Lecture 2: Structure of the skin and Adnexal structures
1) To understand the structure of normal human skin
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The skin is the largest organ of the human body and covers the body being contiguous with mucosal surfaces of the mouth, anus and
genitals and weighs about 4-5kg (16%)of total body weight.

The skin consists of two main parts: the epidermis and a deeper, thicker connective tissue part called the dermis.

The epidermis is keratinized stratified squamous epithelium.

It contains 4 principal cell types: keratinocytes, melanocytes, Langerhans cells and Merkel cells (see P142 of anatomy and physiology
for pictures).
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Keratinocytes are the most numerous of the epidermis and make up about 90% of it. Keratinocytes are arranged into 4/5 layers and
produce a tough fibrous protein called keratin. This helps protect the skin and underlying tissues from heat, microbes and chemicals.
They also produce lamellar granules, which release a water repellent sealant.

Melanocytes produce the pigment melanin, which is then transferred by projections to the keratinocytes. Melanin is a black/brown
pigment that contributes to skin colour and absorbs damaging UV light. Once inside the keratinocyte the melanin granules cluster to
form a protective veil over the nucleus on the side of the surface toward the skin surface. Therefore they shield the nuclear DNA from
being damaged by UV light. Although keratinocytes confer some protection from melanin granules, malnocytes are particularly
susceptible to damage buy UV light.

Langerhans cells arise from red bone marrow and migrate towards the epidermis. They form a network within the epidermis
composed of flattened dendritic cells lying adjacent to the surface of the skin. They represent 1-6% of the epidermal cells but because
of the dendrites cover more than 25% of the surface of the skin. They participate in immune responses mounted against microbes that
invade the skin and are easily damaged by UV light.

Merkel cells are the least numerous of the epidermal cells. They are located in the deepest part of the epidermis, where they contact
the flattened process of a sensory neuron, a structure called a tactile (Merkel) disc. Merkel cells and tactile discs detect different
aspects of touch sensations.

In most regions of the body there are 4 strata/layers of the epidermis: stratum basale, stratum spinosum, stratum granulosum and a
thin stratum corneum.

However, where exposure to friction is greatest e.g. fingertips, palms, the epidermis has 5 layers (same as above plus stratum
lucidum).

Stratum basale is the most immature part of the epidermis where cell division occurs.

The epidermal turnover time or transit time is the time taken for a cell to pass from the basal layer to the surface of the skin. In normal
skin the total time is 52–75 days.

Columnar or cuboidal cells

Mitosis occurs in 50% of basal cells

Keratinocytes held together by desmosomes that contain cadherins

Attach to basement membrane by hemidesmosomes that contain integrins

Tonofilaments attach to desmosomes /stabilise cell layer

Acidic type I keratins and basic type II keratins form tonofilaments

Keratin 5 and 14 genes are expressed
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Straum spinosum (thronlike). Cells in the more superficial portions of this layer become somewhat flattened. These keratinocytes
have the same organelles as cells of the stratum basale, and some of the cells in this layer may retain their ability to undergo cell
division. Each spiny projection in a prepared tissue section is a point where bundles of tonofilaments are inserting into a desmosome,
tightly joining the cells to one another. This arrangement provides both strength and flexibility to the skin. Projections of both
Langerhans cells and melanocytes appear in this straum.
Stratum granulosum Within this layer dense masses of keratohyalin granules and lamellar granules or Odland bodies are found
Stratum lucidium is only present in the thick skin of the fingertips, palms and souls. It consists of layers of dead keratinocytes that
contain large amounts of keratin.
Stratum corneum Corneocytes lack nuclei and cytoplasmic organelles
Keratin filaments highly cross linked by S-S bonds and activity of keratohyalin
Membrane coating granules exocytosed to intracellular space forming lipid barrier
Cross-linking of proteins (involucrin) along inner surface of plasma membrane forms cornified envelope.
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Desquamination by enzyme activity
See pictures on P143 to get an idea of the cellular layout and diagram below.
Below the stratum basale is the dermis.
The dermis is bound externally by the junction with the epidermis and internally by the subcutaneous fat.
The second deeper part of the skin, the dermis, is composed mainly of connective tissue containing collagen and elastic fibres. The
few cells present in the dermis include fibroblasts, macrophages and some adipocytes. Blood, vessels, nerves, glands and hair
follicles are embedded in dermal tissue.

The dermis can be divided into a papillary region and a reticular region.

The papillary region is the superficial part of the dermis (about 1/5 of thickness of total layer.

It consists of areolar connective tissue containing fine elastic fibres.

Surface area is greatly increased by small finger like projections called dermal papillae.

The deeper part of the dermis is called the reticular region. It consists of dense irregular connective tissue containing bundles of
collagen. The bundles of collagen fibres in the reticular region interlace in a net like manner. A few adipose cells, hair follicles, nerves,
sebaceous (oil) glands and sudoriferous (sweat) glands occupy the spaces between fibres.

The combination of collagen and elastic fibres in the reticular region provides the skin with strength, extensibility (readily seen in
obeisity and pregnancy) and elasticity.
2) To be able to recognise adnexal structures in the skin

Adnexal structures can either be internal (apocrine sweat glands eccrine sweat glands, sebaceous glands and hair follicles) or
external (nail and hair).

There are 4 classes of pilosebaceous units:

Terminal on the scalp and beard,

Apopilosebaceous in axillae and groins,

Vellus on the majority of the skin and

Sebaceous on the chest, back and face.

Hair grows from follicles, which are stocking like in-foldings with a superficial epithelium each of, which encloses at its base a small
stud of dermis known as the dermal papilla.

There are 3 types of hair: Lanugo, Vellus and Terminal

Lanugo is fine long hairs formed at 20 weeks and is shed before birth

Vellus is short, fine and light coloured and

Terminal is longer, thicker and darker hair.

The cylinder of hair may be regarded as a holocrine secretion arising by division of cells surrounding the papilla in the region known
as the bulb. Hair follicles are started in the dermis and the longer ones extend into the subcutaneous layer. An oblique muscle,
arrector pilorum, runs from a point in the mid-region of the follicle to the dermo epidermal junction. Above the muscle lie one or more
sebaceous glands and in some regions of the body an apocrine gland also opens into the follicle. Sebaceous glands are holocrine
glands producing an oily excretion that is pumped into the hair follicle and from there on to the surface of the skin. The sebaceous
gland is under direct control of androgens with some impact of ambient temperature.


The nail develops from a nail matrix just under the cuticle of the digit. Its main function is to produce a strong inflexible protective
cover over the dorsal surface at the end of each digit. The nail matrix produces a major part of the nail plate. The basal compartment
of the matrix gives rise to the keratinised cell with no expression of a granular cell layer. The nail plate is attached to the nail bed,
which consists of an epidermal part, an underlying connective tissue closely opposed to the periosteum of the distal phalanx. There is
no subcutaneous fat in the nail bed. Fingernails grow at approximately 1 cm over three months and toenails grow at a third of this
rate. Growth rates will differ on different digits.
The eccrine sweat glands are distributed over the whole skin surface but not in the mucus membranes. The number varies with
sites from 620 per cms2 on the sole to 120 per cms2 on the thigh. The gland consists of a secretory coil in the lower dermis and
subcutaneous tissue and a duct leading through the dermis to the intra-epidermal sweat duct unit. The secretory coil contains two
types of cells, large clear cells that are mainly secretory and small dark cells, which resemble mucus-secreting cells of other organs.
Secretory coils respond to cholinergic stimuli and produce from the plasma a watery isotonic secretion. Eccrine sweat glands allow
cooling of the body by evaporation but also have an important function in moistening the skin of the palm and soles at times of activity,
thus improving their grip.

Apocrine sweat glands develop as part of the pilosebaceous follicle. In the adult they are characteristically distributed in the axillae,
perianal area, areola of the breasts, and they can be found ectopically in other sites. The activity of the glands is androgen
dependent. They are larger than eccrine sweat glands and are situated in the subcutaneous tissue. Each consists of a tubule and a
duct. The duct opens into the neck of the hair follicle above the sebaceous gland. The secretory coil is a simple convoluted tube. It is
lined by a single layer of columnar or cuboidal cells resting on a basement membrane. Apocine glands secrete very small quantities
of an oily fluid, which may be coloured. The secretion is odourless on reaching the surface and bacterial decomposition is
responsible for the characteristic odour. They have no thermo regulatory function in humans but may play some part inhuman
olfactory communication.
3) To understand the importance of the basement membrane zone

The dermo epidermal junction is one of the largest epithelial/mesenchymal junctions in the body. It forms an extensive interface
between the dermis and epidermis. At the base of the basal keratinocyte hemidesmosomes form which are important in
maintaining adhesion between the dermis and epidermis. Immediately beneath the basal plasma membrane is the basement
membrane which consists of three layers, the laminar lucida, the lamina densa and the lamina fibroreticularis. Distributed throughout
the lamina lucida are anchoring filaments which are often difficult to see on electronmicroscopy but are most conspicuous in the
region of the hemidesmosomes. Anchoring filaments are orientated vertically between the laminar densa and the basal plasma
membrane. Anchoring fibrils are the major constituent of the fibre reticular layer of the basement membrane. These are short with no
regularly spaced cross-banding and insert into the lamina densa and extend into the upper part of the dermis. They may also insert
into amorphous bodies in the superficial dermis known as anchoring plaques. The main structural constituent of the lamina densa is
type IV collagen.
4) To recognise the different cell types in the skin

See page 142 of Principles of anatomy and physiology
5) To understand the blood supply and innervation of the skin

Arteries entering the skin form a deep plexus, the fascial network. From here vessels rise to the border between the subcutaneous
adipose tissue and the dermis and these form a cutaneous network. This gives branches to the various cutaneous appendages and
provides ascending arteries to supply a sub-papillary plexus which itself forms capillary loops in the papillary layer between the ridges
of the dermo epidermal frontier. From the capillaries the blood is drained by venules which descend to the intermediate plexus. The
vascular network is more elaborate than would be necessary solely for nutrition of the skin and temperature control is an important
function.
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The skin is innervated by around 1 million afferent nerve fibres. Most terminate in the face and extremities. Relatively few supply the
back. Cutaneous nerves contain axons with cell bodies in the dorsal root ganglia. The main nerve trunks enter the subdermal fatty
tissue and then divide into small bundles. Groups of myelinated fibres fan out in a horizontal plane to form a branching network from
which fibres ascend usually accompanying blood vessels to form a web of interlacing nerves in the superficial dermis. Throughout
their course the axons are enveloped in Schwann cells. Most end in the dermis but some penetrate the basement membrane but do
not travel far into the epidermis. Sensory endings are of two kinds corpuscular, which embrace non-nervous elements and free, which
do not. Corpuscular endings can be subdivided into encapsulated receptors and non-encapsulated receptors exemplified by the
merkel cell within the epidermis. The Pacinian corpuscle is an ovoid structure about 1 mm in length found within the dermis, which is
a striking example of an encapsulated receptor. The corpuscle is laminated in cross-section like an onion and is innervated by
myelinated sensory axons. Free nerve endings, which appear to be derived from non-myelinated fibres, occur in the superficial
dermis and in the overlying epidermis. Those in the dermis are arranged in a tuft like manner and are called penicillate nerve endings.
Hair follicles have nerve terminals of varying degrees of complexity. Fine nerve filaments run parallel to and encircle the hair follicles
forming a palisade. Efferent nerves from the sympathetic nervous system innervate vasculature, eccrine glands, arrector pili muscles
of the pilosebaceous unit
Lecture 3: Development of the skin from conception to old age
1) Foetal development of the skin

The skin is one of the largest structures in the body, it is a complex organ that forms a protective covering for the body. The skin
consists of two layers that are derived from two different germ layer:
- The epidermis is a superficial epithelial tissue, which is derived from the surface of the ectoderm.
- The dermis is a deeper layer composed of dense, irregularly arranged connective tissue, which is derived from the
mesoderm. (mainly from somatopleuric layer of the lateral plate mesoderm and from dermatome subdivisions of the somites)

Skin is first observed in the three week embryo, here the epidermis consists of a single layer of undifferentiated glycogen filled cells
overlying the mesoderm.
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Prospective epidermis is brought into contact with the prospective mesoderm during gastrulation; Mesoderm provides dermis but is
essential for inducing differentiation of epidermal structures ie hair follicle
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The neural crest also makes an important contribution to the skin by providing pigment cells
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Development of epidermis:
- >3weeks: the epidermis consists of a single layer of undifferentiated glycogen filled cells
- 4-6 weeks: The single layer increases to two layers: periderm and stratum germinativum. The periderm is a purely embryonic
structure, which is eventually lost in utero as the true epidermis keratinises beneath it. The periderm probably has two
functions. The first is a protective investment for the foetus before keratinisation of the epidermis; the second is uptake of
carbohydrate from the amniotic fluid. (The exofoliated peridermal cells form part of the white greasy substance –the vernix
caseosa, that covers the foetal skin. Later the vernix contains sebum, which is the secretion from sebaceous glands. The
vernix protects the developing skin from constant exposure to amniotic fluid, with its urine content during fetal period. The
vernix also facilitates birth because of its slippery nature. Note: the baby is covered in vernix at birth).
periderm
basal cells
4 weeks
-
8-11 weeks: The stratum germinativum produces new cells that are displaced into the layers superficial to it. By week 11 the
stratum germinativum will have produced a third layer between the periderm and the germinative layer called the
intermediate layers.
stratum intermedium
basal cells
11 weeks
mesenchymel cells
>16 weeks: the periderm cells develop dome shaped blebs which initially are simple but later become dimpled and enfolded
>24 weeks: the periderm cells start to separate from the embryo and together with shed lanugo hair and sebum and other
material they form the vernix caseosa
- (At 10 weeks, desmosomal proteins are demonstrable in basal keratinocytes and by 14 weeks basal keratins are expressed
by the basal cells, and the skin differentiation keratins are expressed by cells in the middle layer. Flaggrin the protein of the
granular layer is first detectable at fifteen weeks)
Development of hair follicles:
- Earliest development of rudimentary hairs occurs at nine weeks in the region of the eyebrows, upper lip and chin. A hair
follicle begins as a proliferation of the stratum germinativum of the epidermis and tends into the underlying dermis.
-
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stratum intermedium
-
hair
canal
mesenchyme
cells
The ‘hair bud’ soon becomes club shaped forming a hair bulb. The epithelial cells of the hair bulb constitute the germinal
matrix which later produces the hair.
Hair peg stage
-
Hair germ stage
hair canal
mesenchyme cells
hair peg
The hair bulb is soon invaginated by a small mesenchymal ‘hair papilla’.
Bulbous hair peg stage
hair canal
sebaceous gland
rudiment
bulge for developing arrector muscles
developing arrector muscle
dermal papilla
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The peripheral cells of the developing hair follicle form the epithelial root sheath, and the surrounding mesenchymal cells
differentiate into the dermal root sheath
As the cells of the germinal matrix proliferates, cells are pushed towards the surface, where they become keratinized to form
the hair shaft.
hair canal
apocrine rudiment
inner root sheath
sebaceous gland
bulge for attachment of arrector muscle
hair
Later bulbous hair peg stage
dermal papilla
The hair then grows through the epidermis on the upper lip and eyebrows by the end of the twelfth week.
Lanugo hairs are the first hairs to appear, they appear at the twelfth week and are plentiful by the 20th week. These hairs
help to keep the vernix caseosa on the skin.
Development of sebaceous glands:
- Most sebaceous glands develop as buds from the sides of developing epithelial root sheaths of hair follicles. The glandular
buds grow into the surrounding embryonic connective tissue and branch to form the primordia of several alveoli and their
associated ducts.
- The cells contain glycogen but eventually accumulate drops of lipid. The sebaceous gland becomes differentiated at 13-15
weeks.
- The oily secretion, ‘sebum’, that is released into the hair follicles and passes onto the surface of the skin to form part of the
vernix caseosa.
- At the end of foetal life sebaceous glands are well developed and generally large. After birth the size rapidly reduces and
only enlarges to become functional again after puberty
Development of eccrine (sweat) glands
- They are located in the skin thoughout most of the body.
- They develop asepidermal downgrowths into the underlying mesenchyme. As the bud elongates, its end coils to form the
primordium of the secretory part of the gland.
- The epithelial attachment of the developing gland to the epidermis forms the primordium of the duct. The central cells of the
duct degenerate to form a lumen.
- The peripheral cells of the secretory part of the gland differentiate into myoepithelial cells (thought to be specialized smooth
muscle cells that assist in expelling sweat from the gland) and secretory cells.
- Eccrine glands begin to function shortly after birth
- These start to develop on the palms and soles at about three months but not over the rest of the body until the fifth month.
Development of eccrine gland:
-
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Pore
bud
developing
lumen
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duct
Myoepithelial
cells
Nails begin to develop in the third month and by sixteen to eighteen weeks keratinising cells from both dorsal and ventral matrices can
be distinguished. By 24 weeks nails are fully formed
Melanocytes originate from neural crest material. These cells can be identified in early human embryos but pigmented melanocytes
cannot usually be identified before four to six weeks of gestation. (melanoblasts migrate into the hair bulbs to differentiate into
melanocytes
Langerhans cells are of bone marrow origin and enter the epidermis at about twelve weeks gestation
Merkel cells are of ectoderm origin. These appear in the glabrous skin the fingertips, lips, gingiva and nail bed and in several other
organs around sixteen weeks.
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Development of the dermis
- The dermis develops from the mesenchyme which is derived from the mesoderm underlying the surface ectoderm. Most of
the mesenchyme that differentiates into the connective tissue of the dermis originates from the somatic layer of lateral
mesoderm, however some of it is derived from the dermatomes of the somites.
- Initially very cellular (dermis and subcutis are not distinguishable)
- End of 3rd month - fibrillar components appear
- 20 weeks - papillary and reticular layers evident (and regular bands of collagen fibres are evident)
- At the fifth month - connective tissue sheets are formed around the hair follicles
- 22 weeks - elastic fibres detectable
- 24 weeks - fat islands demark the adipose tissue
- At first the under surface of the epidermis is smooth but during the fourth month at the same time as hair follicles start to
develop it becomes irregular developing into the rete ridge pattern.
- Touch pads become recognisable on the hands and fingers and on the toes and feet by the sixth week and reach their
greatest development at the fifteenth week. These areas subsequently determine the pattern of dermoglyphics, which take
their place.
2) To understand the development of acquired melanocytic naevi (moles)
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An acquired melanocytic naevus is defined as a benign cluster of melanocytic naevus cells arising as the result of proliferation of
melanocytes at the dermo-epidermal junction.
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Melanocytic naevi are almost universal and the great majority appear after birth. The number of melanocytic naevi any individual
develops is partially determined by genetic factors and partially by sun exposure (environemental factors).
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The presence of large numbers of melanocytic naevi in childhood is usually associated with sun exposure. Melanocytic naevi are
uncommon in infancy but increase in frequency gradually during childhood and adolescence and then more slowly during early adult
life.
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The incidence plateaus in middle age and it is unusual to develop new melanocytic naevi during old age.
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Development of melanocytic naevi
- Melanocytes are derived from the neural crest cells.
- Melanocytic naevi start as proliferation of melanocytes in the basal layer of the epidermis. This produces a clinically evident
lesion, which is flat and pigmented; this is a junctional naevus. The hallmark of a normal junctional naevus is that it is round
or oval with a clear margin and an even colour. The colours vary from mole to mole from skin coloured through to black.
- As the mole matures the melanocytes migrate deeper into the dermis and proliferate giving rise to a naevus that has both
epidermal and dermal components, a compound naevus.
- With full maturation all the naevus cells migrate into the dermis, the epidermal component is lost. Proliferation of the naevus
cells deep in the dermis leads to the development of an exophytic tumour bulging on to the surface of the skin, this is an
intradermal naevus.
- The rate of maturation of melanocytic naevi varies in different parts of the body and tends to be highest on the face and
lowest on the trunk. Some melanocytic naevi mature extremely quickly and within a few months have fully matured, other
remain junctional throughout the life of the individual.
- The major importance of melanocytic naevi is that the cells involved in the development of the naevi can undergo malignant
change. Malignancy occurs in the epidermal melanocytic component, not within the dermal naevi. Malignant change is
heralded by a radial growth of the cells which is irregular and alteration of colour of the melanocytic naevus.
3) To understand the changes that happen with aging of the skin and the importance of UV irradiation in this process.

The aging process in the skin is a gradual process, which has input from intrinsic ageing as well as the effects of a number of
environmental insults particularly ultraviolet radiation and in women the additional hormonal changes at the menopause.

Environmental factors, such as, UV radiation are of obvious importance in certain communities living in particular parts of the world.
In Caucasian (white) populations living near the equator the effects of UV radiation are much greater than in Afro-Caribbean
populations living in the same geographical area.
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Intrinsic ageing falls into two categories: those engendered within the skin itself and those that result as alterations caused by senile
changes in other organs. An example of those engendered within the skin itself is greying of hair and those that result as alterations
caused by senile changes in other organs: the lowering of sebaceous gland activity consequent on a reduction of androgen secretion.
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It has been suggested that 90% of age associated cosmetic problems on exposed skin are caused by UV radiation rather than
intrinsic ageing of the skin.
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Cumulative DNA damage resulting from recurrent acute DNA injury

Dermis principally affected by UVA; Epidermis principally affected by UVB - little UVB penetrates into the dermis
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Ageing of the epidermis:
- With age the rete ridge pattern of the derma-epidermal junction becomes flattened and in general the epidermis becomes
thinner with age.
- Permeability of the skin also changes with age. This does not seem to affect the capacity of isolated horny layer in vitro to a
straight water loss but does alter percutaneous absorption through the skin.
- With age the skin progressively dryer and flakier and this is partly due to a reduced water binding capacity of the corneum
but also a reduction in function of the sebaceous glands.
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Ageing of the dermis:
- Wrinkling of senescent (ageing) skin is almost entirely result of changes in the dermis.
- Collagen decreases with age and there is also a steady decrease in the number and size of fibroblasts. Elastic fibres
gradually disintegrate with age and after the age of seventy most fibres appear abnormal.
- Collagen bundles become fragmented and disorientated leading to progressive loss of tensile strength and elasticity in the
skin sagging of the dermis and wrinkle formation
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An obvious change in old skin is irregular pigmentation. Melanocytes undergo localised proliferation at the derma-epidermal junction,
giving rise to yellow or brown spots, know as liver spots or senile lentigines

Greying of hair becomes evident at about the age of fifty by which time half the population has about 50% grey or white body hairs.
The bulbs of grey hairs lack tyrosinase activity, which is the enzyme necessary for the first stages of melanin synthesis. Fully white
hairs complete lack melanocytes. It is unknown why grey hairs tend to be thicker and longer than pigmented ones.

With age the density of hair follicles steadily reduces in the scalp. This is most marked on the vertex and least marked on the occiput.
Scalp hair also becomes visibly finer with age.

Sebaceous glands and apocrine glands: Sebum production is at its greatest in early adulthood and decreases with old age. Studies
have suggested that sebum excretion declines steadily through each decade by about 23% in men and 32% in woman. Axillary
apocrine glands also regress with age and produce less odour.
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Eccrine Glands: Spontaneous sweating on the fingertips declines in old age due to a combination of a reduction in the number of
glands and reduction in output per gland
The rate of linear nail growth increases progressively until about the age of twenty five and then progressively decreases. Nail growth in
men is greater than in women until the age of seventy
Lecture 4
Function of the Skin
Dr Tony Chu
Learning Objectives:
1.
To understand the part skin plays in social and sexual interactions
2.
To understand the role of the skin in barrier function
3.
To understand the role of the skin in protection UV radiation
4.
To understand the role of the skin in protection against infection
The skin plays a major part in our social and sexual interactions
To display sexuality or to exert social status it is necessary to have skin and hair which looks, feels and smells
attractive. The importance of the skin in social and sexual interactions is highlighted by the effect of disfiguring
skin conditions or other disfiguring conditions on this important activity. People with disfigurement will often
perceive themselves to be unattractive and this will have an impact on their quality of life and their confidence in
social and other interactions. This may lead to general loss of confidence; unwillingness to partake in various
activities which may display the disfigured areas of skin, reclusiveness, depression and suicidal ideation.
a) Skin as a barrier
The skin acts as a two-way barrier to prevent inward and outward passage of water and electrolytes. Much of this
function resides in the epidermis and much of the epidermal barrier is localised to the stratum corneum. The
barrier depends on both the fibrillar material of the keratinocyte and the intercellular material, particularly lipid.
Within keratinocytes are synthesised both the fibrous protein of keratin and the histidine rich protein known as
keratohyalin or flaggrin. As keratinocytes develop into corneocytes they are surrounded by an envelope formed
by cross-linkage of a precursors of involucrin and keratohyalin which forms an insoluble exoskeleton and acts as a
ridged scaffold for the internal keratin filaments. The intercellular cement is the product of ovoid organelles
known as membrane coated granules or Odland bodies. Odland bodies first become identified in the cells of the
spinus layer and migrate to the cell periphery where they fuse with the plasma membrane in the granular cell layer.
They then discharge their contents into the intercellular spaces, which expand to form 10-40% of the total volume
of the tissue. As keratinocytes mature neutral lipids and sphingolipids in particular ceramides are increased.
Within the Odland bodies biolayers become arranged to form discs which represent flattened uni-lamellar
liposomes. After extrusion in the intercellular space the discs become arranged parallel to the cell membrane and
then fuse to form uninterrupted sheets or intercellular lamellae consist of two lipid biolayers in close apposition.
These intercellular lamellae are the main barrier for transepidermal water loss and also for the prevention of water
absorption through the skin.
b) Percutaneous Absorption
The skin is a target of many different drugs that can be absorbed either locally into the skin for the treatment of
various skin conditions or absorbed into the bloodstream for systemic therapy. Human skin is slightly permeable
to water but is relatively impermeable to sodium, potassium or other ions in aqueous solution. In general, drug
penetrated rates are determined largely by their lipid water co-efficient, water soluble ions and polar molecules
being excluded. Percutaneous absorption is affected by a number of factors, such as, age, environmental
conditions and physical trauma. The efficiency of the barrier also differs between body sites. The scrotum is
particularly permeable and the face, forehead and dorsum of the hands may be more permeable to water than
trunk, arms and legs. In diseased skin, where the stratum corneum is improperly formed, drug absorption may be
greatly increased.
c) Protection against UV damage
The ultraviolet spectrum of terrestrial light is potentially very damaging to the skin. Short wave length UVB is the
main etiological agent implicated in the development of skin cancer. Longer wave length UVA is strongly
implicated in photo ageing of the skin. The skin has three mechanisms by which it can protect against excessive
UV irradiation.
a) Melanin production
b) Thickening of the skin
c) Sun burn reaction
Melanin is produced by melanocytes, which are dendritic cells of neural crest origin. Melanocytes can be found in
nearly every tissue but they are most common in the epidermis, hair follicles, dermis, eye, around blood vessels,
peripheral nerves, sympathetic chain and in the leptomeninges and inner ear. The distribution of epidermal
melanocytes in different parts of the body vary, being greatest on the face and genital areas and lower on the trunk.
The range is 2,900 + per mm2 on the face to 1,100 + 215 per mm2 on the upper arm. There is no sexual or racial
difference in melanocyte distribution. The differences in colour between Caucasoid, Mongoloid and Negroid skin
are due to the amount and arrangement of melanosomes produced by the melanocytes. Skin colour in the different
races is largely determined by the size, packaging distribution and degradation of melanosomes within the
keratinocyte. Melanin pigmentation in the skin in humans is a dual process involving the production of the
melanosome within the melanocyte and then distribution and transfer of these pigmented granules to surrounding
epidermal keratinocytes. Each epidermal melanocyte is surrounded by a group of keratinocytes with which it
maintains functional contact. A single melanocyte supplies melanosomes to a group of about thirty six
keratinocytes.
Melanins are classified into two main groups, the black and brown eumelanins, which are insoluble, and the
yellow and reddish browns phaeomelanins, which are alkali soluble. Both eumelanins and phaeomelanins are
derived from tyrosine. Tyrosine is oxidised to dopa by tyrosinase which then catalyses further oxidation to dopa
quinone. From dopa quinone the eu-melanin and phaeo-melanin pathways diverge. Eumelanins arise from
oxidative polymerisation of 5, 6 dihydroxy indoles. The pathways of phaeomelanins involve the addition of the
SH group of cysteine to dopa quinone to form cysteinyldopa and eventual formation of phaeomelanins.
Genetic factors play the primary role in determining the degree of pigmentation that is normal for an individual i.e.
constitutive skin colour. Response to sunlight causes colour change which is inducible skin colour. Melanin is
synthesised on melanosomes within melanocytes which are then transferred to keratinocytes where they occur as
either discrete particles or aggregates of two or more particles within membrane limited vesicles. Aggregated
melanosomes in keratinocytes appear to undergo a gradual degradation into small electron dense particles.
Transfer of the melanosome from the melanocyte to the keratinocyte may be by cytophagocytosis, direct injection
of melanosomes into keratinocytes or by release of melanosomes into the extra cellular space followed by
incorporation of these melanosomes by keratinocytes.
Increased melanin pigmentation of human skin following sunlight exposure is caused by two separate reactions:
1. Immediate pigment darkening.
2. Delayed tanning reaction.
Immediate pigment darkening is induced by long wavelength ultraviolet light (UVA 320 – 400 nanometers) this
reaches a maximum at two hours and then decreases between 3 and 24 hours later. This reaction is due to an
alteration in the distribution of pre-existing melanosomes within keratinocytes and melanocytes. Delayed tanning
involves a formation of new melanosomes and is a gradual process that occurs 48 – 72 hours following irradiation
of the skin. Dopa reaction and tyrosinase activity are markedly increased and melanocytes are increased in
number and have well developed dendrites. Melanin acts as a chromophore for UV light preventing its damaging
effects on the skin.
Epidermal Thickening
Following UV sunlight exposure the epidermis thickens by an increased number of intermediate layers within the
epidermis. This has the function of providing extra protection to the most sensitive basal cell layer of the
epidermis, which are the most susceptible to UV induced skin damage.
Sunburn
Sunburn is a complex reaction involving increased blood flow through the skin, inflammation, pain and in severe
cases blistering. Sunburn reactions are related to release of various chemicals within the skin including
immunologically active agents that will induce the clinical changes observed. Sunburn should be see as protective
as individuals who have suffered sunburn will then protect their skin against further sun exposure.
Protection against micro-organisms and destructive chemicals
An intact stratum corneum prevents invasion of the skin by normal skin flora or pathogenic micro-organisms.
Minor injury as well as skin disease can provide portals of entry of micro-organisms by breakdown of this barrier
function. Sebaceous lipids are reported to possess antibacterial properties and glycophospho-lipids and free fatty
acids of the stratum corneum have bacterio-static effects selective for pathogenic organisms.
Lecture 5: Secondary sexual changes of the skin, control of hair growth, sebum
production and sweating
1) To understand the effect of secondary sexual development on skin structures including the hair follicle, sebaceous gland and
sweat glands.
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At puberty there is an abrupt transition in the human from an immature actively growing organism to a physically mature and
potentially reproductive organism.
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The process of sexual maturation involves both maturation of primary reproductive traits (activation of the hypothalamic pituitary
gonadal access and the onset of gamete production) as well as maturation of secondary reproductive traits including external
genitalia, breast development in girls and in the skin, control of hair growth and sebum production.
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Experimental evidence from primates and clinical evidence in humans show that primary sexual maturation is initiated by the
establishment of pulsed GnRH released by the hypothalamus.
This leads to increased levels of gonadotrophin hormones (FSH and LH) secreted from the pituitary gland. These act on the gonads
causing testicular enlargement in boys and increases in gonadal steroids (including oestrogen, progesterone and testosterone).
Increasing androgen steroid levels are associated with development of pubic and axillary hair in both sexes and facial hair
in males.
Androgens are also required for male-pattern baldness in predisposed people because the androgens inhibit hair growth.
Androgens are responsible for the development and maintenance of sebum secretion in both sexes.
Sebaceous gland activity is clearly influenced by the presence of androgens, such as, testosterone and 5-alpha dihydrotestosterone.
After birth sebaceous glands regress to become minute during the pre-pubertal period but as androgen levels increase the
glands undergo vast enlargement at puberty with an associated five-fold increase of sebum production in males.
Eunuchs secrete about half as much sebum as normal males and this is thought to be secondary to adrenal androgens.
In women secretion of sebum is only slightly less than in normal men.
Acne vulgaris is the commonest inflammatory skin disease in the world, affecting over 95% of humans at some stage. Increased
sebum production under the influence of androgens is an important factor in pathogenesis of acne.
2 types of sweat gland:
Apocrine glands are poorly developed in childhood but enlarge with the approach of puberty. Their activity is once again
androgen dependent.
Eccrine sweat glands are not influenced by secondary sexual development. Functioning of the eccrine sweat gland is dependent
on intact non-myelinated C-fibres of sympathetic nerves.
The main sympathetic nerve supply of these sweat glands is unusual in that it is cholinergic.
2) To understand the physiology and effect of androgens on the hair follicle.
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Hair grows from follicles, which are stocking like in foldings of the superficial epithelium, which enclose at their base a small stud of
dermis known as the dermal papilla.
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The hair is produced by the excretion of keratins (insoluble cysteine containing proteins) that are produced in the epidermal tissues of
vertebrates and are secreted by division of cells surrounding the papilla in the region known as the hair bulb.
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An oblique muscle the arrector pilorum runs from the mid-point of the follicle wall to the dermo epidermal junction.
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Hair growth is cyclical: each hair grows to a maximum length and then is retained for a time without further growth before eventually
being shed and replaced.
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In humans a pre-natal coat of fine soft unpigmented hair known as lanugo hair is shed in utero in about the eighth to ninth month of
gestation.
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Post-natal hair may be divided into vellus: soft hairs usually less than 2 cms long and terminal hair which is longer, coarser and often
pigmented. Before puberty terminal hair is limited to the scalp, eyebrows and eyelashes.
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After puberty secondary sexual terminal hair develops from vellus hair in various sites.
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The development of facial, trunk and extremity hair in the male, and of pubic and axillary hair in both sexes is dependent on
androgens and increases as levels of androgen secretion rise from the testes, adrenal cortex and ovaries.
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Direct evidence of the role of testicular androgen is that castration reduces growth of the human beard whereas testosterone
stimulates it in eunuchs and elderly men.
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Facial and body hair is normally absent from women because high levels of testosterone are required to stimulate follicles in these
sites.
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Further evidence for the importance of androgens is the successful treatment of hirsute women with the anti-androgen cyproterone
acetate.
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Growth of pubic and axillary hair is also androgen dependent. In testicular feminisation syndrome a condition in which genetic males
develop as females because of a lack of intracellular androgen, hair is deficient.
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Scalp hair does not require androgenic stimulus and paradoxically androgens may actually cause reduced hair growth at this site.
This is known as androgenic alopecia and is seen in both males and females to some extent with advancing age.
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Females, in particular, may develop increasing baldness after the menopause when oestrogen levels decline and a relatively more
androgenic environment exists.
3) To understand the physiology and effects of androgens on the sebaceous glands.
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Sebaceous glands are found over most of the body, although not normally on the palms and soles. They are largest and most
numerous in the mid-line of the back on the forehead and the face and on anogenital surfaces.
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On the scalp, forehead, cheeks and chin there are often over 500 glands per cm 2. The sebaceous gland is holocrine gland meaning
that its secretion is produced by the complete disintegration of glandular cells.
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Glands consist of a series of lobes each lined with a keratinising squamous epithelium. The lobule ducts converge towards the main
sebaceous duct, which opens directly into the hair follicle.
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Sebum produced by the sebaceous gland is, therefore, secreted through the follicles.
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Sebum is the first demonstrable glandular product of the human body.
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The production of sebum is under hormonal control. In utero and in the neonatal period maternal androgen causes sebaceous
glands to be active.
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They then, however, involute and remain quiescent until puberty.
Sebum is a complex mixture of lipids including glycerides, wax esters, squalene and cholesterol esters.
The function of sebum is not fully understood. It probably helps control moisture loss from the epidermis and prevents fungal and
bacterial infection of the skin.
It was believed that sebaceous lipids were important for the barrier function of the skin, this is not, however, correct as pre-pubertal
children who produce no sebum do not have impaired barrier function.
4) To understand the different types of sweat gland and their function.
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Sweat glands are described as merocrine, meaning that their cells are not destroyed in the process of secretion unlike the holocrine
sebaceous glands. Sweat glands may be sub-divided into two major types known as apocrine and eccrine.
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Apocrine Glands:
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Apocrine glands are important in most mammals for thermo regulation and production of odour.
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In the human embryo, apocrine glands are present over the entire skin surface but subsequently disappear, so that in the adult they
are found only in the axillae, perianal region and the areola of the breasts.
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Apocrine glands are poorly developed in childhood but enlarge with the approach of puberty.
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Their activity is androgen dependent.
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The apocrine gland comprises a secretary coil with a duct that opens usually into a hair follicle.
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Apocrine glands secrete very small quantities of an oily fluid. This secretion is odourless but on reaching the surface bacterial
decomposition causes a characteristic odour.
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This may have some function in human olfactory communication.
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The ducts have an androgenic sympathetic nerve supply and are also stimulated by circulating adrenaline.
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Expulsion of apocrine sweat occurs continuously and can be provoked by emotional stimuli.
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Eccrine Glands:
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Eccrine sweat glands have two functions in the human.
1. They allow body cooling by evaporation and have contributed in a major way to adaptation to a hot environment by humans.
2. The other main function is to moisten the skin on the palms and the soles at times of activity and to improve their grip.
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Eccrine glands are distributed over the whole skin surface but not on mucus membranes.
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The number varies from a 120 – 620 per cm2.
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They are developmentally related to the pilosebaceous follicle, unlike the apocrine gland, and usually open directly on to the surface
of the epidermis.
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Sweat is derived from plasma and is hypotonic containing sodium chloride, potassium, urea and lactate. Changes in sweat
composition may occur in certain disease and an increase in sweat electrolytes occurs in cystic fibrosis sufficiently constantly for it to
be a useful diagnostic test for this inherited disorder.
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Functioning of the eccrine sweat gland is dependent on intact non-myelinated C-fibres of sympathetic nerves.
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The activity of sympathetic nerve to the sweat gland is controlled by three stimuli, thermal, mental and gustatory:
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Thermal sweating is controlled by the heat regulating centre in the hypothalamus which is activated by changes in the temperature of
blood, perfusing it, the osmolality of fluid perfusing it, and by afferent stimuli from the skin. Thermo regulatory sweating occurs mainly
on the upper trunk and face.
2.
Mental stimuli may be emotional or intellectual (for example mental arithmetic) and occurs mainly on the palms and soles, perhaps to
improve the grip at times of activity.
3.
Gustatory sweating may occur after ingesting certain foods, such as, hot spices. Gustatory sweating may also occur if there has been
damage to sympathetic or para-sympathetic nerves in the head and neck. As these nerves regenerate abnormal connections may be
made and reflex arcs which normally cause parotid or gastric secretion may cause sweating in a localised area of the skin during
mastication.
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The importance of sweating in temperature control is illustrated by patients with x-linked hypohidrotic ectodermal dysplasia, in which
patients are unable to sweat and develop heat intolerance and unexplained fever.
Lecture 6: The control of body temperature with particular emphasis on the role of
the skin
1) To understand the structure of normal human skin
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The very act of living generates heat - none of the necessary chemical processes is perfect and heat results as a “waste product”.
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The result is that, normally, the body loses heat to the environment at a rate determined by a multitude of factors such as metabolic
rate, clothing, environmental temperature, humidity and draught etc
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And yet the body temperature is remarkably “constant” - and has to be to permit human life………..
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Normal mental processes begin to fail outside a range of 35-40oC
In a study of young healthy adults (in the morning) it was found that the mean temperature was 36.7 ± 0.2 oC. That means that 95% of that
group had temperatures in the range 36.3-37.1oC. This ability to hold body temperature within a very narrow range is a characteristic of
mammals and birds (known as homeotherms). Lower animals without this ability are called poikilotherms and have temperatures that
vary relatively widely at the whim e.g. of the environmental temperature. It presumably infers evolutionary advantage. Such as…...
2) What is meant by body temperature?
What we really mean is deep body, or core, temperature. Yet it is most commonly monitored orally (i.e. in the mouth). This is not the
best (why…?) and rectal temperature is thought to be more representative and is usually at least 0.5oC higher
However there is strictly no such thing as a single universal deep body temperature as different organs vary, e.g. the temperature near the
liver is often a degree or so higher than the average because of its high metabolic rate. So really what is being spoken of is some
representative average for the deep organs.
3) What are the effects of time variation?
So body temperature is not strictly constant at all, but it is held within a very narrow range
4) So how is it controlled?
The heat is generated internally by metabolism, but it is lost from the surface of the body by three main processes
Conduction, convection and radiation
But there are other avenues and these include:Evaporation - sweat, insensible perspiration and breathing
Defecation and urination
5) What controls the control mechanisms?
The basis is a classic negative feed-back process, i.e. receptors, control centre and effector mechanisms
There are both “hot” and “cold” receptors. Both give a baseline output at about 32oC, but the “cold” increases its response as temperature
falls, to peak about 15-20oC; the “hot” increases its response as the temperature rises to peak about 40-45oC
These are scattered about the surface of the body, pharynx and mouth to monitor peripheral temperature. They are also to be found in the
oesophagus and stomach but especially in the hypothalamus, with the vital role of monitoring the deep body temperature .
So what seems to happen is that the deep body temperature is compared with the “set-point” value in the control centre (hypothalamus)
and if these are compatible and compatible with the preferred responses from the peripheral receptors the subject feels comfortable.
Around this is a zone of thermoneutrality there is a range of ambient temperature that can be coped with without change in energy
expenditure or sweating.
Below it, mechanisms such as shivering are called into play, but eventually a zone of hypothermia is reached where the control breaks
down.
Above it mechanisms such as sweating are called into play, but eventually a zone of hyperthermia is reached where again control breaks
down.
6) What are the effector mechanisms?
Conscious control
Clothing, body position, exclusion of draughts etc
Shivering
Can increase the rate of heat production three-fold
Controlled by nervous activity at the muscles ultimately under the control of the hypothalamus
Non-shivering thermogenesis
Probably triggered by increased thyroid hormones
Sweating
Eccrine glands produce the sweat and are controlled through the hypothalamus and sympathetic CHOLINERGIC nerves.
The secretion is isotonic with plasma (water and electrolytes) but much of the Na and Cl are reabsorbed as it passes through the duct of
the gland to the surface of the skin. But the concentration depends on the rate of sweating, so [Na] can vary from 10-60mM. As much as
1-2l/h can be lost. So prolonged sweating can be a problem because of the loss of electrolytes.
Note:
the act of sweating does NOT cause heat loss. The heat loss is due to its evaporation. So heat loss is dependent on
environmental humidity, draughts etc.
Note:
that it allows heat loss even when the environmental temperature is above that of the body.
7) Cutaneous heat transfer
This is the main mechanism for controlling heat loss, especially in the thermoneutral zone. This is illustrated by the fact that generally there
is far more blood flowing in the skin than is necessary to maintain its metabolism. It is the blood that brings the body heat to the surface so
that it can be lost by conduction convection and radiation. This is aided by a wide supply of arterio-venous anastomoses linking the
small arteries and veins in the skin bypassing the nutritive capillaries.
As temperature rises the hypothalamus reduces the sympathetic activity to the anastomoses so they dilate and more blood feeds the
venous plexus so more heat reaches the surface.
In extremes this skin flow can be huge and require cardiovascular
adjustment
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8) Fever
Elevated body temperature usually associated with infections
The hypothalamic “set-point” is raised by pyrogens (probably interleukins released by
monocytes in response to the infection). So the control mechanisms work to the new
set point. The subject may feel cold, vasoconstrict and shiver in order to raise his/her
temperature rises to the new level.
When the fever “breaks” and the “set-point” returns to normal the subject may feel
hot and flushed and start to sweat to bring the temperature down.