⁺-ATPase blocker for ulcers.
• ANTIBIOTICS are employed to fight H. Pylori.
• GASTRIC RESTITUTION: Acid-damaged gastric epithelia are replaced by new tissue.
• Epithelia extend lamellipodia which stretch out over to cover the denuded area.
• Lamellipodia mechanism involves actin and cytoskeleton reorganization.
• PYLORUS: We must be able to distinguish Pylorus from Body of Stomach:
• The Pylorus has very shallow gastric pits or none at all.
• The Pylorus mas more highly branched glands -- almost exclusively mucous.

SMALL INTESTINE:

• CELL-TYPES:
• ENTEROCYTE: The principle absorptive cell, simple columnar epithelium.
• ULTRASTRUCTURE:
• It contains brush-border disaccharidases and peptidases which complete luminal digestion before absorbing nutrients.
• BASAL MEMBRANE: Facilitated diffusion occurs to transport the nutrients into the blood. Concentration gradient for this diffusion is maintained by constant influx of new nutrients.
• Glycocalyx: Rich carbohydrate layer on apical membrane that serves as protection from the digestional lumen, yet it allows for absorption.
• Terminal Web provides cytoskeleton; the cell is a polar epithelial cell.
• CARBOHYDRATE ABSORPTION:
• GLUCOSE / GALACTOSE: Na⁺-Cotransport
• FRUCTOSE: Facilitated transport
• PENTOSES (RIBOSE): Passive diffusion
• AMINO ACID ABSORPTION: Generally also Na⁺-Cotransport.
• FAT ABSORPTION:
• EMULSIFICATION by micelles. Bile salts facilitate the attachment of Pancreatic Lipase to the lipids.
• There is an unstirred water layer right at the villus border. Due to its detergent properties, micelles can penetrate that border.
• DIGESTION: PANCREATIC LIPASE then breaks down the triglyceride ------> monoglyceride + free fatty acids.
• Fatty Acids diffuse through enterocytes by simple diffusion.
• RE-ESTERIFICATION: Fatty acids are re-esterified to triglycerides inside the enterocytes.
• CHYLOMICRON FORMATION: Chylomicrons are formed as protein coats + cholesterol is added to the triglyceride.
• LYMPH: Chylomicrons enter circulation through lacteals ------> lymphatic system.
• Short Chain fats go directly into the portal blood -- not into lymph.
• GOBLET CELL: Secretes mucin in the small intestine. Unicellular exocrine glands distributed all along the villus.
• MUCOUS NECK-CELLS: See stomach.
• PANETH CELL: Protective, bacteriocidal cells that secrete lysozyme to break down bacterial cell walls.
• CRYPTS: Paneth cells are located strictly in Crypts of the villi.
• M-CELL: Overlies Peyer's Patches. Samples the gut lumen and transports it to the submucosa for sampling by Peyer's Patches.
• M-CELL do this by transcytosis of materials.
• Orally administered vaccines have promise to fight several diseases by this mechanism: Orally ingest antigen ------> M-Cell uptake ------> Peyer's Patches ------> Antibody production.
• ENTEROENDOCRINE CELLS:
• BRUNNER'S GLANDS: Produces alkaline fluid (HCO₃^-) which neutralizes stomach acid. Brunner's glands are localized to the crypt.
• CELL-RENEWAL / MIGRATION: Enterocyte lifespan is 4-6 days.
• CRYPT: Contains small population of self-renewing stem-cells that divide infrequently.
• These stem cells are the progenitors for nearly all
• VILLUS: Contains proliferative, migrating cells that divide frequently.
• Most cell types migrate upward toward the villus:
• Enterocytes
• Enteroendocrine Cells
• Paneth cells migrate downward toward the base of the crypt.
• PLICAE CIRCULARIS: Grossly visible folds in the small intestinal lining.
• This, coupled with villi and microvilli, make for a 600-fold increase in total absorptive surface area.
• VILLI:
• VILLUS CELLS: They are primarily absorptive -- i.e. enterocytes.
• CRYPT CELLS: They are primarily secretory. Small intestinal secretion occurs in the crypt.
• PEYER'S PATCHES: Lymphoid tissue in submucosa. The ileum has the highest concentration of Peyer's Patches.
• There is a flattened epithelium over Peyer's patches in the ileum, instead of columnar.
• Crypts of Lieberkühn: Deep crypts in small intestine that contain many goblet cells and few absorptive cells. Just another term for the villous crypts found in the small intestine.

CHOLERA:

• CHOLERA TOXIN STRUCTURE:
• BINDING SUBUNIT: Binds to the sugar portion of Ganglioside, GM1.
• ACTIVE SUBUNIT: It is inserted into membrane once other subunit is bound.
• It ADP-Ribosylates Apical Cl^- channels, blocking them OPEN ------> continual cAMP
• HIGH cAMP LEVELS result in severe secretory diarrhea by two pathways:
• Phosphorylates apical Cl^- channels ------> keeps them OPEN ------> secretory diarrhea
• Phosphorylates apical Na⁺/Cl^- Cotransporters ------> keeps them CLOSED ------> prevents Na⁺ from reentering.
• ORAL REHYDRATION THERAPY: Administer glucose solution, to facilitate Na⁺ resorption (and hence water) via Na⁺-Glucose reuptake.
• STARCH is even more effective than glucose, because it is equivalent in terms of its tonicity yet it provides a lot more glucose to the enterocytes for more water resorption.

LARGE INTESTINE:

• The large intestine has no villi or lamina propria, and the majority of Large Intestinal cells are goblet cells.
• FNXN: Water resorption by active Na⁺ transport.
• Acetylcholine will stimulate cell Goblet Cell secretion. Lost membrane is continually replaced by constitutive pinocytosis.
• SMALL INTESTINE -VS- LARGE INTESTINE: The Small Intestine has a lamina propria and villus, while the large intestine does not. This is the distinguishing feature between the two.

SALIVARY GLANDS:

• SALIVA:
• Salivary Amylase: Secreted primarily by Parotid gland.
• Amylase normally operates at pH 7-8 and is therefore inactivated once in the stomach. However, if it is inside a bolus of food and protected on all sides then it can still be active even in stomach.
• Mucus: Secreted by the other glands (Mandibular and sublingual).
• FNXN: Lubrication of food and it serves as a buffer.
• Lactoferrin: Binds Fe in mouth, preventing bacteria from getting it. It thereby serves as an antibacterial role.
• Lingual Lipase: Released from tongue itself, allows easy movement of fats on the tongue.
• It can serve a backup function in case pancreatic lipase is lacking.
• Secretory IgA: Antibacterial secretions.
• Lysozymes: Antibacterial secretions.
• SALIVARY DUCTS:
• CELL TYPES:
• ACINAR CELLS: Secretory cell secretes saliva into ducts.
• MYOEPITHELIAL CELLS: Contractile cells extend over the acinar cells and ductal cells.
• (SEROUS CELLS): Secrete clear substance containing protein.
• Their cytoplasm stains well.
• Indistinct cell boundaries.
• Parotid Gland is strictly serous; primary secretory of amylase.
• (MUCOUS CELLS): Secrete mucous.
• STRUCTURE: Larger, triangular with apex of triangle projecting toward the lumen of the salivary duct.
• SALIVARY DUCTS: Membrane is water-impermeable ------> hypotonic saliva.
• INTERCALATED DUCTS: They have low cuboidal epithelium and associated myoepithelium.
• STRIATED DUCTS: Contain Striated Ductal Cells: simple columnar.
• They are specifically responsible for resorbing Na⁺ to aid in hypotonic solution. They have characteristic basal infoldings associated with this function.
• INTERLOBULAR DUCTS: Join the main excretory duct that leads to oral cavity; stratified cuboidal or stratified columnar
• PATHWAY of SALIVATION: Acinus ------> Intercalated Ducts ------> Striated Ducts ------> Interlobular Ducts ------> Oral Cavity.
• Parotid Gland: Strictly Serous
• Submandibular Gland: Mixed Seromucous
• Sublingual Gland: Mixed seromucous, but mucous predominates.

SECRETORY IgA: An immobilizing antibody that "traps" pathogens to stop their activity.

• STRUCTURE:
• Two monomeric IgA molecules attached by a J-Chain. This structure is assembled by the antibody cell.
• J-Chain gives protease resistance to the molecule so it is not so rapidly degraded.
• Secretory Component is made by the enterocyte epithelial cell.
• PROCESS:
• Secretory component starts off as an enterocyte membrane receptor.
• Receptor-Mediated Endocytosis of the IgA from the blood space.
• The IgA-Receptor Complex is then cleaved, leaving part of the secretory component on the IgA. This is now called Secretory IgA.
• The secretory IgA is then exocytosed into lumen.

ORAL TISSUES:

• Filiform Papillae: Anterior 2/3 of tongue, covering most of surface; no taste buds.
• Conical in shape.
• Fungiform Papillae: Scattered among the filiform papillae. Taste buds may be found on them. They are larger and more vascular.
• VON EBNER'S GLANDS in tongue secrete lingual lipase.
• Circumvallate Papillae: Posterior 1/3 of tongue, along V-Shaped dividing line between anterior-and posterior of tongue. They have lots of taste buds.

PANCREAS:

• EXOCRINE PANCREAS: PANCREATIC ACINAR CELLS
• GRANULE MATURATION: Secretory proteins "mature" as they progress through the RER and Golgi, and form into granules.
• Condensing Vacuoles are the names of the early secretory granules (containing digestive zymogens) that bud off from the trans-Golgi.
• MATURATION at that point serves two purposes:
• Maturation allows the granules to become relatively anhydrous so that they don't become proteolytically active intracellularly.
• Maturation also allows for compact, efficient storage of zymogens
• Mature Granule is stored in apical part of cell until stimulated for secretion. This is different than hepatocytes which do not store granular material.
• Junctional Complexes create polarized cells; exocytosis only occurs at the apical pole of the cell in pancreatic acinar cells.
• This is again different than hepatocytes, where exocytosis occurs at both ends.
• PANCREATIC SECRETION:
• TANNIC ACID EXPTS: Exocytosis in Pancreas is constitutively balanced by endocytosis.
• Tannic Acid causes proteins to precipitate so that we can "capture" exocytosis in action.
• Tannic also inhibits endocytosis.
• Thus under the influence of Tannic Acid, the pancreas will exocytose all of its membrane!
• SECRETOMOTOR STIMULATION: The pancreas undergoes regulated secretion, via CCK, Secretin and ACh
• Secretin, VIP: beta-Adrenergic secretion (cAMP ------> PROTEIN KINASE A)
• CCK, ACh: alpha-Adrenergic secretion (IP₃ ------> Ca⁺² ------> PROTEIN KINASE C)
• Both act synergistically, i.e. the whole is greater than the sum of the parts
• CONSTITUTIVE EXOCYTOSIS of fluid occurs at the same time as exocytosis of zymogens. Fluid is required to put the zymogens in aqueous environment and thus make them enzymatically active.
• PANCREATIC DUCTS: They modify the acinar secretion by exchanging HCO₃^- for Cl^-, yielding an alkaline secretion.
• Pancreatic Ducts are interlobular ducts.
• ENDOCRINE PANCREAS: ISLET CELLS (Insulin, Somatostatin, Glucagon)
• Endocrine Secretion is less regulated in the pancreas. Secretion is constitutive into the extracellular space, and then hormones are simply absorbed by plentiful capillaries in the region.
• PANCREATITIS: Digestive enzymes wind up getting activated intracellularly and thus destroy pancreatic acinar cells from the insides out.
• Mostly associated with chronic alcoholism
• DIAGNOSIS: Pancreatitis will be shown by high serum levels of digestive enzymes, which shouldn't be in the blood! Pancreatic Amylase is usually tested for.
• CYSTIC FIBROSIS: Pancreatic duct can get clogged, because bicarbonate secretion fails and HCO₃^-/Cl^- channel is faulty.
• CF patients often have little or no pancreatic function remaining. They can take enzyme tablets along with a modified diet to overcome the deficiency.
• PANCREATIC INSUFFICIENCY: It takes 95% insufficiency of the pancreas before severe malnutrition results. There is great redundancy in digestive capacity of enzymes and amount of enzymes secreted.
• ZYMOGEN ACTIVATION CASCADE: Enterokinase is expressed on the brush border of intestinal enterocytes -- not in the pancreas. It starts the activation cascade.

LIVER: The liver is both an endocrine (liver enzymes) and exocrine (bile) gland, performing both secretory and absorptive functions.

• HEPATOCYTE: Epithelial cells with distinct domains
• APICAL POLE faces Bile Canaliculi.
• BASAL POLE faces Liver Sinusoids
• LATERAL MEMBRANE: Gap junctions allows intracellular communication.
• SINUSOIDS: Liver discontinuous and fenestrated endothelial cells.
• SPACE OF DISSE: The extensive space between the sinusoid and hepatocyte, through which rather large particles can traverse.
• The Space of Disse is filled with microvilli from the hepatocytes. These microvilli will perform both absorptive and secretory functions in interacting with the blood.
• ABSORPTIVE: Absorb digested nutrients from portal blood.
• SECRETORY: Secrete liver enzymes
• KUPFFER CELLS: Hepatic Macrophages found in the sinusoidal space.
• They degrade senescent erythrocytes ( ------> spleen), as well as typical immunological functions.
• SECRETIONS:
• ENDOCRINE SECRETIONS: Albumin plus tons of others are secreted into the Liver Sinusoids.
• Liver enzymes are secreted by unregulated constitutive exocytosis. The process of secretion is not regulated. Regulation of liver enzymes occurs only at the synthetic level.
• Apoprotein is also made in SER. Hepatocytes use it to make VLDL particles from chylomicrons that arrive to the liver from the blood. (The chylomicrons first travel from lymph into general blood circulation before reaching the liver).
• BILE SECRETION / RESORPTION: Bile is secreted into the Bile Canaliculi and resorbed into the bile canaliculi.
• Bile Ducts add HCO₃^-, making the bile alkaline.
• Bile Canaliculi are lined with microvilli.
• BILE SECRETION is via facilitated diffusion through apical pole.
• BILE ABSORPTION: Bile absorption is done via Na⁺-Cotransport on the sinusoidal membrane. They think that bile salts are hooked into apoproteins.
• DETOXIFICATION: Occurs at the Smooth ER. Excessive toxicity will lead to proliferation of the Smooth ER, as sign of liver pathology.
• Conjugation of bilirubin to bilirubin glucuronide.
• Addition of glucuronides and sulfates to other toxins and/or drugs
• LIVER ORGANIZATION SCHEMES:
• COUNTERCURRENT FLOW: Blood travels in the opposite direction as bile, making it energetically more efficient for both.
• BLOOD: Portal Vein + Hepatic Artery ------> Sinusoids ------> Central Vein ------> IVC
• BILE: Hepatocytes ------> Bile Canaliculi ------> Hepatic Duct ------> Common Bile Duct
• Incoming (resorbed) bile acids are most concentrated in the most proximal (nearest portal triad) section of each lobule. They will travel down their concentration gradient to reach the bile canaliculi and be resecreted.
• LIVER LOBULE: Classic organization
• CENTRAL VEIN: Carries blood away from the liver. Each lobule has a central vein.
• PORTAL TRIADS (Hepatic Artery branches, Portal Venules, Bile Canaliculi) carry blood to the liver.
• SINUSOIDS are throughout the middle of the lobule, interspersed with HEPATOCYTES.
• Again, blood flows from the portal triad, through the center of the lobule, to the central vein.
• PORTAL LOBULE: The triangle formed by the Central Veins of liver lobules at each vertex, and a Portal Triad in the center.
• This organization emphasizes the functional properties of the liver: All blood within the Portal Lobule Triangle originates from the Portal Triad in the center.
• Thus this organization is an approximate "map" of the blood flow pattern of each section of the liver.
• PROXIMITY to BLOOD TOXINS: The hepatocytes nearest the center of this triangle will be closest to toxins in the blood; hepatocytes nearer the central veins (the edges) are less subject to damage from blood toxins.
• JAUNDICE: Buildup of bilirubin in blood. Indication of liver pathology. Most common causes:
• Bile duct obstruction
• Hemolytic anemia: huge overflow of heme metabolites.
• The liver itself is damaged.
• HEPATITIS-C: It is a very common risk factor for liver disease associated with Alcoholism. Something like 95% of people with Cirrhosis from Alcoholism also had Hepatitis-C infection.

GALLBLADDER: Reservoir for concentrated bile, released under the influence of CCK.

• Gallbladder epithelium absorbs NaCl from the bile, along with water, making the bile concentrated.
• CCK: Two effects
• Gallbladder contraction (of myoepithelial cells) to squeeze out the good stuff.
• Concurrent relaxation of Sphincter of Oddi which holds in bile.

GASTRO-ESOPHAGEAL REFLUX DISEASE (GERD):

• MAJOR CAUSE: Transient inappropriate opening of the LES.
• SYMPTOMS:
• Heartburn
• Regurgitation
• Dysphagia (difficulty swallowing)
• Odynophagia (painful swallowing)

PEPTIC ULCER DISEASE:

• Helicobacter Pylori is responsible for 95% of duodenal ulcer diseases.

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DEVELOPMENT OF THE EYE:

• EARLY DEVELOPMENT:
• OPTIC SULCI: Located on Neural Folds of the neural groove.
• OPTIC VESICLE: Will be formed from the Optic Sulci.
• INDUCTION: OPTIC VESICLE then induces then Surface Ectoderm: Surface Ectoderm ------> Primordium of Lens.
• The lens is formed from surface ectoderm -- not neuroectoderm.
• Len then buds off to form Lens Vesicle.
• CROSS-INDUCTION: THE LENS then induces a change in the Optic Vesicle: Optic Vesicle ------> Optic Cup
• OPTIC CUP: It then forms two layers which are essentially fused together.
• OUTER LAYER will become the Retinal Pigmented Epithelium
• INNER LAYER will become the Neural Retina
• HYALOID ARTERY + HYALOID VEINS: Developmental vessels will become the Central Artery and Vein of the Retina. They perfuse both the lens primordium and optic cup in development.
• OPTIC STALK: Forms from the Optic Cup. It is the primordial optic nerve, with Hyaline Vessels in the middle.
• BIRTH: Optic Nerve is fully formed but myelination is not complete.
• Complete myelination requires light stimuli and O₂ from the external environment.
• DEVELOPMENT OF RETINA:
• Retinal Pigmented Epithelium forms from Outer Layer of Optic Cup
• Neural Retina forms from Inner Layer of Optic Cup.
• Inner Retinal Space: Primitive space between outer and inner layers of optic cups. Trauma can cause the space to reopen in the adult, resulting in RETINAL DETACHMENT.
• DEVELOPMENT OF LENS: It forms from Surface Ectoderm
• Tunica Vasculosa Lentis: Posterior vascular portion of lens in development, originating from Hyaloid vessels.
• PUPILLARY MEMBRANE = clinical condition resulting from developmental failure of the anterior hyaloid vessels to degenerate and retract from the lens.
• CORNEA: Both mesodermal and ectodermal.
• PUPILLARY MUSCLES: They form from neuroectoderm which quite unusual for muscle.
• EYE MALFORMATIONS:
• COLOBOMA: Keyhole life defect in eye.
• Persistence of the Choroidal Fissure during development.
• PERSISTENT PUPILLARY MEMBRANE: Maintenance of Tunica Vasculosa (anterior lens) in adult.
• Congenital Glaucoma: Can be caused by Rubella virus.
• Cataracts can be caused by Congenital Galactosemia, resulting in buildup of galactose on lens.

EAR DEVELOPMENT:

• BRANCHIAL ARCH DERIVATIVES:
• FIRST BRANCHIAL CLEFT: External Auditory Meatus
• FIRST BRANCHIAL ARCH: Malleus and Incus
• SECOND BRANCHIAL ARCH: Stapes
• INTERNAL EAR: It is derived from surface ectoderm in the region of the hindbrain.
• Otic Placode: thickening of surface ectoderm in hindbrain region.
• Otic Vesicle form from this: It will be responsible for all structures associated with Utricle and Saccule, and Vestibular apparatus
• Dorsal Otic Vesicle ------> Utricle
• Ventral Otic Vesicle ------> Saccule
• Endolymphatic Sac will form as extension of dorsal otic vesicle
• DIVERTICULA: Also forms from Otic Vesicle. The middle of each of three diverticular will get eaten away, forming the Semicircular Canals.
• TYMPANIC MEMBRANE: It forms as a meeting together of endoderm and ectoderm: ingrowth of ectoderm and outgrowth of endoderm.
• COCHLEA: It forms.
• PINNA: The hillocks of the pinna are derived from the first two branchial arches.
• FIRST ARCH SYNDROME: Failure of the pinna hillocks to form is a sign of severe congenital abnormalities involving failure of neural crest migration.

PRIMARY INDUCTION: The key induction in development, in which dorsal mesoderm induces ectoderm to form neural structures.

SECONDARY INDUCTIONS: All other inductions in development.

• INSTRUCTIVE: Message-specific. The responding cell will express a specific set of gene in response to the inductive signal from the inducer.
• The optic vesicle instructively induces the lens vesicle to form the lens. Without the adjacent presence of optic vesicle, the lens will not form.
• PERMISSIVE: Non-specific. The responding cell will express the genes it was going to express anyway in the presence of the inducer. The inducer is simply required to allow the differentiation.

INTEGRINS: Regulate interaction of cell with extracellular matrix, and mediate cellular migration through the ECM. Migrating cells will interact with laminin and fibronectin in the ECM. These interactions are essential to development.

CELL ADHESION: Like-cells will adhere to like-cells.

• EXPTS: Mix cells of different germinal layers from different tissues. They will reassociate spontaneously into germinal layers (i.e. endoderm / mesoderm / ectoderm), regardless of the species or tissue from which they came.
• CELL ADHESION MOLECULES (CAM): Surface molecules that mediate adhesion between similar cells.
• NEURAL-CAM (N-CAM): It is highly expressed during the neural tube stage.
• NEURAL CREST MIGRATION: N-CAM expression is ceased so that neural crest cells can dissociate and migrate.
• The presence of Fibronectin, indicating a migratory path, seems to mediate this downregulation.
• When the neural cells reach destination (such as Ganglion cells), N-CAM expression is resumed.
• Again, Fibronectin absence seems to mediate this expression.

LAMININ: It is similar to fibronectin in that it mediates cell migration. It is specific to migration of nerves.

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