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Giles Kisby GE Y1 Dermatology

Dermatology:

Spring Term:

LECTURES:10/01/14: Introduction:

Los (from booklet):1 Explain the concept of the skin as a single organ of the body with its complex intra-relationships

with other organ systems of the body.

2 Describe the basic anatomical structure of the skin and the intra-relationships between the epidermis, dermis and subcutis.

3 Describe the structure of the epidermis and associated adnexal structures its foetal development and regulation of growth.

4 Outline the mechanisms by which the integrity of the dermoepidermal junction is maintained and the results of failures of these mechanisms.

5 Describe the migrant cell populations within the epidermis and detail their origins.

6 Describe the structure of the dermis including the vascular and nerve supply to the skin, the development of the dermis, regulation of collagen formation and events that occur in senescence.

7 Describe skin pigmentation, the development, function and control of melanocytes and the principals of immediate and delayed tanning.

8 Describe the development and maturation of acquired melanocytic naevi and the features of carcinogenic change within these lesions.

9 Describe the development of the hair follicle, its anatomy and regulation of growth through life including the effect of sex hormones and age on hair growth.

10 Describe the principles of barrier function of the skin and its role in controlling percutaneous water loss and absorption and defence against microbial invasion.

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11 Explain the control of body temperature and the role of the cutaneous vasculature in maintaining body temperature.

12 Explain the importance of the skin as an immunological organ and describe the role of individual cell types in the cutaneous immune system.

13 Explain the mechanism of skin wound healing

14 Describe the consequence of skin organ failure and give examples of the impact of this on the body and other organ systems.

Notes:

Introduction to the Skin: Tony Chu

Epidermis dermis adipose layer

- Basic Structure of the Skino The skin has 3 components:

Outer stratified squamous epithelium - epidermis Structural dermis Deep subcutaneous adipose layer

o The components are intimately linked with cross talk between the layers and migration of various cell types between the layers

o The skin is a dynamic not static organ

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- Function of the Skino Barrier function - prevents fluid loss from the body, protection against toxic and

infectious agents, radiation etco Temperature controlo Peripheral outpost of the immune system

- Skin diseaseo Skin is intimately linked to other organ systems of the bodyo Diseases of other organs will affect the skin - yellow skin of jaundice of liver diseaseo Skin signs may be the first evidence of systemic disease

- Additional tests are used to confirm the diagnosis:o Biopsy and histology/immunohistochemistryo Skin scrapings for fungus; swabs for infectiono Gene rearrangement studies for malignancieso Patch testing for allergy

10/01/14: Structure of the epidermis and adnexal structures

Notes:

- Layers of the epidermiso Basal cell layer (stratum basale)o Spinous layer (stratum spinosum)o Granular cell layer (stratum granulosum)o Cornified layer (stratum corneum)

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- THE BASAL LAYERo 1 – 3 layers of cuboidal cellso Main proliferative component of epidermiso Large oval nuclei

Because function is to divide

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o Small basophilic cytoplasm Because not very metabolically active

o Factors that stimulate proliferation : EGF, TGFα, IL-1, IL-6, GM-CSF These factors are produced by keratinocytes, Langerhans cells, dermal

lymphocyteso Factors that inhibit proliferation :

TFG β, IFN α and γ, TNF α Prevent excessive proliferation

- CYTOSKELETON OF MAMMALIAN CELLSo Microfilaments

Actin 7 nm in diameter: smallest

o Microtubules Tubulin + Tau 20 – 25 nm in diameter: biggest

o Intermediate filaments Six types Diameter: 7 – 10 nm: intermediate size Vimentin (mesenchymal cells) Glial fibrillary acidic protein (glial cells) Neurofilaments (neurons) Desmin (muscle) Lamins A, B and C (nuclear matrix) Keratins (all epithelial cells)

THE KERATINSo 20 members, between 40 – 70 kDo Each member a product of a different geneo Divided into 2 groups: acidic and basico Basic keratins: 1 to 8 (12q11 - q13)o Acidic keratins: 9 to 19 (17q12 – q21)o [“ie opposite to pH order”]

THE KERATINSo Keratin filament is formed by assembling one acidic and one

basic keratin type in pairso Different pairs are expressed at different levels of the

epidermiso Basal layer: K5 + K14o Spinous layer: K1 + K10

FILAGGRIN [“filament aggregation (of ketatin filaments)”]o Cationic protein in the stratum corneum (26 – 48 kD)o Profilaggrin: precursor inside keratohyalin granules (500 kD)

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o Forms dense aggregates of keratin filaments CORNIFIED ENVELOPE

o 15-nm thick envelope underneath the plasma membrane of keratinocytes

o Includes involucrin, loricrin, keratolinin, pancornulins, cornifin and cystein-rich envelope protein

o Molecules are cross-linked with transglutaminaseso Keratins become crosslinked to the cornified cell envelope

STRATUM CORNEUMo Major responsible for barrier function of the skino Epidermis is, in large part, devoted to its productiono Results from a sequence of events including:

Synthesis and assembly of keratins Addition of filaggrin Synthesis and assembly of the cornified envelope

- During cornification, the process whereby living keratinocytes are transformed into non-living corneocytes, the cell membrane is replaced by a layer of ceramides which become covalently linked to an envelope of structural proteins (the cornified envelope)

- Pemphigus vulgariso Commonest form of pemphiguso Only affects stratified epithelium

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- IMMIGRANT CELLS TO THE EPIDERMISo Langerhans cells

Are dendritic cellso Melanocyteso Merkel cells

- Sweat glandso Eccrine glands

Present all over except lips, nailbed, glans, foreskin and labia minora Most numerous: palms, plantar and axillae Derive from buds from epidermis One layer of cuboidal cells Positioned at dermo-adipose junction Surrounded by myo-epithelial cells Clear cells: contain glycogen.

Produce the salt + water Dark cells: contain acid GAGs Ducts: absorb salt- sweat is hypotonic Function of glands:

Sweat Drug uptake Wound healing role

Main function of sweat: Evaporative cooling Cholinergic nerves of SNS discharge Ach on the surface of clear cells Thermal and emotional factors

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o Apocrine glands Only in certain areas:

Axillae, anogenital area, ceruminous glands, Moll glands Not true sweat glands, but scent glands

Give BO Regress with age

Originate from hair buds (rather than from epidermis) Surrounded by myo-epithelial cells Acini much larger than eccrine Acini in subcutaneous fat Enlarge under hormonal influences PAS+ columnar cells “Apocrine” secretion

= Decapitation secretiono Elements of membrane are part of the secretions

Milky, odorless, viscous Stored for intermittent release Bacterial action breaks down secretion and produces short-chained

fatty acids that smell of b.o.

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- SEBACEOUS GLANDSo Holocrine

Holocrine secretions are produced in the cytoplasm of the cell and released by the rupture of the plasma membrane, which destroys the cell and results in the secretion of the product into the lumen.

o Present on all skin except palms, soles, dorsal feet [ie matches where hair is found due to gland association with hair follicle]

o Usually associated with hair, except on areolae, labia minora, foreskin, vermillion borders of lips.

o Originate from hairo Outer layer of cuboidal undifferentiated cellso Progressively accumulate intracytoplasmic lipido Cells desintegrate and fall into the ducto Sebum: triglycerides, waxes, cholesterol and squalenes.o Secretion depends on adrenal and gonadal androgenso Prominent at birtho Inconspicuous during childhoodo Size and activity increases in puberty

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10/01/14: Dermis and dermoepidermal junction: Tony Chu

Notes:

- Dermiso Supporting ‘foundation’ for the epidermiso Comparatively non-cellular connective tissueo Contributes 15-20% of the total weight of the bodyo Varies in thickness in different locations – 5mm on back, 1mm on eyelids -

depending on the necessary tensile strength

- Dermiso Consists of supporting matrix or ground substance with protein fibres:

Collagen Elastic fibres

o Cellular Elements Fibroblasts, mast cells, histiocytes, Langerhans cells, lymphocytes,

eosinophilso Embedded in the dermis are:

Nerves Blood vessels Lymph vessels Muscles Pilosebaceous/apocrine units Eccrine sweat units

o Adventitial Dermis Thin zone just under the epidermis (papillary dermis) and dermis around

adnexal structures Thin haphazardly arranged collagen fibrils Delicate branching elastic fibres Numerous fibroblasts Abundant ground substance Highly developed microcirculation

o Reticular Dermis Bulk of the dermis from papillary dermis to subcutaneous fat Irregularly arrayed coarse elastic fibres Thick collagen bundles arranged parallel to the skin surface Fewer fibroblasts and blood vessels than adventitial dermis Less ground substance than adventitial dermis

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- Collageno Most abundant protein of the bodyo 70% dry weight and up to 30% of the volume of the dermiso High tensile strengtho A 1mm diameter collagen fibre can sustain 40kg weighto Collageno 20 or more different proteins now identifiedo Characteristic regular cross banding seen particularly in collagen types I, II and IIIo Skin collagens:

Fibrillar collagens -type I, III Basement membrane collagens, IV, VII, XVII (BPAG2) Non-fibrillar, non-basement membrane collagens – XVI

o Fibillar Collagen Type I – course fibres found in reticular dermis

deep Type III – fine loosely arranged fibres of the adventitial dermis

Superficialo Fibrillar Collagen Formation

Collagen is produced by fibroblasts Intracellularly, procollagen chains form perfect triple helical a chains In the extracellular space triple helices self assemble into irregular

overlapping staggered fibres Hydroxylation of proline of procollagen is the rate limiting step in collagen

synthesis Hydroxyproline stabilises the conformation of the triple helix Cross-linking of collagen molecules to form microfibrils and fibres is

mediated by lysyl oxidase

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- Elastic Fibreso Produced by fibroblastso <1% dry weight of dermiso Highly branched structureso Central core of elastin with peripheral microfibrils – fibrillin 1 and 2, MAGP-1, -2, -3o Important property allowing return of skin to original shape following deforming

forceso Naturally present in contracted formo Capable of extension to twice resting lengtho Absent from scars and striae - stretch marks

- Ground Substanceo Produced by fibroblastso Amorphic extracellular materialo Enmeshes fibrillar and cellular compartment of skino Consists of water, electrolytes, plasma proteins and mucopolysaccharideso 0.2% dry weight of skin but most of the volume of the dermiso Mucopolysaccharides

In dermis: Hyaluronic acid Dermatan sulphate Chondroitin-6-sulphate Heparan sulphate

o Function Salt and water balance – binds large amounts of sodium and water Support for other components of dermis – due to high viscosity Regulates connective tissue metabolism by promoting cell growth, migration

and differentiation

- Fibroblastso Most numerous cell in connective tissueo Highly metabolic cello Produce ground substance, collagen and elastin o Most numerous in the papillary dermis

- Mast Cellso Bone marrow derivedo Found close to blood vessels, nerves and appendages

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o Most numerous in subpapillary dermis 7000/mm3 of normal skino Ovoid or spindle shapedo Contain numerous round cytoplasmic granuleso Reservoir of preformed inflammatory mediatorso Rapidly synthesize other mediators on activation

- Dermoepidermal Junctiono One of the largest epithelial-mesenchymal junctionso Key role in epidermal cell anchorage, adhesion, migration and differentiationo Serves as a barrier and filter

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- Bullous Pemphigoido Problem with:

230 kDa BP Antigen Bullous Pemphigoid Antigen and/or type XVII collagen

- Epidermolysis Bullosa (junctional)o Problem with Type XVII collagen leads to upward displacement of lamina lucida

- Epidermolysis Bullosa (dystrophic)o Problem with Type VII collagen leads to upward displacement of Lamina Lucida and

Lamina Densao Problem is below basal lamina so extensive scarring results

- Summary of Skin Diseases:

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10/01/14: Organisation of the skin immune system: Tony Chu

Notes:

- Skin Immune Systemo Key Players:

Keratinocyte Langerhans cell T cell Monocyte/Macrophage Endothelial cell Mast cell

- Keratinocytes:o Major factories for the production of cytokineso Phagocytico Can be induced to express MHC Class II antigeno Express Toll like receptorso Produce antimicrobial peptides

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o Produce Pro-inflammatory cytokineso BUT also produce down-regulatory cytokines

IL1Ra IL10 a-MSH CXCL10 PGE2

o Produce Growth Factors GM-CSF – moncytes/macrophages IL7 – B cells IL15 – T cells SCF – Mast cells VEGF – blood vessels

o Produce Chemoattractant Cytokines IL1 – neutrophils and macrophages CCL27 – T cells CCL5 – eosinophils and memory T cells CXCL10 – T cells Mig – T cells IP9 – T cells CCL20 – Langerhans cells

o Keratinocytes can be induced to express MHC Class II antigen by g interferon Class II expression is a cardinal feature of antigen presenting cells Keratinocytes lack co-stimulatory molecules Do NOT show antigen presentation

o Toll like receptors respond to highly conserved motifs on micro-organisms Keratinocytes express TLRs: TLR1, TLR2, TLR4 and TLR5

o Antimicrobial Peptides Keratinocytes will produce the cathelicidin peptide LL-37 under

inflammatory conditions Keratinocytes produce human b defensins 1, 2 and 3

- Langerhans cello Dendritic antigen presenting cell of the skino Migrant from bone marrow precursoro Renewed from bone marrow precursors but also locally self replicatingo Represent 2% of the epidermal cell populationo Express a unique combination of surface antigens

HLA-DR (vs prots), CD1a ( vs lipids) (important in lipid antigen presentation to immune system), Langerin (vs carbs)

o Stimulated to mature by GM-CSF, TNFa, IL4 and TGFb

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o In CFS-1 and TGFb1 knock-out mice, no epidermal Langerhans cells are presento Possess a unique intracytoplasmic organelle the Birbeck granule

Trilaminate structure with and extended terminal end look rather like a tennis racket

Initially thought to be a viral inclusion, now considered important in endocytosis

o Langerin is a lectin present on the surface of the Langerhans cells but also found within the Birbeck granule

Birbeck granule = tennis racket shaped: o Precursors able to home to the skin via the CLA receptor which uses E-selectin on

endothelial cells as a ligando Cells express CCR6 receptor for CCL20 produced by keratinocyteso Held in the epidermis by adhesion molecule E-cadherino Reside in the suprabasalar area of the epidermiso Dendritic but unlike other DCs they are flattened and extend along a horizontal

planeo Dendrites cover over 25% of the skin surface making them a very efficient network

for capturing and recognising antigens in the epidermiso Following stimulation, cells change their chemokine receptor to CCR7, lose E-

cadherin and migrate out of the epidermis to the dermal lymphaticso Cells up-regulate CD80 and CD86 and migrate to the para-cortical zone of lymph

nodes to interact with CD4+ T cellso Langerhans cells start to apoptose when they leave the epidermis: do not recycle

back to the epidermis

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- Monocyte/Macrophageso Arise from myeloid precursors in the bone marrowo Circulate as monocytes – 2 to 10% of blood leukocyteso Migrate into various tissues including the skin where they activate as macrophageso Express Toll like receptorso Phagocytico Produce a large range of pro-inflammatory cytokines and growth factorso Produce down-regulatory cytokines to regulate immune responses

- Endothelial cellso Prevent clotting under normal circumstanceso Allow cells to adhere and migrate through them – E-selectino Express receptors for a number of cytokineso Produce a number of cytokines including basic fibroblast growth factor

- T Cello T cells that go to the skin express the skin homing antigen CLAo In the steady state the main T cell that circulates through the epidermis is the CD8+

T cello In inflammatory skin conditions, the major T cell population is the CD4+ helper T cell

– interaction with Langerhans cellso T cells can recycle though the skin

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- Mast Cellso Important effector cells in allergic diseaseo 10,000/mm3 are found in the skin near blood vessels, hair follicles, and sweat glandso Activation is mainly during Type I IgE mediated hypersensitivityo Mast cells express TLR 2, 4, 6, 8o Express C3a and C5a receptors

10/01/14: Pigmentation of the skin

Notes:

- MELANOCYTESo Derived from neural crest cellso Network in basal and suprabasal positiono Epidermal melanin unit = 1 melanocyte for 36 keratinocytes

Melaninocyte injects the pigment to the keratinocytes: the latter hold most of the melanin but do not make the melanosome organelles from which it is dervied

o Divide under stimulio Produce and transfer melanosomes

A melanosome is an organelle found in animal cells, and is the cellular site of synthesis, storage and transport of melanin

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- MELANINo Eumelanin

Black, insolubleo Phaeomelanin

Red. Human red hair. Feathers of red henso Both

Derived from tyrosine by tyrosinase Share initial steps of synthesis

o SYNTHESIS OF EUMELANIN:

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o SYNTHESIS OF PHAEOMELANIN:

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- Use sunscreen every day to prevent aging effects

- FUNCTIONS OF MELANINo Avoids damage to DNA of keratinocyteso Decreases cutaneous carcinogenesiso Eliminates genetically damaged cellso Prevents ageing of the skin

- TANNINGo Immediate

Oxidation of pre-formed melanin UVA

o Delayed Proliferation of melanocytes ↑ tyrosinase activity ↑ transfer of melanosomes UVB

- SKIN PHOTOTYPESo Phototype Sun sensitivity Inducible skin colouro I Burns easily Never tans: red hairo II Always burns Minimal tan: caucasian no tano III Burns moderately Tans gradually (light brown): Caucasian tano IV Burns minimally Tans easily (brown): mediteraniano V Rarely burns Always tans (dark brown): mexicoo VI Never burns Always tans (black): African [intrinsic SPF8]

- RACIAL DIFFERENCES IN MELANOCYTIC FUNCTIONo Caucasians

= number of melanocytes ↓ melanin production by tyrosinase Small melanosomes Lighter melanosomes Fewer melanosomes Clustered melanosomes

o Afro-caribbeans = number of melanocytes ↑ melanin production by tyrosinase Large melanosomes

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Dense melanosomes Numerous melanosomes Singly-distributed

- EFFECTS OF THE SUN ON THE SKINo Dermal elastosis ageing o Decrease in the number of Langerhans cells

Ie immunosuppression by sun Eg eczema or psoriasis recommend sun exposure Eg can cause cold sore flare-ups

o Mutations in keratinocytes cancero Production of free radicals

- Photoageing vs intrinsic ageing:o 10% intrinsic ageing

↓1% collagen synthesis per year of adult life Fewer fibroblasts Decreased number of blood vessels Fewer epidermal layers

o 90% photoageing Limbs: thin skin; easily bruised or torn Solar lentigos Wrinkles Thin epidermis Solar elastosis

- Photodamageo Thinning of the epidermiso Flattening of the rete ridgeso Solar elastosiso Decrease in number of blood vessels

- PENETRATION OF UVRo UVA: 320 < λ < 400 nm: ageing of the skin. Penetrates glass. o UVB: 290 < λ < 320 nm : burns, tumours. Blocked by glass.

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- Xeroderma Pigmentosa:o Can be caused by a range of mutations:

defect in nucleotide excision repair (NER) enzymes

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10/01/14: Blood vessels and nerves

Los (from booklet):Objectives

Blood VesselsCellular StructureAnatomical DistributionFunction

NervesEfferent NervesAfferent NervesSensory Pathway

Notes:

- Blood Vessels – role?:o Contains the blood

Together with the heart make up Cardiovascular systemo Regulates blood flow

Thermoregulation Conduction/convection/radiation

o Selectively permeable membrane Nutritive structures O2, CO2, N2

- Cappilaries and venules:o Capillaries are composed of specific cell types, they are lined by endothelium and

surroundied by pericytes which have limited contractile function. These pericytes do not completely cover the circumference and are often multilayered on the venous side and provide a seal for the vessel. Importantly, capillaries lack smooth muscle.

o They are surrounded by a membrane of type iv collagen and laminin.o Veil cells seen here are unusual, their function is unknown but they are found

surrounding blood vessels in the skin.o Capillaries drain into venules whose basic structure is similar but their lumen is

much larger and there is a thin endothelial cell lining.

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- Vascular plexus:o In the skin, blood vessels form layers of decreasing diameter. In the low dermis /

subcutis fat layer are venules and arterioles known as the deep plexus tributaries supply deep structures such as hair, sweat gland

o Intricate connections to network called the superficial plexus As you ascend – vessels are getting smaller

o Superficial plexus – in the superficial papillary dermis these supply the capillary loops which supply the epidermis. In some areas these papillary loops are more developed such as the face which explains why when men cut themselves shaving they bleed for quite some time.

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- Blood flow regulation:o In the deep plexus there are precapillary sphincters which decrease the diameter of

the communicating vessels and thereby reduce blood flow. They are under the influence of the autonomic nervous system

o Variations in surrounding temperature can have dramatic effects on blood flowo In hot environments, dilatation of these sphincters results in educed peripheral

resistance and increased flow

- Blood Flow – Arteriovenous Anasatomosiso Only present at specific sites exposed to maximal cooling

In some areas of the body there are direct communications between the arteries and veins known as anastamosis.

This are primarily in the hands, feet and earlobeso AV Anastamoses have strong muscular coats innervated by adrenergic

vasosconstrictors

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o In extreme cold constriction of anastamoses results in significant reudction in cutaneous blood flow

- Weibel-Palade Bodyo Secretory granules in vascular endothelial cellso Formed from trans Golgi network o Round/ovoid shape with tubular inclusionso Release vWF and P Selectin in response to injury

- Function – Cell Traffickingo Normal skin has very few lymphocyteso Inflammation and infection require recruitment of circulating lymphocytes

Initial step requires adhesion to vascular endothelium Cellular adhesion molecules (CAM’s) upregulated

ICAMs VCAMs Selectins are expressed – weak adhesion molecules

P selectin (adherence) E selectin (cell arrest at that position)

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- Functions – Response to Injury and Angiogenesiso Following injury, thromboxanes and prostaglandins cause spasm

vasoconstrictiono 20 mins later histamine induced dilatation and increased porosity erythema

swelling and inflammatory cell influxo Angiopoietins released from pericytes in response to trauma:

Angiopoietins Ang-1/2 ligand Tie-1/2 receptor VEGF

o angiogenesiso Stem cells of Endothelial cells from uninjured blood vessels are chemotactically

recruited resulting in neovascularisation. o Pathology of Angiogenesis: Psoriasis and Cancer

Growth factors are secreted in some inflammatory skin conditions Causes the erythema, the histopathology of psoriasis is characterised by

increased vessels Cancer can’t grow greater than 0.5 cm3 volume without hijacking

angiogenesis

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- Afferent Nerveso Transmit numerous sensory modalities

Temperature, touch, vibration, pressure, itch and paino Secrete neuropeptides

Substance P [“powder”], nerve growth factor itching Substance P is released from the terminals of specific sensory nerves, it is

found in the brain and spinal cord, and is associated with inflammatory processes and pain.

o Defined by the nature of the distal sensory organ of the nerve:

o Free Nerve Endings Derived from non-myelinated fibres Located in superficial dermis and epidermis Polymodal

Touch Pain (nociceptors) Pressure Temperature

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Hair follicles are surrounded by fine nerve filaments Detail:

Most common form of nerve and most are in the skin Non-myelinated fibers are seen in the superficial dermis and in the

overlying epidermis (may abut on to Merkel cells). Hair follicles have fine nerve filaments running parallel to and

encircling the follicles; mediating touch sensation. Primary a pain receptor Free nerve endings can detect temperature, mechanical stimuli

(touch, pressure, stretch) or pain (nociception). Thus, different free nerve endings work as thermoreceptors, cutaneous mechanoreceptors and nociceptors. In other words, they express polymodality.

The majority of Aδ (A delta) fibers (group III) and C (group IV) fibers end as free nerve endings.

o Corpuscvular Meissner’s Corpuscule

Texture receptors Glabrous skin (hairless) Thick lamellated capsule 20-40 um diameter 150 um length Detail:

o Sit on the papillary ridges of the dermis . Seen in higher concentration in non hair bearing skin but concentrated in areas especially sensitive to light touch, such as the

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fingertips, palms, soles lips, tongue, face and the male and female prepuce.

o They are primarily located just beneath the epidermis within the dermal papillae

o respond to texture and slow vibrations

Pacinian Corpuscule Encapsulated receptors Ovoid structure 1mm Lamellated cross section – onion like A single myelinated sensory axon at its core Movement and vibration Detail:

o Loss of vibration early in diabetics due to damage to this pathway

o Similar to meissners but larger and fewer of themo They detect gross pressure changeso Also particularly good at deeper sustained touch and

detecting vibrationo They have a large receptive field, more sensitive in the

centre

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Merkel Cell Merkel “Touch Spot” Composed of a number of Merkel cells borne on branches of a

myelinated axon Merkel cells contain a lobulated nucleus and characterisitc granules Embedded in basal layer of epidermis – connects with desmosomes

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- Sensory Modalities

- Adaptationo In response to sustained stimulus

Tickle and Itcho Mild stimulation of pain nerve endings

Group C unmyelinated nerve fibres Itch excites the scratch reflex Physiology of sensory receptors

- Superficial Sensationso Pain, Temp, Crude touch

1st order neuron in posterior root ganglion Ascends in posterior horn (Lissauers tract) 2nd order Crosses in anterior commissure near central canal and ascends

lateral spinothalamic tract Terminates in thalamus 3rd order neuron terminates in sensory area of cerebral cortex

o 2. Deep sensations and fine touch 1st order neuron – posterior root ganglion Directly ascends posterior column (Gracile and Cuneate tracts) ending in

medulla 2nd order neuron - cross to opposite side and ascends to thalamus 3rd order neurone present in thalamus passes up to internal capsule and

sensory area of cerebral cortex

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Function of the Skin: Tony Chu

- Function of the skino Organ of sexual attraction and social interactiono Barrier to loss or absorption of fluid and moleculeso Barrier to infectiono Protection against ultraviolet and other radiationso Temperature controlo Reaction to infection, cancer and foreign substances

- Organ of sexual attraction and social interactiono Social and sexual interactiono Skin and hair are important in sexual displayo Skin and hair are important in exerting social statuso Quality of Life Issues

Dermatological conditions are visible and may have profound impact on quality of life

Facial dermatoses may result in loss of confidence, reclusiveness, depression and social isolation

Scaly skin conditions may make staying overnight difficult Skin loss onto the bedding

Itching may result in bleeding onto clothes and bedding Blood marks on bedding

o Skin and employment Patients with acne were found to have a 50% greater unemployment rate

than age matched individuals without acne Patients with significant acne cannot join the armed forces

o Social Stigma In certain countries, vitiligo, where the skin develops white patches, is a

major social stigma Kaposi Sarcoma is a very visible sign of AIDS and can lead to patients being

ostracised by areas of society

- Barrier to loss or absorption of fluid and moleculeso Skin limits water loss from the bodyo Regulates penetration of water and other chemicals into the body

Barrier to absorption of most substances Permits selective entry of some

o Most barrier function resides in the epidermis within the stratum corneum

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Lipid barrier importanto Keratinocytes synthesise fibrous proteins of keratin and histidine rich proteins –

keratohyalin and filaggrino Odland bodies develop in keratinocytes close to the Golgi apparatus and migrate to

the cell peripheryo Within Odland bodies uni-laminar liposomes rich in sphingolipids and neutral lipids

become arranged in disc formo In the stratum granulosum, Odland bodies fuse with the cell membrane and the

contents are discharged [lipid lamellae ejected and will form continuous barrier around the body]

After discharge from the granules the discs become arranged parallel to the cell membrane and fuse to produce uninterrupted sheets consisting of two lipid bilayers in close apposition

These intercellular lamellae are the main barrier to trans-epidermal water loss and prevent absorption of water through the skin

Ceremides are essential in the formation of the bilamelar lipid membrane Ceremides contain essential fatty acids and deficiencies of these, especially

linoleic acid results in poor barrier function

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o Eczema: In atopic eczema there is an enzyme deficiency of δ6-desaturase which

results in poor incorporation of linoleic acid into ceramides Patients have dry skin with poor barrier function Dry skin is irritable and adds to the itch of the eczema

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o Percutaneous Absorption Skin is slightly permeable to water Permeability increases with lipid solubility Drugs that penetrate the skin are generally soluble in lipids or contained in a

lipid containing medium Topical therapy

To the skin for skin diseaseo Available in vehicles that allow good penetration into the

skin To the skin for diseases of other organs

o Becoming more important in conventional and in genetic treatment

o Important pharmacologically in delivering drugs to organs other than the skin

Patches for nicotine Patches for hormone replacement therapy Topical non-steroidal anti-inflammatory agents in

arthropathies Nitroglycerine for coronary insufficiency

Certain areas show increased absorption:o Scrotumo Faceo Foreheado Dorsum of hands

Through the stratum corneum- principle pathway Through pilosebaceous apparatus or sweat ducts – minor role providing

rapid route of entry for ions, polyfunctional polar compounds and very large molecules

Absorption is through the corneocytes rather than between them In infant and old skin absorption is greater due to the reduced thickness of

the skin In disease skin where barrier function is lost, absorption is greater

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- Barrier to infectiono Protection against Micro-organisms and Destructive Chemicals

Intact stratum corneum prevents invasion by microorganisms Sebum has anti-bacterial properties Glycophospholipids and free fatty acids are bacteriostatic

o Sebum Holocrine excretion produced by sebaceous glands Excreted into the hair follicle and gains access to the surface of the skin Sebaceous gland is active from 26 weeks gestation - sebum contributes to

the vernix caseosa on newborn babies Sebum excretion is mainly controlled by androgens:

Maternal in the foetus Adrenal glands Ovaries in women Testes in men

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Minor role of ambient temperature Function:

In animals, important in coating and waterproofing hair and fur In man role is more speculative Possible role in reducing moisture loss but not a major part of

barrier function Lipids have antibacterial and anti-fungal properties

- Protection against ultraviolet and other radiations- Temperature control- Reaction to infection, cancer and foreign substances

Immunology of the Skin: Tony Chu

- Immunology of the Skino Innate immune responseo Acquired immunity

- Innate Immune Responseo Skin barrier function keeps micro organisms outo Sebum –

Fatty acids and acid pH inhibit growth of micro organismso Sweat –

lysozyme damages cell wall of bacteria (dermcidin constitutively produced and has broad spectrum activity against Gram + and - bacteria and yeasts)

o General: Initial response to bacteria, fungi and viruses Broad spectrum Prevents infection Damages cell wall of micro-organism Removal by ingestion

o Epidermal cells [like those of gut] Toll-like receptor expression by epidermal cells Production of antimicrobial peptides by epidermal cells

o Toll-Like Receptors General:

Cell surface pattern recognition receptors DNA encoded genes Recognise evolutionary conserved proteins within cell wall of

bacteria and fungi Activates cell to produce chemokines and cytokines

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Transmembrane proteins Cytoplasmic domain homologues similar to IL1R1 Respond to highly conserved motifs on different micro organisms –

Pathogen-associated molecular patterns (PAMPs) Ligand binding leads to stimulation of antimicrobial peptides as well

as induction of immune response genes through NF-kB activation Keratinocytes express TLR1, 2, (4) and 5

TLR1, 2 and 5 are constitutively expressed TLR4 expression is controversial with some studies suggesting it is

not functionally active Langerhans cell express TLR2 and TLR4 Targets:

TLR2 – peptidoglycan from Gram + bacteria TLR4 – lipopolysaccharide from Gram – bacteria TLR5 – flagellin TLR2/1 heterodimer – triacylated lipoprotiens

o Antimicrobial Peptides First line defence against infectious agents Multifactorial acting as natural antibiotics but also signalling activation of

host immune cells Cathelicidin and defensin gene families Directly kill Gram + and – bacterial, fungi and some viruses In resting conditions small amounts of AMP are produced in the skin at

potential sites of entry by bacteria – follicular openings, sweat ducts After injury or inflammation there is a rapid increase

o Cathelicidins In humans restricted to a single gene Human cathelicidin – LL-37/hCAP18 Broad spectrum antimicrobial activity Chemoattractant to neutrophils, macrophages mast cells and T cells Observed in human epidermal keratinocytes under inflammatory conditions

– psoriasis and contact dermatitiso Defensins

3 families – a, b and o Only human b defensins have been identified in epidermis – HBD 1, 2 and 3

(2 and 3 upregulated in psoriasis) HBD have broad spectum antimicrobial activity HBD bind to CCR6 and are chemotactic for immature dendritic cells and

memory T cells HBD2 promotes histamine release and PGD2 production by mast cells

- Acquired Immune Response

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o Key players in the skin Keratinocyte Langerhans cell T cell

o Keratinocyte Efficient factory constitutively secreting or induced to secrete a large

number of cytokines Can be induced to express HLA-DR Phagocytic HLA-DR expression

Induced by IFNg In cell lines, IL8 can induce expression

ICAM-1 expression Induced by IFNg and TNFa

Antigen presentation HLA-DR induced IL1 production Phagocytic

Unable to present antigen to T cells - ? Lack of CD80 and CD86 expression Studies suggest HLA-DR+ keratinocytes are able to induce tolerance in T cells

o Langerhans cell Bone marrow derived from CD34+ and CLA+ precursor cell In vitro, GM-CSF, IL4 and TGFb can induce a LC phenotype Resident in the suprabasalar area of the epidermis Represent 2% of the epidermal cells Flattened dendrites extend horizontally covering 25% of the surface of the

skin but do not interconnect CD1a

non-polymorphic , MHC class I like molecule – role in lipid presentation to T cells

Birbeck granules rod or racket shaped intracytoplasmic organelles implicated in the

endocytic pathway – express Lag antigen Langerin CD207

mannose specific C type lectin expressed on the cytoplasmic membrane and in the Birbeck granule

In the skin in a resting state LC are immature Lack CD80 and CD86 expression Active in antigen processing – uptake by endocytosis and macropinocytosis Relatively poor stimulators of T cells (NB differences in murine and human

systems) Maturation

Stimulated by:o Bacterial and viral productso Inflammatory cytokines

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o Antigenso UV radiationo Heat shock protein

Reduced antigen uptake Expression of co-stimulatory molecules Up-regulation of HLA-DR Down regulation of CD1a Migration

Cytokines involved in maturation include IL1b TNFa GM-CSF EGF

Cells lose E-cadherin expression Express CCR7 directing migration towards draining lymph nodes General:

Immune surveillance in the skin Langerhans cells are central to sensitisation and elicitation phases of

contact allergic dermatitis Target for allogeneic skin graft rejection and target in graft verses

host disease Langerhans cell and Cancer Surveillance

Langerhans cells are sensitive to UV radiation with dose dependant reduction in antigen presenting ability

UV radiation is the major cause of skin cancer ? Developmentally, UV suppression of LC function reduces the risk

of autoimmune disease to UV generated neo-antigens in the skin

Contact Dermatitis Sensitisation phase:

o May take many years of skin contact to establish sensitisation

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o Antigen taken up by LC and taken to paracortical zone of draining lymph node where it is presented to naïve T cells

Elicitation phaseo Challenge by antigen results in presentation by LC to

memory T cells and a type 4 response Graft Versus Host Disease

Host dendritic cells expressing self proteins involved in maintenance of tolerance

Donor naïve T-cells are stimulated to mature by host dendritic cells. Donor T-cells mount an immune response against host. Cornea does not contain Langerhans cells so can be transplanted to

anyone

Thermoregulation: Dr S Punjabi

- General:o Almost all birds and mammals have a high temperature almost constant and

independent of that of the surrounding air. This is called homeothermy. o Almost all other animals display a variation of body temperature, dependent on

their surroundings. This is called poikilothermy.- Core temperature

o Most body heat is generated in the deep organs( liver, brain, and heart, and in contraction of skeletal muscles).

o 37°C (98-990 F) is essential for normal function.o Normal mental functions are dramatically impaired outside the 35-40°C range.o Skin plays a decisive role as both radiator and insulator.

- Peripheral temperatureo The skin assists in homeostasis.o It does this by reacting differently to hot and cold conditions so that the inner body

temperature remains constant. o Vasodilation and sweating are the primary modes by which humans attempt to lose

excess body heat. - Variation:

o Temperature variations throughout the day by 1 degree or so peaking in the afternoon 4pm ish as a result of circadian rhythm. Lowest point is 2nd half of sleep cycle – nadir.

o Diurnal variationo Ageo External temperatureo Exercise

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o Ovulation Within 24 hours of ovulation, women experience an elevation of 0.15 - 0.45

°C (0.2 - 0.9 °F) due to the increased metabolic rate caused by sharply elevated levels of progesterone.

- Thermoreceptors (Heat and cold receptors)o Anterior Hypothalamus

-preoptic areao Deep Organs

-spinal cord -great veins -abdominal viscera

o Skin Temperature receptors: more cold ones than hot ones.

- Hypothalamus – the thermostato Hypothalamic centre (preoptic area) o sensors are set at critical temperatures(set points)o More finely controlled than the thermoreceptors of the skin.(a fall as small as 0.30C

in the blood reaching the sensors, produces an effect similar to a drop of 100C on skin).

o Helpful, as we live in environments with wide swings of temperature.- Heat loss:

o Radiation 60%

o Evaporation 25% Insensible water loss : Skin and lungs (15 calories/hr).

o Conduction 12%

o Convection 3%

- Role of Skin in Thermoregulationo If skin temperature is greater than that of the surroundings, the body can lose heat

by radiation and conduction.o But if the temperature of the surroundings is greater than that of the skin, the body

actually gains heat by radiation and conduction. o In such conditions, the only means by which the body can rid itself of heat is by

evaporation.

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- Feedback loop:

- Coolingo Vasodilation

Blood flow thro the skin is 10 to 20 times greater than that needed for cutaneous metabolism. Approx 10% of cardiac output flows thro skin under basal conditions.

o Sweating Eccrine sweat glands

Several million over most skin surface. Under neurological control. Secretes an ultrafiltrate of plasma like fluid. Resorption of sodium by the duct to produce hypotonic sweat. Humidity affects thermoregulation by limiting sweat evaporation

and thus heat loss

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o Decrease heat production inhibition of shivering and chemical thermogenesis.

o Behaviour move, wear less clothes, drink cold drink

- Warmingo (Reduce sweating)o Vasoconstrictiono Piloerection

Arrector Pili muscle

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o Shivero Chemical Thermogenesiso Behaviour

- Determinants of body temperatureo Production of heat by metabolic processeso Mechanisms for sensing changes (thermoreceptors)o Mechanisms for control of blood flow through skin (warming or cooling)o Mechanisms for exporting heat through lungs and skin

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o Mechanisms for conserving body heat- Fever

o A temporary increase in the set point as a result of infectiono Pyrogen production

IL1 production by macrophages Prostaglandin production Reduced by Aspirin and Paracetamol

- Anhidrotic ectodermal dysplasiao X linked recessive genetic disorder : complete or near complete absence of sweat

glands.o Hypotrichosis, hypohydrosis and abnormal teeth.o All heat loss occurs through radiation.o Evaporative cooling plays no role.o Overheating and death from exercise. o Heat loss may be increased by a simple measure.(exogenous spraying of water

frequently)

Hair and nails: Dr A Charakida

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- Telogen Effluviumo Premature termination of anogen Telogeno Diffuse Hair Losso Regrowth over 3-6 months if pregnancy related

- Androgenic Alopecia [= male pattern baldness]o Androgen Sensitive

• 50% men over 50y • >80% men over 70y • Polygenic • Treat with –5α reductase inhibitors/minoxidil

o Hamilton-Norwood classificationo May occur in women : Ludwig scale

- Autoimmune Alopecia Areatao Immune privileged status of anagen hair breaks down

- Infection/Inflammationo Most common pathology of hair follicle

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Healing of skin wounds: Fernanda Teixeira

- Healing: 2 typeso Regeneration

(labile cells)o Repair

formation of fibrotic scar

- processes:o Epidermis:

regenerateso Dermis:

repairs: scar will be left cleansing of all necrotic tissue demolition of the clot stimulation of blood vessels collagen synthesis

- Acute inflammation [is necessary for healing]o Vasodilatation

(of arterioles) histamine prostaglandins

hence NSAIDs give reduced removal of acid from stomach ulcero Increased permeability

(of post-capillary venules) histamine leukotrienes

- Adhesiono Expression of adhesion moleculeso Mediated by many molecules, including

PAF (platelets, endothelium, macrophages) Leukotrienes

- Emigrationo Neutrophils arrive firsto Attracted by chemotactic factors, as products of cell deatho Macrophages arrive latero EXUDATE

- Functions of the exudateo Demolish dead cells

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o Demolish inflammatory debriso Demolish old, damaged collageno Stimulate regeneration of epidermiso Stimulate collagen deposition in the wounded dermis

- Macrophagic growth factorso Factories of growth factorso Stimulate formation of granulation tissueo IL-1o PDGFo TGF betao VEGF

- Granulation tissueo Very vascularised granular tissue o Fills defecto Formed by:

Proliferated capillaries Increased intercellular matrix Collagen type III

- Vascular proliferationo VEGF

- Maturation of granulation tissueo Progressive decrease in number of capillarieso Increased deposition of collageno Change from collagen III to collagen I

- Mediators of epithelial proliferationo Epidermal growth factoro Produced in small amounts by normal epitheliumo Larger amounts by epithelium surrounded wound

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- Healing by first intentiono Sutured woundso Borders approximatedo Smaller scar

- Healing by second intentiono Used in infected woundso Good for concave areaso Takes longero All healing processes are more voluminous in healing by second intention

- Complications of healingo Diabetes mellitus

Non-enzymatic glycosylation: adhesion molecules of immune system etc work less well due to the glycosylation

Defective margination, phagocytosis Poor perfusion due to the microangiopathy Tendency for infection due to high sugar in blood

o Keloids Scars that are much bigger than the original insult Causes poorly understood ? TGF beta

o Dehiscence Caused by:

Tension at closure Poor circulation Infection Bleeding

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- Why do fetuses heal without scarring?o Sterile amniotic fluido Rapid epithelializationo More HA o Nonsulfated GAGso TGF 3 isoformo More fibroblast migrationo High proportion PCIIIo No inflammatory effector cello Dry contaminated environmento Slow epithelializationo Less HAo Sulfated GAGso TGF 1 isoformo Slower fibroblast migrationo Low proportion PCIIIo Effector: macrophage

Failure of skin functions: F Teixeira

- Twenty Nail Dystrophyo Idiopathic nail dystrophy o Appears in early childhood. o Excessive ridging, with longitudinal striations and discolouration. o The nails very slowly return to normality. o This condition is not seen in adults.

- Hypohidrotic ectodermal dysplasiao Hypotrichosiso Anodontiao Hypohidrosis

o Prominent supraorbital ridgeo Thin lower faceo Hypotrichosiso X-linked recessive or autosomal dominant (2q11-13)

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o Intermittent hyperpyrexia in infantso Decreased sweating o The mortality rate approaches 30%o Recurrent high fever may also lead to seizures and neurological sequelae

- (Oculocutaneous) Albinismo Disruption of melanocyte migrationo Disruption of melanin synthesis (oculocutaneous albinism)o Disruption of melanosome formationo Disruption of transfer of melanosomes to keratinocytes

o Four types, all autosomal recessive 40% (type 1): mutations in tyrosinase gene 50% (type 2): mutations in P gene (membrane transport)

”yellow albinos” Improved with age

o Photophobiao White hair and skin [white hair gives reduced sun protection]

- Vitiligo [dhtk details]o Mutations in the NALP1 gene (17p13)o Regulates inflammation and cell deatho NALP 1 expressed in T lymphocytes and Langerhans cellso Products: Caspases 1 and 5, that activate IL 1- an inflammatory cytokine

- Toxic epidermal necrolysiso 95%- drug inducedo Fever, cough, sore throat, malaiseo Red macules- blisters - sheetlike epidemal detachmento Mucosas firsto Cell-mediated cytotoxic reactiono Target: epidermal cellso Dead cells peel offo Death rate: 30-40%o Dehydration:

>50% involvement: 4L made worse by g-i involvement

o Protein loss: (blister fluid: 40g/L protein)o Heat losso Increased energy expenditure (200 g protein per day)- IL-1o Renal tubular necrosiso Bacterial sepsis: S.aureus, Gram - ; Hypothermia

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- Epidemolysis bullosao Often get squamous cell carcinoma subsequently

- Cancer and immunosuppressiono Immune system defends skin against cancer

Hence if are immunocompromised must not expose self to suno CD8 lymphocytes destroy cancer cells, detected by changed surface antigens.o Azathioprine sensitizes DNA to UVA.o 6-thioguanine incorporates into the DNA of patient’s skin cellso UVA transform thioguanine into guanine 6 sulfonate, which is mutagenic

The breakdown for the Support Systems exam is as follows:

30 SBAs4 EMQs2 SAQs

Mark Breakdown:Alimentary – 11 marksCVS – 17 marks [7 SBAs 1 SAQ]Renal – 16 marksRespiratory – 21 marks [1 SAQ…]Skin - 5 marks

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