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mixed2 Flashcards

1
Q

Skin layers

A

1) stratum corneam (keratinised)
2)stratum lucindum (more so in thick skin, organelles lost)
3)stratum granulosum (produces keratin)
4)stratum spinosum (has desmosomes, provides strength against sheer forces. Also has more langerhans)
5) stratum basale (has melanocytes and meckel cells)
BM

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2
Q

Barriers in skin

A

Barriers include:
Tight junctions ( found largely in stratum basale - prevent paracellular diffusion).
Hemidesmosomes (between basal layer and basement membrane)
Desmosomes (between cell layers)
Keratin
Phospholipid waterproofing

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3
Q

Skin Cell types

A

95% keratinocytes (keratinised, stratified, squamous epithelium)
Melanocytes (basal layer - derived from neural crest, produce melanin (more active in darker skin)
Langerhans cells (dendritic cells - found in all layers plus dermis, but more numerous in spinosum)
Meckel cells (basal layer, clear cells, ahve neuroendocrine function and connect to keratinocytes and nerves)

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4
Q

Basement membrane made of

A

Composed mainly of type IV collagen, glycoproteins (laminin from epithelial cells, fibronectin from fibroblasts) and GAGs.
The basement membrane allows adhesion, barrier (permeability), cellular organisation (controls growth and differentiation).

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5
Q

Blistering disorders

A
  • Pemphigus (IgG auto antibodies to components of desmosomes (acantholysis - desmosome breakdown)
    • Bullous pemphigold (deposition of IgG autoantibodies to BM proteins)
      Dermatitis herpetiformis (linked with coeliac disease. Involves deposition of IgA auto-antibodies to fibrils that bind BM to dermis).
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6
Q

acantholysis

A

Desmosome breakdown

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7
Q

Epidermolysis bullosa

A

Group of rare, inherited conditions causing separation of dermis from epidermis with minimal sheer force - no inflammatory cell infiltrate
- EB simplex -defective basal cell cytoskeleton which causes sheering along lower part of basal cell. Has a relatively good prognosis as blisters can heal without scarring
- Junctional EB - defective hemidesmosomes. This is lethal variant. Presents at birth but child only survives weeks. Occurs everywhere on body.
Dystrophic EB - defect element in BM collagen - leads to dermal scarring and tissue damage.

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8
Q

Acute dermatitis

A

Dermatitis involves epidermis and dermis)

utricaria is acute

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9
Q

Chronic dermatitis

A

Dermatitis involves both dermis and epidermis.
psoriasis, lichen planus (lichen planus is autoimmune skin disease that causes flat bumps on mucous membranes)
Non Specific inflammation: eczema

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10
Q

Eczema

A

Group of diseases that causes red, itchy (pruritic) skin with tiny blisters. Skin is scaly, cracking and bleeding.
Skin dries, waterproof barrier lost. Leads to allergen influx causes H/S and lymphocytic infiltration. Swelling occurs in the epidermis (spongiosis (fluid accumulating in epidermis).
The redness is due to dilated blood vessels.
If untreated, leads to thickening (esp in spinosum (spinosum thinkening is acanthosis)) - hyperkeratosis also occurs.
Oedema also occurs as well as fibrosis (due to inflammation).
Rete ridges occur in areas with high sheer forces anyway, but in chronic eczema, the rete ridges elongate.

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11
Q

psoriasis

A

This is chronic dermatitis that has neutrophilic infiltration.
Causes red, raised plaques covered by thick white scale (bleeding occurs on removal (due to thinning of skin and near proximity of blood vessels).
The epidermis has a rapid rate of cell renewal (therefore thickening doesn’t get a chance to happen). Cells are thin with parakeratosis (retention of nuclei in the upper layers of cells of the epidermis).
Oedema occurs in the dermis.
Long rete ridges also form to help increase connections between dermal and epidermal layers.

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12
Q

Comparison of Eczema and psoriasis

A

Eczema is thick skin (Spinosum), dry, itchy skin. Has long rete ridges. Epidermal swelling and oedema occurs. H/S mediated.
Psoriasis has thin skin with rapid turnover (parakeratosis). Oedema in dermis.
Long rete ridges form.

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13
Q

Impetigo:

A

Caused by staph and strep bacteria. Causes subcorneal bullae (+/- neutrophils) - these burst and spread with yellow crusting (highly contagious, often see outbreaks in children).

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14
Q

Cellulitis:

A

Caused by strep pyogenes/staph bacteria.
Extends into the dermis and can spread into fascia. Can lead to necrotising fasciitis. Can involve mixed bacteria at necrotising fasciitis and is difficult to treat.
Limbs are particularly susceptible through penetrating injuries and bites.

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15
Q

Boils:

A

Infection in hair follicles

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16
Q

Acne:

A

Infected follicle blocked with keratin plug

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17
Q

Skin Cancer

A

Can be basal cell (from stratum basale), squamous cell carcinoma (from any epidermal layer other than corneal layer as they need a nucleus to proliferate) or melanoma (from neural crest cells).

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18
Q

Basal cell carcinoma

A

Most common skin cancer, rare in dark skinned people. Linked to cummulative sun exposure, so tends to be on high sun exposure areas.
It is a non-metastasising cancer of basal cells (but called a carcinoma as it is invasive (invades into dermis from epidermis).
Diagnosed by biopsy, removal is curative.

Appearance can be varied:

- Smooth, translucent nodule (flesh coloured/pink) with telangeictatic  (spidery ) blood vessels under surface
- Can also be flat, scaly erythematous plaque with vessels and nodular borders - often mimics ezcema but with unusual presentation of "isolated patch"
- Can also extend wide/deep with central depression and ulceration
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19
Q

Squamous cell carcinomas

A

10-20% skin cancers. Linked to cummulative sun exposure (face, nose, lip, hand) but also occupational exposure (arsenic/coal) that means higher historical prevelance in men.

Starts in upper epidermal layers (not corneum as needs nucleus), then becomes intraepidermal and can stay there for years. Can then invade down (breach BM, etner blood supply and metastesise).
The invasion can come from the intrapeidermal spread itself or other-premalignant lesions (e.g. actinic keratosis via spinosal thickening in response to prolonged sun exposure).
It is curable, but if metastesised then 25% 5y survival.
Appearance is often red, scaly, slightly elevated with irregular border. Leads to ulceration with raised red border and crusts (chronic - with no blood vessels or rolled borders).

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20
Q

skin cancer dysplasia

A

Disordered cells (may see basal cells in upper layers). Can be reversible if stimulus is removed.

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21
Q

actinic keratosis

A

dysplasia in upper dermis

22
Q

carcinoma in situ

A

Full thickness dysplasia

23
Q

function of melanin

A

Scatters UV light to protect skin

24
Q

ephelides

A

Increased melanocyte activity (focal) - > freckle

25
Q

Lentigo maligna

A

Melanocyte hyperplasia (increased number) - often linked to sun exposure and seen in elderly people

26
Q

Albinism

A

melanocytes present but tyrosinase enzyme absent and therefore can’t make melanin

27
Q

Vitiligo

A

macules of de-pigmented skin that enlarge over time (cause unknown)

28
Q

Nevocellular Nevi

A

proliferation of melanocytes in the epidermis and dermis. They are deep brown, uniformly pigmented with well defined borders.
Junctional nevi are nests of rounded melanocytes at junction of the epidermis and dermis.
Compound nevi grow in dermis as nests/cords and show more elevation than the others.
Dermal nevi show disappearance of nests in epidermis, with more growth in the dermis. These show even more elevation.

The more growth in the dermis, the more elevated.

29
Q

Melanoma

A

Can be from existing nevi that turns dsyplastic, or from new nevi.
Show uneven surface with irregular borders, slightly raised. Tend to be black/brown in colour.
Can be:
- Lentigo malignant melanoma (spreads along stratum basale)
- Superficial spreading (lots of nests of cells in epidermis, these then break into dermis)
Nodular (vertical invasion into dermis)
More common in areas with intermittent sun exposure (back of legs) and in indoor workers.

30
Q

Melanoma identififcation and staging

A

Detecting melanoma: ABCD (E )

A-asymmetry
B-border (irregular, as well as indistinct border with skin)
C-colour
D-diameter
E-evolution
Needs biopsy to see type.
They are staged by Breslow thickness (measures deepest melanoma cell to the stratum granulosum of the epidermis). If <0.76mm then risk of metastasis is low, if >1.5mm then risk of metastasis is high

31
Q

Melanoma risk factors

A

Melanoma risk factors:
- Excessive exposure to UV light (melanocytes protect against sunburn by increasing melanin production)
- Increased risk in fair skin, red/blonde hair and those who burn/freckle easily
- Increased with FHx
- Hx of 3 or more blistering sunburns under 20 years old
Previous PUVA therapy, immunosuppression or dysplastic nevi

32
Q

Other skin cancers

A 
Other Skin cancers:
	- Merkel cell carcinomas (neuroendocrine derived cancer)
	- Kaposi sarcoma. Is actually from endothelial cells from dermal blood vessels. Often widespread)
Histiocytosis X (langerhans cell histiocytosis). This is technically not a cancer, but is a dermal infiltrate of Langerhans cells (bean shaped nuclei, birbeck granules, S-100 positive). Can involve many organ system.
33
Q

HIV virus type/origin

A

Retroviruses
Have RNA genome, but have a reverse transcriptase to make cDNA (replication intermediate) - HIV is a retrovirus.

HIV 1 is more common in west and is derived from SIV (chimpanzee).
HIV-2 is more common in africa and is non-pandemic (thought to be less transmissable), has less lethal profile and is derived from SIV from sooty mangabay (may have some protective effect against HIV 1)

34
Q

HIV viral contents

A 
2 copies of RNA
reverse transcriptase enzyme
integrase enzyme
viral capsid
GP120 (for CD4+ attachment),  with GP41 attachment to virus
35
Q

HIV replication cycle`

A

1) attachment (via GP120 (also, CCR5), CXRC4)
2) Entry, gp41 facilitates this
3) uncoating
4) Replication : RT converts ssRNA - >RNA-DNA complex, then dsDNA (provirus). Provirus inserted into host DNA with integrase enzyme
5) assembly
6) release

36
Q

Mother to baby transmission

A

Can be transplacental - less common and difficult to prevent),perinatally (in birth canal - exposure to maternal blood), postnatally (in breast milk)

37
Q

HIV seroconversion

A

This is the initial, primary infection.
Patient is febrile, with lymphadenopathy (as virus is transported to lymph nodes and lymph nodes are stimulated) and sore throat (glandular fever).
Can have rash due to immune complex deposition in skin.
Can have night sweats.

38
Q

CD4 level when AIDS expected

A

<200 - can also have AIDS defining disease (CDC lists 26)

39
Q

In terms of HIV infection, what is set point?

A

Initial viral left after seroconversion (lowest point able to acheive)duced earlier)

40
Q

If homozygous for delta CCR5?

A

Effectively resistent to HIV

41
Q

HIV diagnosis

A

Antibodies take around 6-7 weeks to develop. 4th gen testing combines antibody test with HIVp24 antigen (that is normally produced earlier
If positive then must resample and retest

42
Q

NRTI

A

NRTIs are all analogies of native nucleosides, sharing common motifs (lack of 3’ OH), and must be phosphorylated by cellular kinases in order to work.

E.g. AZT, ddC, ddI,D4T, 3TC,ABC
Phosphorylated by HOST cells! Acts as chain terminator and RT inhibitor.

ADEs of NRTIs tend to be inhibiting normal cellular DNA polymerases (e.g. mitochondrial DNA pol-y). Effects include lactic acidosis, hepatic steatosis, peripheral neuropathy, myopathy and lipoatrophy.
There may also be interference with cYP450 enzymes, giving drug-drug interactions

43
Q

Tenofovir DF

A

the only ‘nucleotide’ analogue RT inhibitor

It is a nucleotide analogue of adenosine monophosphate.

44
Q

Are any HIV RT mutations useful?Yes,

A

: The 184 mutation that confers resistance to 3TC renders the virus more susceptible to AZT. And therefore, combination therapies are useful to evading resistance.

45
Q

NNRTIs

A

Non-nucleoside reverse transcriptase inhibitors
They are structurally unrelated and bind to a different site within reverse transcriptase (they are non-competitive RT inhibitors that induce conformation changes within RT that distort ative site.).
Combining NRTIs and NNRTIs sets higher threshold for mutations.
Examples: Nevirapine, efavirenz, etravirine.
These drugs are substrates of CYP enzymes, and therefore there is a high potential for drug-drug interactions.
Combination therapy of NRTI +NNRTI gives better viral load control for longer.

46
Q

Protease inhibitors

A

HIV aspartyl protease cleaves gag and gol polyproteins into integrase and RT.
Protease inhibitors inhibit this process, and since the viral protease is structurally different then it can select viral particles from host proteases. The viral particles can still be made, but they are rendered non infectious.
Mutations in the binding pocket allow resistance development.
PI ADEs: dyslipidaemia can be problematic, and can lead to insulin resistance. Commonly get lower GI symptoms.
Also, drug-drug interactions can occur due to CYP450 inhibition.
Ritonavir is a weak protease inhibitor, but a potent CYP450 inhibitor, and therefore often given as an add-on as a booster as it enhances the effects of other drugs, and allows lower doses.
Examples are: Saquinavir, indinavir, ritonavir, nelfinavir, 141 W 94 (these are first generation, but subsequent generations are available with better resistance profiles - atazanavir, darunavir)
Lopinavir is generally given with ritonavir as a single drug (kaletra)

47
Q

HIV-1 Entry inhibitors

A

Can be coreceptor target :CCR5 Antagonists (E.g. maraviroc)
Can be virus/cell fusion inhibitor that prevents the gp41 from bringing the membranes together (e.g. enfuvirtide)
Experimental drugs in development to prevent CD4 binding.

48
Q

Integrase strand transfer inhibitors (INSTI)

A

HIV integrase catalyses both cDNA processing and strand transfer.
The inhibitors block this reaction in both HIV1 and HIV2.
Raltegravir was first approved.
All have suffix -gravir.
There is a low genetic barrier to resistance.

49
Q

FLT for HIV

A

FLT
Preferred regimes: Two NRTIs plus either a NNRTI; nitonavir boosted PI; an INSTI
Preferred NRTIs (tenofovir/abacavir)
Preferred NNRTI (efavirenz)
Preferred boosted PI (darunavir/atazanavir/lopinavir)

50
Q

Types of HIV therapies

A
  • NRTI (block synthesis and inhibit RT)
  • NNRTI (block RT)
  • PI (prevents cleavage of precursor for integrase and RT)
  • INSTI (blocks integrase)

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