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MD2002 > WEEK 10 > Flashcards

WEEK 10 Flashcards

1
Q

What is the role of HOX genes in normal limb development?

A 
HOX determine the body axis & position of the limbs.
They are expressed along the long axis of the embryo from head to tail.
The products of HOX genes belong to a class of proteins known as transcription factors, which bind to DNA & thereby regulate the transcription of other genes.
Once the cranio caudal position is set, limb growth is regulated along 3 axes.
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2
Q

What are the 3 axes that limb growth is regulated along?

A
  1. Proximo-distal
  2. Antero-posterior
  3. Dorso-ventral
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3
Q

What occurs within the proximo-distal axis?

A
  1. PROXIMO-DISTAL AXIS
    - controlled by apical ectodermal ridge (AER)
    - the limb bud consists of a core fo mesenchyme derived from the parietal layer of lateral plate mesoderm and ectoderm which forms the outer covering of the limbs (epidermis)
    - ectoderm is thickened at the apex of the developing ridge to form the AER
    - AER = key structure, induces underlying tissue to remain as a population of undifferentiated, rapidly proliferating cells (known as the progress zone)
    - as cells move further away from the AER, they begin to differentiate into cartilage & muscle
    (1) HOX-8 controls the position of the limb on the long axis of the body
    (2) Initiation of outgrowth of the forelimbs controlled by TBX5 and FGF10 (TBX4 in LL)
    (3) AER secretes FGF4 and FGF8 to maintain the progress zone & further development of proximo-distal axis
    (4) As growth progresses, mesenchymal cells are left behind the advancing ridge & so they begin to differentiate
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4
Q

What occurs within the antero-posterior axis?

A

The Zone of Polarising Activity (ZPA) regulates this axis
A cluster of cells near the posterior border of the limb form the ZPA
- it ensures that the thumb grows on the cranial side of the limb bud
- ZPA expresses the protein sonic hedgehog (SHH). ZPA moves distally with the AER
- an experiment in chicks showed that adding a ZPA to the limb bud results in a mirror image duplication of the digits.

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5
Q

What occurs within the dorso-ventral axis?

A

BMPs (bone morphogenic proteins) in the ventral ectoderm induce EN1

  • EN1 expresses WNT7 restricting its expression to the dorsal limb ectoderm
  • WNT7 induces LMX1, which then specifies the cells to be dorsal
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6
Q

What is expression of the HOX genes dependent on?

A

SHH
FGFs
WNT7a

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7
Q

What other abnormalities are limb defects often associated with?

A

CVS
GU system
Craniofacial structures

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8
Q

Define the following: (i) Amelia (ii) Meromelia (iii) Phocomelia (iv) Micromelia.

A

(i) Complete absence of limbs
(ii) Partial absence of limbs
(iii) Absence of long bones
(iv) Segments are abnormally short

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9
Q

What impact does thalidomide seem to have on limb development?

A

resulted in a high incidence of babies being born with phocomelia (or amelia)

  • they also had intestinal atresia and/or cardiac abnormalities
  • it would block the ZPA and AER sites, resulting in cell death in the progress zone
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10
Q

What are the causes which may lead to limb abnormalities? (HINT: there’s 2)

A

(1) abnormal gene expression

(2) chemical teratogens

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11
Q

What is holt oram syndrome?

A

TBX5 mutation which leads to the failure of limb bud development
- including UL deformities & heart defects

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12
Q

Define the following defects: (i) Brachyactyly (ii) Syndactyly (iii) Polydactyly (iv) Cleft foot.

A

(i) short digits
(ii) fused digits (lack of apoptosis)
(iii) extra digits
(iv) lobster claw deformity

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13
Q

What is intramembranous ossification?

A

The formation of bone in fibrous connective tissue, which is formed from condensed mesenchymal cells
- this process occurs during flat bone formation (e.g. of mandible & flat bones of skull)

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14
Q

What is mesenchyme?

A

Generalised embryonic connective tissue which is derived from mesoderm

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15
Q

Define the following (i) Colonisation (ii) Infection (iii) Bacteraemia

A

(i) presence fo a microbe in the body that does not cause an infection or a specific immune response
(ii) occurence fo inflammation due tot he presence of a microbe
(iii) the presence of viable bacteria in the blood

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16
Q

What is SIRS? What factors highlight SIRS

A

Systemic Inflammation Response Syndrome
- A patient with 2 or more of the following symptoms:
Temp >/ 38 or 100bpm
RR >20/min
Leukocyte count >16,000, 10% immature cells

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17
Q

Define sepsis, severe sepsis and septic shock.

A

SEPSIS = SIRS + a documented infection site (i.e. positive cultres for organisms from that site)
SEVERE SEPSIS = sepsis associated with organ dysfunction, hypoperfusion abnormalities (including lactic acidosis, oliguria, acute alteration in mental status) or hypotension
SEPTIC SHOCK= sepsis induced hyptension despite fluid resuscitation PLUS hypoperfusion abnormalities
- mortality increases with the increasing no. of SIRS symptoms & in severity of the disease

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18
Q

What are potential complications of sepsis? (HINT: there’s 6)

A

Acute respiratory distress syndrome (ARDS)
Disseminated intravascular Coagulation (DIC)
Acute renal failure
Liver failure
CNS dysfunction
Cardiac failure & death

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19
Q

What are the risk factors for sepsis? (HINT: there’s 6)

A 
Diabetes
Splenic atresia
Severe wound/burn
Prosthetic device
Cancer 
Immunosuppression (e.g. chemo, steroids, immunosuppressants)
20
Q

What common pathogens are associated with sepsis?

A 
Staphylococcus aureus (including MRSA)
Neisseria meningitidis
Streptococcus (e.g. group A strep)
Strep. pneumoniae
Gram -ve bacilli
Candida species
21
Q

Explain what is meant by ‘The Sepsis Six’.

A

A set of interventions/investigations

  • the aim is to carry them out within the first hour of admission to increase survival chance
    (1) Administer high flow oxygen
    (2) Take blood cultures
    (3) Give broad spectrum Ab
    (4) Give IV fluid challenges
    (5) Measure serum lactate & haemoglobin
    (6) Measure accurately urine output
22
Q

How is an infection diagnosed?

A 
BLOOD TESTS
- WCC
- CRP
- Platelets
- Clotting
VIRAL STUDIES
- NAAT
- PCR
MICROBIOLOGY
- blood culture
- stool 
- urine
- wound
- tissue cultures
- sputum
- CSF
SEROLOGICAL BLOOD TESTS
- for antibodies
23
Q

What is done if the patient is NOT improving?

A 
CHECK: correct antibiotic(s), dosage and route of administration
HAVE YOU GOT SOURCE CONTROL OR IS THERE:
- abscess
- deep infection
- medical device with biofilm
- new infection
- selection out of resistant strains?
24
Q

Describe, briefly, each of the following; (i) impetigo (ii) erysipelas (iii) cellulitis (iv) necrotising fasciitis

A

(i) contagious bacterial skin infection, forming pustules & yellow crusty sores
(ii) acute, sometimes recurrent disease caused by a bacterial infection, characterised by raised red patches on the skin
(iii) inflammation of subcutaneous connective tissue
(iv) acute inflammation of fasciae of muscles/other organs, resulting in rapid destruction of overlying tissues

25
Q

What is the basic management of bites? Including lab investigation, radiology and wound management.

A 
FULL HISTORY
- country of exposure (abroad...rabies)
- immunodeficiency
RADIOLOGY
- clenched fist
- scalp bites in children
(NOTE: these all should have x-rays as it is easy for fragments to get in)
WOUND EXPLORATION
- irrigate/debride = Source Control
- delayed closure
ANTIBIOTIC THERAPY
- prophylaxis
- treatment
26
Q

What is prophylaxis?

A

The treatment given/action taken to prevent disease
Duration of treatment usually about 7 days
- all after primary closure
- puncture wounds
- cat bite to hand/wrist
- crush wounds
- clenched fist
- host risk factors (prosthetics, asplenia, mastectomy, diabetes)

27
Q

What is the typical antibiotic treatment for both mild-moderate and severe animal bites?

A 
MILD-MODERATE
co-amoxyclav
doxycycline + metronidazole (if penicillin allergy)
clindamycin +ciprofloxacin
SEVERE
co-amoxyclav
benzyl penicillin + ciprofloxacin + metronidazole
meropenem + clindamycin
28
Q

What two types of treatment should NEVER be used for animal bites?

A

Erythromycin or clindamycin monotherapy

29
Q

What is the typical treatment duration for (i) cellulitis (ii) tenosynovitis (iii) septic arthritis (iv) osteomyelitis

A

(i) 7-10 days
(ii) 21 days
(iii) 28 days
(iv) 42 days (so long due to bone turnover)

30
Q

What are the 3 major theories that explain stress? Describe them.

A
  1. STRESS AS A STIMULUS
    - focuses on the environment
    - an event/circumstance (=stressor) is the cause of stress
  2. STRESS AS A RESPONSE
    - focuses on an individual’s reaction to stressors
    - psychological & physiological responses
    - the responses are known as ‘strain’
  3. STRESS AS A TRANSACTION
    - focusses on stress as a process (stressors & strain)
    - relationship between the person & the environment
    - continuous interactions & adjustments (= transactions)
31
Q

What are the typical signs of stress? (HINT: there’s 5)

A 
Biochemical
Physiological
Behavioural
Cognitive
Emotional
32
Q

What does the term ‘stress’ mean?

A

the perceived discrepancy between the demands & resources appraised by the individual

33
Q

What are the two responses for short term and long term stress?

A

Short term = FIGHT OR FLIGHT
The physiological reaction to emergencies, “adaptive” response
- homeostasis is threatened
- response to acute, short lived stress
- external threats elicit fORf response
- increase in physiological arousal which enables fight or flight
-HOWEVER, a prolonged state of high arousal can be harmful to health
Long term = GENERAL ADAPTATION SYNDROME
Stressor:
- ALARM (mobilisation to fend off threat/stressor)
- RESISTANCE (continued fight against stressor)
- EXHAUSTION (depletion of resources, ability to resist may collapse)

34
Q

What are the 2 processes of stress appraisal in the ‘stress-coping’ paradigm?

A

PRIMARY APPRAISAL
= danger assessment
SECONDARY APPRAISAL
= coping strategy

35
Q

Explain the 2 step physiological response for stress.

A
  1. SYMPATHETIC ACTIVATION
    - under stress, the SNS is stimulated
    - catecholamines produced
    - quick response system (usually seconds)
  2. HYPOTHALAMIC-PITUITARY-ADRENOCORTICAL (HPA) ACTIVATION
    - high levels of corticosteroids
    - raised levels of brain opioids beta endorphin & enkephalin
    - slower response system (mins to hours)
36
Q

What are the two causes of cancer?

A
  1. Mutations in DNA resulting in production of altered cells which have changes in proliferating mechanisms
  2. Changes in DNA caused by covalent modification
    - spontaneous genetic predisposition
    - ionising radiation/UV radiation
    - chemical carcinogens
37
Q

What are the 3 main approaches to treating cancer?

A
  1. Surgical excision
  2. Radiotherapy
  3. Chemotherapy
38
Q

Name the 4 types of tradition agent.

A

Alkylating Agents
Antimetabolites
Cytotoxic Antibodies
Plant derivatives

39
Q

Describe the mechanism of action of alkylating agents.

A
  • Can form covalent bonds with suitable nucleophilic substances inside the cell (under certain physiological conditions)
  • they form intrastrand crosslinks with the DNA

Normally, Guanine residues in DNA exist mainly in the KETO tautomer - allowing them to make Watson-crick base pairs by H bonding with cytosine
- When the 7N of guanine is alkylated it becomes MORE acidic, and the ENOL tautomer is formed
- This modified guanine can mispair with thymine residues during DNA synthesis
Alkylation of the 7N destabilises the imidazole ring
- opening of the imidazole ring
- depurination excision of guanine residues
The resulting damage to DNA by alkylating agents triggers PCD (by apoptosis)

40
Q

What are the 3 major groups of alkylating agents? Describe them.

A

(A) NITROGEN MUSTARDS - e.g. cyclophosphamide
-Cyclophosphamide: activated in the liver by p450 mixed function oxidases
- Aldophosphamide: transported to other tissues where it forms phosphoramide (which is cytotoxic) and acrolein (but mesna counteracts the effects of this)
(B) NITROSOUREAS - e.g. lomustine, carmustine
-Lomustine & carmustine are lipid soluble and can therefore pass the blood brain barrier (used against tumours of the brain & meninges)
- Busulphan has a selective effect on bone marrow, depressing the formation of granulocytes&platelets in low dosage, and red cells in higher dosage. It has little to no effect on lymphoid tissue or GI tract and is used in Chronic Granulocytic Leukaemia
(C) PLATINUM BASED COMPOUNDS - e.g. cisplatin
- Cisplatin = water soluble planar coordination complex containing a central Pt atom surrounded by 2 Cl and 2 NH3 groups.
- Its action is analogous to that of alkylating agents. When it enters the cell Cl- dissociates leaving a reactive complex which reacts with water & then interacts with DNA.
- It causes intrastrand cross-linking which results in local denaturation of the DNA chain

41
Q

What are the 3 groups of Antimetabolites? Describe each of them.

A

(A) ANTIFOLATES - e.g. methotrexate
= folate analogue, usually given orally (can be IM, IV or intrathecally also)
- has low lipid solubility (doesn’t cross blood-brain barrier)
- polyglutamated so can be retained in cells for weeks
(B) ANTIPYRIMIDINES - e.g. 5-FU, gemcitabine
- Fluorouracil (5-FU) interferes with thymidylate synthesis (DTMP)
- it is converted into a fraudulent nucleotide (FDUMP) which CANT be converted to DTMP
- Cytarabine = analogue of cytosine, but has arabinose & not ribose attached. It undergoes phosphorylation giving cytosine arabinoside triphosphate (this inhibits DNA polymerase)
Gemcitabine = analogue of cytarabine
(C) ANTIPURINES - e.g. mercaptopurine, thioguanine, fludarabine
- Mercaptopurine is converted to 6-mercaptopurine ribose phosphate called “lethal synthesis”. This inhibits a no. of enzymes in the de novo synthesis of purines. They are fraudulent nucleotides
- Fludarabine (in its triphosphate form) inhibits DNA polymerase

42
Q

Cytotoxic Antibiotics produce their effects mainly by direct action on DNA. What are the 4 types of cytotoxic antibiotic? Describe them.

A

(1) ANTHRACYCLINES - e.g. doxorubicin (main anti-cancer Ab), daunorubicin, idarubicin, epirubicin, aclarubicin&mitoxantrone
- Binds to DNA & inhibits both DNA & RNA synthesis. Its main cytotoxic action is mediated through an effect on topoisomerase II (the activity of which is markedly increased in proliferating cells)
- during replication of the DNA helix, reversible swivelling needs to take place round the replication fork in order to prevent the daughter DNA becoming inextricably entangled during mitotic segregation
- the ‘swivel’ is produced by topoisomerase II, which nicks both DNA stands & subsequently reseals the breaks
- Doxorubicin intercalates the DNA & its effect is to stabilise the DNA-topoisomeraseII complex after the strands have been nicked, thus causing the process to seize up at this point
(2) DACTINOMYCIN
- intercalates in minor groove of DNA between adjacent G-C pairs, interfering with the movement of RNA polymerase along the gene, thus preventing transcription (also evidence it has similar action on topoisomerase II as anthracyclines)
(3) BLEOMYCINS
- group of metal-chelating glycopeptide Ab’s that degrade preformed DNA, causing chain fragmentation & the release of free bases
- Their action on DNA is thought to involve chelation of ferrous iron&interaction w.oxygen (resulting in the oxidation of the Fe & generation of superoxide and/or hydroxyl radicals)
- most effective in G2 phase of cell cycle&mitosis, but also active against non-dividing cells
(4) MITOMYCIN
- after enzymatic activation in the cell, it functions as a bi-functional alkylating agent - alkylating preferentially at O6 of G
- cross links DNA & may also degrade DNA through the generation of free radicals

43
Q

What are the 4 types of plant radicals? Describe them.

A

(A) VINCA ALKALOIDS - e.g. vincristine, vinblastine
- bind microtubulin & prevent polymerisation into microtubules
(B) TAXANES - e.g paclitaxel (taxol), docetaxel
- stabilise (freeze) microtubules
(C) CAMPTOTHECINS - e.g. irinotecan
- bind to, and inhibit, topoisomerase I
(D) ETOPOSIDE
- inhibits mitochondrial function, nucleoside transport & topoisomerase II

44
Q

What are the various miscellaneous agents that are anti cancer drugs? (HINT: there’s 6)

A

HORMONE ANTAGONISTS: e.g. tamoxifen used in breast cancer to block oestrogen effects
PROCARBAZINE: inhibits DNA & RNA synthesis & interferes with mitosis
HYDROXYCARBAMIDE (hydroxyurea) inhibits riboucleotide reductase
CRISANTASPASE: active against acute lymphoblastic leukaemia cells, which cannot synergise asparagine
AMSACRINE: acts on topoisomerase II
MITOTANE: synthesis of adrenocortical steroids

45
Q

What are 3 types of novel targeted agents? What do they target?

A

RITUXIMAB
- targets a B cell surface protein & is used for B cell lymphomas
TRASTUZUMAB (herceptin)
- targets epidermal growth factor receptor & is used for breast cancer
IMATINIB (gleevec)
- inhibits brc-abl gene signalling pathways & is used for CML

46
Q

What are the main drawbacks of the current chemotherapy of cancer?

A
  1. Targets cell proliferation, not the more lethal properties of invasiveness & metastasis
  2. Non-specific cell killers rather than being aimed at the particular changes which make a cell malignant
  3. The development of resistance (particularly multidrug resistance) to anticancer drugs
  4. Remaining cells (TSC), since total elimination of malignant cells is not possible using therapeutic doses, & the host’s immune response is often not adequate to deal with the reminder
  5. Pt compliance due to side effects (not completing the therapy regimen)

MD2002 (17 decks)

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